Sudden cardiac death in the young incidence and consequences by mikesanye

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									Sudden cardiac death in the young:
   incidence and consequences




           Anneke Hendrix
A. Hendrix, the Netherlands, 2010

ISBN:            978-90-5335-352-3
Printing:				    Ridderprint	BV,	Ridderkerk
Lay-out:	 			    Simone	Vinke,	Ridderprint	BV,	Ridderkerk
Cover	design:	   Nikki	Vermeulen,	Ridderprint	BV,	Ridderkerk
Cover art:       Marieke Hendrix
             Sudden cardiac death in the young:
                incidence and consequences



           Plotselinge	hartdood	op	jonge	leeftijd,	incidentie	en	gevolgen
                     (met	een	samenvatting	in	het	Nederlands)




                                     Proefschrift




ter	verkrijging	van	de	graad	van	doctor	aan	de	Universiteit	Utrecht	op	gezag	van	de	
rector	magnificus,	prof.	dr.	G.J.	van	der	Zwaan,	ingevolge	het	besluit	van	het	college	
  voor	promoties	in	het	openbaar	te	verdedigen	op	donderdag	21	april	2011	des	
                                   middags te 2.30 uur




                                        door




                                Anneke Hendrix
                  geboren	op	23	december	1980	te	Maartensdijk
Promotoren:        Prof. dr. P.A.F.M. Doevendans
                   Prof. dr. A.A.M. Wilde
                   Prof. dr. M.L. Bots

Co-promotor:       Dr. A. Mosterd




Financial	support	by	the	Netherlands	Heart	Foundation	and	the	Heart	&	Lung	Foundation	
Utrecht	for	the	publication	of	this	thesis	is	gratefully	acknowledged.

Additional	 financial	 support	 was	 provided	 by	 the	 J.E.	 Jurriaanse	 stichting,	 Stichting	
Cardiovasculaire	Biologie	and	Stichting	Wetenschappelijk	Onderzoek	Hart	en	Vaatziekten	
Amersfoort.
Voor mijn ouders
Contents

Chapter 1   General	introduction		         	        	                                     11

Chapter 2   Sudden cardiac death in the young                                             17

2.1         Sudden	cardiac	death	in	the	young,	an	overview		                              19	

2.2         Rationale	and	design	of	the	CAREFUL	study	       	                            37	

Chapter 3   Incidence and causes                                                          47

3.1					    Sudden	death	in	persons	younger	than	40	years:		          	
            incidence and causes                                                          49

3.2				     Regional	differences	in	incidence	of	sudden	cardiac		     	          	
            death in the young                                                            63

3.3					    Incidence	and	causes	of	sudden	death	in	the	young:	first	results	
	           of	the	CAREFUL	study	        	        	                                       77

3.4					    Sudden	death	in	the	young	(1-44	years)	in	the	Netherlands:	autopsy		
            rate	and	characteristics	associated	with	the	performance	of	autopsy									93

Chapter 4   Consequences                                                                105

4.1				     Cardiogenetic	screening	of	first-degree	relatives	after	sudden		     	
            cardiac	death	in	the	young:	a	population	based	approach		                   107	

4.2			      Screening	for	familial	hypertrophic	cardiomyopathy:	
	           a	cost-effectiveness	analysis	 	        	      	          	         											123	

Chapter 5   General	discussion	 	          	                                            141

Chapter 6   Summary                                                                     151
	           Samenvatting	           	      	                                            157
	           Dankwoord	 	            	      	                                            163
	           Curriculum	Vitae	       	      	        	                                   167
	           List	of	publications	   	      	        	                                   171
Chapter        1
General	introduction
                                                                                         Introduction


         	
Introduction
The	sudden	cardiac	death	(SCD)	or	sudden	unexplained	death	(SUD)	of	a	young	person	                      1
                                                        	
has	 an	 enormous	 impact	 on	 those	 who	 are	 left	 behind.	 It	 evokes	 severe	 feelings	 of	
                                                               	
anxiety	 and	 incomprehension	 because	 such	 a	 dramatic	 event	 was	 not	 anticipated.	  	
                           		
During	the	last	ten	to	fifteen	years	it	has	become	clear	that	inherited	cardiac	diseases	
   	
often	 underlie	 the	 sudden	 death	 of	 a	 young	 person.1,2	 Premature	 atherosclerotic	          	
coronary	artery	disease,	as	observed	in	familial	hyperlipidemia,	is	a	common	cause	of	
                                                                             	
sudden death in the young.3	Also,	cardiomyopathies	(e.g.	hypertrofic	cardiomyopathy)	
or	primary	arrhythmia	syndromes	(e.g.	congenital	long-QT	syndrome)	may	cause	fatal	
arrhythmias that lead to sudden death.
      	                                  	
Relatives	of	young	SCD	and	SUD	victims	have	an	increased	risk	of	carrying	the	inherited	
              	                                        		 	
predisposition	to	develop	cardiac	disease.4-9 Identification	of	inherited	diseases,		followed	
                                                                          	
by	 early	 treatment	 may	 reduce	 the	 risk	 of	 SCD	 in	 asymptomatic	 carriers	 of	 inherited	
cardiac diseases.   10-13
                                                                                      	           	
                          However	 as	 sudden	 cardiac	 arrest	 in	 the	 young	 is	 often	 the	 first	
                                                            		 	            		cult	 in	 apparently	
‘symptom’	 of	 inherited	 cardiac	 disease,	 early	 identification	 is	 diffi
                                                          	 	
healthy young individuals.14-16	Post-mortem	investigation	of	sudden	death	victims	might	 	
                              	
be	an	important	diagnostic	tool	to	detect	inherited	cardiac	diseases	among	families.17
When	an	inherited	cardiac	disease	is	diagnosed	or	suspected	based	on	autopsy	findings,	      	
                 	                	               	                  	
pre-symptomatic	cardiogenetic	screening	of	first-degree	relatives	of	SCD	and	SUD	victims	        	
            	                                       	
can	be	initiated	to	enable	early	treatment	in	affected	relatives.	
                                                      	
The	purpose	of	this	thesis	is	to	provide	information	on	the	incidence	and	causes	of	SCD	
                                                                        	
and	SUD	in	the	young	(1-44	years)	in	the	Netherlands	and	to	estimate	the	proportion	of	        	
underlying	inherited	cardiac	diseases.	Furthermore,	we	set	out	to	determine	the	autopsy	
                                    	                                              	
rate	in	young	sudden	death	victims	and	to	study	the	yield	of	cardiogenetic	screening	of	
 	                 	                                	
first-degree	relatives	in	the	usual	care	to	identify	inherited	cardiac	diseases.	Finally,	we	
                        	 	                 	
evaluate	the	cost-effectiveness	of	genetic	cascade	screening,	cardiologic	follow-up	and	
                     	          	
treatment	of	relatives	of	patients	with	HCM.

Outline	of	the	thesis
In Chapter 2 issues	 related	 to	 sudden	 death	 in	 the	 young	 are	 described.	 Chapter 2.1
                                     	 	
provides	an	overview	of	the	definitions	and	the	background	of	SCD	in	the	young.	Also	
                                 	               	
the	 current	 view	 on	 the	 optimal	 care	 after	 the	 sudden	 death	 of	 a	 young	 person	 is	
described.	 Chapter 2.2	 describes	 the	 rationale	 and	 design	 of	 the	 CAREFUL	 (The	 yield	
                                               	
                	                  	                 	
of cardiogenetic	screening in first-degree	relatives	of	sudden	cardiac	and	unexplained
          	                                                                  	
death	victims	<45	years)	study:	a	Dutch	study	with	the	primary	objective	to	identify	an	  	
   	                                                               	 	
optimal	 strategy	 to	 increase	 the	 rate	 of	 post-mortem	 investigations	 in	 young	 sudden	
          	                                               	               	                 	
death	victims	(1-44	years)	and	the	rate	of	cardiogenetic	screening	of	first-degree	relatives	


                                                                                                   13
Chapter 1


of	 young	 sudden	 death	 victims.	 The	 secondary	 objective	 of	 CAREFUL	 is	 to	 provide	
complete	information	on	the	incidence	and	causes	of	sudden	death	in	the	young	and	
the	presence	of	inherited	cardiac	diseases	in	first-degree	relatives.	Chapter 3 addresses
the	 incidence	 and	 causes	 of	 sudden	 (cardiac)	 death	 in	 the	 young	 in	 the	 Netherlands.	
In chapter 3.1,	the	incidence	and	causes	of	sudden	death	in	the	young	are	presented.	
Incidence	 estimates	 and	 causes	 of	 death	 were	 determined	 by	 using	 death	 certificate	
data	of	out-of-hospital	sudden	deaths	recorded	by	Statistics	Netherlands	from	1996	to	
2006.	To	define	sudden	death,	International	Classification	of	Diseases	(ICD)	codes	were	
selected	 based	 on	 a	 systematic	 review	 of	 the	 literature	 assessing	 the	 most	 common	
causes of sudden death in the young. In chapter 3.2,	regional	differences	in	SCD	rates	
among	young	individuals	are	presented.	For	this	study	the	same	ICD	codes	were	used	
as	described	in	chapter	3.1.	Regional	incidence	estimates,	categorised	for	gender	and	
age,	were	related	to	regional	socio-economic	status.	The	results	of	the	first	year	of	the	
CAREFUL	 study	 (June	 2008-June	 2009)	 are	 presented	 in	 chapter 3.3.	 In	 this	 chapter	
the	population	based	incidence	of	SCD	in	the	young	and	the	proportion	of	underlying	
inherited	diseases	is	described.	Chapter 3.4	addresses	the	autopsy	rate	of	young	sudden	
death	 victims	 in	 the	 Netherlands.	 Between	 June	 2006	 and	 June	 2008,	 young	 sudden	
death	victims,	were	identified	by	reviewing	death	declaration	certificates	of	the	public	
health	services	in	four	study	regions.	Factors	relating	to	the	performance	of	a	clinical	
autopsy	in	the	Netherlands	were	investigated.	Chapter 4 addresses the consequences
of	a	sudden	death	of	a	young	person	for	the	surviving	relatives.	Chapter 4.1	describes	
the	causes	 of	 death	of	 unselected	victims	of	 (aborted)	SCD	 and	 SUD	 and	 the	yield	 of	
cardiogenetic	 screening	 in	 first-degree	 relatives	 of	 victims	 of	 (aborted)	 SCD	 and	 SUD	
in	a	population	based	setting.	In	chapter 4.2,	the	cost-effectiveness	of	genetic	cascade	
screening,	cardiologic	follow-up	and	treatment	of	relatives	of	a	patient	with	HCM	and	a	
sudden	death	victim	in	whom	HCM	is	diagnosed	is	addressed.	
Chapter 5	 provides	 the	 general	 discussion	 of	 the	 studies	 described	 in	 this	 thesis	 and	
recommendations	for	future	research.




14
                                                                                                     Introduction


References
(1)		 Wilde	AA,	Bezzina	CR.	Genetics	of	cardiac	arrhythmias.	Heart 2005;91:1352-1358.
                                     	                                                                                1
(2)		 Wilde	 AA,	 van	 Langen	 IM,	 Mannens	 MM,	 Waalewijn	 RA,	 Maes	 A.	 Sudden	 death	 at	 young	
      age	 and	 the	 importance	 of	 molecular-pathologic	 investigation.	 Ned Tijdschr Geneeskd
                                                                         	 	
      2005;149:1601-1604.
(3)		 Wiesbauer	F,	Blessberger	H,	Azar	D,	Goliasch	G,	Wagner	O,	Gerhold	L	et	al.	Familial-combined	
      hyperlipidaemia	 in	 very	 young	 myocardial	 infarction	 survivors	 (<	 or	 =40	 years	 of	 age).	 Eur
                                                              	
      Heart J 2009;30:1073-1079.
(4)		 Behr	E,	Wood	DA,	Wright	M,	Syrris	P,	Sheppard	MN,	Casey	A	et	al.	Cardiological	assessment	of	
       	                	
      first-degree	relatives	in	sudden	arrhythmic	death	syndrome.	Lancet 2003;362:1457-1459.
(5)		 Hofman	N,	Tan	HL,	Clur	SA,	Alders	M,	van	Langen	IM,	Wilde	AA.	Contribution	of	inherited	  	
      heart disease to sudden cardiac death in childhood. Pediatrics 2007;120:e967-e973.
                                        	
(6)		 Behr	ER,	Dalageorgou	C,	Christiansen	M,	Syrris	P,	Hughes	S,	Tome	Esteban	MT	et	al.	Sudden	
                                                           	        		
      arrhythmic	 death	 syndrome:	 familial	 evaluation	 identifies	 inheritable	 heart	 disease	 in	 the	
      majority	of	families.	Eur Heart J 2008 ;29:1670-1680.
(7)		 Schwartz	K,	Carrier	L,	Guicheney	P,	Komajda	M.	Molecular	basis	of	familial	cardiomyopathies.	
      Circulation 1995;91:532-540.
                                                	
(8)		 Garson	A,	Jr.,	Dick	M,	Fournier	A,	Gillette	PC,	Hamilton	R,	Kugler	JD	et	al.	The	long	QT	syndrome	
      in	children.	An	international	study	of	287	patients.	Circulation 1993;87:1866-1872.
                                	                        	
(9)		 van	der	Werf	C,	Hofman	N,	Tan	HL,	van	Dessel	PF,	Alders	M,	van	der	Wal	AC	et	al.	Diagnostic	               	
      yield	in	sudden	unexplained	death	and	aborted	cardiac	arrest	in	the	young:	The	experience	of	
      a	tertiary	referral	center	in	The	Netherlands.	Heart Rhythm 2010;7:1383-1389.
             	
(10)		Maron	BJ,	Spirito	P,	Shen	WK,	Haas	TS,	Formisano	F,	Link	MS	et	al.	Implantable	cardioverter-
          	                       	
      defibrillators	and	prevention	of	sudden	cardiac	death	in	hypertrophic	cardiomyopathy.	JAMA
      2007;298:405-512.
(11)		Watanabe	H,	Chopra	N,	Laver	D,	Hwang	HS,	Davies	SS,	Roach	DE	et	al.	Flecainide	prevents	
      catecholaminergic	 polymorphic	 ventricular	 tachycardia	 in	 mice	 and	 humans.	 Nat Med
      2009;15:380-383.
                                                    	
(12)		Hobbs	 JB,	 Peterson	 DR,	 Moss	 AJ,	 McNitt	 S,	 Zareba	 W,	 Goldenberg	 I	 et	 al.	 Risk	 of	 aborted	
      cardiac	arrest	or	sudden	cardiac	death	during	adolescence	in	the	long-QT	syndrome.	JAMA
      2006;296:1249-1254.
(13)		Moss	AJ,	Zareba	W,	Hall	WJ,	Schwartz	PJ,	Crampton	RS,	Benhorin	J	et	al.	Effectiveness	and	 	 	
      limitations	of	beta-blocker	therapy	in	congenital	long-QT	syndrome.	Circulation 2000;101:616-
               	
      623.
(14)		Drory	Y,	Turetz	Y,	Hiss	Y,	Lev	B,	Fisman	EZ,	Pines	A	et	al.	Sudden	unexpected	death	in	persons	
      less than 40 years of age. Am J Cardiol 1991;68:1388-1392.
                                                                                                               	
(15)		Amital	 H,	 Glikson	 M,	 Burstein	 M,	 Afek	 A,	 Sinnreich	 R,	 Weiss	 Y	 et	 al.	 Clinical	 characteristics	
      of	 unexpected	 death	 among	 young	 enlisted	 military	 personnel:	 results	 of	 a	 three-decade	
                  	
      retrospective	surveillance.	Chest 2004;126:528-533.
(16)		Wisten	A,	Forsberg	H,	Krantz	P,	Messner	T.	Sudden	cardiac	death	in	15-35-year	olds	in	Sweden	
      during 1992-99. J Intern Med 2002;252:529-536.
(17)		Basso	C,	Burke	M,	Fornes	P,	Gallagher	PJ,	de	Gouveia	RH,	Sheppard	M	et	al.	Guidelines	for	
      autopsy	investigation	of	sudden	cardiac	death.	Virchows Arch 2008;452:11-18.
                      	 	




                                                                                                               15
           Chapter          2
Sudden cardiac death in the young
                                  Chapter	2.1

Sudden	cardiac	death	in	the	young,	an	overview
                                                       Sudden cardiac death in the young, an overview


         	
Introduction
Sudden	unexpected	death	in	the	young	is	rare	but	has	an	enormous	impact	on	those	left	           	
                	              	
behind.	Relatives	of	the	victim	frequently	wonder	if	they	are	at	increased	risk	of	sudden	
death	as	well.	In	the	last	decades,	it	has	become		clear	that	inherited	cardiac	diseases	
often	underlie	the	sudden	death	of	a	young	person.1,2	Identification	of	the	cause	of	death	
   	                                                              		 	                                  2.1
is	important	for	diagnosing	inherited	cardiac	diseases	among	families.	Pre-symptomatic	        	
              	                       	                                   	        	
cardiogenetic	 screening	 of	 relatives	 might	 be	 indicated	 to	 identify	 relatives	 with	 an	
inherited cardiac disease.
                                             	 	
In	 this	 chapter	 an	 overview	 of	 the	 definitions	 and	 the	 background	 of	 sudden	 cardiac	
death	(SCD)	in	the	young	are	presented	and	the	current	opinion	on	strategies	to	diagnose	
                                                  	                      	
inherited	cardiac	diseases	in	surviving	relatives	of	young	SCD	victims	are	described.	In	
      	                          	      	
addition,	the	value	of	preparticipation	screening	of	young	athletes	is	discussed.

   	 	
Definitions
Sudden	death	in	young	persons	can	be	divided	in	natural	(death	due	to	a	disease)	or	
non-natural	 (e.g.	 car	 accident	 or	 suicide)	 causes	 of	 death.	 The	 natural	 deaths	 can	 be	
subdivided	in	non-cardiac	deaths,	cardiac	deaths	and	unexplained	deaths.	These	latter	         	
                                                                   	
two	categories	comprise	the	cardiac	deaths	due	to	potentially	inherited	cardiac	diseases	
                                                         	
and	will	be	discussed	further	in	this	chapter	(see	figure	1).	
                                                            	
The	terminology	that	is	used	to	describe	SCD	is	often	confusing	due	to	the	variety	of	
     	 	                                                          	 	
definitions	 that	 are	 being	 used	 in	 the	 literature.	 A	 distinction	 can	 be	 made	 between	
sudden death in the young and the sudden infant death syndrome. The term ‘sudden
                                                               	          	 	
death	 in	 the	 young’	 covers	 a	 broad	 spectrum	 of	 different	 definitions,	 but	 in	 general	
                	                                                          	 	
comprises	victims	between	1	and	45	years	of	age.	The	general	definition	of	sudden	infant	
death	syndrome	(SIDS)	is	‘sudden	unexpected	death	of	an	infant	<1	year	of	age,	with	
onset	of	the	fatal	episode	apparently	occurring	during	sleep,	that	remains	unexplained	
  	                       	 	
after	a	thorough	investigation,	including	performance	of	a	complete	autopsy	and	review	
                                                                           	 	
of	the	circumstances	of	death	and	the	clinical	history’.3	The	distinction	between	these	
                                                                        	
two	age	categories	(<1	year	and	>1	year)	is	based	on	the	differences	in	incidence	and	
causes.	For	example,	the	occurrence	of	SIDS	is	strongly	associated	with	sleeping	position	    	
    	               	
(after	 an	 international	 public	 health	 campaign	 to	 place	 infants	 on	 their	 back	 while	
sleeping,	the	incidence	of	SIDS	decreased	with	50-90%).4	Although	there	is	an	overlap	
between	the	causes	of	death	in	SIDS	(e.g.	the	congenital	long-QT	syndrome	(LQTS))	and	
                                                                              	
sudden	death	in	the	young,	we	will	focus	in	this	review	on	SCD	victims	of	one	year	and	
older.




                                                                                                  21
Chapter 2.1


Figure 1. Flow	chart	sudden	death	and	inherited	cardiac	diseases

                           Sudden death


              Ante-mortem and/or post-mortem investigation



 Natural death                              Non-natural death
                                            - Suicide
                                            - Other causes


        Non-cardiac sudden death
        - Asthma
        - Epilepsy
        - Pulmonary embolism
        - Intracranial hemorrhage
        - Gastro-intestinal hemorrhage
        - Other causes


        Cardiac death
        - Coronary artery disease
        - Cardiomyopathy
        - Primary arrhythmia syndromes
        - Coronary anomalies
        - Aortic aneurysm/dissection
        - Valvular disease                                      Including inherited
        - Other causes                                          cardiac diseases

        Unexplained death
        - No autopsy performed
               Comprising all causes of death (also
               primary arrhythmia syndromes)
        - Autopsy-negative sudden deaths
               Comprising mainly primary arrhythmia
               syndromes




SCD	was	recently	defined	as	‘death	due	to	any	cardiac	disease	that	occurs	out-of-hospital,	
in	an	emergency	department,	or	in	an	individual	reported	death	on	arrival	at	a	hospital’.5
The	term	‘sudden	unexplained	death’	(SUD)	is	used	when	no	diagnosis	can	be	established	
based	 on	 ante-mortem	 and	 post-mortem	 investigation	 (autopsy-negative	 sudden	
deaths).6 However,	SUD	might	also	refer	to	cases	in	which	the	cause	of	death	remains	
uncertain	because	no	autopsy	is	performed.	In	the	absence	of	structural	abnormalities	
on	 autopsy,	 the	 term	 ‘sudden	 arrhythmic	 death	 syndrome’	 has	 been	 proposed.7,8
Although	the	assumption	is	that	many	of	the	autopsy-negative	sudden	deaths	are	due	
to	an	electrical	heart	disease	or	a	cardiomyopathy	with	minor	histopathologic	changes,	
other	 causes	 should	 be	 excluded	 (e.g.	 epileptic	 seizure,	 hypoglycemia,	 electrolyte	


22
                                                       Sudden cardiac death in the young, an overview


                	           	
abnormalities,	intoxication).
                                                                  	 	
In	 the	 literature,	 the	 1	 hour,	 6	 hours	 and	 24	 hours	 definitions	 are	 used	 in	 the	 SCD	
      	 	                           	 	                                        	
definition. The	 use	 of	 definitions	 that	 are	 based	 on	 the	 duration	 of	 preceding	
               9-11

                         	               	                                          	
symptoms	has	limitations.	In	the	first	place,	prodromal	symptoms	(e.g.	fatigue	or	fever)	
         	                                                                            	
are	often	present	for	a	period	longer	than	24	hours.	Secondly,	in	daily	practice	it	can	be	             2.1
diffi                                      	
     		cult	to	determine	the	exact	duration	of	symptoms	before	dying,	especially	because	
                   	                                            	
this	information	always	needs	to	be	collected	retrospectively	and	no	witness	is	present	
                                                                        	
in	40%	of	the	sudden	cardiac	arrests.11	In	the	third	place,	victims	may	die	a	few	days	
   	                            	
after	a	successful	resuscitation	because	of	irreversible	damage	(e.g.	brain	death).12 These
      	             	
victims	are	often	not	included	in	sudden	death	studies	while	the	causes	of	death	and	the	
                      	           	
clinical	implications	for	relatives	are	the	same.	Surviving	a	sudden	cardiac	arrest	depends	
mainly	on	external	factors	like	early	and	adequate	cardiopulmonary	resuscitation	and	       	
             	
early	defibrillation. 	

Incidence
                         	
In	 the	 general	 population	 (over	 all	 ages),	 SCD	 accounts	 for	 approximately	 one	 death	
                                                                                     	
per	1000	person-years.13 In	the	young	(<40	years)	the	incidence	of	SCD	is	estimated	to	
be	a	100-fold	lower	and	lies	between	0.8	and	4.1	per	100,000	person-years.10,14-17 The
incidence	of	SCD	in	athletes	ranges	from	0.6	to	3.6	per	100,000	person-years.15,18
               	                                                             	
Incidence	estimates	vary	considerably	between	studies.	The	collection	of	data	on	this	
topic	 is	 complicated	 because	 most	 cases	 of	 sudden	 death	 occur	 out-of-hospital	 and	
   	             	                                        	                	           	
often	information	needs	to	be	collected	retrospectively.11 In	addition,	traumatic	deaths	
                                            	
like	car	accidents	or	drownings	can	initially	be	caused	by	a	cardiac	arrhythmia,	but	are	
   	                                               	                               	
often	not	taken	into	account	in	incidence	estimates.	Present	studies	are	often	restricted	
                       	                                                       	
to	 regional	 observations,	 where	 socio-economical	 status,	 racial	 differences	 and	 the	
                              	                               	                  	
presence	of	founder	mutations	predisposing	to	a	specific	cardiogenetic	disorder	might	
    	                                                                    		
influence	the	occurrence	of	SCD. Studies	based	on	death	certificate	data	might	over-
                                    9,19

             	                                                         	
or	underestimate	the	number	of	SCD	cases	in	the	young	population,	due	to	the	presence	
                           	 	
of	considerable	misclassification.20,21

Causes
                                                                              	
SCD	 in	 persons	 older	 than	 40	 years	 is	 mainly	 due	 to	 atherosclerotic	 coronary	 artery	
disease	that	results	in	myocardial	ischemia	and	fatal	arrhythmias.	It	has	been	estimated	   	
                                            	
that	80%	of	the	cardiac	deaths	in	victims	over	40	years	of	age	are	caused	by	coronary	
artery	disease,	10-15%	by	cardiomyopathies	and	5%	by	other	(less	common)	causes.22
However,	 in	 the	 young	 (1-40	 years)	 inherited	 cardiac	 causes	 are	 more	 frequently	
                                                                                 	
observed.	 Recently,	 a	 review	 was	 published	 that	 included	 publications	 from	 1980	
to	 2007	 on	 causes	 of	 death	 in	 the	 young.	 All	 studies	 were	 included	 in	 which	 autopsy	

                                                                                                  23
Chapter 2.1


was	 performed	 in	 >70%	 of	 the	 sudden	 death	 victims.14	 	 Seventeen	 publications	 were	
identified,	including	3528	cases	of	SCD	in	the	age	group	1-39	years	that	were	collected	
between	1967	and	2004.	The	most	common	causes	of	SCD	in	persons	aged	1-39	years	
in	 the	 general	 population	 were	 atherosclerotic	 coronary	 artery	 disease	 (accounting	
for	 23%	 of	 the	 cases),	 followed	 by	 cardiomyopathies	 (13%)	 and	 myocarditis	 (6%).	
In	 athletes,	 cardiomyopathies	 were	 the	 most	 common	 causes	 of	 SCD	 (accounting	 for	
48%	of	the	cases),	followed	by	(non-atherosclerotic)	coronary	pathology	(e.g.	coronary	
artery	 aneurysm	 and	 vasculitis)	 (16%)	 and	 atherosclerotic	 coronary	 artery	 disease	
(7%).	A	considerable	proportion	of	the	sudden	deaths	remained	unexplained	(autopsy-
negative	sudden	deaths),	accounting	for	16%	of	the	SCD	in	the	general	population	and	
4%	in	the	athlete	population.	This	latter	group	most	likely	comprised	primary	arrhythmia	
syndromes	 (e.g.	 LQTS,	 catecholaminergic	 polymorphic	 ventricular	 tachycardia	 (CPVT)	
and	the	Brugada	syndrome	(BS)).23,24	The	proportion	of	deaths	due	to	coronary	artery	
disease	increases	with	age.	In	addition,	myocarditis	and	primary	arrhythmia	syndromes
are	relatively	more	common	in	the	younger	population	(1-25	years).14,25,26

Demographics	
Information	 on	 regional,	 racial	 and	 gender	 differences	 in	 SCD	 in	 the	 young	 is	 scarce.	
However,	 it	 seems	 that	 the	 incidence	 and	 causes	 of	 SCD	 (over	 all	 ages)	 differ	 among	
regions	and	populations.27,28	This	might	be	due	to	several	factors,	including	the	regional	
distribution	 of	 age	 and	 gender	 and	 the	 prevalence	 of	 inherited	 cardiac	 diseases	 and	
coronary	 artery	 disease.	 Several	 studies	 reported	 clustering	 of	 inherited	 diseases	 in	
populations	 (and	 regions);	 in	 Southeast	 Asia	 for	 example,	 especially	 in	 Cambodia,	
Philippines,	Thailand	and	Japan	the	incidence	of	nocturnal	sudden	death	among	young	
men	 was	 estimated	 to	 be	 as	 high	 as	 26-38	 per	 100,000	 person-years.	 Cardiogenetic	
screening	suggested	that	a	primary	arrhythmia	syndrome	similar	to	the	BS	is	underlying	
these sudden deaths.29-32 Furthermore, SCD occurs more frequently in African Americans
than	 in	 white	 Americans.26	 Hypertrophic	 cardiomyopathy	 (HCM)	 is	 the	 most	 common	
cause	of	SCD	in	young	athletes	in	the	United	States,	while	in	the	Veneto	region	in	Italy,	
arrhythmogenic	 right	 ventricular	 cardiomyopathy	 (ARVC)	 appears	 to	 account	 for	 the	
majority	of	deaths	among	young	athletes.18,33,34
Overall,	SCD	in	the	young	(1-40	years)	is	more	common	in	men	(2.27	per	100,000	person-
years)	than	in	women	(0.95	per	100,000	person-years).14	This	difference	can	be	partly	            	
explained	 by	 the	 high	 proportion	 of	 deaths	 due	 to	 coronary	 artery	 disease	 which	 is	
increasing	over	age	(especially	>30	years)14,6	and	perhaps		because	women	are	relatively	
protected	for	the	development	of	atherosclerosis	in	the	premenopausal	period.35-37	Yet,	
even	at	younger	ages	there	seems	to	be	a	male	predominance	of	the	occurrence	of	SCD.



24
                                                      Sudden cardiac death in the young, an overview


                    	 	                     	                 	
Post-mortem	investigation	of	young	SUD	victims	and	SCD	victims		
                                              	 	                            	
A	dedicated	and	focused	post-mortem	investigation	as	compared	to	a	‘routine’	cardiac	
                     	 	            	            	         	
post-mortem	investigation	is	essential	in	detecting	potential	inherited	cardiac	diseases	
                        	                                                	 	
in	 sudden	 death	 victims	 and	 among	 families.	 Post-mortem	 investigation	 includes	
      	 	                                          	 	               	
investigation	of	the	circumstances	of	death,	verification	of	the	victim’s	medical	history	             2.1
and	family	history,	autopsy	and	DNA	storage.12,38

Circumstances of death, verification of the victim’s medical history and family history
      	                                                     	
An	effort	should	be	made	to	obtain	relevant	information	from	health	care	professionals	
                 	
(e.g.	resuscitation	team)	and	other	witnesses	of	the	event	regarding	the	circumstances	
                                                	                                  	
of	death	(e.g.	occurring	during	sleep,	emotional	stress	or	during	or	shortly	after	exercise),	
                     	
the	type	and	duration	of	preceding	symptoms	(e.g.	chest	pain,	dizziness,	nausea,	fever	
                               	                              	                      		
or	headache)	and	the	location	of	the	fatal	event.	Relatives	and	general	practitioners	can	
                                   	                                                    	
be	 a	 useful	 source	 of	 information	 on	 medical-and	 family	 history	 and	 potential	 use	 of	
          	
medications.	 	 Circumstances	 of	 death	 can	 provide	 important	 clues	 to	 the	 underlying	
                                                                             	
causes	of	death,	since	triggers	of	sudden	cardiac	arrest	might	be	specific	for	the	underlying	
                                                                                 	
disease.	 Arrhythmias	 may	 be	 triggered	 by	 (strenuous)	 exercise	 in	 patients	 with	 HCM,	
                                              	
ARVC,	LQTS	type	1	or	CPVT,	while	in	patients	with	BS	or	LQTS	type	3,	fatal	arrhythmias	
          	                                                  	              	
more	often	occur	during	sleep.	Furthermore,	information	on	the	victim’s	medical	history	
                                            	                      	                      	
should	 be	 collected	 (e.g.	 recent	 infections,	 surgical	 operations	 or	 comorbidities	 (e.g.	
                                                                               	
hypertension,	neuromuscular	diseases,	asthma	or	epilepsy).	Medication	use	as	well	as	
        	
cigarette	exposure,	alcohol	-and	substance	abuse	should	be	reported.	
                   	
Besides,	the	victim’s	family	history	with	respect	to	sudden	death	and	inherited	cardiac	
                                                            	              	
or	neuromuscular	diseases	can	reveal	important	additional	information.	When	available,	
                        	 	
ante-mortem	 investigations	 (e.g.	 electrocardiogram,	 echocardiography,	 results	 of	
               	
exercise	testing,	or	CT-scan)	should	be	evaluated.12,38

Autopsy
         		cult	to	compare	autopsy	studies	of	sudden	death	in	the	young	as	autopsies	have	
It	is	diffi
not	been	performed	according	to	a	standardized	protocol.12 	When	autopsy	is	limited	to	
                         	                                                       	
macroscopic	examination	of	the	heart	without	histological	sampling	of	cardiac	tissue	or	
                         	                          	
toxicological	examination,	focal	cardiac	abnormalities	or	extra-cardiac	causes	such	as	an	
            	
intoxication	may	remain	undetected.	In	79%	of	the	cases	of	SCD	without	macroscopic	
              	                              	
abnormalities,	histopathological examination	of	the	heart	revealed	local	pathology	like	
                    	                           	                    	
focal	myocarditis	or	the	presence	of	conduction	system	abnormalities.9	Revision	of	the	
heart	by	a	cardiac	expert	pathologist	is	recommended	when	no	cause	of	death	can	be	
                                       	
established.	A	toxicological	examination	for	drugs	(e.g.	opiates,	amphetamine),	alcohol	
                	                                                         	 	
and	medication	may	be	considered	necessary	in	cases	with	autopsy-negative	findings.39,40


                                                                                                 25
Chapter 2.1


Recently,	international	guidelines	for	autopsy	in	SCD	and	SUD	in	the	young	have	been	
published.12 	Standardization	of	autopsy	is	an	important	tool	in	research	on	causes	of	SCD	
and	SUD	and	facilitates	comparison	and	pooling	of	data	from	various	sources.

DNA storage
Storage	of	the	victim’s	DNA	enables	genetic	testing	when	relatives	consult	a	cardiologist	
or	clinical-geneticist	for	cardiogenetic	screening.	Autopsy	allows	tissue	to	be	collected	
and	stored	in	a	tissue	bank.	Usually,	only	paraffin-embedded	tissue	is	stored	when	a	SCD	
victim	or	SUD	victim	is	autopsied,	which	is	not	an	optimal	source	for	extensive	genetic	
testing.	Guidelines	have	supported	the	notion	that	it	is	desirable	to	store	EDTA-blood	
and/or	 frozen	 muscle,	 liver	 or	 spleen	 tissue	 that	 can	 be	 obtained	 during	 autopsy.6,41
When	no	autopsy	is	performed,	a	skin	biopsy	might	be	taken	(with	permission	of	the	
victim’s	relatives).	Prior	to	the	biopsy,	the	skin	needs	to	be	disinfected	with	alcohol.	The	
obtained	tissue	needs	to	be	stored	in	a	sterile	vial	with	physiological	isotonic	saline	and	
sent	to	a	DNA	laboratory.42


Cardiogenetic	screening	of	first-degree	relatives	of	young	SUD	
victims	and	SCD	victims
Cardiogenetic clinic
When	 an	 inherited	 cardiac	 disease	 is	 suspected	 or	 when	 the	 cause	 of	 death	 remains	
unknown,	 cardiogenetic	 screening	 of	 relatives	 might	 be	 indicated.43	 Cardiogenetic	
screening	 entails	 several	 aspects	 that	 need	 careful	 consideration	 upfront.	 These	
include	 difficulties	 in	 establishing	 a	 final	 diagnosis,	 the	 interpretation	 of	 genetic	 test	
results	 and	 the	 ethical	 considerations	 concerning	 genetic	 testing.44	 Relatives	 should	
be	 informed	 about	 the	 advantages	 and	 disadvantages	 of	 cardiogenetic	 screening.	
Therefore,	dedicated	cardiogenetic	outpatient	clinics	have	been	established	that	provide	
integrated	cardiogenetic	care	by	combining	expertise	from	the	fields	of	ethics,	genetics	
and cardiology.

Genetic testing
Recent	cardiogenetic	developments	have	resulted	in	the	identification	of	many	different	
mutated	genes	related	to	specific	cardiac	pathology,	and	consequently	lead	to	a	better	
understanding	of	the	pathophysiology	of	clinical	syndromes	such	as	HCM	and	LQTS.45
However,	genetic	testing	does	not	always	reveal	a	genetic	mutation	when	an	inherited	
cardiac	 disease	 is	 suspected.	 Not	 all	 causative	 mutations	 have	 been	 discovered	 yet	
and	many	clinical	syndromes	show	genetic	heterogeneity.	In	individuals	with	LQTS,	the	
current	yield	of	genetic	testing	is	estimated	to	be	50-70%.46 For many other diseases (e.g.
dilated	cardiomyopathy	(DCM))	the	yield	of	genetic	testing	is	less.43	In	autopsy-negative	

26
                                                              Sudden cardiac death in the young, an overview


                      	           	       	                                               	
sudden	 death	 victims,	 genetic	 testing	 is	 complicated,	 expensive	 and	 time-consuming,	
                                	
especially	when	no	specific	clinical	diagnosis	is	suspected	based	on	careful	evaluation	                   	
                                                                                 	
of	circumstances	of	death	and	past	medical	history	of	the	victim.	Genetic	testing	in	49	     	     	
                  	                        	                           	
autopsy-negative	sudden	death	victims	revealed	a	mutation	in	LQTS	associated	genes	in	
                    	                 	
20%	of	the	victims	and	a	mutation	in	CPVT	associated	genes	in	14%	of	the	victims.23,24               	            2.1
                                    	        	                                        	
Yet,	since	such	extensive	genetic	testing	is	not	feasible	in	daily	practice,	it	seems	logical	
                    	
that	the	detection	rate	of	inherited	cardiac	diseases	is	lower	in	the	clinical	setti                  		ng.	In	
                                                                                   	
the	future,	a	molecular	autopsy	might	become	possible	for	victims	of	autopsy-negative	                      	
                                                               	
sudden	 death.	 Molecular	 autopsy	 comprises	 testing	 of	 a	 large	 amount	 of	 genes	 that	
underlie	primary	arrhythmia	syndromes.47
Because	 most	 inherited	 cardiac	 diseases	 show	 an	 autosomal	 dominant	 pattern	 of	             	
                	                 	                    	                    	
inheritance,	first-degree	relatives	of	SCD	victims	with	genetic	disease	have	a	50%	risk	of	
                                                         	
being	carrier	of	the	same	disease.45	As	mentioned	before,	recent	studies	showed	that,	
                                               	                     	                     	
with	 thorough	 clinical	 assessment	 of	 first-degree	 relatives	 of	 SUD	 victims,	 a	 cause	 of	
death	 can	 be	 established	 in	 22-53%	 of	 the	 families.      7,8,48,49
                                                                                               	 	
                                                                           	 A	 Dutch	 investigation	 of	 43	
                        	
families	of	SUD	victims	of	whom	22	were	autopsied,	found	an	inherited	cardiac	disease	
                                                           	
in	17	of	the	43	families	that	explained	the	victims	sudden	death.48 Furthermore, a study
executed	in	the	United	Kingdom,	revealed	an	inherited	cardiac	disease	in	53%	of	the	57	
                              	                              	
families	of	autopsy-negative	sudden	death	victims	aged	4-64	years.8
                      	     	            	                                        	
The	yield	of	genetic	testing	in	relatives	is	high	when	the	causative	mutation	is	known.50    	
                                                       	                             	
However,	 it	 should	 be	 realized	 that	 a	 relative	 carrying	 the	 mutation	 of	 an	 inherited	
cardiac	disease	will	not	necessarily	develop	signs	or	symptoms	of	the	clinical	syndrome	
                                        	
that	 is	 associated	 with	 the	 mutation.	 Penetrance	 of	 the	 phenotype	 may	 vary	 among	
                                                  	
individuals	of	the	same	family	and	sometimes	secondary	factors	(or	double	mutations)	                    	
        	
can	influence	the	phenotype	expression.          43,45




Cardiogenetic screening of first-degree relatives
                                        	             	               	               	
Three	scenarios	for	the	pre-symptomatic	cardiogenetic	screening	of	first-degree	relatives	
                  	                 	             	            	
of	young	SCD	victims	and	SUD	victims	can	be	distinguished	(figure	2);
              	         	                 	
a)	The	causative	mutation	in	the	SCD	victim	is	known.
                                                        	                               	
b)	An	inherited	cardiac	disease	is	suspected	in	the	victim,	but	not	established	by	genetic	
    	
testing.	
                        	
c)	The	cause	of	the	victim’s	death	is	unknown	(with	or	without	extensive	autopsy).




                                                                                                           27
Chapter 2.1


Figure 2. Flow	chart,	cardiogenetic	screening	of	first-degree	relatives	of	a	sudden	(cardiac)	death	
victim
     Sudden death victim                          First-degree relative


         DNA diagnosis (a)                           Genetic testing


                                                              yes
  Clinical diagnosis of deceased                       Suspected
  based on ante-mortem and /or                         diagnosis?
  post-mortem investigation (b)



     Cause of death unknown (c)                   Cardiologic evaluation



Scenario	(a)	allows	for	a	targeted	approach	by	genetic	testing	of	the	victims’	relatives.	
Cascade	genetic	screening,	starting	with	genetic	testing	of	the	(genetically)	first-degree	
relatives	 (which	 include	 the	 parents,	 children,	 brothers	 and	 sisters)	 of	 an	 affected	
individual	 might	 lead	 to	 identification	 of	 the	 causative	 mutation	 in	 one	 or	 more	
relative(s).	 Subsequently	 the	 screening	 can	 be	 extended	 to	 the	 connecting	 branch	 of	
the	pedigree.43	Absence	of	the	mutation	rules	out	the	presence	of	the	disease,	and	no	
further	investigation	of	the	pedigree	is	needed.	In	case	a	causative	mutation	is	present	in	
a	relative,	cardiologic	evaluation	and/or	diagnostic	follow-up	is	usually	indicated.	
In	scenario	(b),	the	cardiogenetic	screening	of	relatives	is	more	complicated.	The	post-
mortem	findings	in	the	victim	may	raise	the	suspicion	of	an	inherited	cardiac	disease.	
Based	on	this,	targeted	cardiologic	screening	of	the	relatives	can	be	performed.	Based	
on	the	results	of	the	cardiologic	screening	of	relatives,	targeted	genetic	testing	can	be	
performed	in	the	victim	(if	victims	DNA	is	available)	or	in	the	clinically	affected	relative	
(with	 cardiac	 abnormalities). If	 a	 mutation	 is	 found,	 cascade	 genetic	 screening	 in	 the	
pedigree	 might	 be	 indicated	 (see	 scenario	 a).	 In	 case	 no	 mutation	 can	 be	 detected,	
cardiologic	 screening	 (guided	 by	 the	 findings	 in	 the	 affected	 relative	 or	 post-mortem	
findings	 in	 the	 sudden	 death	 victim)	 of	 all	 first-degree	 relatives	 may	 be	 considered.	
As	 the	 penetration	 of	 the	 phenotype	 may	 differ	 among	 individuals,	 the	 absence	 of	
abnormalities	 on	 cardiologic	 evaluation	 does	 not	 automatically	 rule	 out	 the	 presence	
of	 an	 inherited	 disease.	 In	 some	 diseases	 symptoms	 might	 develop	 at	 older	 age	 (e.g.	
HCM,	DCM	and	ARVC),	which	may	mandate	diagnostic	follow-up	in	these	individuals.	
In	 scenario	 (c),	 the	 cause	 of	 sudden	 death	 is	 unknown	 and	 no	 clues	 are	 available	 for	
a	 specific	 diagnosis,	 which	 makes	 cardiogenetic	 screening	 of	 relatives	 less	 feasible.	 A	
cardiac	examination	of	the	relatives	may	reveal	a	relevant	diagnosis.	Examination	should	
include	the	following	aspects;	(1)	medical	history	(2)	physical	examination	(3)	standard	


28
                                                           Sudden cardiac death in the young, an overview


     	                                                                                     	
resting	 12	 lead	 electrocardiogram	 and	 12	 lead	 electrocardiogram	 with	 specific	 right	
                  	
precordial	positioning	of	the	leads	(leads	-V1,	-V2,	-1V1	and	-1V2	(4)	echocardiography	
                                           	
(5)	 Holter	 recording	 (6)	 exercise	 testing,	 and	 (7)	 measurement	 of	 serum	 lipid	 levels.51
           	             	                                       	       	
If	the	initial	examination	raises	the	possibility	of	a	specific	genetic	disorder,	additional		
       	 	                                                          	        	
investigations	may	be	indicated	which	may	include	provocation	testing	(e.g.	ajmaline/                        2.1
 	                                                    	     	
flecainide	challenging),	cardiac	MRI,	and	genetic	testing.7,8,48,49


        	 	                      	                	
Cost-effectiveness	of	cardiogenetic	screening	of	first-degree	
     	
relatives
                  	 	                            	                   	
The	 cost-effectiveness	 of	 pre-symptomatic	 cardiogenetic	 screening	 of	 relatives	 of	      	
             	                 	
SCD	 victims	 and	 SUD	 victims	 depends	 on	 the	 balance	 between	 the	 probability	 of	
          	                                                      	             	
detecting	an	inherited	cardiac	disease	(and	the	causative	mutation)	and	its	associated	
                	          	                                                   	
therapeutic	 (risk	 reduction	 through	 treatment)	 and	 prognostic	 consequences	 (risk	
                                          	                   	                 	
when	no	treatment	is	given).	This	differs	from	situation	to	situation.	Since	the	costs	of	
        	         	
genetic	testing	are	associated	with	the	number	and	size	of	the	analyzed	genes,	targeted	
        	                    	
genetic	 screening	 of	 relatives	 	 (scenarios	 a	 and	 b)	 is	 likely	 to	 result	 in	 a	 higher	 yield	
             	      	
of	genetic	testing	and	lower	costs.47	When	the	cause	of	death	is	unknown	(scenario	c)	
                                 	                                           	      	
and	 no	 structural	 abnormalities	 are	 found	 with	 autopsy,	 genetic	 testing	 is	 less	 (cost)-
  	 	
effective. 	Limited	analyses	of	only	those	genes	that	are	responsible	for	the	major	part	
               52

of	 the	 clinical	 syndromes	 seems	 to	 increase	 effi 		ciency.	 To	 date,	 only	 a	 few	 studies	 on	
                        	 	                           	                           	
the	yield	and	cost-effectiveness	of	cardiogenetic	screening	of	relatives	of	patients	with	    	
                                                                                          	 	
inherited	cardiac	diseases	have	been	published.53,54,55	Recently,	the	cost-effectiveness	of	
   	                                                                                       	
different	 screening	 strategies	 in	 families	 with	 HCM	 was	 examined.	 Genetic	 testing	 of	   	
      	               	                                            	 	
relatives	of	a	patient	with	HCM	proved	to	be	more	cost-effective	in	the	prevention	of	SCD	    	
                        	                                                            	
than	the	clinical	testing	strategies.55	Another	study,	that	simulated	different	treatment	
                                   	
strategies	in	high	risk	HCM	patients,	reported	that	ICD	therapy	was	more	cost-effective	          	 	
than	amiodarone	therapy	or	no	therapy. 	Furthermore,	in	symptomatic	LQTS	patients,	
                                              54
                                                                                      	             	
        	         	                         	 	
genetic	testing	was	found	to	be	cost-effective	in	comparison	to	no	testing.56       	
            	 	
Cost-effectiveness	 analyses	 through	 modeling	 are	 necessary	 to	 provide	 additional	             	
             	                                	                          	
information	on	the	value	of	cardiogenetic	screening	of	relatives	for	different	diseases		
                                                                	                    	
and scenarios.14	Based	on	future	studies,	recommendations	can	be	drafted	regarding	the	
                  	                  	               	
cardiogenetic	screening	of	relatives	of	SCD	victims	and	SUD	victims.	      	

       	     	
Preparticipation	screening	of	athletes
                      	
Being	 physically	 active	 is	 generally	 regarded	 as	 a	 measure	 to	 prevent	 (cardiovascular)	
                             	
disease,	but	vigorous	activity	can	also	acutely	and	transiently	increase	the	risk	of	acute	
                               	
cardiac	 events	 in	 susceptible	 persons.57	 Physical	 activity	 can	 trigger	 fatal	 arrhythmias	
                                                            	


                                                                                                      29
Chapter 2.1


in	 persons	 with	 cardiomyopathies	 (e.g.	 HCM	 or	 ARVC),	 CPVT	 and	 LQTS	 or	 provoke	
coronary	plaque	rupture	in	those	with	coronary	artery	disease.57,58 The sudden death of
an	apparently	healthy	athlete	inevitably	leads	to	discussions	if	death	could	have	been	
prevented	by	preparticipation	screening.59,60
Approximately	5-14%	of	all	SCDs	in	the	young	occur	during	physical	activity.61-63 However,	
it	is	still	largely	unclear	whether	young	athletes	have	an	increased	risk	of	SCD	compared	
to	non-athletes.	An	Italian	study	reported	that	the	risk	of	sudden	death	was	2.5	(95%	CI;	
1.8-3.4)	times	higher	in	young	athletes	than	in	non-athletes.64	One	of	the	limitations	of	
this	study	was	that	events	not	directly	associated	with	physical	activity	were	also	taken	
into	 account.	 The	 Physicians’	 Health	 Study	 among	 middle	 aged	 men	 reported	 a	 16.9	
times	higher	risk	of	sudden	death	(95%	CI;	10.5	to	27.0)	during	physical	activity	and	the	
30	minutes	after	physical	activity	than	during	episodes	of	low	activity,	but	an	association	
between	the	frequency	of	physical	activity	and	the	long	term	risk	of	sudden	death	could	
not	be	established.63	A	moderate	to	intensive	level	of	physical	activity	was	associated	
with	a	significant	decrease	in	SCD	in	a	study	of	7735	middle	aged	men.65
In	2005,	the	section	of	sports	cardiology	of	the	European	Society	of	Cardiology	issued	
recommendations	 for	 routine	 preparticipation	 cardiovascular	 screening	 of	 young	
competitive	 athletes.	 The	 screening	 consists	 of	 a	 questionnaire,	 physical	 examination	
and an electrocardiogram.66 An	 electrocardiogram	 is	 not	 part	 of	 the	 preparticipation	
screening	 recommended	 by	 the	 American	 Heart	 Association	 that	 essentially	 relies	 on	
medical	history	and	physical	examination.67	The	European	recommendations	are	largely	
based	on	the	Italian	experience,	suggesting	that	the	introduction	of	a	screening	program	
in young athletes led to a decline in the incidence of SCD. In Italy, 55 cases of SCD aged
12	to	35	years	among	screened	athletes	were	registered	between	1997	and	2004.	The	
incidence	of	SCD	dropped	from	4.19	(95%	CI;	1.78-7.59)	to	0.87	(95%	CI;	0.46-1.28)	per	
100,000	athletes	per	year.15
The	 European	 preparticipation	 screening	 recommendations	 have	 led	 to	 a	 stream	 of	
pro-contra	 discussions.59,60	 The	 main	 criticisms	 of	 the	 recommendations	 are	 the	 lack	
of	 randomised	 studies	 to	 support	 the	 recommendations,	 the	 absence	 of	 validated	
questionnaires	 and	 validated	 electrocardiographic	 criteria,	 and	 the	 potential	 of	 false	
positive	findings	among	screened	athletes,	especially	given	the	rare	occurrence	of	SCD	
in young athletes.59	The	interpretation	of	the	electrocardiogram	of	athletes	is	hampered	
by	 physiological	 adaptation	 to	 systematic	 training,	 known	 as	 the	 athletes	 heart.68	 Up	
to	40%	of	the	electrocardiograms	taken	in	athletes	demonstrate	variations	that	can	be	
deemed	abnormal,	such	as	sinus	bradycardia,	atrial	fibrillation	and	ST-segment	changes	
in	 the	 right	 precordial	 leads.69	 Furthermore,	 it	 has	 been	 estimated,	 that	 only	 a	 small	
proportion	of	the	athletes	that	suddenly	died	would	have	been	previously	identified	as	
being	at	increased	risk	for	SCD	by	the	preparticipation	program.59


30
                                                      Sudden cardiac death in the young, an overview


                       	
The	Netherlands	Institute	for	Public	Health	and	Environment	calculated	that	a	randomised	
                 	                 	      	                                     	
study	of	the	effects	of	preparticipation	screening	(assuming	a	50%	reduction	in	the	rate	
of	SCD	-from	4	to	2	per	100,000	athletes	per	year-,	with	80%	power)	would	call	for	2	
groups	with	1,200,000	person-years	of	follow-up.	Taking	this	into	account,	it	is	unlikely	
          	 	                         	                       	    	
that	 definitive	 evidence	 supporting	 the	 use	 of	 preparticipation	 screening	 will	 ever	 be	     2.1
                                            	
presented	 since	 it	 will	 need	 a	 huge	effort	 with	 tremendous	 budgetary	consequences.	
A	search	for	adequate	and	valid	intermediate	outcome	measures	as	an	alternative	for	      	
SCD,	such	as	for	example	a	risk	score,	might	facilitate	randomised	comparisons	in	a	much	
smaller	group	of	athletes.		
                                        	
Raising	 awareness	 of	 the	 potential	 consequences	 of	 symptoms	 during	 exercise	 (e.g.	
                                  	           	
collaps,	 chest	 discomfort,	 fatigue	 and	 flu-like	 symptoms)70,	 improving	 the	 availability	
                                	                                     	
of	 automated	 external	 defibrillators	 and	 careful	 cardiogenetic	 screening	 of	 young	
           	                      	                 	                      	
SCD	 victims	 and	 their	 relatives	 may	 constitute	 sound	 alternatives	 to	 mandatory	
        	      	
preparticipation	screening.	Given	the	higher	absolute	number	of	acute	cardiac	arrests	in	
older	athletes,	in	whom	coronary	artery	disease	is	far	more	common,	this	group	should	
not	be	neglected.71




                                                                                                 31
Chapter 2.1


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                                                                                                             33
Chapter 2.1


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34
                                                               Sudden cardiac death in the young, an overview


          	                                	
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                                                                                                             35
                                       Chapter	2.2

Rationale	and	design	of	the	CAREFUL	study	
   The yield of cardiogenetic screening in first-degree
         relatives of sudden cardiac and unexplained
                              death victims <45 years
Chapter 2.2


Abstract	
Background:	Sudden	cardiac	death	(SCD)	in	the	young	(1-44	years)	is	a	strong	risk	factor	
for	 the	 presence	 of	 inherited	 cardiac	 diseases	 in	 surviving	 first-degree	 relatives.	 Post-
mortem	 investigation	 of	 the	 victim	 and	 cardiogenetic	 screening	 of	 the	 first-degree	
relatives	 is	 indicated	 to	 detect	 inherited	 cardiac	 diseases	 and	 treat	 relatives	 at	 an	
early	stage	to	prevent	SCD.	In	the	Netherlands,	post-mortem	investigation	is	often	not	
performed	and	relatives	of	SCD	and	sudden	unexplained	death	(SUD)	victims	are	rarely	
evaluated for inherited cardiac diseases.

Methods:	A	prospective	population	based	follow-up	study	carried	out	in	two	intervention	
regions	 and	 two	 control	 regions.	 In	 the	 intervention	 regions	 a	 comprehensive	
intervention	 (stimulate	 autopsy	 and	 DNA	 storage	 of	 victims	 and	 the	 referral	 of	 first-
degree	 relatives	 for	 cardiogenetic	 screening)	 is	 applied	 in	 a	 ‘top-down’	 and	 ‘bottom-
up’	mode.	In	each	region,	young	sudden	death	victims	are	registered	and	for	all	cases	
performance	of	autopsy	and	screening	of	relatives	in	a	cardiogenetics	out-patient	clinic	
will	be	determined.	

Expected results:	The	study	will	provide	information	on	the	incidence	of	sudden	death	
in	the	young	and	the	proportion	of	diagnosed	inherited	cardiac	diseases.	Moreover,	the	
additional	 value	 of	 the	 introduction	 of	 two	 different	 preventive	 strategies	 directed	 at	
early	detection	of	inherited	cardiac	diseases	in	first-degree	relatives	in	the	usual	care	
will	be	evaluated.		

Conclusion:	The	CAREFUL	study	will	help	to	set	a	new	standard	of	care	in	the	screening	
of	young	sudden	death	victims	and	their	relatives	to	identify	the	presence	of	inherited	
cardiac	diseases,	in	order	to	prevent	sudden	death.




38
                                                              Rationale and design of the CAREFUL study


         	          	
Introduction	and	rationale
Sudden	cardiac	death	(SCD)	and	sudden	unexplained	death	(SUD)	before	the	age	of	45	
years	are	strong	risk	factors	for	the	presence	of	inherited	cardiac	diseases	in	surviving	
 	                  	
first-degree	relatives.1-6	In	western	countries	the	incidence	of	SCD	in	persons	aged	1-40	
              	
years	is	estimated	to	be	0.9-1.6	per	100,000	person-years.7
Inherited	cardiac	diseases	can	be	subdivided	into	three	main	categories:	cardiomyopathies,	
premature	atherosclerosis,	and	primary	arrhythmia	syndromes	(e.g.	long-QT	syndrome).	
In	 approximately	 half	 of	 SCD	 cases,	 cardiac	 arrest	 is	 the	 first	 manifestation	 of	 the	
                                                                        	                	                 2.2
underlying disease.8
                                                                               	
As	most	inherited	cardiac	diseases	show	an	autosomal	dominant	pattern	of	inheritance,	
 	                  	                  	
first-degree	relatives	of	SCD	victims	have	50%	risk	of	being	carrier	of	an	inherited	cardiac	
disease.	In	case	of	a	SUD,	i.e.	when	autopsy	does	not	reveal	the	cause	of	death	or	is	
not	performed,	an	inherited	cardiac	disease	can	be	detected	in	22-53%	of	families	by	
                	                                 	
cardiogenetic	screening.1-3;6 	Early	detection	of	inherited	cardiac	diseases	in	families	offers	  	
              	                                                          	 	
opportunities	to	prevent	SCD.	These	may	include	lifestyle	modifications,	pharmacological	
                               	                                                           	
treatment	 and	 implantation	 of	 a	 pacemaker	 or	 implantable	 cardioverter	 defibrillator	
(ICD).	
                       	 	
Post-mortem	 investigation	 including	 autopsy	 and	 DNA	 storage	 is	 recommended	 after	          	
                                                                     	
a	sudden	death	of	a	young	person,	since	detailed	information	on	the	victim’s	cause	of	 	
                                             	
death	 is	 relevant	 for	 surviving	 relatives.9	 When	 autopsy	 reveals	 a	 (possible)	 inherited	
cardiac	disease	or	does	not	reveal	any	cause	of	death	(in	which	case	a	primary	arrhythmia	
syndrome	 should	 be	 suspected	 as	 the	 cause	 of	 death),	 prompt	 expert	 assessment	 of	
                  	                                                   	
surviving	relatives	has	been	recommended.10	Storage	of	victims	DNA	enables	molecular	
       	    	                                           	     	                      	
confirmation	of	a	suspected	disorder,	when	relatives	attend	a	cardiogenetic	clinic.	Ideally,	
                	                	                   	                                        	
cardiogenetic	 screening	 of	 first-degree	 relatives	 should	 be	 performed	 soon	 after	 the	
     	                      	                           	        	
victim’s	death	at	a	multidisciplinary	cardiogenetic	out-patient	clinic,	currently	located	in	
each	of	eight	university	hospitals	and	in	a	few	(satellite)	non-university	hospitals	in	the	
                                      	               	
Netherlands.	First-degree	relatives	are	genetically	and	cardiologically	evaluated	based	
                           	 	                                               	
on	the	results	of	investigations	in	the	deceased	or	other	symptomatic	relatives.       	
                                           	 	                                   	
Unfortunately,	post-mortem	investigation	of	young	sudden	death	victims	is	not	always	
                                               	     	                    	
performed	 in	 the	 Netherlands.	 Emotional,	 financial	 and	 logistic	 factors	 may	 underlie	
                              	          	
this	 problem.11	 Confronting	 relatives	 with	 a	 request	 for	 autopsy	 might	 be	 diffi   		cult	 in	
           	
the	 emotional	 turmoil	 following	 the	 sudden	 death	 of	 a	 young	 person.	 Besides,	 many	
physicians	seem	not	to	be	familiar	with	the	procedure	to	request	and	arrange	an	autopsy.	
   	
After	 a	 person	 is	 declared	 dead,	 the	 health	 insurance	 ceases	 immediately.12 Costs for
                                  	
transport	and	autopsy	are	often	not	reimbursed	for	those	who	died	out-of-hospital.	In	
         	
addition,	it	appears	that	insuffi                	 	                               	
                                    		cient	attention	is	directed	towards	relatives,	despite	the	
                        	                  	                       	
considerable	potential	for	prevention.	As	a	result,	potential	inherited	cardiac	diseases	

                                                                                                    39
Chapter 2.2


will	remain	undetected.	
The	 primary	 objective	 of	 the	 CAREFUL	 study	 (The	 yield	 of	 cardiogenetic	 screening in
first-degree	relatives	of	sudden	cardiac	and	unexplained	death	victims	<45	years)	is	to	
identify	an	optimal	strategy	to	increase	the	rate	of	post-mortem	investigation	in	young	
sudden	death	victims	(1-44	years),	and	the	rate	of	cardiogenetic	screening	of	first-degree	
relatives.	The	secondary	objective	is	to	provide	complete	information	on	the	incidence	
and	 causes	 of	 sudden	 death	 in	 the	 young	 and	 the	 presence	 of	 (treatable)	 inherited	
cardiac	diseases	in	first-degree	relatives.	
We	expect	that	the	information	obtained	in	this	study	will	contribute	to	the	development	
of	 a	 more	 general	 strategy,	 aiming	 at	 the	 prevention	 of	 SCD	 in	 the	 young	 in	 the	
Netherlands.

Design
The	CAREFUL	study	is	a	prospective	population	based	follow-up	study	carried	out	in	two	
intervention	regions	and	two	control	regions	in	the	Netherlands.	
The	regions	Noord-Holland	and	Midden-Nederland	will	serve	as	intervention	regions	in	
which	an	intervention	modality	will	be	introduced	to	structure	the	usual	care	following	
a case of sudden death in a young individual. In the control regions Hollands Midden
and	 Groningen,	 the	 care	 following	 a	 case	 of	 sudden	 death	 will	 be	 observed	 without	
intervention.	Together,	these	four	regions	comprise	approximately	28%	of	the	general	
Dutch	population	aged	1-44	years.	Data	collection	has	been	started	the	1st	of	June	2008	
and	will	be	continued	for	three	years.	

Definitions
Sudden	death	is	defined	as	unexpected	death	due	to	a	natural	cause	of	disease	within	
24	hours	after	the	onset	of	symptoms.	In	addition,	when	unwitnessed	death	occurred	
within	24	hours	after	the	person	was	seen	alive,	this	is	also	defined	as	sudden	death.	
SCD	is	sudden	death	caused	by	any	cardiac	disease	or	aortic	root	disease	(e.g.	due	to	
Marfan	syndrome).	SUD	is	defined	as	sudden	death	in	which	no	cause	of	disease	can	be	
established	based	on	clinical	findings,	post-mortem	studies	or	cardiogenetic	screening	
of	relatives.		

Population
Two	different	study	populations	can	be	distinguished;	the	sudden	death	victims	(index	
patients)	and	their	first-degree	relatives:	
(1)	All	victims	of	sudden	death	aged	1-44	years	in	the	study	regions	will	be	included	in	
the	study	when	a	natural	cause	of	death	is	likely	or	cannot	be	excluded	based	on	clinical	
findings	and	post-mortem	investigation,	when	performed.	Also,	non-natural	deaths	that	

40
                                                            Rationale and design of the CAREFUL study


are	probably	due	to	cardiac	arrhythmias	(e.g.	sudden	and	unexplained	drowning	of	an	
                                  	
experienced	swimmer)	are	initially	included	in	the	study.	All	other	non-natural	deaths	
will	be	excluded	from	the	study	(e.g.	suicide).
         	                	                   	                   	
(2)	All	first-degree	relatives	of	the	SCD	victims	and	SUD	victims	(parents,	children	and	
                     	                                                      	     	
siblings)	of	the	victims	as	described	in	sub	(1)	are	eligible	for	study	participation.

Usual care after a SCD or a SUD of a young person
In	 the	 Netherlands,	 when	 someone	 dies,	 physicians	 are	 legally	 obliged	 to	 inspect	 the	
                                                                                                        2.2
                                         		
corpse	and	complete	a	death	certificate	form.	If	a	natural	cause	of	death	is	suspected,	
                                                        	          	                          	
a	 clinical	 autopsy	 can	 be	 requested	 if	 the	 victims’	 relatives	 grant	 permission.	 Often	 a	
                 		                                      	
general	 practitioner	 is	 responsible	 for	 requesting	 an	 autopsy,	 because	 most	 cases	 of	
SCD	 occur	 out-of-hospital.13	 To	 request	 a	 clinical	 autopsy,	 the	 nearest	 hospital	 with	 a	
pathology	department	can	be	contacted.	
When	 a	 non-natural	 cause	 of	 death	 cannot	 be	 excluded,	 a	 coroner	 (who	 has	 to	 be	 a	
physician	in	the	Netherlands)	is	contacted.	If	the	possibility	exists	that	the	corpse	could	
                                                               	
serve	as	evidence	in	a	crime,	the	corpse	can	be	confiscated	by	the	public	prosecutor.	
                         	
If	 the	 corpse	 is	 confiscated,	 a	 judicial	 autopsy	 can	 be	 performed	 by	 the	 Netherlands	
               	
Forensic	Institute	(NFI),	or	the	corpse	is	released	and	a	clinical	autopsy	can	be	requested	
                       	
by	the	former	treating	physician.
                                                            		
Besides	the	request	for	autopsy,	the	general	practitioner	also	plays	an	important	role	
                                	                   	                      	
in	the	referral	of	surviving	first-degree	relatives	to	a	cardiogenetics	clinic.	However,	the	
                    	                                            	                  		          	
referral	 of	 relatives	 can	 be	 complicated	 when	 the	 victim’s	 general	 practitioner	 differs	
                           		                   	     	
from	the	general	practitioner	of	the	victim’s	first-degree	relatives.	 	

Registration of sudden death patients, autopsy rates and referral of first-degree relatives
                     	                            	                                  	
Sudden	death	victims	are	registered	by	continuously	reviewing	the	resuscitation	records	
                          	        		
and	the	death	declaration	certificates	on	possible	sudden	death	cases	aged	1-44	years.	
                                                                                   	
Assessment	 of	 the	 probable	 cause	 of	 death	 and	 whether	 or	 not	 the	 victim	 is	 eligible	
for	inclusion	in	the	CAREFUL	study	will	be	performed	by	an	expert	panel	consisting	of	    	
                                                	                         		
a	cardiologist,	pathologist,	a	clinical	geneticist	and	a	general	practitioner.	Based	on	the	
                     	                                                        	
available	information,	the	(possible/probable)	cause	of	death	is	classified	as	one	of	five	   	
categories	 (see	 table	 1).	 The	 majority	 of	 pathologic	 laboratories	 record	 autopsy	 data	
                                                                                	
centrally	 in	 the	 PALGA	 (Pathologisch-Anatomisch	 Landelijk	 Geautomatiseerd	 Archief)	
                  	
database,	a	nationwide	network	and	registry	of	autopsy-,	histo-	and	cytopathology	in	
the Netherlands.14	The	number	of	autopsies	is	estimated	by	extraction	of	data	from	the	
                                                       	                   	
                                                         	
PALGA	database	and	the	Netherlands	Forensic	Institute	databases.	




                                                                                                  41
Chapter 2.2


Table 1. Categories of causes of sudden death

Category                   Definition                           Example
A.	Definite	SCD                                            Hypertrophic	cardiomyopathy	
                           Cardiac	disease	is	established	by	
                           post-mortem	investigation       established	by	autopsy	
B.	Probable	SCD                                            Sudden death during soccer
                           Cardiac disease is the most likely
                           cause of death                  game	in	a	person	with	prior	
                                                           history	of	syncopal	episodes	and	
                                                           palpitations
C.	Possible	SCD          Both cardiac and non-cardiac      Unwitnessed	death,	no	additional	
                         diseases	are	possible	causes	of	  information	on	the	circumstances	
                         death                             of	the	victim’s	death.	No	family	
                                                           history of sudden death
D. Non-cardiac sudden Non-cardiac disease is the most      Acute onset of severe hematesis
   death                 probable	cause	of	death           followed	by	collapse	and	sudden	
                                                           death
E.	Probable	non-natural	 Non-natural cause of death is     Car	accident	in	which	the	
   sudden death          the	most	probable	cause,	but	an	 underlying cause of the accident
                         underlying natural cause of death remains	unexplained
                         cannot	be	excluded



All	 eight	 cardiogenetics	 departments	 in	 the	 Netherlands	 record	 relatives	 of	 young	
SCD/SUD	victims	that	are	referred	to	their	clinics.	When	these	relatives	give	informed	
consent,	further	data	on	the	process	and	outcome	of	cardiogenetic	screening	is	collected.	
Furthermore,	 six	 months	 after	 the	 victim’s	 death,	 the	 general	 practitioner	 will	 be	
contacted	and	interviewed	through	a	structured	questionnaire	on	the	previous	medical	
history	of	the	patient,	the	(possible)	request	for	autopsy	and	the	(possible)	referral	of	
first-degree	relatives	to	a	cardiogenetics	department	or	cardiologist.	

Intervention
The	 intervention	 modality	 consists	 of	 two	 elements;	 1)	 Stimulate	 autopsy	 and	 DNA	
storage	 in	 SCD	 victims	 and	 SUD	 victims	 aged	 1-44	 years;	 2)	 Stimulate	 referral	 of	 first-
degree	 relatives	 in	 an	 early	 stage	 to	 a	 cardiogenetics	 department	 by	 the	 general	
practitioner.	
The	intervention	is	implemented	in	usual	care	in	two	different	ways.	In	region	Midden-
Nederland	an	‘optimal’	intervention	modality	(‘bottom-up’	strategy)	is	introduced,	which	
aims	 at	 educating	 and	 thereby	 changing	 the	 behavior	 of	 the	 individual	 professional.	
During	the	first	six	months	of	the	study	period,	the	general	practitioners	and	coroners	are	
informed	about	the	importance	of	autopsy	and	cardiogenetic	screening	of	first-degree	
relatives	 by	 a	 letter	 and	 information	 meetings.	 In	 case	 of	 a	 sudden	 death	 in	 a	 young	
individual,	the	emergency	medical	services	are	instructed	to	leave	an	information	letter	

42
                                                           Rationale and design of the CAREFUL study


                                                                                   		
for	the	professional	who	inspects	the	corpse	and	completes	the	death	certificate	form.
                                     	
The	 second	 ‘maximal’	 intervention	 modality	 (’top-down’	 strategy)	 is	 implemented	 in	
region	Noord-Holland.	A	central	24/7	study	telephone	number	and	a	dedicated	website	
are	available	for	the	professionals	involved	in	a	case	of	sudden	death	in	a	young	person.	
            	                                             	
By	 contacting	 the	 telephone	 number	 and/or	 visiting	 the	 website,	 the	 professional	
                                                                       	                 	
is	 informed	 about	 the	 importance	 of	 autopsy	 and	 referral	 of	 first-degree	 relatives	 for	
              	
cardiogenetic	 screening	 (if	 indicated).	 Moreover,	 the	 professional	 receives	 specific	   	
                     	
detailed	 information	 on	 how	to	execute	both	 the	autopsy	request	and	 the	referral	 of	
                                                                                                       2.2
      	                                                                       	
relatives.	The	study	telephone	number	is	only	promoted	during	the	first	six	months	of	
                       	                	        	                    	
the	 study	 by	 a	 letter	 and	 information	 meetings.	 Both	 modalities	 will	 be	 compared	 in	
                                                     	 	
terms	of	autopsy	rates,	referral	rates,	and	cost-effectiveness.

Baseline measurement
The	 increased	 awareness	 of	 inherited	 cardiac	 diseases	 as	 a	 possible	 cause	 of	 sudden	
death	 of	 a	 young	 person	 might	 result	 in	 an	 improvement	 of	 the	 usual	 care	 in	 both	
                            	                                                               	
the	 control	 and	 intervention	 regions	 during	 the	 study	 period.	 To	 measure	 the	 effect	
                                                       	
of	 increased	 awareness	 in	 the	 separate	 intervention	 regions	 compared	 to	 the	 control	
regions,	 a	 baseline	 measurement	 is	 performed	 in	 all	 study	 regions	 over	 the	 two-year	
period	preceding	the	CAREFUL	study	(June	2006-May	2008).	Based	on	this	measurement,	
                     	
the	change	over	time	with	respect	to	the	performance	of	autopsy	and	the	referral	of	
 	                 	                                           	
first-degree	relatives	in	the	control	regions	and	intervention	regions	can	be	monitored	
and	a	comparison	among	regions	will	be	made.

Data analysis
              	                                                              	
The	 proportion	 of	 post-mortem	 studies	 in	 young	 sudden	 death	 victims	 is	 the	 sum	 of	
autopsies	as	recorded	in	the	PALGA	and	the	NFI	databases	divided	by	the	number	of	SCD	
    	                    	                  	       	                 	
victims	and	SUD	victims.	The	proportion	of	first-degree	relatives	of	young	SCD	victims	        	
                	            	                    	                                	
and	 SUD	 victims	 that	 attend	 a	 cardiogenetics	 clinic	 within	 six	 months	 after	 the	 event	
                                      	                	              	
is	determined	as	the	number	of	first-degree	relatives	that	attend	a	cardiogenetic	clinic	  	
                                              	        	
divided	by	the	total	number	of	the	victims’	living	first-degree	relatives.	
                                              	
The	primary	outcomes	are	the	proportion	of	post-mortem	studies	in	young	SCD	victims	           	
                 	                        	       	                 	
and	 SUD	 victims,	 and	 the	 proportion	 of	 first-degree	 relatives	 of	 young	 SCD	 victims		
                	      	                        	                                           	
and	 SUD	 victims	 attending	 a	 cardiogenetics	 department	 within	 six	 months	 after	 the	
                                 	
event	between	the	intervention	regions	and	the	control	regions	and	between	the	two	
          	                             	
intervention	regions.	These	proportions	are	compared	by	using	the	Chi-square	or	Fisher’s	
                           	                                 	 	
Exact	 tests,	 or	 logistic	 regression	 models	 when	 statistical	 adjustment	 for	 potential	  	
                                                              	         	
confounders	is	deemed	necessary.	Similarly,	the	proportion	of	first-degree	relatives	who		
                                   	
receive	treatment	or	diagnostic	follow-up	because	of	an	increased	risk	of	sudden	death	


                                                                                                 43
Chapter 2.2


identified	with	cardiogenetic	screening	will	be	compared.	
In	addition,	the	incidence	rate	of	SCD	and	SUD	per	100,000	person-years	is	estimated	
as	the	total	number	of	cases	of	SCD	and	SUD	divided	by	the	number	of	person-years	of	
the	population	at	risk	in	the	relevant	age	category,	in	the	study	regions	and	during	the	
study	period.	Causes	of	death	will	be	presented	by	overall	percentages	and	specified	by	
gender	and	age.	In	addition,	sub-analyses	will	be	performed	for	victims	that	are	known	
to	have	died	within	one	hour	after	the	onset	of	symptoms	(instead	of	24	hours)	to	allow	
comparisons	with	other	studies	(that	use	the	one	hour	definition).

Summary
The	aim	of	the	CAREFUL	study	is	to	investigate	and	improve	the	care	following	a	case	of	
sudden	death	in	the	young	by	increasing	the	proportion	of	post-mortem	investigations	
in	young	sudden	death	victims	and	the	proportion	of	cardiogenetically	screened	first-
degree	 relatives.	 With	 this	 study,	 we	 will	 investigate	 the	 effectiveness	 of	 introducing	
a	 stimulation	 program	 to	 increase	 the	 autopsy	 rate	 in	 SCD	 victims	 and	 the	 referral	 of	
their	first-degree	relatives.	Also,	information	on	incidence	and	causes	of	sudden	death	
in	the	young	will	be	generated.	We	anticipate	that	the	results	of	this	study	will	help	to	
set	a	new	standard	of	care	in	the	screening	of	young	SCD	victims	and	SUD	victims	and	
their	first-degree	relatives	to	identify	the	presence	of	inherited	cardiac	diseases,	and	to	
prevent	sudden	cardiac	death.




44
                                                                Rationale and design of the CAREFUL study


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      position	statement. Heart 2008;94:502-507.
            	
                                                                                       		
(11)		Oppewal	 F,	 Meyboom-de	 Jong	 B.	 Issues	 involved	 in	 Dutch	 general	 practitioners’	 failure	 to	
      request	 autopsy:	 report	 from	 three	 focus	 groups. Ned Tijdschr Geneeskd 2003;147:1315-
      1318.
(12)		College	van	zorgverzekeraars.	Bijlage	bij	pakketadvies,	2007	(www.cvz.nl).			
(13)		de	 Vreede-Swagemakers	 JJ,	 Gorgels	 AP,	 Dubois-Arbouw	 WI,	 van	 Ree	 JW,	 Daemen	 MJ,	
                                                                                   	
      Houben	LG	et	al.	Out-of-hospital	cardiac	arrest	in	the	1990’s:	a	population-based	study	in	the	
      Maastricht	area	on	incidence,	characteristics	and	survival. J Am Coll Cardiol 1997;30:1500-
                                                    	
      1505.
(14)		Casparie	M,	Tiebosch	AT,	Burger	G,	Blauwgeers	H,	van	de	Pol	A,	van	Krieken	JH	et	al.	Pathology	
                                                                                                  	
      databanking	 and	 biobanking	 in	 The	 Netherlands,	 a	 central	 role	 for	 PALGA,	 the	 nationwide	
      histopathology	and	cytopathology	data	network	and	archive. Cell Oncol 2007;29:19-24.




                                                                                                       45
Chapter        3
Incidence and causes
                                   Chapter	3.1	

Sudden	death	in	persons	younger	than	40	years:	
                          incidence and causes
Chapter 3.1


Abstract
Background:	Worldwide	the	problem	of	(natural)	sudden	death	in	the	young	is	currently	
debated	 and	 measures	 for	 prevention	 are	 evaluated.	 Information	 on	 the	 incidence	
and	 causes	 of	 sudden	 (cardiac)	 death	 in	 the	 young	 (1-39	 years)	 is	 essential	 for	 the	
development	of	preventive	strategies.

Methods:	 Incidence	 estimates	 and	 causes	 of	 death	 were	 determined	 using	 death	
certificate	data	of	out-of-hospital	sudden	deaths	recorded	by	Statistics	Netherlands	from	
1996	 to	 2006.	 To	 define	 sudden	 death,	 International	 Classification	 of	 Diseases	 codes	
were	selected	based	on	a	systematic	review	of	the	literature	assessing	the	most	common	
causes	of	(natural)	sudden	death	in	the	young.	

Results:	The	incidence	of	sudden	death	was	2.1	(95%	confidence	interval	(CI);	2.0-2.2)	per	
100,000	person-years.	The	incidence	was	higher	for	men	(2.9	per	100,000	person-years)	
than	for	women	(1.2	per	100,000	person-years)	and	increased	by	age.	The	majority	of	
sudden	deaths	were	of	cardiac	origin.	The	sudden	cardiac	death	incidence	was	1.6	(95%	
CI;	1.5-1.7)	per	100,000	person-years.	In	9%	the	cause	of	death	remained	unexplained.

Conclusion:	 The	 incidence	 of	 sudden	 death	 in	 the	 young	 is	 2.1	 per	 100,000	 person-
years.	Treatable	cardiac	causes	(like	atherosclerotic	coronary	artery	disease)	are	often	
underlying	a	sudden	death	in	the	young.	This	information	is	helpful	in	the	development	
of	preventive	strategies.




50
                                    Sudden death in persons younger than 40 years: incidence and causes


         	
Introduction	
Sudden	death	in	young	individuals	has	a	major	impact	on	the	community	since	apparently	
                           	
healthy	 persons	 are	 affected.	 The	 value	 of	 screening	 programmes	 to	 prevent	 sudden	
                                                                           		 	
cardiac	death	(SCD)	is	currently	debated	worldwide1,2	as	identification	of	individuals	at	
                                                        	 	
risk	may	allow	early	treatment	or	lifestyle	modifications,	which	subsequently	may	lead	
to	a	decline	in	sudden	death	cases.	The	yield	of	screening	might	be	high	in	relatives	of	     	
                     	
sudden	 death	 victims	 because	 of	 their	 increased	 risk	 of	 carrying	 an	 inherited	 cardiac	
disease.3,4	 Furthermore,	 physical	 activity	 might	 enhance	 fatal	 cardiac	 arrhythmias	 in	
                                           	
                                  	
individuals	with	(asymptomatic)	cardiac	diseases.5 A reduced incidence of SCD in athletes
                                         	                           	       	
below	35	years	in	Italy	has	been	attributed	to	the	preparticipation	screening	program	
consisting	of	clinical	investigation	and	an	electrocardiogram.6	Based	on	these	notions	the	
          	                     	 	                                                         	             3.1
                                       	                                               	
Swedish,	 Italian	 and	 Irish	 authorities	 have	 recommended	 cardiac	 examination	 of	 high	
                           	                  	           	
risk	 groups,	 including	 first-degree	 relatives	 of	 patients	 with	 inherited	 cardiac	 diseases	
                                                                   	                	
and	athletes,	in	order	to	prevent	sudden	death.7,8	In	addition,	the	International	Olympic	
        	
Comittee	and	the	European	Society	of	Cardiology	have	recommended	a	preparticipation	      	     	
cardiovascular	 screening	 programme	 for	 young	 athletes. 	 Yet,	 we	 think	 that	 the	
                                                                      9,10

   		cacy	of	these	preventive	screening	programmes	is	still	unclear	and	more	insight	in	
effi                          	                                  	
the	 prevalence	 and	 incidence	 of	 sudden	 death	 is	 necessary	 before	 development	 and	
               	
implementation	 of	 these	 strategies.	 Studies	 on	 the	 incidence	 and	 causes	 of	 sudden	
                                            	
death	in	the	young	(1-40	years)	are	often	restricted	to	athletes	5,11,12	or	are	mostly	based	
on	regional	observations	rather	than	nationwide	coverage.13-15	Therefore,	the	primary	
                        	                       	
        	                           	             	
objective	of	this	study	is	to	estimate	the	nationwide	incidence	of	out-of-hospital	sudden	
death	and	SCD	in	the	young	using	data	on	primary	cause	of	death	(cause	of	death	coded	
                                                     	              	 	
according	to	the	tenth	revision	of	the	International	Classification	of	Diseases	(ICD-10))16
                   	 	
recorded	by	Statistics	Netherlands.	In	order	to	create	an	evidence	based	group	of	ICD-
                                                                                  	
10	codes	that	could	be	used	as	a	proxy	for	sudden	death	and	SCD	we	first	performed	a	
literature	review	on	the	causes	of	sudden	death	and	SCD	in	the	young.

Methods
Definitions
                                	                                                   	
Sudden	death	in	the	young	is	defined	as	unexpected	natural	death	within	24	hour	after	
                                                              	
the	onset	of	symptoms	in	persons	aged	1-39	years.17	SCD	is	defined	as	sudden	death	due	
to a cardiac cause.

Causes of death register
   	
1after	the	death	of	any	person.	These	reports	contain	data	on	primary	and	secondary	
                                                  	 	
causes	of	death	and	are	centrally	recorded	by	Statistics	Netherlands.		
Incidence of sudden death


                                                                                                    51
Chapter 3.1


To	estimate	the	incidence	of	sudden	death,	nationwide	data	on	primary	cause	of	death	
recorded	by	Statistics	Netherlands	over	the	period	1996-2006	were	used.	
Death	certificates	do	not	include	information	on	the	duration	of	preceding	symptoms	
and	the	actual	time	of	cardiac	arrest,	which	makes	it	difficult	to	distinguish	the	‘sudden’	
deaths.	 To	 overcome	 this	 problem,	 we	 defined	 sudden	 death	 as	 death	 taking	 place	
outside	the	hospital.18,19	Because	no	dedicated	ICD	code	exists	for	‘sudden	death’,	we	
reviewed	 the	 literature	 to	 define	 the	 most	 common	 causes	 of	 sudden	 death.	 Next,	
corresponding	ICD-10	codes	were	selected	to	compose	a	proxy	for	sudden	death.	
The	review	was	performed	in	Embase,	Medline	and	the	Cochrane	Library.	We	included	
all	studies	on	SCD	and	sudden	death	in	the	young	(1-39	years)	that	were	published	from	
1980	until	2007	and	in	which	over	70%	of	the	cases	autopsy	was	performed.	

Data analysis
For	the	literature	review,	studies	were	selected	that	dealt	with	‘athletes’	and	‘general	
population’.	 We	 analysed	 both	 populations	 separately.	 The	 results	 were	 presented	 as	
prevalence	estimates	(with	corresponding	95%	confidence	intervals	(95%	CI)).
The	 incidence	 (with	 corresponding	 95%	 CI)	 of	 out-of-hospital	 sudden	 death	 in	 the	
Netherlands	 is	 reported	 by	 age	 and	 sex.	 Person-years	 were	 based	 on	 the	 number	 of	
subjects	in	the	relevant	age	category	from	1996-2006.	All	analyses	on	incidence	were	
performed	in	agreement	with	Dutch	privacy	legislation	at	Statistics	Netherlands.20


Results
Causes of sudden death, literature review
In	 total,	 17	 relevant	 publications12-15,21-33	 were	 identified	 of	 which	 six	 reported	 both	
cardiac	and	non-cardiac	causes	of	sudden	death	(table	1).	




52
     Table 1. Studies	reviewed	to	determine	the	prevalence	of	various	causes	of	sudden	death
               	
        Population       1st Author              Inclusion                 Location
                                                                                	                  Age        Time from onset               SD causes            N
                                                  period                                           (yrs)                 	
                                                                                                            symptoms	until	death
          General        Anderson21             1977-1988             New	mexico,	USA              5-39            <24	h                    scd + sncd          452
                         Burke22                1981-1988              Maryland,	USA              14-40              <24	h                     scd              639
                                      23
                         Corrado                1979-1996            Veneto	region,	Italy          1-35               <1	h                     scd              206
                         Corrado13              1979-1998            Veneto	region,	Italy          1-35               <1	h                     scd              256
                                     24
                         Doolan                 1994-2002             New	South	Wales,	            1-35              <24	h                  scd + sncd          425
                                                                         Australia
                         Drory25                1976-1985                  Israel                  9-39              <24	h                  scd + sncd          162
                         Molander14             1974-1979                  Sweden                  1-20            unknown                     scd              20
                                          28
                               	
                         Morentin               1991-1998                North	Spain               1-35               <6	h                     scd              107
                         Puranik29              1995-2004             Sydney, Australia            5-35              <24	h                     scd              427
                         Quigley	30             1993-2002               Dublin,	Ireland           12-34               <6	h                     scd              67
                         Steinberger31          1967-1992              Minnesota,	USA              1-21              <24	h                     scd              50
                                 32
                         Topaz                  1960-1983              Minnesota,	USA              7-35               <6	h                     scd              49
                         Wisten33               1992-1999                  Sweden                 15-35              <24	h                     scd              162
                         Wren15                 1985-1994                  England	                1-20              <24	h                  scd + sncd          128
                         *           22
          Athletes           Burke              1981-1988              Maryland,	USA              14-40              <24	h                     scd              34
                         *
                             Corrado23          1979-1996            Veneto	region,	Italy          1-35               <1	h                     scd              47
                                     27
                         Maron                  1985-1995                    USA                  12-40            unknown                  scd + sncd          138
                         Maron26                1976-1979                    USA                  13-30            unknown                     scd              26
                                           12
                         Van	Camp               1983-1993               California,	USA           13-24               <1	h                  scd + sncd          133
                                                                                                                         	                                          	
     SCD	=	sudden	cardiac	death,	SNCD	=	sudden	non-cardiac	death,	SD	=	sudden	death,	N	=	number	of	cases,	* Study	is	mentioned	twice	in	this	table,	because	information	
                           	
     on	the	general	population	and	the	athletes	was	available




53
                                                                                                                                                                           Sudden death in persons younger than 40 years: incidence and causes




                                                                                                                       3.1
Chapter 3.1


The	majority	of	deaths	were	of	cardiac	origin.	In	the	general	population,	neurological	
(9%	(95%	CI;	8%-10%))	and	respiratory	diseases	(8%	(95%	CI;	7%-9%))	were	frequently	
reported	non-cardiac	causes	of	sudden	death.	Causes	of	death	that	were	based	on	the	
literature	review	and	their	corresponding	ICD-10	codes	are	provided	in	table	2.

Table 2. Prevalence	(%)	with	95%	confidence	interval	(95%	CI)	of	reported	causes	of	sudden	death,	
by	study	population

Causes of death                                 ICD-10 code         General	population         Athletes
                                                                      N       %	(95%	CI)       N     %		(95%	CI)
Sudden cardiac death
Atherosclerotic	disease                        E78.4,	I21,	I24       726      23	(22-25)      27       7	(5-10)
Conduction	disorders                            I45.6, I45.8,         44        1	(1-2)        5        1	(0-3)
                                             I45.9, I49.0, I49.9
Myocarditis                                       I40, I41           195        6	(5-7)       16        4	(2-6)
Cardiomyopathy      1
                                                 I42.0-I42.9         397      13	(11-14)      181     48	(43-53)
Coronary	pathology	(non-ischemic)2                  I25.4             73        2	(2-3)       61      16	(12-20)
Congenital cardiac diseases3                 Q20-Q24,	Q87.4           37        1	(1-2)        2        1	(0-1)
Valve	abnomalities4                             I34.1, I35.0         120        4	(3-5)       22        6	(4-8)
Other	cardiovascular	diseases                        I46             230        7	(6-8)        8        2	(1-4)
Sudden	death	with	unknown	cause                      R96             519      16	(15-18)      16        4	(2-6)
Sudden non-cardiac death
Respiratory5                                   I26,	J450-J459        244        8	(7-9)        8        2	(1-4)
Neurologic6                                  G40-G41,	I60-I62        289       9	(8-10)        2        1	(0-1)
Other	non	cardiac	deaths                                             249        8	(7-9)       22        6	(4-8)
Abdominal	aneurysma7                                 I71              27        1	(1-1)        8        2	(1-4)


Total sudden deaths                                                 3,150         100         378         100
ICD	= International	Classification	of	Diseases,	N	=	number	of	cases
1
 Arrhythmogenic	 right	 ventricular	 cardiomyopathy,	 dilated	 cardiomyopathy,	 left	 ventricular	 hypertrophy,	
diffuse	fibrosis,	endocardial	fibroelastosis,	myocardial	fibrosis,	idiopathic	myocardial	scarring,	right	ventricular	
dysplasia,	fibroelastosis	cordis
2
  Coronary	abnormalities,	coronary	bridging,	vasculitis,	coronary	artery	aneurysm
3
  Marfan syndrome, tetralogy of Fallot
4
  Mitral	valve	prolapse,	mitral	valve	insufficiency,	aortic	valve	insufficiency
5
  Asthma,	pulmonary	embolism	
6
 	Epilepsy,	subarachnoidal	haemorrhage,	intracranial	haemorrhage,	meningitis


Incidence and causes of out-of-hospital sudden death; causes from death register
Over	 the	 period	 1996-2006,	 1,908	 subjects	 (age	 1-39	 years)	 died	 suddenly	 during	
92,374,043	person-years	(table	3).	The	overall	incidence	of	sudden	death	was	2.1	(95%	



54
                                                                    	
     Table 3. Incidence	 per	 100,000	 person-years	 with	 95%	 confidence	 interval	 (95%	 CI)	 of	 out-of-hospital	 sudden	 death	 in	 the	
     Netherlands,	over	the	period	1996-2006,	by	gender	and	age

                                                   SCD                                SNCD                                    SD
                    Person-          N            I          95%	CI	        N         I         95%	CI         N          I         95%	CI
                    years
                                                                                                                                                  sudden	death	increased	by	age	(table	3).




     Men            47,035,010     1,070        2.27        2.14-2.41      274       0.58     0.51-0.65     1,344      2.86        2.71-3.01
     Women          45,339,033      430         0.95        0.86-1.04      134       0.30     0.25-0.35      564       1.24        1.14-1.35

     1-14 yrs       30,278,317      72          0.24      0.18-0.29        30        0.10     0.06-0.14      102       0.34        0.27-0.40
     15-29 yrs      33,711,409      297         0.88      0.78-0.98        152       0.45     0.38-0.52      449       1.33        1.21-1.46
     30-39 yrs      28,384,317     1,131        3.98      3.75-4.22        226       0.80     0.69-0.90     1,357      4.78        4.53-5.04

     Total          92,374,043     1,500        1.62      1.54-1.71        408       0.44     0.40-0.49     1,908      2.07        1.97-2.16
     SCD	=	sudden	cardiac	death,	SNCD	=	sudden	non-cardiac	death,	SD	=	sudden	death,	I	=	incidence,	N	=	number	of	cases,	*	Incidence	of	out-of-
                                                  		
     hospital	sudden	death	according	to	death	certificate	data




55
                                                                                                                                                                                                                                               Sudden death in persons younger than 40 years: incidence and causes


                                                                                                                                                  CI;	2.0-2.2)	per	100,000	person-years	and	was	higher	for	men	(2.9	(95%	CI;	2.7-3.0))	than	
                                                                                                                                                  for	women	(1.2	(95%	CI;	1.1-1.4)).	The	incidence	of	sudden	death,	SCD	and	non-cardiac	




                                                                                                                    3.1
Chapter 3.1


The	majority	of	deaths	were	of	cardiac	origin	with	an	incidence	of	SCD	of	1.6	(95%	CI;	
1.5-1.7)	per	100,000	person-years.	Atherosclerotic	coronary	artery	disease	was	the	most	
common	underlying	cause	of	sudden	death	35%	(95%	CI;	33%-38%)	in	men,	29%	(95%	
CI;	26%-33%)	in	women,	followed	by	primary	arrhythmia	syndromes	5%	(95%	CI;	4%-6%)	
in	men,	6%	(95%	CI	4%-8%)	in	women	and	cardiomyopathies	4%	(95%	CI;	3%-5%)	in	men,	
6%	(95%	CI;	4%-8%)	in	women	(table	4).	Of	the	sudden	non-cardiac	deaths,	epilepsy	was	
reported	to	be	the	most	common	cause	of	death,	accounting	for	14%	(95%	CI;	12%-16%)	
in	men,	and	15%	(95%	CI;	12%-18%)	in	women	of	the	total	sudden	death	cases.	For	a	
considerable	number	of	cases	no	cause	of	death	was	reported	(9%	(95%	CI;	7%-11%)	in	
men	and	10%	(95%	CI;	8%-13%)	in	women).	

Discussion
The	 incidence	 of	 sudden	 death	 in	 the	 young	 was	 2.1	 (95%	 CI;	 2.0-2.2)	 per	 100,000	
person-years).	The	incidence	was	higher	in	men	than	in	women	and	increased	by	age.	
The	majority	of	sudden	deaths	were	of	cardiac	origin.	In	up	to	9%	the	cause	of	death	
remained	unexplained.

Sudden death
The	 incidence	 of	 (natural)	 sudden	 death	 ranges	 from	 3.3	 to	 4.6	 per	 100,000	 person-
years14,31	 with	 our	 estimate	 being	 lower	 (2.1	 per	 100,000	 person-years).	 This	 may	 be	
attributed	 to	 differences	 across	 studies	 in	 age	 and	 gender	 distribution.	 Also,	 ethnic	
differences	 may	 contribute	 to	 differences	 in	 incidences	 as	 the	 black	 population	 has	
higher risks.34	 The	 Dutch	 population	 however,	 is	 mainly	 Caucasian	 (90%).	 Methods	 of	
identification	also	affect	incidence	estimates.	We	focussed	in	our	study	on	out-of-hospital	
deaths,	other	studies	focussed	on	sudden	unexpected,	unwitnessed	or	exercise	related	
deaths	reported	in	(forensic)	autopsy	reports.21,24,25 Also, not all causes of death could
be	translated	into	ICD-10	codes.	Yet,	the	most	important	ICD-10	codes	were	included,	
because	ICD-10	codes	were	selected	based	on	a	review	of	clinico-pathological	studies	on	
causes of sudden death.

Sudden cardiac death
In	contrast	with	the	relative	low	incidence	of	sudden	death,	we	reported	a	relative	high	
incidence	of	SCD	in	comparison	with	other	studies.
The	 incidence	 of	 SCD	 ranges	 from	 0.9	 to	 1.3	 per	 100,000	 person-years14,33,35	 while	 an	
incidence	of	1.6	per	100,000	person-years	was	reported	in	the	present	study.	This	might	
be	explained	by	the	age	of	the	sudden	death	victims	that	were	included	in	our	study	(1-39	
years)	which	was	relatively	high	in	comparison	to	other	studies	(1-22	years).	It	has	been	
demonstrated that the SCD incidence is increasing over age,28,33,36	which	is	most	likely	due	

56
                                        Sudden death in persons younger than 40 years: incidence and causes


Table 4. Causes	of	sudden	death	and	SCD	based	on	data	on	primary	cause	of	out-of-hospital	death	
                 	 	
recorded	by	Statistics	Netherlands	over	the	period	1996-2006	(non-natural	causes	of	death	e.g.	
suicide,	accidents	were	excluded)

Cause of death                              ICD code     Total    Men      Women      1-14    15-29 30-39
                                                                                      yrs     yrs   yrs
Sudden cardiac death                                     1,500    1,070    430        72      297 1,131
  Atherosclerotic disease
		Familiar	hypercholesterolaemia            E78.4        0        0        0          0       0       0
                      	
		Myocardial	infarction                     I21          639      473      166        2       80      557
		Other	acute	ischaemic	heart	diseases		    I24          0        0        0          0       0       0
  Cardiomyopathy
		Dilated	cardiomyopathy                    I42.0        13       8        5          2       6       5
           	
		Obstructive	hypertrophic	                 I42.1        0        0        0          0       0       0
   cardiomyopathy
                                                                                                                  3.1
		Other	hypertrophic	cardiomyopathy         I42.2       11        8        3          0       4       7
		Other	cardiomyopathies                    I42.3-I42.9 70        42       28         8       14      48
		Total	cardiomyopathy                      I42         94        58       36         10      24      60
  Conduction disorders
		Cardiac	arrhythmia,	unspecified	          I49.9        62       40       22         -       23      39
		Ventricular	tachycardia                   I47.2        3        -        -          -       -       -
               	       	        	 	
		Ventricular	fibrillation	and	flutter      I49.0        34       24       10         -       4       30
             	
		Pre-exitation	syndrome                    I45.6        4        4        0          -       -       -
                 	
		Other	conduction	disorders			             I45.8        3        -        -          -       -       -
                             	
		Total	number	of	conduction	disorders      I45.6,       106      71       35         2       29      75
                                            I45.8,
                                            I47.2, I49
  Congenital cardiac diseases
		Congenital	cardiac	malformations	         Q20-Q24      99       61       38         21      40      38
		Marfan’s	syndrome                         Q87.4        10       8        2          0       5       5
  Other cardiac causes
		Mitral	(valve)	prolapse                   I34.1        4        2        2          0       -       -
       	
		Aortic	(valve)	stenosis                   I35.0        9        -        -          0       3       6
		Acute	myocarditis 	                       I40          23       16       7          4       11      8
             	                  	
		Myocarditis	in	diseses	classified	        I41          0        0        0          0       0       0
   elsewhere
  Cardiac arrest                            I46          338      252      86         9       64      265
  Coronary artery aneurysm                  I25.4        0        0        0          0       0       0
  Sudden death with unknown cause
		Sudden	death	with	unknown	cause           R96          178      121      57         24      40      114
Sudden Non-cardiac death
		Epilepsy                                  G40-G41      277      192      85         23      109     145
		Pulmonary	embolism                        I26          0        0        0          0       0       0
                	
		Non-traumatic	cerebral	hemorrhage	        I60-I62      94       59       35         2       30      62
  Asthma                                    J450-J459    37       23       14         5       13      19
Total                                                    1,908    1,344    564        102     449     1,357
              	            	 	
ICD	= International	Classification	of	Diseases,	-	=	low	number	of	cases,	data	not	presented	because	of	privacy	
       	
regulations


                                                                                                            57
Chapter 3.1


to	the	increasing	number	of	myocardial	infarctions	in	the	high	age	groups.	Furthermore,	
different	methods	of	identification	also	affect	incidence	estimates.14,28,29	In	addition,	we	
used	ICD-10	code	I21	(acute	myocardial	infarction)	to	determine	sudden	cardiac	death.	
However,	it	has	been	shown	that	the	usage	of	ICD	codes	that	correspondents	with	acute	
myocardial	infarction	tends	to	overestimate	the	incidence	of	cardiac	deaths.19
Male	predominance	has	been	found	in	many	studies.26,33,37	This	may	be	due	to	an	earlier	
development	of	atherosclerotic	coronary	artery	disease	in	man	as	compared	to	women.38

Implication
Several	 national	 initiatives	 have	 been	 taken	 up	 to	 prevent	 SCD	 through	 screening	 of	
athletes	or	first-degree	relatives	of	sudden	death	victims.	A	(randomised)	comparison	
between	screening	and	no	screening	is	likely	to	suffer	lack	of	power	given	an	incidence	of	
2.1	per	100,000	person-years.	Therefore,	cost-effectiveness	analysis	through	modelling	
may	provide	additional	information	on	the	advantages	and	disadvantages	of	screening.	
Such	 approach	 needs	 information	 on	 incidence	 and	 causes	 of	 SCD	 and	 on	 mortality	
rates	associated	with	inherited	cardiac	diseases.	Several	studies	reported	that	inherited	
diseases	can	be	detected	in	22-53%	of	the	families	of	victims	with	an	unexplained	sudden	
death.3,4,39,40	In	addition,	information	is	needed	on	treatment	options	and	risk	reduction	
through treatment.
In	conclusion,	the	incidence	of	sudden	death	in	the	young	is	2.1	per	100,000	person-
years.	Often	treatable	cardiac	causes	(like	atherosclerotic	coronary	artery	disease)	are	
responsible	for	the	sudden	death	of	a	young	person.	This	information	is	helpful	in	the	
development	of	preventive	strategies.




58
                                        Sudden death in persons younger than 40 years: incidence and causes


References
                                                  	
(1)	 Corrado	D,	Thiene	G.	Protagonist:	routine	screening	of	all	athletes	prior	to	participation	in		   	
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     2007;4:520-524.
                                    	                                                	       	           		
(2)	 Viskin	 S.	 Antagonist:	 routine	 screening	 of	 all	 athletes	 prior	 to	 participation	 in	 competitive	
     sports	should	be	mandatory	to	prevent	sudden	cardiac	death.	Heart Rhythm 2007;4:525-528.
                                         	
(3)	 Behr	ER,	Dalageorgou	C,	Christiansen	M,	Syrris P, Hughes S, Tome	Esteban	MT et al. Sudden
                                                         	            		
     arrhythmic	 death	 syndrome:	 familial	 evaluation	 identifies	 inheritable	 heart	 disease	 in	 the	
     majority	of	families.	Eur Heart J 2008;29:1670-1680.
(4)	 Tan	HL,	Hofman	N,	van	Langen	IM,	van	der	Wal	AC,	Wilde	AA.	Sudden	unexplained	death:	
                                  	                                      	          	
     heritability	and	diagnostic	yield	of	cardiological	and	genetic	examination	in	surviving	relatives.	 	
     Circulation 2005;112:207-213.
                                                                                     	
(5)	 Corrado	D,	Basso	C,	Rizzoli	G,	Schiavon	M,	Thiene	G.	Does	sports	activity	enhance	the	risk	of	
     sudden death in adolescents and young adults? J Am Coll Cardiol 2003;42:1959-1963.                           3.1
                                                                    	
(6)	 Pelliccia	A,	Di	Paolo	FM,	Corrado	D,	Buccolieri C, Quattrini	FM, Pisicchio C	et	al.	Evidence	for	
       		cacy	 of	 the	 Italian	 national	 pre-participation	 screening	 programme	 for	 identification	 of	
     effi                           	               	    	                                          		 	
     hypertrophic	cardiomyopathy	in	competitive	athletes.	Eur Heart J 2006;27:2196-2200.
                                                    		
                                                                               	       	
(7)	 Corrado	D,	Basso	C,	Schiavon	M,	Pelliccia	A,	Thiene	G.	Pre-participation	screening	of	young	
     competitive	athletes	for	prevention	of	sudden	cardiac	death.	J Am Coll Cardiol 2008;52:1981-
               		                          	
     1989.
                  	
(8)	 Hernelahti	M,	Heinonen	OJ,	Karjalainen	J,	Nylander	E,	Borjesson	M.	Sudden	cardiac	death	in	
     young	athletes:	time	for	a	Nordic	approach	in	screening?	Scand J Med Sci Sports 2008;18:132-
                         	
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(9)	 Bille	 K,	 Figueiras	 D,	 Schamasch	 P,	 Kappenberger	 L, Brenner	 JI, Meijboom	 FJ et al. Sudden
     cardiac	 death	 in	 athletes:	 the	 Lausanne	 Recommendations.	 Eur J Cardiovasc Prev Rehabil
                                                                        	
     2006;13:859-875.
                                                                  			
(10)	Corrado	 D,	 Pelliccia	 A,	 Bjornstad	 HH,	 Vanhees	 L,	 Biffi A,	 Borjesson	 M	 et	 al.	 Cardiovascular	
                	    	                                   		                                	
     pre-participation	 screening	 of	 young	 competitive	 athletes	 for	 prevention	 of	 sudden	 death:	
     proposal	for	a	common	European	protocol.	Consensus	Statement	of	the	Study	Group	of	Sport	
                                                                       	
     Cardiology	of	the	Working	Group	of	Cardiac	Rehabilitation	and	Exercise	Physiology	and	the	
     Working	Group	of	Myocardial	and	Pericardial	Diseases	of	the	European	Society	of	Cardiology.	
     Eur Heart J 2005;26:516-524.
(11)	Maron	BJ.	Sudden	death	in	young	athletes.	N Engl J Med 2003;349:1064-1075.
                                                                                         	
(12)	Van	Camp	SP,	Bloor	CM,	Mueller	FO,	Cantu	RC,	Olson	HG.	Nontraumatic	sports	death	in	high	
     school and college athletes. Med Sci Sports Exerc 1995;27:641-647.
(13)	Corrado	D,	Basso	C,	Thiene	G.	Sudden	cardiac	death	in	young	people	with	apparently	normal	
     heart. Cardiovasc Res 2001;50:399-408.
(14)	Molander	 N.	 Sudden	 natural	 death	 in	 later	 childhood	 and	 adolescence.	 Arch Dis Child
     1982;57:572-576.
(15)	Wren	C.	Screening	children	with	a	family	history	of	sudden	cardiac	death.	Heart 2006;92:1001-
     1006.
                	          	 	         	 	
(16)	International	Statistical	Classification	of	Diseases	and	Related	Health	Problems.Tenth	revision.	
                                           	
     Geneva:	World	Health	Organization,	1992.		
(17)	de	 Vreede-Swagemakers	 JJ,	 Gorgels	 AP,	 Dubois-Arbouw	 WI,	 van	 Ree	 JW,	 Daemen	 MJ,	
                                                                                         	
     Houben	LG	et	al.	Out-of-hospital	cardiac	arrest	in	the	1990’s:	a	population-based	study	in	the	
     Maastricht	area	on	incidence,	characteristics	and	survival.	J Am Coll Cardiol 1997;30:1500-
                                                       	
     1505.



                                                                                                           59
Chapter 3.1


(18)	Iribarren	 C,	 Crow	 RS,	 Hannan	 PJ,	 Jacobs	 DRJr.,	 Luepker	 RV.	 Validation	 of	 death	 certificate	
     diagnosis	of	out-of-hospital	sudden	cardiac	death.	Am J Cardiol 1998;82:50-53.
(19)	Fox	 CS,	 Evans	 JC,	 Larson	 MG,	 Lloyd-Jones	 DM,	 O’Donnell	 CJ,	Sorlie	 PD	 et	 al.	 A	comparison	
     of	death	certificate	out-of-hospital	coronary	heart	disease	death	with	physician-adjudicated	
     sudden cardiac death. Am J Cardiol 2005;95:856-859.
(20)	Reitsma	 JB,	 Kardaun	 JW,	 Gevers	 E,	 de	 Bruin	 A,	 van	 der	 Wal	 J,	 Bonsel	 GJ.	 Possibilities	 for	
     anonymous	 follow-up	 studies	 of	 patients	 in	 Dutch	 national	 medical	 registrations	 using	 the	
     Municipal	Population	Register:	a	pilot	study.	Ned Tijdschr Geneeskd 2003;147:2286-2290.
(21)	Anderson	 RE,	 Hill	 RB,	 Broudy	 DW,	 Key	 CR,	 Pathak	 D.	 A	 population-based	 autopsy	 study	 of	
     sudden,	unexpected	deaths	from	natural	causes	among	persons	5	to	39	years	old	during	a	
     12-year	period.	Hum Pathol 1994;25:1332-1340.
(22)	Burke	 AP,	 Farb	 A,	 Virmani	 R,	 Goodin	 J,	 Smialek	 JE.	 Sports-related	 and	 non-sports-related	
     sudden cardiac death in young adults. Am Heart J 1991;121:568-575.
(23)	Corrado	 D,	 Basso	 C,	 Schiavon	 M,	 Thiene	 G.	 Screening	 for	 hypertrophic	 cardiomyopathy	 in	
     young athletes. N Engl J Med 1998;339:364-369.
(24)	Doolan	A,	Langlois	N,	Semsarian	C.	Causes	of	sudden	cardiac	death	in	young	Australians.	Med
     J Aust 2004;180:110-112.
(25)	Drory	Y,	Turetz	Y,	Hiss	Y,	Lev B, Fisman	EZ, Pines A	et	al.	Sudden	unexpected	death	in	persons	
     less than 40 years of age. Am J Cardiol 1991;68:1388-1392.
(26)	Maron	BJ,	Roberts	WC,	McAllister	HA,	Rosing	DR,	Epstein	SE.	Sudden	death	in	young	athletes.	
     Circulation 1980;62:218-229.
(27)	Maron	BJ,	Shirani	J,	Poliac	LC,	Mathenge	R,	Roberts	WC,	Mueller	FO.	Sudden	death	in	young	
     competitive	athletes.	Clinical,	demographic,	and	pathological	profiles.	JAMA 1996;276:199-
     204.
(28)	Morentin	 B,	 Suarez-Mier	 MP,	 Aguilera	 B.	 Sudden	 unexplained	 death	 among	 persons	 1-35	
     years old. Forensic Sci Int 2003;135:213-217.
(29)	Puranik	R,	Chow	CK,	Duflou	JA,	Kilborn	MJ,	McGuire	MA.	Sudden	death	in	the	young.	Heart
     Rhythm;2:1277-1282.
(30)	Quigley	F,	Greene	M,	O’Connor	D,	Kelly	F.	A	survey	of	the	causes	of	sudden	cardiac	death	in	
     the	under	35-year-age	group.	Ir Med J 2005;98:232-235.
(31)	Steinberger	J,	Lucas	RV	Jr.,	Edwards	JE,	Titus	JL.	Causes	of	sudden	unexpected	cardiac	death	in	
     the	first	two	decades	of	life.	Am J Cardiol 1996;77:992-995.
(32)	Topaz	O,	Edwards	JE.	Pathologic	features	of	sudden	death	in	children,	adolescents,	and	young	
     adults. Chest 1985;87:476-482.
(33)	Wisten	A,	Forsberg	H,	Krantz	P,	Messner	T.	Sudden	cardiac	death	in	15-35-year	olds	in	Sweden	
     during 1992-99. J Intern Med 2002;252:529-536.
(34)	Zheng	ZJ,	Croft	JB,	Giles	WH,	Mensah	GA.	Sudden	cardiac	death	in	the	United	States,	1989	to	
     1998. Circulation 2001;104:2158-2163.
(35)	Driscoll	DJ,	Edwards	WD.	Sudden	unexpected	death	in	children	and	adolescents.	J Am Coll
     Cardiol 1985;5:118B-121B.
(36)	Chugh	SS,	Reinier	K,	Teodorescu	C,		Evanado	A,	Kehr	E,	Al	Samara	M	et	al.	Epidemiology	of	
     sudden	cardiac	death:	clinical	and	research	implications.	Prog Cardiovasc Dis 2008;51:213-
     228.
(37)	Thiene	G,	Nava	A,	Corrado	D,	Rossi	L,	Pennelli	N.	Right	ventricular	cardiomyopathy	and	sudden	
     death	in	young	people.	N Engl J Med 1988;318:129-133.
(38)	Sozzi	FB,	Danzi	GB,	Foco	L,	Ferlini M, Tubaro	 M, Galli	M	et	al.	Myocardial	infarction	in	the	
     young:	a	sex-based	comparison.	Coron Artery Dis 2007;18:429-431.


60
                                   Sudden death in persons younger than 40 years: incidence and causes


(39)	Behr	E,	Wood	DA,	Wright	M,	Syrris	P,	Sheppard	MN,	Casey	A	et	al.	Cardiological	assessment	of	
      	                	
     first-degree	relatives	in	sudden	arrhythmic	death	syndrome.	Lancet 2003;362:1457-1459.
                                                                                 	
(40)	Hofman	N,	Tan	HL,	Clur	SA,	Alders	M,	van	Langen	IM,	Wilde	AA.	Contribution	of	inherited	
     heart disease to sudden cardiac death in childhood. Pediatrics 2007;120:e967-e973.




                                                                                                         3.1




                                                                                                   61
                               Chapter	3.2

Regional	differences	in	incidence	of	sudden	
                 cardiac death in the young
Chapter 3.2


Abstract
Background:	Observational	data	on	sudden	cardiac	death	(SCD)	in	the	young	are	scarce,	
but	the	SCD	incidence	seems	to	differ	among	regions	and	races.	The	objective	of	this	
study	 is	 to	 examine	 regional	 differences	 in	 SCD	 incidence	 within	 a	 population	 among	
young	individuals	(<40	years)	and	to	assess	whether	regional	incidences	are	associated	
with	socio-economic	status	(SES).	

Methods: SCD	cases	<40	years	old	were	identified	in	12	provinces	of	the	Netherlands	by	
using	death	certificates	recorded	during	1996-2006	by	Statistics	Netherlands.	Regional	
incidence	estimates	were	standardized	for	age	to	the	Dutch	population	and	assessed	for	
two	age	categories;	1-29	years	and	30-39	years.	Regional	SCD	incidence	was	related	to	
regional	SES	with	a	Spearman	correlation	coefficient.	

Results:	The	nationwide	incidence	of	SCD	aged	1-39	years	was	1.6	(95%	CI;	1.5-1.7)	per	
100,000	person-years	and	the	incidence	increased	substantially	after	30	years	of	age.	
Significant	differences	in	regional	incidences	were	assessed	for	both	age	categories	(1-29	
years	and	30-39	years).	Although	in	the	population	aged	1-29	years	significant	differences	
were	found	in	the	SCD	incidence	between	regions,	no	relation	could	be	found	with	SES.	
In	men	aged	30-39	years,	the	incidence	of	SCD	was	inversely	related	to	SES;	a	low	socio-
economic	status	was	associated	with	a	relative	high	incidence	of	SCD.	

Conclusion:	Between	regions,	statistically	significant	differences	in	SCD	incidence	exist	
in	young	individuals.	The	nationwide	incidence	of	SCD	increased	substantially	after	30	
years	of	age	and	was	inversely	related	to	SES	in	men	aged	30-39	years.	




64
                                    Regional differences in incidence of sudden cardiac death in the young


         	
Introduction			
                                                                          	
The	 incidence	 of	 sudden	 cardiac	 death	 (SCD)	 in	 the	 young	 is	 estimated	 to	 be	 0.9-1.6	 	
                                     	
per	 100,000	 person-years.1	 Often,	 cardiac	 diseases	 like	 cardiomyopathies,	 primary	
                                       	                     	
arrhythmia	syndromes,	myocarditis	or	atherosclerotic	coronary	artery	disease	are	the	
                                                                 	
underlying causes of SCD in the young.1-3	In	the	SCD	victims	aged	30-39	years,	coronary	
                                          	
artery	 disease	 accounts	 for	 a	 relatively	 high	 percentage	 of	 deaths	 in	 comparison	 to	
                    	                            	
younger	SCD	victims	in	whom	monogenetic	inherited	diseases	and	congenital	diseases	
                             	                                 	                          	
prevail. 	 Atherosclerotic	 coronary	 artery	 disease	 is	 attributed	 to	 both	 genetic	 factors	
         1,4

(for	 example	 the	 presence	 of	 familial	 hypercholesterolemia)	 and	 lifestyle	 factors	 like	
                    	                                	
smoking	or	inactivity.	In	the	general	population	(all	ages),	a	low	socio-economic	status	
                	
(SES)	 is	 positively	 associated	 with	 the	 presence	 of	 cardiovascular	 risk	 factors	 and	 the	
occurrence	of	premature	cardiac	death.5-11
            	              	
Observational	 population	 based	 data	 on	 SCD	 in	 the	 young	 are	 scarce,	 but	 it	 seems	
                                                    	
that	the	incidence	of	SCD	(over	all	ages)	differs	among	races	and	between	regions.11-16                      3.2
However,	the	comparability	of	studies	on	incidence	is	poor	as	most	former	studies	were	
                                                  	                           	
restricted	to	only	a	single	regional	observation	without	focusing	on	differences	across-or	
                             	                                         	
within	regions.17,18	Multiple	factors	might	be	responsible	for	differences	in	the	regional	
                                                                            	
SCD	incidence,	among	which	the	regional	age	and	gender	distribution	and	the	regional	
                                                                                               	
prevalence	 of	 inherited	 cardiac	 diseases	 and	 coronary	 artery	 disease.19-25	 In	 addition,	
              	                                                      	
regional	differences	in	accessibility	of	care	may	also	explain	differences	in	out-of-hospital	
SCD among regions.26,27
                       	                                                      	
The	primary	objective	of	the	current	study	is	to	examine	regional	differences	in	SCD	at	
                                                                                      	
young	age	(1-39	years)	and	to	assess	whether	regional	incidences	in	SCD	differ	between	
                                                                                        	
age	 categories	 (<30	 years	 and	 30-39	 years)	 and	 are	 associated	 with	 differences	 in	
regional	SES.	



Materials and methods
Definitions
          	                                                                        	
SCD	is	defined	as	sudden	unexpected	death	due	to	a	cardiac	cause	within	24	hours	after	
the	onset	of	symptoms. 1




Incidence of sudden death
       	                                                           	
To	 estimate	 the	 regional	 incidence	 of	 SCD	 we	 used	 nationwide	 data	 on	 the	 primary	
                                     	 	
cause	of	death	recorded	by	Statistics	Netherlands 	over	the	period	1996-2006.	Death	
                                                           28

    		                                  	                    	
certificates	do	not	include	information	on	the	duration	of	preceding	symptoms	and	the	
         	                                               		cult	 to	 identify	 the	 ‘sudden’	 deaths.	
actual	 time	 of	 cardiac	 arrest,	 which	 makes	 it	 diffi               	


                                                                                                       65
Chapter 3.2


To	solve	this	problem,	we	defined	sudden	death	as	death	taking	place	out-of-hospital,	
assuming	that	these	deaths	occurred	unexpected	and	within	a	few	hours	after	the	onset	
of	severe	symptoms.29,30	Because	no	dedicated	ICD	code	exist	for	‘SCD’,	we	reviewed	the	
literature	to	define	the	most	common	causes	of	SCD	and	selected	corresponding	ICD-10	
codes	to	compose	a	proxy	for	SCD	as	we	have	described	earlier	(see	also	table	1).1

Table 1.	Overview	of	selected	ICD	codes	that	were	used	as	a	proxy	for	sudden	cardiac	death

Selected causes of cardiac death                              Corresponding	ICD	codes
Atherosclerotic	coronary	artery	disease                       E78.4,	I21,	I24
Conduction	disorders                                          I45.6, I45.8, I45.9, I49.0, I49.9
Myocarditis                                                   I40, I41
Cardiomyopathy                                                I42.0-I42.9
Coronary	pathology	(non-atherosclerotic)                      I25.4
Congenital cardiac diseases                                   Q20-Q24,	Q87.4
Valve	abnormalities                                           I34.1, I35.0
Other	cardiovascular	diseases                                 I46
Sudden	death	with	unknown	cause                               R96
ICD	= International	Classification	of	Diseases


Study regions
The	study	regions	were	defined	by	the	boundaries	of	the	12	provinces	of	the	Netherlands.	
Information	 on	 the	 regional	 age	 and	 gender	 distribution	 was	 derived	 from	 Statistics	
Netherlands.	For	every	region,	scores	for	socio-economic	status	(SES)	were	derived	from	
the	Netherlands	Institute	for	Social	Research	(SCP)	over	2006.	This	SES	score	is	based	
on	 income,	 unemployment	 and	 level	 of	 education	 per	 postal	 (zip)code.	 Scores	 were	
converted	into	factor	scores	by	a	principal	component	analysis	as	described	before.31 For
the	purpose	of	this	study,	the	factor	scores	of	each	postal	code	were	aggregated	to	the	
study	regions	weighted	by	the	number	of	inhabitants.

Data analysis
The	crude	incidence	rates	(with	corresponding	95%	confidence	intervals	(CI))	of	out-of-
hospital	SCD	were	reported	by	age,	gender	and	study	region.	Age	was	categorised	into	
two	subgroups	(1-29	years	and	30-39	years).	These	subgroups	were	chosen	because	the	
percentage	of	deaths	due	to	coronary	artery	disease	increases	with	age	(especially	after	
30	years	of	age)	and	a	low	SES	is	related	to	a	high	prevalence	of	vascular	risk	factors	and	
coronary artery disease.5-8
Person-years	 were	 based	 on	 the	 number	 of	 subjects	 in	 the	 relevant	 age	 categories	


66
                                                                 Regional differences in incidence of sudden cardiac death in the young


                                             	
per	study	region	from	1996-2006.	In	addition,	comparability	of	the	study	regions	was	
                                                                               	
obtained	by	standardizing	the	overall	incidence	rates	to	the	Dutch	population	for	age	
and gender.
                                                                      	        		cient	 was	
Because	 aggregated	 data	 were	 used,	 a	 Spearman	 ranking	 correlation	 coeffi
                            	                                                	
chosen	to	describe	the	relation	of	SCD	incidence	and	SES.	Two-tailed	significance	levels	
of p	<0.05	were	used.	All	analyses	were	performed	in	agreement	with	privacy	legislation		
in the Netherlands. 32




Results
Nation-wide incidence estimates
During	 the	 study	 period	 1996-2006,	 1,458	 cases	 of	 SCD	 were	 reported	 coming	 form	
                                                            	
92,374,043	person-years	of	follow-up.	This	yielded	a	nationwide	crude	incidence	of	SCD	
of	1.6	(95%	CI;	1.5-1.7)	per	100,000	person-years.	The	incidence	of	SCD	increased	with	                                                   3.2
                                               	
age	and	was	higher	in	men	than	in	women	(figure	1).	

Figure 1.	 Nationwide	 incidence	 (per	 100,000	 person-years)	 of	 sudden	 cardiac	 death	 in	 persons	
              	
aged	1-39	years,	for	men	and	women	over	the	period	1996-2006
                                     9

                                     8          Men
                                                Women
                                                95% CI
                                     7
Incidence per 100,000 person-years




                                     6

                                     5

                                     4

                                     3

                                     2

                                     1

                                     0
                                         1-4   5-9       10-14       15-19      20-24       25-29      30-34      35-39
                                                                        Age groups


          	                                                              	
A	substantial	increase	in	SCD	incidence	was	seen	especially	in	men	after	30	years	of	age.	
       	
The	nationwide	incidence	of	SCD	in	1-29	years	old	men	was	0.8	(95%	CI;	0.7-0.9)	per	
100,000	 person-years	 and	 in	 women	 0.3	 (95%	 CI;	 0.3-0.4)	 per	 100,000	 person-years.	
       	
The	nationwide	incidence	of	SCD	in	30-39	years	old	men	was	5.5	(95%	CI;	5.1-5.9)	per	

                                                                                                                                    67
Chapter 3.2


100,000	 person-years	 and	 in	 women	 2.2	 (95%	 CI;	 1.9-2.4)	 per	 100,000	 person-years	
(table	2).

Table 2.	 Incidence	 (per	 100,000	 person-years)	 of	 sudden	 cardiac	 death	 in	 young	 persons	 (1-39	
years)	in	the	Netherlands,	by	age	(1-29	years	and	30-39	years),	sex	and	region,	over	the	period	
1996-2006

                                           Men                                     Women
                Age	(years)                Incidence           95%		CI             Incidence          95%		CI
Groningen       1-29                       1.772               1.63-191            0.712              0.62-0.80
                30-39                      6.562               6.14-6.98           2.802              2.52-3.08
Friesland       1-29                       0.982               0.88-1.09           0.652              0.56-0.74
                30-39                      7.702               7.25-8.15           4.932              4.56-5.30
Drenthe         1-29                       0.98                0.87-1.09           0.121              0.08-0.16
                30-39                      6.572               6.15-6.99           2.842              2.56-3.12
Overijssel      1-29                       0.72                0.63-0.81           0.542              0.46-0.62
                30-39                      5.44                5.06-5.82           2.34               2.09-2.59
Gelderland      1-29                       0.81                0.71-0.91           0.47               0.39-0.55
                30-39                      7.372               6.93-7.81           2.62               2.35-2.89
Flevoland       1-29                       1.182               1.06-1.30           0.001              0.00-0.00
                30-39                      3.451               3.15-3.75           0.621              0.49-0.75
Utrecht         1-29                       0.89                0.79-0.99           0.38               0.31-0.45
                30-39                      3.691               3.38-4.00           1.531              1.32-1.74
Noord-Holland   1-29                       0.401               0.33-0.47           0.161              0.12-0.20
                30-39                      4.121               3.79-4.45           1.261              1.07-1.45
Zuid-Holland    1-29                       0.65                0.56-0.74           0.25               0.19-0.31
                30-39                      5.59                5.20-5.98           2.17               1.93-2.41
Noord-Brabant 1-29                         1.252               1.13-1.37           0.33               0.27-0.39
                30-39                      4.271               3.93-4.61           2.722              2.45-2.99
Zeeland         1-29                       0.541               0.46-0.62           0.29               0.23-0.35
                30-39                      6.28                5.87-6.69           2.37               2.11-2.63
Limburg         1-29                       0.97                0.86-1.08           0.492              0.41-0.57
                30-39                      7.752               7.30-8.20           1.471              1.27-1.67
The Netherlands 1-29                       0.77                0.67-0.87           0.34               0.28-0.40
                30-39                      5.52                5.14-5.90           2.17               1.93-2.41
CI	 =	 confidence	 interval	 1 incidence	 statistically	 significant	 lower	 than	 nationwide	 incidence,	 2 Incidence
statistically	significant	higher	than	the	nationwide	incidence


Regional incidence estimates
Regional	incidence	estimates	with	corresponding	95%	confidence	intervals	are	presented	
in	 table	 2.	 Statistically	 significant	 differences	 in	 incidence	 estimates	 of	 regional	 SCD	
incidences	compared	to	the	nationwide	SCD	incidence	were	found	in	both	age	categories	


68
                                   Regional differences in incidence of sudden cardiac death in the young


                                                                            	
for	both	men	and	women.	However,	no	clear	north-south	or	east-west	patterns	emerged.	
                        	                                            	
Regional	 incidence	 estimates	 standardized	 to	 the	 Dutch	 population	 are	 presented	 in	
 	
figure	2a	and	2b.	In	both	age	categories	(1-29	years	and	30-39	years)	the	incidence	varies	
between	regions	for	both	men	and	women.		

Figure 2a and b.	 Regional	 incidence	 (per	 100,000	 person-years)	 of	 sudden	 cardiac	 death	 in	
                                                                                          	
persons	aged	1-29	years	(a)	and	30-39	years	(b),	standardized	for	age	to	the	Dutch	population.	The	
regions	presented	at	the	X-axis	are	ordered	from	the	north	of	the	Netherlands	to	the	south	of	the	
Netherlands
a.




                                                                                                            3.2




b.




                                                                                                      69
Chapter 3.2


Regional SES
A	 low	 factor	 score	 represents	 a	 high	 socio-economic	 status.	 The	 relations	 between	
regional	 incidence	 estimates	 for	 SCD	 (standardized	 to	 the	 Dutch	 population)	 in	 the	
young	and	SES	are	presented	in	figure	3a-3c.	
                      10
                  Incidence per 100,000 person-years




                       9
Figure 3a-c.	Regional	incidence	of	sudden	cardiac	death	(per	100,000	person-years)	and	regional	
socio-economic	status	(factor	score),	in	men	aged	1-29	years	(a),	in	men	aged	30-39	years	(b),	in	
                       8
women	30-39	years	(c)7
a.                     6
                       5
                      10
Incidence per 100,000 person-years




                       4
                       9
                       3
                       8
                       2
                       7
                       1
                       6
                       0
                       5
    0.4       0.2         0       0.2       0.4      0.6        0.8        1
                       4
                       3           Factor score
                       2
                       1
                       0
    0.4       0.2         0       0.2       0.4      0.6        0.8        1
                                                       Factor score
A	low	factor	score	represents	a	high	socio-economic	status,	and	a	high	factor	score	indicates	a	low	socio-
economic	status.	Zero	represents	a	mean	socio-economic	status

b.
                        10
                  Incidence per 100,000 person-years




                         9
                         8
                         7
                         6
                         5
                        10
Incidence per 100,000 person-years




                         4
                         9
                         3
                         8
                         2
                         7
                         1
                         6
                         0
                         5
    0.4         0.2         0         0.2       0.4         0.6        0.8          1
                         4
                         3            Factor score
A	low	factor	score	represents	a	high	socio-economic	status,	and	a	high	factor	score	indicates	a	low	socio-
                         2
economic	status.	Zero	represents	a	mean	socio-economic	status
                         1
                         0
70 0.4          0.2         0         0.2       0.4         0.6        0.8          1
                                                       Factor score
                                                          Regional differences in incidence of sudden cardiac death in the young


  c.
                                                 10
Incidence per 100,000 person-years



                                                  9
                                                  8
                                                  7
                                                  6
                                                  5
                                                  4
                                                  3
                                                  2
                                                  1
                                                  0
                                     0.4   0.2        0   0.2       0.4        0.6        0.8          1
                                                          Factor score
A	 low	 factor	 score	 represents	 a	 high	 socio-economic	 status,	 and	 a	 high	 factor	 score	 indicates	 a	 low	 socio-        3.2
economic	status.	Zero	represents	a	mean	socio-economic	status



                	                         	            	
In	younger	victims	(1-29	years)	no	significant	association	could	be	established	between	
the	incidence	of	SCD	and	SES	(in	men	1-29	years,	the	Spearman’	s	rho	was	-0.03	(p	=	
0.93),	in	women	1-29	years,	the	Spearman’	s	rho	was	0.55	(p	=	0.07).	In	30-39	years	old	
                      	
men,	an	inverse	relation	was	found	between	the	SCD	incidence	and	SES;	a	low	SES	was	
                                                                                 	 	
associated	with	a	higher	incidence	of	SCD	in	this	age	category.	In	women	no	statistically	
      	             	
significant	correlation	could	be	established	(in	men	>30	years,	the	Spearman’s	rho	was	
0.76 (p	<0.01),	in	women	>30	years,	the	Spearman’s	rho	was	0.53	(p =	0.08).



Discussion
          	
Disparities	 in	 SCD	 incidence	 in	 the	 young	 were	 found	 among	 study	 regions	 and	 age	
categories	 (1-29	 and	 30-39	 years).	 In	 30-39	 years	 old	 men,	 the	 incidence	 of	 SCD	 was	
inversely	related	to	SES.	In	men	and	women	aged	1-29	years	and	in	women	aged	30-39	
                 	               	
years,	no	significant	association	with	SES	and	SCD	incidence	could	be	observed.
In	 the	 young,	 cardiomyopathies,	 primary	 arrhythmia	 syndromes	 and	 congenital	 heart	
diseases are common causes of SCD.1,4	 Clustering	 of	 (inherited)	 cardiac	 diseases	 in	
          	                                                     	
populations	 (and	 regions)	 can	 be	 responsible	 for	 differences	 in	 SCD	 incidence	 as	 is	
previously	 described	 by	 others.  23,25,33
                                            	 An	 example	 is	 the	 high	 prevalence	 of	 a	 primary	
arrhythmia syndrome similar to the Brugada syndrome in the southeast of Asia that
is	 responsible	 for	 a	 high	 number	 of	 SCD	 cases	 in	 that	 region.23,33 In the Netherlands,
                   	
a	founder	mutation	that	causes	hypertrophic	cardiomyopathy	in	the	majority	of	cases	


                                                                                                                             71
Chapter 3.2


is	predominantly	detected	in	the	northwestern	part	of	the	country.25 Furthermore, a
haplotype	 (associated	 with	 familiar	 idiopathic	 ventricular	 fibrillation)	 was	 recently	
identified,	which	originates	from	the	centre	of	the	Netherlands.20 In the current study, no
clear	patterns	in	SCD	incidence	in	the	young	(1-29)	were	found	that	might	be	explained	
by	these	regional	clustering	of	inherited	diseases.	However,	the	low	incidence	rates	of	
SCD	and	the	presence	of	other	factors	that	are	associated	with	the	occurrence	of	SCD	
might	have	obscured	such	an	association.	
Little	is	known	about	the	relation	between	SES	and	SCD	in	the	young.	In	the	older	age	
categories	 (>30	 years),	 coronary	 artery	 disease	 is	 responsible	 for	 a	 high	 proportion	
of	 SCD,	 especially	 in	 men.4,34,35	 Because	 a	 low	 SES	 is	 related	 to	 a	 high	 prevalence	 of	
vascular	risk	factors	and	prevalence	of	coronary	artery	disease,	this	might	explain	the	
increased	incidence	of	SCD	at	older	age	in	regions	with	a	relative	low	SES.5-8	Our	findings	
correspond	with	the	findings	from	other	studies.	Hall	and	coworkers	reported	that	SES	
(by	deprivation	index	which	was	based	on	unemployment,	overcrowding,	car-ownership	
and	home-ownership)	was	inversely	associated	with	all	cause	mortality	in	0-74	years	old	
persons	and	with	cardiovascular	disease	mortality.7	In	people	aged	25	to	64	years,	a	low	
SES	is	associated	with	a	higher	rate	of	myocardial	infarction	and	death	due	to	coronary	
artery disease.6	We	investigated	the	association	between	SES	and	SCD	in	the	young.	Yet,	
below	30	years	of	age,	no	significant	association	could	be	established	between	SES	and	
SCD incidence.
The	 strength	 of	 the	 current	 study	 is	 the	 nation-wide	 approach	 leading	 to	 a	 large	
number	 of	 cases	 of	 sudden	 cardiac	 death.	 The	 study	 has	 also	 some	 limitations	 that	
need	 to	 be	 addressed.	 First,	 ecological	 fallacy	 might	 have	 weakened	 the	 associations	
of	 SCD	 incidence	 and	 SES.	 No	 individual	 information	 on	 SES	 was	 available;	 scores	
assessed	 for	 each	 postal	 code	 were	 aggregated	 to	 regions	 which	 might	 have	 lead	 to	
an	 underestimation	 of	 the	 reported	 associations.	 Secondly,	 racial	 dispersion	 was	 not	
taken	into	account	in	the	current	study,	although	this	might	be	partly	incorporated	in	
SES.	Racial	differences	are	associated	with	the	prevalence	of	hypertension	and	obesity,	
and	the	development	of	coronary	artery	disease.5	As	mentioned	before,	also	inherited	
cardiac diseases that underlie SCD in the young may cluster among races.23,25,33 Thirdly,
we	 were	 not	 able	 to	 collect	 information	 on	 the	 survival	 rates	 of	 cardiac	 arrest	 in	 the	
young	in	the	Netherlands,	while	survival	rates	might	be	influenced	by	the	presence	of	
a	witness	or	by	the	mean	response	times	of	emergency	medical	services.26,27	However,	
in	 contrast	 to	 other	 countries,	 the	 differences	 in	 mean	 response	 times	 of	 emergency	
medical	services	are	relative	small	in	the	Netherlands.36,37
The	current	study	was	primarily	designed	to	investigate	differences	in	incidence	of	SCD	
in	 the	 young	 across	 regions.	 More	 studies	 are	 needed	 to	 investigate	 the	 underlying	
mechanisms	that	are	responsible	for	disparity	in	regional	SCD	incidences.	A	nationwide	


72
                                   Regional differences in incidence of sudden cardiac death in the young


               	
disease-specific	 registry	 of	 all	 SCD	 cases	 at	 young	 age	 might	 be	 helpful	 to	 identify		
predictors	or	causal	factors	that	are	related	to	the	occurrence	of	SCD.	This	information	       	
                                                              	
may	be	of	value	for	the	future	development	of	preventive	strategies	directed	to	high	risk	
        	
populations	or	regions.	
                       	         	
In	 conclusion,	 significant	 differences	 in	 the	 SCD	 incidence	 in	 young	 individuals	 across	
                                                	
study	 regions	 were	 observed.	 The	 nationwide	 incidence	 of	 SCD	 was	 substantially	     	
             	
increasing	after	30	years	of	age	especially	in	men.	The	SCD	incidence	in	men	aged	>30	
years	seems	to	be	inversely	related	to	SES.	This	might	be	due	to	the	increasing	percentage	
of	deaths	due	to	coronary	artery	disease	with	age.




                                                                                                            3.2




                                                                                                      73
Chapter 3.2


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                                                                                                            75
                                         Chapter	3.3

Incidence and causes of sudden death in the
    young:	first	results	of	the	CAREFUL	study
     The yield of cardiogenetic screening in first-degree
           relatives of sudden cardiac and unexplained
                                death victims <45 years
Chapter 3.3


Abstract	
Background:	The	purpose	of	the	current	study	is	to	provide	population	based	data	on	
the	incidence	and	causes	of	(presumed)	natural	sudden	death	in	the	young	(1-44	years),	
data	to	 be	used	 for	 assessing	 the	most	optimal	 screening	 strategy	to	 prevent	sudden	
cardiac	death	(SCD).

Methods:	A	comprehensive,	population	based	follow-up	study	was	carried	out	in	four	
regions	 in	 the	 Netherlands.	 Data	 of	 the	 first	 study	 year	 are	 presented.	 Sudden	 death	
victims	aged	1-44	years	were	identified	by	systematically	reviewing	resuscitation	records	
and	 death	 declaration	 certificates.	 Autopsy	 results	 were	 collected	 for	 all	 victims	 on	
whom	autopsy	had	been	performed.

Results:	175	sudden	death	cases	were	registered	in	a	population	of	2,566,454	inhabitants	
aged	1-44	years;	mean	age	34	years	(range	1-44),	70%	male.	142	(81%	(95%	confidence	
interval	 (CI);	 75%-87%))	 were	 classified	 as	 definite,	 probable	 or	 possible	 SCD.	 The	
incidence	of	sudden	death	and	SCD	was	6.8	(95%	CI;	5.8-7.8)	and	5.5	(95%	CI;	4.6-6.4)	
per	100,000	person-years	respectively.	The	incidence	of	sudden	death	was	higher	in	men	
than	in	women	and	increased	with	age.	An	inherited	cardiac	disease	was	suspected,	or	
could	not	be	excluded,	in	79%	of	all	sudden	death	victims.

Conclusion:	The	incidence	of	sudden	death	in	subjects	1-44	years	is	higher	than	reported	
in	 most	previous	 studies.	 An	inherited	cardiac	 disease	 is	 suspected	in	 the	majority	of	
young	 sudden	 death	 victims	 with	 or	 without	 relevant	 medical	 history.	 Based	 on	 the	
results	 of	 this	 study,	 cardiogenetic	 screening	 of	 relatives	 of	 SCD	 victims	 should	 be	
considered	for	timely	detection	of	inherited	cardiac	diseases.




78
                     Incidence and causes of sudden death in the young: first results of the CAREFUL study


         	
Introduction	
Sudden	cardiac	death	(SCD)	and	sudden	unexplained	death	(SUD)	in	the	young	are	often	          	
associated	with	inherited	cardiac	diseases.1,2	Inherited	cardiac	diseases	can	be	subdivided	
into	 three	 major	 categories;	 cardiomyopathies	 (e.g.	 hypertrophic	 cardiomyopathy),	
primary	arrhythmia	syndromes	(e.g.	long-QT	syndrome),	and	premature	atherosclerosis	
            e
            	                                                       	
(e.g.	 du	 	 to	 familiar	 hypercholesterolemia).3,4	 Early	 detection	 of	 inherited	 cardiac	
diseases	enables	early	treatment	and	might	prevent	future	sudden	deaths.5 Measures to
                                                                               	 	
prevent	sudden	death	in	the	young	are	being	discussed	as	the	most	effective	approach	
                                                  	
has	not	been	established	yet.	Pre-symptomatic	screening	has	been	proposed	in	selected	
          	                      		                                       	              	
populations	 such	 as	 competitive	 athletes6,7	 or	 high	 risk	 populations	 like	 relatives	 of	
                     	               	
sudden	death	victims.8-12	Population	based	data	on	the	incidence	and	causes	of	sudden	
death	in	the	young	are	a	prerequisite	to	develop	approaches	to	prevent	sudden	death	
in the young.
                                             	
At	present,	there	is	a	paucity	of	population	based	data	on	the	incidence	of	SCD	in	the	
                           	
young	 and	 the	 proportion	 of	 inherited	 cardiac	 diseases	 underlying	 the	 sudden	 death	
of	young	persons.	Most	previous	studies	focused	only	on	SCD	in	selected	populations	         	
                                                            		
like	 apparently	 healthy	 young	 individuals13	 or	 competitive	 athletes6,14 and as such are               3.3
                   	                           	
not	 representative	 for	 the	 general	 population.	 Moreover,	 incomplete	 (or	 biased)	 data	
        	
collection	precludes	the	generalizability	of	some	of	the	previous	studies.	For	example,	
in	 some	 studies	 only	 cases	 in	 which	 emergency	 medical	 services	 were	 involved	 were	
                                                                      	
included,15,16	 or	 data	 on	 causes	 were	 collected	 through	 national	 death	 declaration	  	
     		                                                    	 	
certificates,	a	method	prone	to	considerable	misclassification.     17,18

                                                                             	
The	purpose	of	the	current	study	is	to	provide	comprehensive,	population	based	data	on	
                                                                           	
the	incidence	of	sudden	(cardiac)	death	in	the	young	and	to	quantify	the	proportion	of	    	
(possible)	underlying	inherited	cardiac	diseases.	



Methods
Study design
                                                                     	                 	
Data	 were	 derived	 from	 the	 CAREFUL	 (The	 yield	 of	 cardiogenetic	 screening in first-
             	                                                    	
degree	relatives	of	sudden	cardiac	and	unexplained	death	victims	<45	years)	study;	a	
        	
population	based	follow-up	study	carried	out	in	four	regions	in	the	Netherlands	aiming	
               	                                      	
at	the	evaluation	and	improvement	of	usual	care	after	a	sudden	death	of	an	individual	
                                       	
aged	1-44	years.	The	design	and	rationale	of	this	study	have	been	published	before.19
Data	presented	in	the	current	study	were	collected	between	June	1st,	2008	and	June1st,
                 	 	                               	
2009.	 The	 Institutional	 Medical	 Ethical	 Committee	 of	 Nieuwegein,	 the	 Netherlands,	
approved	the	study.	


                                                                                                       79
Chapter 3.3


Population
The	four	study	regions	comprise	approximately	28%	of	the	total	Dutch	population	aged	
1-44	years	and	cover	both	urban	and	rural	communities,	including	2,566,454	inhabitants	
1-44	years	(1,290,151	men,	1,276,303	women)	in	2008.
All	deceased	individuals	aged	1-44	years	in	the	study	regions	were	included	in	the	study	
when	death	(or	the	event	leading	to	death)	occurred	suddenly,	unexpectedly	and	a	natural	
cause	of	death	was	likely	or	could	not	be	excluded	on	the	basis	of	clinical	findings.	Death	
was	considered	 sudden	 when	 one	 of	 the	following	 criteria	was	met;	1)	cardiac	 arrest	
followed	 by	 an	 unsuccessful	 resuscitation	 attempt	 leading	 to	 death;	 2)	 unwitnessed	
death	occurring	within	24	hours	after	the	person	was	seen	alive	and	in	good	health;	3)	
unwitnessed	death	in	which	inspection	of	the	corpse	and	the	surrounding	area	indicated	
a	 sudden,	 loss	 of	 consciousness	 (e.g.	 television	 switched	 on);	 4)	 death	 that	 occurred	
during	sleep;	or	5)	unwitnessed	death	in	which	the	day	of	death	could	be	determined	
with	 complete	 certainty	 (modified	 from	 Hua	 et	 al.20).	 Sudden	 death	 victims	 were	 not	
included	when	the	cardiac	arrest	occurred	in-hospital	(except	for	the	emergency	room).	
Death	was	considered	unexpected	when	the	victim	was	not	suffering	a	terminal	illness.	
SCD	was	defined	as	sudden	death	caused	by	any	cardiac	disease	or	aortic	root	disease	
(e.g.	due	to	Marfan	syndrome).	SUD	was	defined	as	sudden	 death	in	which	no	cause	
of	 death	 could	 be	 established	 on	 the	 basis	 of	 clinical	 findings	 and/or	 autopsy	results.	
When	the	cause	of	death	was	known	based	on	clinical	information	(including	autopsy,	
if	 performed),	 atherosclerotic	 coronary	 artery	 disease,	 cardiomyopathies	 (including	
unexplained	left	ventricular	hypertrophy)	and	dissection	or	rupture	of	the	thoracic	aorta	
were	considered	possibly	inherited	cardiac	diseases,	as	inheritance	is	certain	or	cannot	
be	excluded	for	these	conditions.	Cases	in	which	the	cause	of	death	was	unknown	(before	
and/or	after	autopsy)	were	also	considered	possibly	inherited.	All	other	diagnoses	were	
considered	non-inherited	cardiac	diseases.	The	victim’s	medical	history	was	considered	
relevant	when	the	disease	(or	treatment)	might	be	associated	with	an	increased	risk	for	
sudden	death	(e.g.	diabetes,	hypertension).

Data collection
Usual	care	following	sudden	death	in	the	young	and	the	data	collection	of	the	CAREFUL	
study	have	previously	been	described.19	In	short,	sudden	death	victims	were	registered	by	
continuously	reviewing	the	resuscitation	records	of	the	emergency	medical	services	and	
the	death	declaration	certificates	of	the	public	health	services	on	possible	sudden	death	
victims	aged	1-44	years.19	Extraction	of	clinical	data	and	event	related	data	from	these	
records	was	performed	by	the	investigators	(A.H.	and	C.v.d.W.)	and	included	information	
on	medical	history,	circumstances	and	location	of	the	event	and	the	presence	of	previous	
symptoms	 (acute	 and	 prodromal	 symptoms).	 When	 available,	 data	 of	 the	 victims’	


80
                     Incidence and causes of sudden death in the young: first results of the CAREFUL study


                                                       	                	
hospital	medical	records	were	searched	for	additional	information	on	medical	history.	
         	                   		
The	victims’	general	practitioners	were	contacted	and	interviewed	through	a	structured	
      	                                                         	
questionnaire	on	the	previous	medical	history	of	the	patient	and	the	(possible)	request	
                       	
for	autopsy.	Information	on	the	performance	of	autopsy	was	obtained	by	extraction	of	      	
                                                                      	
data	 from	 the	 Pathologisch-Anatomisch	 Landelijk	 Geautomatiseerd	 Archief	 (PALGA)21
database	 in	 which	 data	 on	 clinical	 autopsies	 are	 collected	 and	 from	 the	 Netherlands	
             	
Forensic	Institute	(NFI)	databases	in	which	data	from	the	judicial	autopsies	are	collected.	
Assessment	of	the	probable	cause	of	death	and	whether	or	not	the	sudden	death	victim	         	
was	eligible	for	inclusion	in	the	CAREFUL	study	was	performed	by	two	researchers	(A.H.	
                                                    	
and	 C.v.d.W.).	 Based	 on	 the	 available	 information,	 the	 (possible	 and	 probable)	 causes	
                       	
of	death	were	classified	as	one	of	four	categories	(A-D)	as	given	in	table	1.	In	case	of	
                                                  	
discrepancy	(n	=	35),	an	expert	panel	consisting	of	a	cardiologist,	pathologist,	a	clinical	
      	                          		
geneticist	and	a	general	practitioner	was	consulted.	

Table 1. Categories of causes of sudden death

Category                    	 	
                         Definition                          Example
A.	Definite	SCD
      	                  Cardiac	disease	is	established	
                                                    Hypertrophic	cardiomyopathy	                             3.3
                                                	 	 established	by	autopsy	
                         by	post-mortem	investigation
B.	Probable	SCD          Cardiac disease is the mostSudden death during soccer game in a
                         likely cause of death      person	with	prior	history	of	syncopal	
                                                                          	
                                                    episodes	and	palpitations
C.	Possible	SCD                                                                   	
                      Both cardiac and non-cardiac Unwitnessed	death,	no	additional	
                                                              	
                      diseases	are	possible	causes	 information	on	the	circumstances	of	
                      of death                              	
                                                    the	victim’s	death.	No	family	history	of	
                                                    sudden death
D. Non-cardiac sudden Non-cardiac disease is the    Acute onset of severe hematesis
   death              most	probable	cause	of	death followed	by	collapse	and	sudden	
                                                    death



Data analysis
Data	were	analyzed	with	SPSS	for	Windows	17.0.	Incidence	rates	of	sudden	death	and	
              	
SCD	were	estimated	as	the	total	number	of	sudden	death	or	SCD	divided	by	the	number	
                                  	                   	           	
of	 person-years	 of	 the	 population	 at	 risk.	 Victims	 classified	 in	 categories	 A-D	 were	
                                                        	           	
considered	as	being	sudden	death	cases	and	victims	classified	in	categories	A-C	were	
                                                  	
considered	as	being	SCD	cases.22	Incidence	estimates	are	reported	by	four	age	categories	
(1-9	years,	10-19	years,	20-29	years	and	30-44	years)	and	by	gender.




                                                                                                       81
Chapter 3.3


Results
Incidences of sudden death and SCD
In	 total,	 175	 subjects	 1-44	 years	 met	 the	 inclusion	 criteria	 of	 sudden	 death	 (category	
A-D).	Of	these	subjects,	69	were	included	by	the	emergency	medical	services,	61	by	the	
public	health	services	and	45	by	both	services.
The	 incidence	 of	 sudden	 death	 in	 persons	 aged	 1-44	 years	 was	 6.8	 (95%	 confidence	
interval	(95%	CI);	5.8-7.8)	per	100,000	person-years	and	the	incidence	of	SCD	5.5	(95%	
CI;	4.6-6.4)	per	100,000	person-years	(table	2).	The	incidence	of	sudden	death	and	SCD	
was	generally	higher	for	men	than	for	women.	In	men	aged	1-44	years,	the	incidence	
of	sudden	death	was	9.5	(95%	CI;	7.8-11.1)	per	100,000	person-years	and	the	incidence	
of	SCD	was	8.1	(95%	CI;	6.6-9.7)	per	100,000	person-years.	In	women	aged	1-44	years,	
the	incidence	of	sudden	death	was	4.2	(95%	CI;	3.0-5.3)	per	100,000	person-years	and	
the	incidence	of	SCD	was	2.9	(95%	CI;	2.0-3.8)	per	100,000	person-years.	The	incidence	
of	both	sudden	death	and	SCD	increased	with	age.	The	majority	(128	(73%))	of	sudden	
death	victims	were	older	than	30	years	(table	2).	

Table 2.	Incidence	and	95%	confidence	interval	(CI)	of	sudden	death	and	sudden	cardiac	death	per	
100,000	person-years	

Age     Gender       Person-      SD cases    SCD cases Incidence	SD	(CI)      Incidence	SCD	(CI)
(years)              years        (N)         (N)

1-9      Male        242,796      3           0            1.24	(0.16-2.63)    -
         Female      231,782      2           1            0.86	(0.33-2.10)    0.43	(0.41-1.28)
         Total       474,578      5           1            1.05	(0.13-1.98)    0.21	(0.20-0.62)
10-19    Male        262,305      7           4            2.67	(0.69-4.65)    1.52	(0.03-3.02)
         Female      253,737      2           1            0.79	(0.30-1.88)    0.39	(0.04-1.17)
         Total       516,042      9           5            1.74	(0.60-2.88)    0.97	(0.12-1.82)
20-29    Male        282,336      16          11           5.67	(2.89-8.44)    3.90	(1.59-6.20)
         Female      294,271      17          12           5.78	(3.03-8.52)    4.08	(1.77-6.39)
         Total       576,607      33          23           5.72	(3.77-7.68)    3.99	(2.36-5.62)
30-44    Male        502,714      96          90           19.10	(15.28-22.92) 17.90	(14.20-21.60)
         Female      496,513      32          23           6.44	(4.21-8.68)    4.63	(2.74-6.53)
         Total       999,227      128         113          12.51	(10.32-14.70) 11.30	(9.22-13.39)
1-44     Male        1,290,151 122            105          9.46	(7.78-11.13)   8.14	(6.58-9.70)
         Female      1,276,303 53             37           4.15	(3.03-5.27)    2.90	(1.96-3.83)
         Total       2,566,454 175            142          6.82	(5.81-7.83)    5.53	(4.62-6.44)
SD	=	sudden	death,	SCD	=	sudden	cardiac	death,	N	=	number	of	cases




82
                        Incidence and causes of sudden death in the young: first results of the CAREFUL study


Characteristics of sudden death victims
                                                                                 	
The	 mean	 age	 at	 death	 was	 34	 years	 (range	 1-44),	 and	 122	 (70%)	 victims	 were	 men	
(table	3a).	The	majority	of	events	(n	=	126	(75%))	occurred	at	home.	In	93	(53%)	victims	    	
          	            	
resuscitation	was	attempted	by	the	emergency	medical	services.	In	122	(70%)	sudden	
           	               	
death	victims,	information	regarding	the	circumstances	of	death	was	available;	78	(64%)	
    	                                                                 	
victims	 died	 at	 rest,	 27	 (22%)	 during	 sleep,	 seven	 (6%)	 victims	 died	 during	 physical	
   	          	                       	
activity	and	five	(4%)	during	emotion	(e.g.	anger).

Table 3a.	Characteristics	of	175	sudden	death	victims	1-44	years
                      	                           	

Variable                                                                 N
Male	(%)                                                                 122	(70)
Age	years	(SD*)                                                          34	(9,5)
Resuscitation	attempt (%)
          	     	        1
                                                                         93	(53)
Circumstance	of	event	known	(%)                                          122	(70)
     -    sleep	(%)                                                       27	(22)
     -    rest	(%)                                                        78	(64)
     -                  	
          physical	activity	(%)                                           7	(6)
     -    emotion	(%)
                	                                                         5	(4)                                 3.3
     -    other	(%)                                                       5	(4)
     	
Location	of	cardiac	arrest	known	(%)                                     167	(95)
     -    home	(%)                                                        126	(75)
     -    street	(%)                                                      13	(8)
     -                	
          other	location	(%)                                              28	(17)
Acute	symptoms	known	(%)                                                 61	(35)
     -    dyspnoea	(%)                                                    8	(13)
     -    nausea	(%)                                                      17	(28)
     -    chest	pain	(%)                                                  7	(11)
     -    headache	(%)                                                    4	(7)
     -    pain	back/shoulders/arms/abdomen	(%)                            5	(8)
     -    dizziness/syncope	(%)                                           8	(8)
     -    none	(%)                                                        25	(41)
Prodromal	symptoms	known	(%)                                             76	(43)
     -    fatigue	(%)
             	                                                            7	(9)
     -    fever	(%)                                                       13	(17)
     -    chest	pain	(%)                                                  9	(12)
     -    swollen	leg	(%)                                                 4	(5)
     -    dyspnoea	(%)                                                    5	(7)
     -    other	(%)                                                       19	(25)
     -    none	(%)                                                        34	(45)
                                          	
N	=	number	of	cases,	SD*	=	standard	deviation, 1 Variable	unknown	in	2	cases.




                                                                                                          83
Chapter 3.3


An	overview	of	the	victims’	medical	histories	is	provided	in	table	3b.	Psychiatric	diseases	
(e.g.	 schizophrenia	 and	 depression),	 epilepsy,	 and	 hypertension	 were	 most	 prevalent.	
Four	patients	were	known	with	structural	congenital	heart	disease	and	eight	patients	
with	an	acquired	cardiac	disease.	Furthermore,	drug	abuse	was	reported	in	18	patients,	
and	16	patients	were	known	with	alcohol	abuse.	

Table 3b.	Medical	history	sudden	death	victims	1-44	years	

Medical history                                                                N
Medical	history	known	(%)                                                     133	(76)
     -	 epilepsy	(%)                                                          			17	(13)
     -							psychiatric	disease1	(%)                                         			21	(16)
     -       congenital heart disease2	(%)                                    			4	(3)
     -							diabetes	(%)                                                     			10	(8)
     -							hypertension	(%)                                                 			14	(11)
     -							hypercholesterolemia	(%)                                         			8	(6)
     -       cardiac disease3	(%)                                             			8	(6)
     -       other4 (%)                                                       			42	(32)
     -							none	(%)                                                         			38	(29)
N	=	number	of	cases
1
  schizophrenia,	depression
2
  Eisenmenger	syndrome,	atrial	septal	defect,	atrioventricular	septal	defect,	ventricular	septal	defect	
3
  myocardial	 infarction,	 hypertrophic	 cardiomyopathy,	 heart	 failure,	 aortic	 dissection	 treated	 with	 Bentall	
procedure
4
  most	common:	liver	cirrhosis,	tuberculosis,	renal	disease,	chronic	
obstructive	pulmonary	disease


Causes of death
The	 causes	of	 death	 were	based	 on	 all	 available	 information	 (comprising	 clinical	 data	
from	 emergency	 medical	 services,	 public	 health	 services,	 hospital	 records,	 general	
practitioner	and	autopsy	reports).	142	(81%	(95%	CI;	75%-87%))	of	all	175	sudden	death	
victims	were	classified	as	having	died	from	a	definite,	probable	or	possible	cardiac	cause.	
33	 (19%)	 victims	 were	 classified	 as	 definite	 cardiac	 deaths	 (category	 A),	 24	 (14%)	 as	
probable	cardiac	deaths	(category	B),	and	85	(49%)	as	possible	cardiac	deaths	(category	
C).	 In	 33	 (19%	 (CI;	 13%-25%))	 victims,	 a	 non-cardiac	 cause	 of	 death	 was	 diagnosed	
(category	D).	The	proportion	of	non-cardiac	causes	of	death	declined	with	age	(table	4).	
In	children	less	than	ten	years	old,	non-cardiac	causes	of	death	were	identified	in	four	out	
of	five	victims.	Causes	of	death	in	children	aged	1-9	years	were	sepsis,	gastric	bleeding,	
subarachnoidal	 hemorrhage	 due	 to	 arteriovenous	 malformation,	 unrecognized	 B-cell	
lymphoma	and	viral	myocarditis.




84
                         Incidence and causes of sudden death in the young: first results of the CAREFUL study


Table 4.	 Classification	 of	 causes	 of	 death	 for	 different	 age	 categories,	 based	 on	 all	 available	
                 	 	                                     	
        	
information	(including	autopsy,	if	performed)

Age	(years)     Category A:     Category B:     Category C:     Category        Category D: Total,	N	(%)
                    	
                Definite	       Probable	       Possible	       A-C:            Non-cardiac
                SCD,	N	(%)      SCD,	N	(%)      SCD,	N	(%)      SCD,	N	(%)      SD,	N	(%)
1-9             1	(20)          0               0	(0)           1	(20)          4	(80)      5	(29)
10-19           2	(22)          2	(22)          1	(11)          5	(56)          4	(44)         9	(5)
20-29           5	(15)          2	(6)           16	(49)         23	(70)         10	(30)        33	(19)
30-44           25	(20)         20	(16)	        68	(53)         111	(87)        15	(12)        128	(73)
1-44            33	(19)         24	(14)         85	(49)         142	(81)        33	(19)        175	(100)
N	=	number	of	cases,	SCD	=	sudden	cardiac	death,	SD	=	sudden	death

Autopsy	 was	 performed	 in	 61	 (35%)	 of	 the	 175	 cases	 (including	 53	 clinical	 autopsies	
                                                  	
and	 8	 judicial	 autopsies)	 and	 led	 to	 a	 definite	 cardiac	 cause	 of	 death	 in	 32	 (52%)	 of	
                                            	                                           	
61	 cases	 (table	 5).	 Myocardial	 infarctions	 due	 to	 premature	 atherosclerotic	 coronary	
                                                                                 	         	
artery	 disease	 was	 the	 most	 frequent	 cause	 (n	 =	 17,	 28%).	 Most	 victims	 suffering	 an	
                           	
acute	myocardial	infarction	were	30	years	or	older	(mean	age	37	years,	range	29-44).	A	
cardiomyopathy	was	diagnosed	in	seven	(11%)	SCD	victims	(mean	age	37	years,	range	
                                                                 	                                               3.3
                     	                                         	
21-44).	Myocarditis	was	established	in	two	female	victims,	both	younger	than	20	years.	
                                                  	
In	 11	 (18%)	 of	 the	 61	 sudden	 death	 victims,	 autopsy	 did	 not	 reveal	 any	 structural	
             	           	
abnormalities,	suggesting	an	(inherited)	arrhythmic	cause	of	death.2	Yet,	in	one	of	these	
    	
victims,	who	had	a	history	of	insulin	dependent	diabetes	mellitus,	the	sudden	decease	
                                                                      	
was	explained	by	hyperglycemia.	In	18	(29%)	of	the	61	victims	in	whom	autopsy	was	
performed	a	non-cardiac	cause	of	death	was	diagnosed.	Among	the	non-cardiac	causes	
                  	
of	death,	infectious	diseases	were	most	common,	followed	by	intracranial	hemorrhage	
and	pulmonary	embolism.	

Inherited cardiac diseases
                                            	
In	138	(79%)	of	the	175	sudden	death	victims,	an	inherited	cardiac	disease	was	suspected	
                                                            	
or	 could	 not	 be	 excluded	 based	 on	 available	 information.	 Furthermore,	 in	 41	 of	 the	
               	
61	 (67%)	 victims	 in	 whom	 autopsy	 was	 performed,	 an	 inherited	 cardiac	 disease	 was	
                                                        	
suspected	or	diagnosed	(table	5).	Myocardial	infarction	due	to	premature	atherosclerotic	      	
                                                                   	
coronary	artery	disease,	cardiomyopathies	and	autopsy-negative	deaths	(suggesting	an	     	
inherited	 cardiac	 disease)	 were	 the	 most	 common	 findings.3,8-11,23	 In	 three	 victims	 in	
                                                          	                               	
                 	                                                                 	
whom	a	dissection	of	the	aorta	ascendens	was	diagnosed	(including	one	victim	who	had	
                                              	
had	a	Bentall	procedure),	an	inherited	aortic	disorder	could	not	be	not	excluded.	
                                                                               	
The	presence	(or	suspicion)	of	inherited	cardiac	diseases	was	not	significantly	different	 	
                                 	
(p	=	0.85)	for	sudden	death	victims	with	(71/95,	75%)	or	without	(29/38,	76%)	a	relevant	
medical history.

                                                                                                           85
Chapter 3.3


Table 5.	Causes	of	sudden	death	in	victims	1-44	years,	established	by	autopsy	(including	53	clinical	
autopsies	and	8	judicial	autopsies)

Autopsy	findings                                       N	=	61 %             Number	of	cases	with	probable	
                                                                            inherited cardiac diseases
Cardiac causes                                         32         52
    Myocardial	infarction	due	to	                      17         28        17
    atherosclerotic	coronary	artery	disease
				Cardiomyopathy1                                    7          11        7
				Myocarditis                                        2          3         -
				Aortic	dissection                                  2          3         2
				LVH	with	ischemia                                  3          5         3
				Vegetations	graft	Bentall	procedure       2
                                                       1          2         1
No	structural	abnormalities                            11         18        103
Non-cardiac causes                                     18         29
     Intracranial hemorrhage                           5          8         -
				Pulmonary	embolism       4
                                                       3          5         -
				Infectious	disease                                 7          11        15
     Malignancy                                        1          2         -
				Other	(non-cardiac	causes)      6
                                                       2          3         -
N	=	number	of	cases,	LVH	=	left	ventricular	hypertrophy
1
  Dilatation	of	left	and	right	ventricle,	left	ventricular	hypertrophy	with	dilatation	of	left	and	right	ventricle,	
unexplained	 diffuse	 myocardial	 fibrosis,	 hypertrophic	 cardiomyopathy,	 unspecified	 cardiomyopathy,	 dilated	
cardiomyopathy,	left	ventricular	hypertrophy	(unspecified)
2
  Bentall	procedure	after	thoracic	aorta	dissection
3
  Primary	arrhythmia	syndromes	are	a	likely	cause	of	death	when	no	structural	abnormalities	can	be	found,	one	
victim	died	due	to	hyperglycemia
4
  Non-cardiac	 inherited	 diseases	 (e.g.	 thrombophilia	 due	 to	 factor	 V	 Leiden)	 might	 underlie	 an	 pulmonary	
embolism	at	young	age
5
  One	patient	was	known	with	ischemic	heart	disease
6
  Ileus	with	pneumonia	due	to	aspiration,	gastric	perforation




86
                     Incidence and causes of sudden death in the young: first results of the CAREFUL study


Discussion
                            	
This	comprehensive	population	based	study	shows	that	the	incidence	of	sudden	death	
and	SCD	in	persons	aged	1-44	years	is	6.8	(95%	CI;	5.8-7.8)	and	5.5	(95%	CI;	4.6-6.4)	per	
                               	
100,000	 person-years,	 respectively.	 An	 inherited	 cardiac	 disease	 including	 premature	
atherosclerosis	was	diagnosed,	suspected	or	could	not	be	excluded	in	79%	of	all	sudden	
          	                                           	
death	victims,	and	in	67%	of	the	sudden	death	victims	who	underwent	autopsy.	

Incidence
                    	
The	 incidence	 estimates	 of	 sudden	 death	 and	 SCD	 in	 persons	 aged	 1-44	 years	 in	 the	
                                                   	
current	study	are	considerably	higher	than	estimates	from	most	former	studies.13,24,25
Former	studies	reported	a	sudden	death	incidence	of	2.4	per	100,000	person-years	in	
non-hospitalized	healthy	persons	aged	1	to	35	years13	and	a	SCD	incidence	of	0.8-0.9	per	
100,000	person-years	in	persons	aged	12-35	years.6,25	However,	one	population	based	  	
                                                                                	
study	performed	in	the	United	States	reported	SCD	incidences	of	respectively	6	and	17	
per	100,000	person-years	in	persons	aged	25-34	and	35-44	years	which	is	in	agreement	
with	our	results.26
                                  	                         	
Several	factors	might	explain	differences	in	incidence	estimates	among	studies.	First,	the	                  3.3
                                    	       	           	
age	(range)	of	the	study	population	affects	the	estimated	mean	sudden	death	and	SCD	
incidences	because	the	incidence	of	sudden	death	and	SCD	increases	rapidly	with	age.27
                             		 	                                        	
Second,	methods	of	identification	of	sudden	death	cases	might	differ.	For	example,	in	a	
                                              		                   	 	
former	study	that	was	based	on	death	certificate	data,	misclassification	and	the	erroneous	
      	                  	          	 	                                       	
selection	of	International	Classification	of	Diseases	(ICD)	codes	to	identify	cases	might	
                           	    	
have	 led	 to	 an	 underestimation	 of	 sudden	 death	 and	 SCD	 cases.24	 Third,	 the	 applied	
                                          	      	                  	
inclusion	criteria	of	sudden	death	victims	affect	the	incidence	estimates	of	sudden	death	
in	the	young.	Our	aim	was	to	use	clinically	relevant	sudden	death	and	SCD	definitions	  	 	
                       	                           	
that	are	representative	for	the	general	population,	leading	to	lenient	inclusion	criteria	in	
                                                          	
the	present	study	compared	to	previous	studies.	Victims	with	a	relevant	medical	history	
                                                    	
were	also	included	in	our	study,	as	well	as	victims	with	vague	symptoms	for	more	than	
                                                      	
24	hours	preceding	the	cardiac	arrest.	The	application	of	too	strict	inclusion	criteria	leads	
                 	    	
to	an	underestimation	of	the	sudden	death	and	SCD	incidence,	as	information	on	the	 	
                                        	
circumstances	 of	 death	 (e.g.	 duration	 of	 symptoms)	 is	 frequently	 missing	 in	 cases	 of	
                                                                       	
unwitnessed	death	(e.g.	cases	that	are	not	included	when	the	victim	was	not	seen	alive	
within	24	hours	before	death	occurred).	Also,	the	regional	age	and	gender	distribution	     	
and	the	regional	prevalence	of	inherited	cardiac	diseases	and	premature	atherosclerotic	      	
                                      	
coronary	artery	disease	might	influence	the	incidences	of	sudden	death	and	SCD	in	the	
young.




                                                                                                       87
Chapter 3.3


Characteristics and causes of death
The	majority	of	deaths	occurred	at	rest	or	during	sleep,	with	only	a	minority	(6%	(95%	
CI;	 2%-10%))	 of	 the	 sudden	 death	 cases	 being	 exercise	 related.	 This	 is	 in	 agreement	
with	 earlier	 studies	 that	 reported	 5%-14%	 of	 deaths	 being	 associated	 with	 physical	
activity.28,29	Overall,	the	causes	of	death	that	were	found	in	our	study	are	in	line	with	
results	 of	 previous	 studies.24,4	 In	 young	 children	 (1-9	 years),	 non-cardiac	 causes	 were	
most	common	while	cardiac	causes	predominated	in	older	sudden	death	victims.	The	
incidence	 of	 SCD	 increased	 particularly	 in	 men	 older	 than	 30	 years	 as	 compared	 to	
women.	This	might	be	explained	by	the	increasing	number	of	deaths	due	to	premature	
atherosclerotic	coronary	artery	disease	after	30	years	of	age	especially	in	men,	which	is	
in	line	with	the	findings	of	others.25,26

Strengths and limitations
Because	 of	 the	 population	 based	 data	 collection,	 missing	 data	 were	 inevitable.	 Most	
victims	died	out-of-hospital	and	often	unwitnessed.	Therefore,	the	presence	and	duration	
of	acute	complaints	could	be	determined	in	only	35%	of	the	cases.	Furthermore,	autopsy	
was	conducted	in	 only	 35%	of	 the	cases.	 Consequently,	the	causes	 of	 death	found	 at	
autopsy	 might	 not	 be	 representative	 for	 the	 general	 population.	 The	 percentage	 of	
cardiac	deaths	(including	the	unexplained	deaths)	found	with	autopsy	(70%	(95%	CI;	57%-
81%))	was	not	significantly	lower	as	compared	to	the	percentage	of	definite,	probable	
and	possible	cardiac	deaths	(categories	A-C)	found	in	all	victims	that	were	included	(81%	
(95%	CI;	75%-87%)).	
The	strength	of	the	current	study	is	that	collection	of	data	in	four	regions	covers	both	
urban	and	rural	communities	and	comprises	28%	of	the	Dutch	population.	Furthermore,	
population	 based	 data	 were	 obtained	 without	 a	 selection	 of	 cases,	 and	 victims	 with	
relevant	medical	history	or	prodromal	symptoms	were	also	included.	As	such,	the	results	
of	the	present	study	are	likely	to	be	representative	for	the	general	population.

Implications
Sudden	death	in	the	young	is	often	caused	by	inherited	cardiac	diseases.1,30 We found
that	the	percentage	of	suspected	or	diagnosed	inherited	cardiac	diseases	was	equal	in	
sudden	death	victims	with	or	without	relevant	medical	history.	This	supports	the	notion	
that	autopsy	to	identify	or	exclude	inherited	(cardiac)	diseases	should	not	be	limited	to	
only	sudden	death	victims	without	a	relevant	medical	history.	Based	on	autopsy	results,	
those	relatives	who	are	at	increased	risk	for	being	carrier	of	an	inherited	cardiac	disease	
should	be	informed	and	targeted	cardiogenetic	screening	of	the	victims’	relatives	might	
be	initiated	to	prevent	SCD	in	affected	relatives.31	Furthermore,	autopsy	might	also	be	
useful	to	detect	other	(non-cardiac)	inherited	diseases	(e.g.	thrombophilia	due	to	factor	


88
                     Incidence and causes of sudden death in the young: first results of the CAREFUL study


                                                       	
V	Leiden)	which	might	be	relevant	for	surviving	relatives.
                      	                        	
Although	the	population	based	incidence	estimates	of	SCD	are	higher	than	previously	
                      	                                          	 	
reported	 and	 preventive	 measures	 are	 feasible,	 the	 cost-effectiveness	 of	 such	 family-
                                                                         	
based	 screening	 approach	 to	 reduce	 cardiovascular	 events	 in	 relatives	 of	 young	 SCD	
    	
victims	remains	to	be	addressed.	

Conclusion
            	
The	population	based	incidence	of	sudden	death	in	the	young	established	in	this	study,	
is	considerably	higher	than	previously	reported	and	cardiac	disease	is	the	main	cause	of	
death.	The	incidence	of	sudden	death	increases	with	age	and	is	higher	in	men	than	in	
women.	Because	inherited	cardiac	diseases	predominate	as	underlying	cause	of	death	
                           	             	             	                   	
in	young	sudden	death	victims,	systematic	cardiogenetic	screening	of	relatives	of	young	
                  	
sudden	death	victims	might	be	useful	to	prevent	SCD.




                                                                                                             3.3




                                                                                                       89
Chapter 3.3


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                        Incidence and causes of sudden death in the young: first results of the CAREFUL study


                                                                                    	                   		
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                                                                                                            91
                                 Chapter	3.4

Sudden	death	in	the	young	(1-44	years)	in	the	
Netherlands:	autopsy	rate	and	characteristics	
 associated	with	the	performance	of	autopsy
Chapter 3.4


Abstract
Background:	Autopsy	of	young	sudden	death	victims	is	important	for	the	diagnosis	or	
exclusion	 of	 inherited	 cardiac	 diseases,	 in	 particular	 for	 the	 preventive	 benefit	 of	 the	
victims’	relatives.	In	the	Netherlands,	autopsy	is	not	mandatory	in	cases	of	natural	death.	
We	determined	the	clinical	autopsy	rate	among	young	sudden	death	victims	(1-44	years)	
and	the	factors	related	to	the	performance	of	autopsy.

Methods:	An	observational	study	was	performed	over	a	two-year	period	(2006-2008)	
in	four	regions	in	the	Netherlands.	Sudden	death	victims	were	identified	by	reviewing	
death	 declaration	 certificates	 of	 the	 public	 health	 services.	 The	 autopsy	 rate	 in	 these	
cases	was	determined.	The	characteristics	of	sudden	death	victims	associated	with	the	
performance	of	autopsy	were	analyzed	by	multivariate	logistic	regression	analysis.

Results:	Two-hundred	twenty-four	sudden	death	victims	(mean	age	of	death;	34	years	
(range	1-44),	52	(23%)	women)	were	registered.	Clinical	autopsy	was	performed	in	48	
sudden	 death	 victims	 (21%	 (95%	 CI;	 16%-27%)).	 In	 33	 (69%)	 of	 the	 victims	 in	 whom	
autopsy	 was	 performed,	 a	 structural	 cardiac	 disease	 was	 established	 and	 in	 30	 (63%)	
cases	 an	 inherited	 cardiac	 disease	 was	 diagnosed	 or	 considered	 possible.	 Autopsies	
were	significantly	more	often	performed	in	victims	who	had	been	resuscitated	(adjusted	
OR	3.67	(95%	CI;	1.46-9.25))	and	in	victims	without	relevant	comorbidities	(adjusted	OR	
3.13	(95%	CI;	1.44-6.79)).	

Conclusion: Clinical	autopsy	is	performed	in	a	minority	of	young	sudden	death	victims	
and	therefore	inherited	cardiac	diseases	probably	remain	undetected.	Autopsy	is	more	
frequently	performed	in	resuscitated	victims	and	in	apparently	healthy	victims.




94
                         SCD, autopsy rate and characteristics associated with the performance of autopsy


         	
Introduction
                                    	
Inherited	cardiac	diseases	are	often	underlying	sudden	cardiac	death	(SCD)	in	a	young	
person.1	Examples	of	common	inherited	cardiac	diseases	are	atherosclerotic	coronary	   	
artery	disease	caused	by	familiar	hyperlipidemia,	cardiomyopathies	(e.g.	hypertrophic	
cardiomyopathy	 or	 arrhythmogenic	 right	 ventricular	 cardiomyopathy)	 and	 primary	
arrhythmia	syndromes	(e.g.	long-QT	syndrome).	In	the	majority	of	cases,	the	absence	
of	 alarming	 symptoms	 preceding	 a	 cardiac	 arrest	 complicates	 early	 diagnosis	 and	
          	                                                	
prevention	of	SCD.2,3	Autopsy	of	sudden	death	victims	(unexplained,	cardiac	and	non-
cardiac	 deaths)	 is	 an	 important	 tool	 for	 the	 diagnosis	 of	 inherited	 (cardiac)	 diseases	
among	 families.	 Since	 most	 inherited	 cardiac	 diseases	 show	 an	 autosomal	 dominant	
                              	                        	                                 	
mode	 of	 inheritance,	 relatives	 of	 an	 index	 patient	 (e.g.	 a	 sudden	 death	 victim)	 carry	
a	50%	risk	of	being	carrier	of	the	same	disease. When an inherited cardiac disease is
                                                         4

                                                         	               	
diagnosed	or	suspected	in	the	sudden	death	victim,	cardiogenetic	screening	of	relatives	       	
                                             	 	
needs	to	be	considered.	Lifestyle	modifications,	medical	treatment	and	implantation	of	      	
                                                        	
a	pacemaker	or	an	implantable	cardioverter	defibrillator	might	prevent	SCD	in	affected	     	
       	
relatives.	If	a	non-inherited	(cardiac)	disease	is	diagnosed	with	autopsy	(e.g.	myocarditis),	   	
       	                                               	 	
relatives	can	be	reassured	and	no	further	investigations	are	needed.	
In	the	Netherlands,	autopsy	is	not	mandatory	in	young	sudden	death	victims	when	a	   	
natural	cause	of	death	is	suspected.	The	overall	autopsy	rate	in	individuals	that	die	out-
                                                     	
of-hospital	 is	 approximately	 1%.5	 The	 proportion	 of	 autopsies	 in	 young	 sudden	 death	             3.4
     	
victims	might	be	higher,	because	the	post-mortem	diagnosis	might	be	relevant	for	the	
                 	
surviving	relatives.	However,	to	our	knowledge,	the	autopsy	rate	in	young	sudden	death	
     	
victims	in	the	Netherlands	has	not	been	studied	yet.	The	purpose	of	the	current	study	
                                                                        	
is	 to	 determine	 the	 autopsy	 rate	 of	 young	 sudden	 death	 victims	 (1-44	 years)	 in	 the	
                           	
Netherlands	and	investigate	the	factors	associated	with	the	performance	of	autopsy.

Methods
Current usual care after the sudden death of a young individual in the Netherlands
                                       	
When	a	person	has	died,	the	treating	physician	completes	the	death	certificate	form.			
Moreover,	 if	 a	 non-natural	 death	 is	 suspected	 or	 can	 not	 be	 excluded,	 the	 coroner	 is	
asked	to	inspect	the	corpse	and	the	circumstances	of	death	and	to	judge	whether	the	
cause of death is natural or non-natural. If a natural cause of death is declared, a clinical
                                           	         	
autopsy	 can	 be	 requested	 if	 the	 victims’	 relatives	 grant	 permission.	 Autopsy	 results	
                                                                                          	
of	 autopsies	 performed	 in	 the	 Netherlands	 are	 centrally	 recorded	 in	 the	 nationwide	
                                                                                 	
PALGA	database	(PALGA;	Pathologisch	Anatomisch	Landelijk	Geautomatiseerd	Archief).6
In	 contrast,	 when	 a	 non-natural	 cause	 of	 death	 is	 suspected	 (e.g.	 a	 crime)	 the	 public	
                                 	                              	
prosecutor	 is	 allowed	 to	 confiscate	 the	 corpse	 and	 initiate	 a	 judicial	 autopsy	 by	 the	


                                                                                                      95
Chapter 3.4


Netherlands	Forensic	Institute.	Unpublished	data	of	the	Netherlands	Forensic	Institute	
show	that	from	2008-2009	a	judicial	autopsy	was	performed	in	approximately	5%	of	the	
sudden	death	victims	aged	1-44	years.	When	a	non-natural	cause	of	death	is	suspected,	
but	judicial	autopsy	if	not	performed,	clinical	autopsy	can	still	be	requested.

Study design
Clinical	data	were	retrieved	from	the	CAREFUL	(The	yield	of	cardiogenetic	screening in
first-degree	relatives	of	sudden	cardiac	and	unexplained	death	victims	<45	years)	study.	
The	rationale	and	design	have	been	published	before.7	One	of	the	aims	of	the	CAREFUL	
study	is	to	obtain	population	based	information	on	the	incidence	and	causes	of	sudden	
and	unexplained	death	in	young	victims.	Another	purpose	is	to	compare	strategies	that	
aim	 to	 increase	 the	 proportion	 of	 post-mortem	 investigations	 in	 young	 sudden	 death	
victims	and	the	proportion	of	first-degree	relatives	referred	to	cardiogenetic	clinics.	The	
Institutional	Medical	Ethical	Committee	of	Nieuwegein,	the	Netherlands,	approved	the	
study.

Population and data collection
Data	of	the	current	study	were	collected	in	four	regions	of	the	Netherlands	(Groningen,	
Midden-Nederland,	Hollands	Midden	and	Noord-Holland)	from	June	1st	2006	until	June	
1st	2008.	These	study	regions	comprised	2,566,454	inhabitants	aged	1-44	years	in	2008	
and	cover	28%	of	the	total	Dutch	population	aged	1-44	years.	Two	researchers	(A.H.	and	
C.v.d.W.)	reviewed	all	individual	death	declaration	reports	of	the	public	health	services	
to	identify	sudden	death	victims	aged	1-44	years.
All	deceased	individuals	aged	1-44	years	in	the	study	regions	were	included	in	the	study	
when	death	(or	the	event	leading	to	death)	occurred	suddenly,	unexpectedly	and	a	natural	
cause	of	death	was	likely	or	could	not	be	excluded	on	the	basis	of	clinical	findings.	Death	
was	considered	 sudden	 when	 one	 of	 the	following	 criteria	was	met;	1)	cardiac	 arrest	
followed	 by	 an	 unsuccessful	 resuscitation	 attempt	 leading	 to	 death;	 2)	 unwitnessed	
death	occurring	within	24	hours	after	the	person	was	seen	alive	and	in	good	health;	3)	
unwitnessed	death	in	which	inspection	of	the	corpse	and	the	surrounding	area	indicated	
a	 sudden,	 loss	 of	 consciousness	 (e.g.	 television	 switched	 on);	 4)	 death	 that	 occurred	
during	sleep;	or	5)	unwitnessed	death	in	which	the	day	of	death	could	be	determined	
with	 complete	 certainty	 (modified	 from	 Hua	 et	 al.8).	 Sudden	 death	 victims	 were	 not	
included	when	the	cardiac	arrest	occurred	in-hospital	(except	for	the	emergency	room).	
Death	was	considered	unexpected	when	the	victim	was	not	suffering	a	(known)	terminal	
illness.	SCD	was	defined	as	sudden	death	caused	by	any	cardiac	disease	or	aortic	root	
disease	 (e.g.	 due	 to	 Marfan	 syndrome).	 When	 the	 cause	 of	 death	 was	 known	 (based	
on	clinical	information	(including	autopsy,	if	performed),	atherosclerotic	coronary	artery	


96
                         SCD, autopsy rate and characteristics associated with the performance of autopsy


                                                           	
disease,	 cardiomyopathies	 (including	 unexplained	 left	 ventricular	 hypertrophy)	 and	
       	
dissection	or	rupture	of	the	thoracic	aorta	were	considered	possibly	inherited	cardiac	
                                                                                	
diseases,	as	inheritance	is	certain	or	cannot	be	excluded	for	these	conditions.	Victims	     	
in	whom	the	cause	of	death	was	unknown	were	also	considered	possibly	inherited.	All	
                                                                                           	
other	 diagnoses	 were	 considered	 to	 be	 non	 (inherited)	 cardiac	 diseases.	 The	 victims’	
           	
comobidities	 were	 considered	 relevant	 when	 the	 disease	 (or	 treatment)	 might	 be	
associated	with	an	increased	risk	for	sudden	death	(e.g.	diabetes,	hypertension).
                                                                           	
The	autopsy	rate	of	all	sudden	death	cases	was	determined	by	extracting	data	from	the	
                                     	                       		
PALGA	database.	Based	on	information	of	the	death	certificate	reports	and	the	autopsy	
results,	the	causes	of	death	were	established	by	two	researchers	(A.H	and	C.v.d.W.).

Data analysis
                                                     	
The	 clinical	 autopsy	 rate	 of	 sudden	 death	 victims	 that	 were	 seen	 by	 a	 coroner	 was	
calculated	 by	 dividing	 the	 number	 of	 autopsies	 by	 the	 number	 of	 registered	 sudden	
           	                                   	                           	
death	victims	(1-44	years).	The	characteristics	of	sudden	death	victims	with	and	without	
autopsy	were	compared	by	Chi-square	test	or	Fisher’s	Exact	test	(dichotomous	variables)	
                                               	                                        	
or	 the	 independent	 samples	 T-test	 (continuous	 variables).	 Crude	 odds	 ratios	 were	
calculated	 with	 univariate-logistic	 regression	 analysis.	 All	 variables	 with	 p <0.20	 were	
                                     	
                   	               	
entered	in	a	multivariate	logistic	regression	model	to	study	determinants	of	performing	
                                                                                      	
a	clinical	autopsy.	Variables	with	a	two-tailed	p	<0.05	were	considered	significant.	Data	
                                                                                                            3.4
were	analyzed	with	SPSS	for	Windows	version	17.0.

Results
                                               	
During	the	study	period	224	sudden	death	victims	aged	1-44	years	were	registered	by	
                                                       	
the	public	health	services.	152	(68%)	sudden	death	victims	died	out-of-hospital.	Mean	
                                               	
age	was	34	years	(range	1-44)	and	52	(23%)	victims	were	female	(table	1).	




                                                                                                      97
Chapter 3.4


Table 1.	 Characteristics	 of	 sudden	 death	 victims	 1-44	 years	 that	 were	 registered	 by	 the	 public	
health services, 2006-2008

Variable                                                               N	=	224	
Female	(%)                                                             52	(23)
Mean	age,	years	(±SD*)                                                 34	(24-44)
Deceased	in-hospital	(%)                                               72	(32)
Cardiopulmonary	resuscitation	(%)                                      99	(44)		
Circumstances	of	sudden	decease	known	(%)                              177	(79)
             -       Rest/sleep	(%)                                       135	(76)
             -       Physical	activity	(%)                                19	(11)
             -       Emotion	(%)                                          12	(7)
             -       Other	(%)                                            11	(6)
Relevant	medical	comorbidities	known	(%)	                              192	(86)
         -       None	(%)                                                 55	(29)
         -       Yes	(%)                                                  137	(71)
                 -     Alcohol-/drugs	abuse	(%)                             54	(39)
                 -     Psychiatric	medical	history	(%)	                     38	(28)
                 -     Epilepsy	(%)                                         21	(15)
                 -     Physically	disabled/	muscular	disease	(%)            14	(10)
                 -     Diabetes	mellitus	(%)                                14	(10)
                 -     Other	cardiac	medical	history	(%)	                   10	(7)
                 -     Infection	(%)                                        6	(4)
                 -     Congenital	cor	vitium	(%)                            5	(4)
                 -     Heart	surgery	(%)                                    3	(2)
                 -     Malignancy	(%)                                       2	(1)
Acute	preceding	symptoms 	known	(%)     1
                                                                       51	(23)
     -           None	(%)                                                 7	(14)
     -           Yes	(%)                                                  44	(86)
Clinical	autopsy	(%)                                                   48	(21)
N	=	number	of	cases,	SD*	=	standard	deviation			1	collapse,	dyspnoea,	chest	pain,	nausea	en	headache




98
                              SCD, autopsy rate and characteristics associated with the performance of autopsy


Clinical	autopsy	was	performed	in	48	of	224	cases	(21%	(95%	CI;	16%-27%)).	In	33	(69%)	
                           	
of	the	48	sudden	death	victims	in	whom	autopsy	was	performed	a	cardiac	cause	of	death	
was	established,	in	10	(21%)	a	non-cardiac	cause	of	death	was	established	and	in	5	(10%)	
                         	                       	
no	structural	abnormalities	were	found,	suggesting	an	(inherited)	arrhythmic	cause	of	
death	(table	2).	

Table 2. Causes	of	sudden	death	in	victims	1-44	years,	established	by	post-mortem	investigation
                                       	                                                	 	

         	
Autopsy	findings                                                N	=	48         %          Number	of	cases	with	
                                                                                          probable	inherited	
                                                                                          cardiac diseases
Cardiac causes                                                  33             69
                     	                       	
   Myocardial	infarction	due	to	atherosclerotic	                11*            23         11
   coronary artery disease
             	
   Myocarditis	                                                 6              13
            	
   Hypertrofic	cardiomyopathy                                   4*             8          4
   LVH	with	ischemia                                            3*             6          3
       	         	
   Aortic	dissection	(type	A)                                   2*             4          2
   Aritmogenic	right	ventricular	cardiomyopathy		               1*             2          1
             	
   Endocarditis	                                                1              2
   Other1                                                       5*             15         5
No	structural	abnormalities2
                        	                                       5*             10         4                               3.4
Non cardiac causes                                              10             21
   Pulmonary	embolism        3
                                                                3              6
   Intracranial hemorrhage                                      2              4
   Other	(non-cardiac)	causes       4
                                                                5              10
                                                                                                           	
N	=	number	of	cases	*	An	inherited	cardiac	disease	was	suspected	or	could	not	be	excluded	in	30	patients,	based	
                                                     	                                     	
on	autopsy	data	and	medical	history	(including	patients	in	whom	myocardial	infarction	due	to	atherosclerotic	       	
coronary	artery	disease	was	diagnosed)
1
                                                                                                                  	
  Coronary	 anomaly,	 stricture	 pacemaker	 (congenital	 heart	 block),	 heart	 failure	 (not	 further	 specified),	
        	                                        	         	           	
conduction	system	disease	(not	further	specified),	aortic	coarctation	with	LVH	and	old	infarction    	
2
          	
  One	victim	with	severe	epilepsy
3
  Non-cardiac	 inherited	 diseases	 (e.g.	 thrombophilias	 due	 to	 factor	 V	 Leiden)	 might	 underlie	 an	 pulmonary	
embolism	at	young	age
4
            	                    	                                                 		
  Analfylactic	 shock,	 peritonitis	 (due	 to	 appendiceal	 rupture),	 pancreatitis,	 pneumonia,	 metachromatic	    	
leukodystrophy




                                                                                                                   99
Chapter 3.4


The	most	common	cardiac	causes	were	myocardial	infarction	(n	=11),	myocarditis	(n	=	6)	
and	hypertrophic	cardiomyopathy	(n	=	4).	In	total	30	(63%)	cases	were	due	to	possible	or	
certain	inherited	cardiac	diseases.	The	most	common	non-cardiac	causes	of	death	were	
pulmonary	embolism	(n	=	3)	and	intracranial	hemorrhage	(n	=	2).		
Unadjusted	 analysis	 showed	 that	 the	 autopsy	 rate	 was	 significantly	 higher	 in	 female	
sudden	death	victims	(crude	OR	=	2.2		(95%	CI;	1.1-4.4)).The	autopsy	rate	of	victims	that	
died	 in-hospital	 was	 higher	 than	 the	 autopsy	 rate	 of	 victims	 that	 died	 out-of-hospital	
(38%	vs	14%,	crude	OR	=	3.7	(95%	CI;	1.9-7.3).	In	addition,	autopsy	rates	were	higher	
when	cardiopulmonary	resuscitation	had	been	performed	(crude	OR	=	5.4	(95%	CI;	2.6-
11.1))	or	when	the	victim	did	not	have	relevant	comorbidities	(crude	OR	=	3.5	(95%	CI;	
1.7-7.1))	(table	3).	Multivariate	logistic	regression	analysis	revealed	that	two	variables	
were	significantly	associated	with	the	performance	of	clinical	autopsy;	cardiopulmonary	
resuscitation	 (adjusted	 OR	 =	 3.7	 (95%	 CI;	 1.5-9.5))	 and	 the	 absence	 of	 relevant	
comorbidities	(adjusted	OR	=	3.1	(95%	CI;	1.4-6.8))	(table	3).	


Discussion
This	 study	 shows	 that	 in	 only	 21%	 (95%	 CI;	 16%-27%)	 of	 sudden	 death	 victims	 aged	
1-44	 years	 in	 the	 Netherlands	 that	 were	 investigated	 by	 a	 coroner,	 a	 clinical	 autopsy	
was	performed.	The	autopsy	rate	was	significantly	higher	in	resuscitated	sudden	death	
victims	and	in	victims	without	relevant	comorbidities.	
The	low	autopsy	rate	in	sudden	death	victims	in	the	Netherlands	may	have	consequences	
for	the	detection	of	inherited	(cardiac)	diseases.	In	69%	of	the	sudden	death	victims	in	
whom	autopsy	was	performed,	a	structural	cardiac	disease	was	established	and	in	63%	of	
the	cases	an	inherited	cardiac	disease	was	diagnosed	or	considered	possible.	The	results	
of	previous	clinico-pathological	studies	show	that	in	approximately	70%	of	young	SCD	
victims,	structural	cardiac	diseases	can	be	diagnosed	of	which	the	majority	is	possibly	
inheritable.9,10	A	recent	study	in	patients	aged	1-50	years	who	survived	a	cardiac	arrest	
demonstrated	an	inherited	cardiac	disease	in	45%	(31/69)	of	the	patients.1 Furthermore,
the	cardiogenetic	screening	of	140	families	of	sudden	unexplained	death	victims	(aged	
1-50	years)	yielded	an	inherited	cardiac	disease	in	47	(33%)	families.1 Thus, increasing
the	autopsy	rate	of	sudden	death	victims	will	probably	lead	to	increased	detection	of	
inherited	(cardiac)	diseases	in	family	members	of	the	victims.
Apart	 from	 the	 relevance	 of	 identifying	 inherited	 (cardiac)	 diseases	 for	 the	 families	
involved,	the	results	of	autopsy	might	have	more	benefits.	It	has	been	demonstrated	that	
an	autopsy	can	decrease	feelings	of	guilt	or	doubts	considering	the	medical	treatment	in	
surviving	relatives.	In	addition,	knowing	the	cause	of	death	will	help	in	the	grief	process	
of the survivors of deceased.11


100
                                   	             	                                     	
      Tabel 3. Univariate	and	multivariate	logistic	regression	analysis	of	characteristics	that	relate	to	the	performance	of	a	clinical	autopsy,	crude	and	
                       	                                	
      adjusted	odds	ratios	and	corresponding	95%	confidence	intervals	(95%	CI)

      Characteristics
                  	                       Autopsy	         No	autopsy	         Crude	odds	ratio	
                                                                                              	                 p-value   Adjusted	odds	ratio	
                                                                                                                                           	     p-value
                                          N	=	48           N	=	176             (95%	CI)                                   (95%	CI)
      Female	(%)                          17	(35)          35	(20)             2.21	(1.10-4.44)                 0.03      2.18	(0.98–4.83)       0.06
      Age	in	years	(mean,	±SD*)           31	(12)          35	(9)              0.97	(0.94-1.00)                 0.06      0.99	(0.96–1.02)       0.60
      Deceased	in-hospital	(%)            27	(56)          45	(26)             3.74	(1.93-7.27)                 <0.01     1.51	(0.62-3.66)       0.36
      Cardiopulmonary	                    36	(75)          63	(36)             5.38	(2.61-11.10)                <0.01     3.67	(1.46-9.25)       <0.01
                	
      resuscitation	(%)
                          	
      Relevant	comorbidities*
      Absent	(%)                          22	(40)          33	(19)             3.48	(1.72-7.06)                 <0.01     3.13	(1.44-6.79)       <0.01
      Unknown	(%)                         4	(8)            28	(16)             0.75	(0.24-2.34)                 0.62      0.70	(0.21-2.33)       0.56
                                                           	                                              	
      *	Reference	category:	presence	of	relevant	comorbidities,	N	=	number	of	cases,	SD*	=	standard	deviation
                                                                                                                                                              SCD, autopsy rate and characteristics associated with the performance of autopsy




101
                                                                                 3.4
Chapter 3.4


We	 observed	 a	 higher	 percentage	 of	 autopsies	 in	 patients	 without	 relevant	
comorbidities.	This	observation	is	understandable,	because	the	victims’	comorbidities	
might	 be	 a	 possible	 explanation	 for	 the	 victim’s	 death.	 However,	 the	 presence	 of	
relevant	comorbidities	does	not	exclude	the	presence	of	an	inherited	cardiac	disease.	
The	use	of	certain	medications	or	fever	may	trigger	fatal	arrhythmias	in	inherited	cardiac	
diseases	 like	 long-QT	 syndrome	 and	 Brugada	 syndrome.12	 Thus,	 also	 in	 patients	 with	
comorbidities,	performing	an	autopsy	can	add	in	the	detection	rate	of	inherited	(cardiac)	
diseases.
The	 autopsy	 rate	 in	 sudden	 death	 victims	 differs	 between	 countries,	 because	 the	
usual	care	after	the	sudden	unexplained	decease	of	a	young	person	is	different	among	
countries.	In	England,	all	unexplained	deaths	are	investigated	by	a	coroner,	who	is	a	legal	
expert.	 The	 coroner	 can	 decide	 whether	 an	 autopsy	 should	 be	 performed.13,14 In the
United	States,	the	treating	physician	is	only	allowed	to	complete	the	death	certificate	
when	 a	 natural	 death	 is	 stated.	 In	 all	 remaining	 cases	 the	 coroner	 is	 the	 professional	
who	should	inspect	the	corpse	and	decide	whether	an	autopsy	should	be	performed.14
The	overall	autopsy	rate	in	the	United	States	in	the	general	population	was	8.3%.15 In
Sweden,	 Norway,	 Finland	 and	 Denmark,	 all	 sudden	 unexpected	 deaths	 are	 reported	
to	 the	 police	 for	 medico-legal	 investigation.16	 In	 Sweden,	 autopsy	 is	 performed	 in	 the	
majority	of	unwitnessed	deaths.17
The	low	autopsy	rate	in	the	Netherlands,	especially	among	the	out-of-hospital	sudden	
death	victims,	can	be	explained	by	several	factors.	In	the	first	place,	unawareness	that	
finding	 an	 inherited	 cardiac	 disease	 with	 autopsy	 might	 have	 consequences	 for	 the	
relatives	 involved.	 Secondly,	 unclear	 logistics	 and	 emotional	 resistance	 to	 requesting	
an	 autopsy	 in	 treating	 physicians	 may	 contribute.18	 A	 third	 explanation	 could	 be	 the	
financial	barriers.	After	a	person	is	declared	death,	the	victim’s	health	insurance	ceases	
immediately.	Costs	of	transportation	to	a	hospital	and	mortuary	costs	are	therefore	not	
reimbursed	and	need	to	be	paid	by	surviving	relatives.19	The	costs	of	autopsy	are	currently	
incurred	by	the	pathology	departments	or	by	the	hospitals,	without	any	reimbursement.	
For	victims	of	sudden	unexplained	death	less	than	18-year	old,	a	new	procedure	(Nader	
Onderzoek	DoodsOorzaak	(NODO)	procedure)	will	be	introduced	in	the	Netherlands.	This	
procedure	 involves	 collaboration	 between	 a	 pediatrician,	 a	 pathologist	 and	 a	 coroner	
who	together	will	investigate	the	cause	of	death.20	The	primary	purpose	of	the	NODO	
procedure	 is	 to	 identify	 the	 causes	 of	 death	 in	 the	 young	 and	 to	 exclude	 non-natural	
causes	of	death	(e.g.	death	due	to	child	abuse).	We	expect	that	the	NODO	procedure	will	
also	lead	to	an	increased	autopsy	rate	in	the	pediatric	population,	which	might	result	in	
an	increased	detection	of	inherited	cardiac	diseases.	
A	 limitation	 of	 the	 present	 study	 is	 that	 information	 on	 the	 performance	 of	 judicial	
autopsies	was	not	available	over	this	period.	We	expect	that	a	judicial	autopsy	is	more	
often	performed	in	cases	of	unwitnessed	out-of-hospital	death	which	might	lead	to	a	

102
                        SCD, autopsy rate and characteristics associated with the performance of autopsy


                                                            	
decline	 of	 clinical	 autopsies	 performed	 in	 these	 victims.	 When	 summing	 the	 clinical	
                                   	
autopsy	rate	(21%)	and	the	estimated	judicial	autopsy	rate	(5%,	based	on	unpublished	
                                                         	
data	 over	 the	 period	 2008-2009	 in	 which	 information	 from	 the	 Netherlands	 Forensic	
    	                                                                                 	
Institute	was	available)	the	total	autopsy	rate	is	approximately	26%	in	young	victims	of	
sudden	death.	Furthermore,	some	factors	(e.g.	gender)	might	have	shown	no	significant	  	
         	
association	in	the	current	study	because	of	a	limited	sample	size.	With	a	larger	number	
of	cases,	more	factors	that	probably	relate	to	autopsy	can	be	studied.
In	conclusion,	clinical	autopsy	is	currently	performed	in	a	minority	of	young	sudden	death	
    	
victims	in	the	Netherlands	and	therefore	inherited	cardiac	diseases	remain	undetected.	
                                           	                               	              	
The	clinical	autopsy	rate	is	higher	in	victims	without	relevant	comorbidities	and	in	victims	
                                         	
in	whom	cardiopulmonary	resuscitation	is	performed.	We	expect	that	the	autopsy	rate	
will	increase	not	only	by	emphasizing	the	importance	of	autopsy	to	physicians,	coroners	
                                                             	
and	the	lay	public,	but	also	by	improvement	of	logistics	and	the	removal	of	currently	
      	    	                                                                               	
existing	financial	barriers.	These	measures	will	lead	to	higher	autopsy	rates	and	resulting	
                	
higher	detection	rates	of	inherited	cardiac	diseases	among	families.




                                                                                                           3.4




                                                                                                    103
Chapter 3.4


References
(1)	 van	der	Werf	C,	Hofman	N,	Tan	HL,	van	Dessel	PF,	Alders	M,	van	der	Wal	AC	et	al.	Diagnostic	
     yield	in	sudden	unexplained	death	and	aborted	cardiac	arrest	in	the	young:	The	experience	of	
     a	tertiary	referral	center	in	The	Netherlands.	Heart Rhythm 2010;7:1383-1389.
(2)	 Drory	Y,	Turetz	Y,	Hiss	Y,	Lev B, Fisman	EZ, Pines A	et	al.	Sudden	unexpected	death	in	persons	
     less than 40 years of age. Am J Cardiol 1991;68:1388-1392.
(3)	 Amital	 H,	 Glikson	 M,	 Burstein	 M,	 Afek	 A,	 Sinnreich	 R,	 Weiss	 Yet	 al.	 Clinical	 characteristics	
     of	 unexpected	 death	 among	 young	 enlisted	 military	 personnel:	 results	 of	 a	 three-decade	
     retrospective	surveillance.	Chest 2004;126:528-533.
(4)	 Priori	 SG,	 Barhanin	 J,	 Hauer	 RN,	 Haverkamp	 W, Jongsma	 HJ, Kleber	 AG	 et	 al.	 Genetic	 and	
     molecular	 basis	 of	 cardiac	 arrhythmias:	 impact	 on	 clinical	 management	 parts	 I	 and	 II.	
     Circulation 1999;99:518-528.
(5)	 Wabeke	E.	Weinig	obducties	bij	thuis	overledenen.	Verslag	van	een	enquête.	Medisch Contact
     1988; 43:1457-1458.
(6)	 Casparie	M,	Tiebosch	AT,	Burger	G,	Blauwgeers	H, van de Pol A, van	Krieken	JH et al. Pathology
     databanking	 and	 biobanking	 in	 The	 Netherlands,	 a	 central	 role	 for	 PALGA,	 the	 nationwide	
     histopathology	and	cytopathology	data	network	and	archive.	Cell Oncol 2007;29:19-24.
(7)	 Hendrix	A.,	van	der	Werf	C,	Bots	ML,	Birnie	E, van	der	Smagt	JJ, Borleffs	CJ	et	al.	Rationale	and	
     design	of	the	CAREFUL	study,	the	yield	of	cardiogenetic	screening	in	first	degree	relatives	of	
     sudden	cardiac	and	unexplained	death	victims	<45	years.	Neth Heart J 2010;18:286-290.
(8)	 Hua	W,	Zhang	LF,	Wu	YF	et	al.	Incidence	of	sudden	cardiac	death	in	China:	analysis	of	4	regional	
     populations.	J Am Coll Cardiol 2009;54:1110-1118.
(9)	 van	der	Werf	C,	van	Langen	IM	Wilde	AA.	Sudden	death	in	the	young:	what	do	we	know	about	
     it	and	how	to	prevent?	Circ Arrhythm Electrophysiol 2010;3:96-104.
(10)	Vaartjes	 I,	 Hendrix	 A,	 Hertogh	 EM,	 Grobbee	 DE, Doevendans PA, Mosterd A et al. Sudden
     death	in	persons	younger	than	40	years	of	age:	incidence	and	causes.	Eur J Cardiovasc Prev
     Rehabil 2009;16:592-596.
(11)	Oppewal	F,	Meyboom-de	JB.	Family	members’	experiences	of	autopsy.	Fam Pract 2001;18:304-
     308.
(12)	Kaufman	 ES.	 Mechanisms	 and	 clinical	 management	 of	 inherited	 channelopathies:	 long	 QT	
     syndrome,	Brugada	syndrome,	catecholaminergic	polymorphic	ventricular	tachycardia,	and	
     short	QT	syndrome.	Heart Rhythm 2009;6:S51-S55.
(13)	Bowker	TJ,	Wood	DA,	Davies	MJ,	Sheppard	MN,	Cary	NR,	Burton	JD	et	al.	Sudden,	unexpected	
     cardiac	or	unexplained	death	in	England:	a	national	survey.	QJM 2003;96:269-279.
(14)	Das	C,	van	der	Wal	G.	The	role	of	physicians	in	the	case	of	death,	and	professional	secrecy	in	the	
     Netherlands,	Belgium,	Germany,	England	and	the	US.	Ned Tijdschr Geneeskd 2002;146:2044-
     2047.
(15)	Nemetz	PN,	Tanglos	E,	Sands	LP,	Fisher	WP,	Jr.,	Newman	WP,	III,	Burton	EC.	Attitudes	toward	
     the	autopsy—an	8-state	survey.	MedGenMed 2006;8:80.
(16)	Saukko	P.	Medicolegal	investigative	system	and	sudden	death	in	Scandinavia.	Nihon Hoigaku
     Zasshi 1995;49:458-465.
(17)	Wisten	A,	Forsberg	H,	Krantz	P,	Messner	T.	Sudden	cardiac	death	in	15-35-year	olds	in	Sweden	
     during 1992-99.J Intern Med 2002;252:529-536.
(18)	Oppewal	F,	Meyboom-de	JB.	Issues	involved	in	Dutch	general	practitioners’	failure	to	request	
     autopsy:	report	from	three	focus	groups.	Ned Tijdschr Geneeskd 2003;147:1315-1318.
(19)	van	Zwieten.	Sparen	voor	obductie.	Medisch Contact 2006;61:1418-141.
(20)	Tiessen	 JJ.	 Doodsoorzaak	 onbekend,	 gemeentelijk	 lijkschouwer	 standaard	 inschakelen	 bij	
     overleden kinderen. Medisch Contact 2007;62:70-7.


104
Chapter   4
   Consequences
                                     Chapter	4.1

Cardiogenetic	screening	of	first-degree	relatives	
       after	sudden	cardiac	death	in	the	young:	
                  a	population	based	approach
Chapter 4.1


Abstract	
Background:	 Previous	 studies	 on	 cardiogenetic	 screening	 of	 first-degree	 relatives	 of	
sudden	 death	 victims	 were	 carried	 out	 in	 tertiary	 referral	 centers	 with	 a	 selection	 of	
sudden	unexplained	death	(SUD)	victims.	The	purpose	of	this	study	is	to	investigate	the	
yield	of	cardiogenetic	screening	of	first-degree	relatives	of	young	sudden	cardiac	death	
(SCD)	and	SUD	victims	in	a	population	based	setting.	

Methods: A	population	based	study	carried	out	between	2000	and	2006	in	the	region	
adhering	 to	 the	 Meander	 Medical	 Center	 in	 Amersfoort,	 the	 Netherlands.	 Records	 of	
the	 hospital,	 death	 declaration	 certificates	 and	 resuscitation	 records	 were	 reviewed	
for	SCD	and	SUD	cases	(1-40	years).	Information	on	autopsy	results	and	cardiogenetic	
screening	of	the	victims’	first-degree	relatives	was	collected.	Relatives	were	invited	for	
additional	 cardiogenetic	 screening	 when	 this	 had	 not	 yet	 been	 performed	 in	 routine	
clinical	practice.

Results:	The	search	led	to	16	cases	of	SCD	and	SUD	and	four	cases	of	aborted	SCD	and	
SUD.	 Autopsy	 was	 performed	 in	 11	 of	 16	 SCD	 and	 SUD	 victims.	 Causes	 of	 SCD	 were	
myocardial	 infarction	 (n	 =	 3),	 arrhythmogenic	 right	 ventricular	 cardiomyopathy	 (n	
=	 2),	 long-QT	 syndrome	 (n	 =	 1),	 hypertrophic	 cardiomyopathy	 (n	 =	 2),	 left	 ventricular	
hypertrophy	due	to	aortic	stenosis	(n	=	1)	and	unknown	cause	of	death	(n	=	7).	Causes	
of	 aborted	 SCD	 were	 myocardial	 infarction	 (n	 =	 2),	 idiopatic	 ventricular	 fibrillation	 (n	
=	1)	and	Brugada	syndrome	(n	=	1).	The	cardiogenetic	screening	of	37	relatives	of	12	
victims	led	to	a	diagnosis	of	Brugada	syndrome	in	three	relatives	and	a	high	probability	
of	arrhythmogenic	right	ventricular	cardiomyopathy	in	two	relatives.	The	total	yield	of	
screening	 of	 these	 surviving	 first-degree	 relatives	 was	 14%	 (95%	 confidence	 interval;	
3%-25%).

Conclusion:	In	routine	clinical	practice,	the	first-degree	relatives	of	(aborted)	SCD	and	
SUD	victims	are	often	not	referred	for	cardiogenetic	screening.	Screening	is	often	not	
performed	 according	 to	 a	 systematic	 approach	 and	 the	 detection	 rate	 of	 inherited	
diseases	 in	 relatives	 of	 (aborted)	 SCD	 and	 SUD	 victims	 in	 a	 population	 based	 setting,	
although	substantial,	is	lower	than	expected	based	on	previous	studies.




108
                   Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young


         	
Introduction	
Sudden	cardiac	death	(SCD)	and	sudden	unexplained	death	(SUD)	before	the	age	of	40	
                   	                                                                     	
years	are	often	caused	by	an	inherited	cardiac	disease.1,2	Structural	abnormalities	of	the	
heart	or	primary	arrhythmia	syndromes	can	cause	fatal	arrhythmias	that	may	lead	to	
                         	                                             	
sudden	death.	Relatives	of	young	(aborted)	SCD	and	SUD	victims	have	an	increased	risk	
of carrying an inherited cardiovascular disease. Since most inherited cardiac diseases
                                                         3-9

                                        	                                     	
show	an	autosomal	dominant	pattern	of	inheritance	and	de	novo	mutations	are	relatively	       	
         	                  	         	
rare,	first-degree	relatives	of	victims	with	diagnosed	inherited	cardiac	disease	have	a	50%	
                                           	
risk	 of	 having	 the	 same	 predisposition.10,11 Furthermore, an inherited cardiac disease
                                                                 	
could	be	detected	in	22-53%	of	the	families	of	SUD	victims.3-6 As sudden cardiac arrest
                       	        	                                                          		 	
in	the	young	is	often	the	first	‘symptom’	of	inherited	cardiac	disease,	early	identification	
        		cult	 in	 apparently	 healthy	 individuals. 	 Timely	 detection	 of	 inherited	 cardiac	
is	 diffi                                            12-14
                                                                         	
diseases	may	help	to	prevent	SCD	through	life	style	advices,	risk	factor	management,	
                                                             	             	
medical	treatment	or	device	implant.	Pre-symptomatic	cardiogenetic	screening	of	high	
                                                               	                	
risk	 groups	 has	 been	 proposed,	 aiming	 primarily	 at	 first-degree	 relatives	 of	 SCD	 and	
             	                                      	                	                	
SUD	victims.	Previous	studies	on	cardiogenetic	screening	of	first-degree	relatives	of	SUD	
     	                                	                                    	
victims	were	carried	out	in	tertiary	referral	centers	with	an	expertise	in	cardiogenetic	       	
                              	                                                 	
diseases. 	No	information	is	available	about	the	yield	of	cardiogenetic	screening	in	a	
               3-6

           	
population	based	setti                               	
                           		ng	without	prior	selection	of	SCD	and	SUD	cases.	
                                                         	
The	purpose	of	the	current	study	was	to	investigate	the	causes	of	death	of	unselected	
     	                                                                 	               	
victims	of	(aborted)	SCD	and	SUD	and	the	yield	of	cardiogenetic	screening	in	first-degree	
       	             	                                             	
relatives	of	victims	of	(aborted)	SCD	and	SUD	in	a	population	based	setti      		ng.	
                                                                                                               4.1
Methods
Definitions
                                         	
Sudden	cardiac	death	(SCD)	was	defined	as	sudden	death	caused	by	any	cardiac	disease	
                     	
within	 24	 hour	 after	 the	 onset	 of	 symptoms.15 Sudden	 unexplained	 death	 (SUD)	 was	
    	
defined	 as	 sudden	 death	 in	 which	 no	 cause	 could	 be	 established	 based	 on	 clinical	
 	
findings	 and/or	 autopsy.	 All	 survivors	 of	 cardiac	 arrest	 that	 died	 at	 the	 intensive	 care	
        	                             	
unit	 after	 a	 successful	 resuscitation	 because	 of	 irreversible	 damage	 (e.g.	 brain	 death)	
                                 	 	                      	
were	included	in	the	SCD	definition.	Autopsy-negative	sudden	death	was	defined	as	SUD	   	
                             	
in	 which	 no	 abnormalities	 were	 established	 by	 autopsy.16	 Aborted	 cardiac	 death	 was	
    	                                                       	
defined	as	sudden	cardiac	arrest	within	24	hour	after	the	onset	of	symptoms	that	was	
aborted	by	cardiopulmonary	resuscitation.		 	




                                                                                                        109
Chapter 4.1


Diagnostic criteria
The	Schwartz	score	was	used	for	diagnosing	the	long-QT	syndrome.17 Arrhythmogenic
right	ventricular	cardiomyopathy	(ARVC)	was	diagnosed	according	to	the	definition	of	
the	International	Task	Force	of	the	European	Society	of	Cardiology	and	the	International	
Society	 and	 Federation	 of	 Cardiology.18 Standard	 diagnostic	 criteria	 for	 the	 Brugada	
syndrome	were	used.19	Idiopathic	ventricular	fibrillation	was	diagnosed	when	following	
a	cardiac	arrest	no	structural	heart	disease	could	be	found	with	extensive	cardiologic	
screening.20	 Autosomal	 dominant	 hypercholesterolemia	 was	 diagnosed	 by	 using	
generally	accepted	criteria.11
All	DNA	tests	related	to	this	study	were	carried	out	at	the	department	of	cardiogenetics	
of	the	Academic	Medical	Center,	Amsterdam	or	the	University	Mecical	Center	Utrecht,	
following	consultation	of	their	cardiogenetic	team.

Identification of SCD victims and their relatives
The	 study	 was	 carried	 out	 between	 2000	 and	 2006	 in	 the	 region	 adhering	 to	 the	
Meander	Medical	Center	in	Amersfoort,	the	Netherlands.	This	region	covers	3%	of	the	
total	 Dutch	 population	 of	 1-40	 years	 and	 counts	 approximately	 239,000	 inhabitants	
between	 1-40	 years	 of	 age (Statistics	 Netherlands,	 Den	 Haag).	 The	 Meander	 Medical	
Center,	 a	 large	 regional	 teaching	 hospital,	 is	 the	 only	 hospital	 in	 this	 area	 fulfilling	 a	
central	role	in	medical	care.	Records	of	the	hospital,	death	declaration	certificates	of	the	
public	health	services	and	the	resuscitation	reports	of	the	emergency	medical	services	
were	systematically	searched	for	(aborted)	SCD	and	SUD	victims	aged	1-40	years.	When	
necessary,	 additional	 information	 of	 general	 practitioners	 or	 other	 regional	 hospitals	
was	used	to	identify	cases.	

Collection of information of SCD and SUD victims and their first-degree relatives
Demographic	 information	 of	 (aborted)	 SCD	 and	 SUD	 victims	 was	 collected	 as	 well	 as	
information	on	the	circumstances	of	death.	For	each	victim,	it	was	determined	if	post-
mortem	 investigation	 (clinical	 examination	 and/or	 autopsy)	 had	 been	 performed	 and	
if	 the	 cause	 of	 death	 or	 cardiac	 arrest	 had	 been	 reported.	 Subsequently,	 the	 general	
practitioner	of	each	(aborted)	SCD	and	SUD	victim	was	approached	to	assess	whether	
first-degree	 relatives	 had	 been	 referred	 for	 cardiogenetic	 screening.	 First-degree	
relatives	 in	 whom	 no	 cardiogenetic	 screening	 had	 been	 performed	 in	 routine	 clinical	
care	following	the	index	event	were	invited	by	the	researchers	(A.H.,	J.J.vd.S.	and	A.M.)	
for	 screening	 in	 an	 outpatient	 cardiogenetics	 setting.	 The	 study	 was	 approved	 by	 the	
Institutional	 Medical	 Ethical	 Committee	 in	 Nieuwegein,	 the	 Netherlands.	 All	 patients	
who	 underwent	 additional	 cardiogenetic	 screening	 signed	 informed	 consent,	 prior	 to	
study	participation.


110
                   Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young


Cardiogenetic screening of first-degree relatives
            	                     	                     	
The	 additional	 cardiogenetic	 screening	 of	 relatives	 was	 guided	 by	 the	 post-mortem	
                                          	                                                  	
diagnosis	 of	 the	 SCD	 and	 SUD	 victim	 or	 results	 from	 (previous)	 clinical	 evaluation	 of	
                           	                                                      	
the	(aborted)	SCD	victim.	In	general,	three	scenarios	for	the	cardiogenetic	screening	of	
 	                   	                                  	                	
first-degree	relatives	of	young	SCD	and	SUD	victims	were	distinguished;	a)	a	causative	        	
        	                                   	          		                              	
mutation	 in	 the	 (aborted)	 SCD	 victim	 is	 identified	 (which	 is	 rare	 in	 routine	 clinical	
      	                                                                	
practice;	b)	an	inherited	cardiac	disease	is	suspected	in	the	victim,	but	not	established	by	
       	       	                              	
genetic	testing;	c)	the	cause	of	the	victim’s	(aborted)	death	is	unknown	(with	or	without	
                   	 	
autopsy	investigation).	Scenario	a)	allowed	for	a	targeted	approach	by	genetic	testing	  	     	
                                                                   	
(when	indicated)	and/or	cardiologic	screening	of	mutation	carriers.21	In	scenario	b)	the	
                   	                   	
post-mortem	findings	in	the	victim	raise	the	suspicion	of	an	inherited	cardiac	disease.	
                     	                                                       	
Based	on	these	findings,	targeted	cardiologic	screening	of	the	relatives	was	performed	
                                                  	          	                       	
(e.g.	electro-	and	echocardiography	in	relatives	of	victims	diagnosed	with	left	ventricular	
hypertrophy).	In	scenario	c)	the	cause	of	death	was	unknown	and	no	clues	were	available	
              	                                                            	
for	a	specific	diagnosis.	For	these	cases,	a	cardiologic	examination	of	the	relatives	was	 	
                                                                       	
performed	 that	 included	 medical	 history,	 physical	 examination	 and	 standard	 resting	   	
12	lead	electrocardiogram	and	one	or	more	of	the	following	aspects;	1)	transthoracic	
                                                               	
echocardiography;	2)	Holter	recording;	3)	exercise	testing	and	4)	measurement	of	serum	
                                	                                      	            	 	
lipid	 levels.	 At	 the	 discretion	 of	 the	 study	 physicians	 additional	 investigations	 were	
                                                 	                    	
performed,	including	pharmacological	testing	(e.g.	ajmaline/flecainide),	cardiac	MRI,	or	
       	       	
genetic	testing.3-6
                 	                   	                           	
Cardiogenetic	screening	of	relatives	of	aborted	SCD	victims	was	guided	by	the	underlying	
cause	of	the	cardiac	arrest	in	the	aborted	SCD	victim.    	
                                                                                                               4.1
Data analysis
                                                                   	
Data	 were	 analyzed	 in	 SPSS	 14.0	 for	 Windows.	 Incidence	 estimates	 were	 reported	 by	
                                               	
person-years	and	calculated	for	the	population	at	risk	(aged	1-40	years).	

Results
(aborted) SCD and SUD victims
                                              	
During	the	study	period	2000-2006,	20	victims	of	(aborted)	SCD	and	SUD	(1-40	years)	
           		                                                       	
were	identified,	of	which	four	could	be	successfully	resuscitated	(figure	1).
                                                            	
As	such,	the	incidence	of	(aborted)	SCD	and	SUD	(20	victims	during	six	years	(143,400	
person-years))	is	1.4	per	100,000	person-years	(95%	CI;	0.78-2.01)	in	persons	from	1	to	40	
                 	                                      	
years	of	age.	Fifteen	(75%)	(aborted)	SCD	and	SUD	victims	were	men	and	the	mean	age	
was	26	years	(range	1-40).	Symptoms	preceding	a	sudden	cardiac	arrest	were	present	in	
                        	
at	least	25%	of	all	victims	(table	1)	and	four	(20%)	had	a	family	history	of	sudden	death	
              	                           	
<40	years	in	first-or	second	degree	relatives.

                                                                                                        111
Chapter 4.1


Figure 1. Flowcart	of	(aborted)	SCD	and	SUD	victims	and	the	cardiogenetic	screening	of	the	first	
degree	relatives

                                                (Aborted) SCD and SUD victims
                                                              N = 20




                              Aborted cardiac arrest                           SCD and SUD victims
                                       N=4                                               N = 16




 Possible inherited cardiac disease                 No inherited cardiac disease                  Possible inherited cardiac disease
                  N=2                                           N=3                                              N = 15




          Screening                      No screening                            Screening                         No screening
      performed in usual               performed in usual                    performed in usual                  performed in usual
             care                             care                                  care                                care
           1 family                          1 family                               7 families                        8 families




                                      Additional screening                                                      Additional screening
                                           0 families                                                                 4 families




   Brugada syndrome                                                                No diagnosis                ARVC suspected in 1
  diagnosed in 1 family                                                                                         family (2 relatives)
       (3 relatives)




112
                                    	                                   	
      Table 1.	Baseline	characteristics	of	20	(aborted)	SCD	and	SUD	victims,	mean	age	26	years

      Case nr   Index   Gender Circumstances   Medical    Previous       Family      Autopsy      Autopsy	          	
                                                                                                              Genetic	      DNA      Clinical    Inherited
                event                          history   symptoms       history of                findings
                                                                                                   	              	
                                                                                                              testing     diagnosis Diagnosis     disease
                                                                           SCD
         1       SD       M         in a         no      no	reported	       no         yes         ARVC         no           -        ARVC         highly
                                discotheque              complaints                                                                              suspected
         2       SD       M      swimming        no      no	reported	      no          yes        autopsy-   LQT1,	LQT2     no        LQTS1        highly
                                                         complaints                                    	
                                                                                                  negative     LQT3                              suspected
         3       SD       M       physical	      no      no	reported	      no          yes       HCM/ARVC       no           -        ARVC         highly
                                      	
                                   activity              complaints                                                                              suspected
         4       SD       M          in a        no      no	reported	      yes         yes         HCM          no          no        HCM          highly
                                discotheque              complaints                                                                              suspected
         5       SD       M          rest        no       chestpain        yes         yes         HCM          no           -        HCM          highly
                                                                                                                                                 suspected
         6       SD       M         rest         no      no	reported	      yes         yes        autopsy-     SCN5A         no     unknown        highly
                                                         complaints                                    	
                                                                                                  negative                                       suspected
         7       SD       F           	
                                 emotional	      no      no	reported	      yes         yes        autopsy-      no           -      unknown        highly
                                  distress               complaints                                    	
                                                                                                  negative                                       suspected
         8       SD       F         rest         no         fever          no          no            -          no           -      unknown       possible
         9       SD       M       physical	      AS      no	reported	      no          no            -        MYBPC3         -      LVH	(with	   possible
                                     	
                                  activity               complaints                                                                   AS)2
         10      SD       M         rest         no      no	reported	      no          no            -          no           -      unknown      possible
                                                         complaints
         11      SD       F        sleep         no       chestpain        no          yes          MI          no           -         MI        possible
         12      SD       M         rest         no       chestpain     unknown        no            -          no           -      unknown      possible
         13      SD       M       physical	    unknown no	reported	     unknown        yes          MI          no           -         MI        possible
                                     	
                                  activity              complaints
         14      SD       F         rest       collapse no	reported	       no        unknown         -          no           -      unknown      possible
                                                        complaints
                                                                                                                                                             Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young




113
                                                              4.1
114
                                                                                                                                                                              Chapter 4.1




      Table 1 (Continued)

       Case nr   Index   Gender Circumstances       Medical      Previous       Family         Autopsy       Autopsy	       Genetic	     DNA      Clinical      Inherited
                 event                              history     symptoms       history of                    findings       testing    diagnosis Diagnosis       disease
                                                                                  SCD
         15       SD        M        unknown           no         fever        unknown           yes         autopsy-         no           -       unknown      possible
                                                                                                             negative
         16       SD        M           rest           no      no	reported	       no             yes            MI            no           -          MI           no3
                                                               complaints
         17      A SCD      M         physical	        no      no	reported	       no              -              -          SCN5A         yes       Brugada established
                                      activity                 complaints                                                                          syndrome
         18      A SCD      M           rest           no      no	reported	       no              -              -            no                      IVF    possible
                                                               complaints
         19      A SCD      M         physical	        no       chestpain         no              -              -            no                      MI           no3
                                      activity
         20      A SCD      F           rest           no       no	reported	       no               -            -             no                     MI          no3
                                                                 complaints
      SD	=	sudden	death,	A	SCD	=	aborted	SCD,	ARVC	=	arrythmogenic	right	ventricular	cardiomyopathy,	LQTS	=	long-QT	syndrome,	AS	=	aortic	stenosis,	LVH	=	left	ventricular	
      hypertrophy,	HCM	=	hypertrophic	cardiomyopathy,	MI	=	myocardial	infarction,	IVF=	idiopathic	ventricular	fibrillation	1LQTS	diagnosed	based	on	prolonged	QT	interval	
      at	ECG	ante-mortem.	No	mutation	accounting	for	LQTS	could	be	established	by	genetic	testing	for	LQTS1,	LQTS2,	LQTS3. 2Diagnosis	based	on	ante-mortem	transthoracic	
      echocardiography.	3 Defined	as	not	being	‘possible	inherited’,	because	of	normal	lipid	spectrum	measured	prior	to	cardiac	arrest
                   Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young


                                                                    	
Autopsy	was	performed	in	11	of	16	(70%)	SCD	and	SUD	victims.	Causes	of	death	based	
                                                    	 	
on	 post-mortem	 and/or	 ante-mortem	 investigation	 were	 myocardial	 infarction	 (n	 =	   	
3),	ARVC	(n	=	2),	hypertrophic	cardiomyopathy	(n	=	2),	long-QT	syndrome	(n	=	1),	left	             	
                                           	
ventricular	hypertrophy	due	to	aortic	stenosis	(n	=	1)	and	unknown	cause	of	death	(n	
            	
=	 7).	 Left	 ventricular	 hypertrophy was	 demonstrated	 on	 ante-mortem	 transthoracic	
                                  	
echocardiography	 in	 one	 victim	 in	 whom	 no	 autopsy	 was	 performed.	 The	 long-QT	
                                             	
syndrome	was	suspected	in	one	victim	that	died	during	swimming,	based	on	an	ante-
mortem	electrocardiogram	that	showed	a	corrected	QT	interval	of	475	ms	(at	normal	
                                                  	                                       	
body	 temperature).	 However,	 no	 mutation	 could	 be	 established	 with	 genetic	 testing	     	
                        	                        	
(table	1).	In	two	victims,	no	abnormalities	were	found	with	autopsy,	but	an	inherited	
                                                             	
cardiac	disease	was	highly	suspected	based	on	a	positive	family	history	for	SCD	at	young	
age	(<50	years).
                         	                                                    	
Diagnoses	of	the	victims	of	aborted	SCD	were:	myocardial	infarction	(n	=	2),	Brugada-
                                                     	      	
syndrome	 (n	 =	 1)	 and	 idiopathic	 ventricular	 fibrillation	 (n	 =	 1).	 Idiopathic	 ventricular	
 	        	                            	
fibrillation	 was	 diagnosed	 after	 elaborate	 cardiologic	 screening,	 including	 an	
electrocardiography,	 a	 cardiac	 MRI-scan,	 a	 coronary	 angiography	 and	 a	 myocardial	
SPECT-scan.
                      	                                        	 	
Based	on	clinical	findings	 and/or	post-mortem	investigation	(if	available),	in	eight	out	
                                         	
of	20	(aborted)	SCD	and	SUD	victims	an	inherited	cardiac	disease	was	highly	suspected	
                                    	
or	was	established.	In	nine	victims	an	inherited	cardiac	disease	could	not	be	excluded	
                            	                                                                 	
(e.g.	 myocardial	 infarction	 or	 unknown	 cause	 of	 (aborted)	 death).	 In	 three	 victims	 of	
                                               	
(aborted)	SCD	due	to	myocardial	infarction,	serum	lipid	levels	measured	prior	to	cardiac	
                                                        	
arrest	were	normal.	These	three	cases	were	classified	as	being	‘not	inherited’.	In	the	two	
                                                                                                               4.1
              	                                                  	
other	victims	of	(aborted)	SCD	due	to	myocardial	infarction,	serum	lipid	levels	prior	to	
cardiac	arrest	were	unknown.	
        	       	                                                                	
Genetic	testing	had	been	performed	in	four	(aborted)	SCD	and	SUD	victims	and	a	disease	
                  	                  	
causing	mutation	(SCN5A	mutation)	was	found	in	one	aborted	SCD	victim.	           	

Screening of first-degree relatives of (aborted) SCD and SUD victims
              	                   	                	               	
Cardiogenetic	 screening	 of	 first-degree	 relatives	 of	 17	 victims	 (8+9,	 see	 previous	
                                                                                           	
paragraph)	 with	 (possible)	 inherited	 cardiac	 diseases	 was	 performed	 in	 the	 routine	
               	                                                	       	                	
clinical	practice	in	eight	(47%)	families	(table	2).	No	information	on	first-degree	relatives	
                        	
could	be	retrieved	in	five	(29%)	families.	In	the	four	(24%)	remaining	families	of	(aborted)	
                    	                  	
SCD	and	SUD	victims	no	cardiogenetic	screening	had	been	performed	as	part	of	routine	      	
                           	                                 	
clinical	care.	These	relatives	were	invited	for	cardiogenetic	screening	by	the	researchers.	 	
              	                        	                 	
Cardiogenetic	screening	of	29	of	32	first-degree	relatives	of	eight	(aborted)	SCD	and	SUD	
    	              	            	           	                                          	
victims	(3.6	relatives	per	victim)	in	routine	clinical	care	revealed	a	SCN5A	mutation	in	
            	                            	
three	relatives	of	an	aborted	SCD	victim	diagnosed	with	the	Brugada	syndrome.	


                                                                                                        115
      Table 2.	Cardiogenetic	screening	of	relatives	of	17	(aborted)	SCD	and	SUD	victims	with	possible	or	definite	inherited	cardiac	disease




116
       Case Aborted	 Diagnosis      Cardiogenetic	     Diagnostic	tests	     Evaluated	first-      Diagnosis in        Additional	     Diagnostic	test	      Diagnosis in
                                                                                                                                                                                Chapter 4.1



        Nr   SCD/     victim          screening           performed	        degree	relatives1   victims’	relatives	   cardiogenetic	     performed	       victims’	relatives	
             SUD                     relatives	in	     initial	screening	                       initial	screening       screening        additional	          additional	
                                   routine	clinical	        relatives                                                    relatives       screening            screening
                                        care?                                                                                             relatives
        1      SD       ARVC             yes            ECG,	Lab,	TTE,	          (2/2)          no	abnormalities      not indicated           -           no	abnormalities
                                                         X-ECG,	MRI,	
                                                            Holter
        2      SD        LQTS            yes             ECG,	X-ECG             (9/10))         no	abnormalities      not indicated           -           no	abnormalities
        3      SD       ARVC             no                    -                    -                                      yes          ECG,	Lab,	TTE,	   probable	ARVC
                                                                                                                                        X-ECG,	Holter,	
                                                                                                                                             MRI
        4      SD        HCM             yes           ECG,	TTE,	X-ECG           (2/2)          no	abnormalities      not indicated           -                   -
        5      SD        HCM             yes            ECG,	Lab,	TTE            (6/6)          no	abnormalities      not indicated           -                   -
        6      SD      autopsy-          yes              ECG,	Lab,	             (3/3)          no	abnormalities      not indicated           -                   -
                       negative                          TTE,	X-ECG,	
                                                       pharmacological	
                                                         challenging
        7      SD      autopsy-          yes            ECG,	Lab,	TTE,	          (1/2)          no	abnormalities      not indicated           -                   -
                       negative                            X-ECG
        8      SD      unknown           no                    -                    -                                      yes         ECG,	TTE,	Holter   no	abnormalities
                                                                                                                                2
        9      SD     LVH	(with	         yes            ECG,	Lab,	TTE            (1/2)          no	abnormalities          yes           ECG,	Lab,	TTE,	   no	abnormalities
                         AS)                                                                                                            X-ECG,	Holter
        10     SD     unknown            no                    -                    -                                      yes          ECG,	Lab,	TTE,	   no	abnormalities
                                                                                                                                        X-ECG,	Holter
        11     SD         MI             no                    -                    -                                      yes               Lab          no	abnormalities
        12     SD      unknown       unknown                   -                    -               unknown           no	response             -                   -
        13     SD         MI         unknown                   -                    -               unknown           not	possible            -                   -
      Table 2 (Continued)

       Case Aborted	 Diagnosis                      	
                                       Cardiogenetic	                	
                                                          Diagnostic	tests	     Evaluated	first-
                                                                                           	          Diagnosis in               	
                                                                                                                          Additional	               	
                                                                                                                                          Diagnostic	test	      Diagnosis in
        Nr   SCD/         	
                      victim             screening           performed	                    	
                                                                               degree	relatives1   victims’	relatives	
                                                                                                       	         	                    	
                                                                                                                         cardiogenetic	     performed	           	         	
                                                                                                                                                             victims’	relatives	
             SUD                              	
                                        relatives	in	         	
                                                          initial	screening	                       initial	screening
                                                                                                       	                   screening              	
                                                                                                                                            additional	               	
                                                                                                                                                                 additional	
                                           	
                                      routine	clinical	             	
                                                               relatives                                                         	
                                                                                                                            relatives       screening            screening
                                            care?                                                                                                 	
                                                                                                                                             relatives
        14       SD      unknown             no                   -                    -               unknown           not	possible            -                   -
        15       SD       autopsy-       unknown                  -                    -               unknown           not	possible            -                   -
                                	
                          negative
        17     A SCD      Brugada-          yes            ECG,	genetic	
                                                                     	              (5/5)              Brugada           not indicated           -                   -
                         syndrome                                 	
                                                             testing                                  syndrome
        18     A SCD         IVF             no                  -                     -              unknown            not indicated           -                   -
                                                                                                                                               	                    	
      SD		sudden	death,	A	SCD	=	aborted	SCD,	ARVC	=	arrythmogenic	right	ventricular	cardiomyopathy,	LQTS	=	long-QT	syndrome,	AS	=	aortic	stenosis,	LVH	=	left	ventricular	
                                                                                  	                                   	     	
      hypertrophy,	HCM	=	hypertrophic	cardiomyopathy,	MI	=	myocardial	infarction,	IVF	=	idiopathic	ventricular	fibrillation		ECG	=	electrocardiogram,	Lab	=	measurement	
                                                                                        	         	                            	                   	
      of	serum	lipid	levels,	TTE	=	transthoracic	echocardiography,	X-ECG	=	exercise	testing1 Relatives	eligible	for	cardiogenetic	screening.2 Additional	screening,	because	not	
           	                	
      all	first-degree	relatives	were	yet	evaluated
                                                                                                                                                                                   Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young




117
                                                                        4.1
Chapter 4.1


Eight	relatives	of	four	SCD	and	SUD	victims	underwent	cardiogenetic	screening	initiated	
by	this	study.	This	led	to	the	suspicion	ARVC	in	two	relatives	of	a	SCD	victim,	who	was	
diagnosed	 as	 having	 hypertrophic	 cardiomyopathy	 with	 fibro-fatty	 replacement	 at	
autopsy.	Revision	of	the	victim’s	heart	by	a	specialized	cardiac	pathologist	revealed	an	
ARVC-like	histopathology	with	predominantly	left	ventricular	involvement.	

Discussion
To	the	best	of	our	knowledge	this	is	the	first	study	to	assess	the	yield	of	cardiogenetic	
screening	of	first-degree	relatives	of	young	(aborted)	SCD	and	SUD	victims	in	a	population	
based	setting	without	prior	selection	of	SCD	and	SUD	cases.	The	incidence	of	SCD	and	
SUD	was	estimated	to	be	1.1	(95%	CI;	0.6-1.7)	per	100,000	person-years	in	persons	from	
1	to	40	years	of	age	which	is	relatively	similar	to	an	estimate	by	a	previous	study	of	1.6	
per	100,000	person-years1.
Initial	 cardiogenetic	 screening	 of	 relatives	 in	 routine	 care	 was	 performed	 in	 eight	 out	
of	 17	 (47%)	 families	 of	 (aborted)	 SCD	 and	 SUD	 victims	 with	 a	 possible	 or	 established	
inherited	cardiac	disease.	Four	families	underwent	cardiogenetic	screening	initiated	by	
this	study.	Cardiogenetic	screening	of	a	total	of	37	relatives	revealed	a	SCN5A	mutation	
in	three	relatives	and	led	to	the	suspicion	of	ARVC	in	two	relatives.	The	yield	of	screening	
in	the	current	study	is	(5/37	x	100)	14%	(95%	CI;	3%-25%).	These	results	represent	the	
lower	limit	of	potentially	identifiable	cardiogenetic	disorders,	since	not	all	disorders	can	
be	diagnosed	with	certainty	at	this	moment	in	time.		
Although	impressive	in	terms	of	screening,	this	yield	is	lower	than	anticipated	based	on	
information	from	previous	studies.	Recent	studies	performed	in	tertiary	referral	centers	
reported	that	with	thorough	clinical	assessment	of	first-degree	relatives	of	SUD	victims,	
a	cause	of	death	can	be	established	in	22-53%	of	the	families.3-6	A	Dutch	investigation	
of	families	of	43	SUD	victims	of	whom	22	were	autopsied,	found	an	inherited	cardiac	
disease	 in	 47	 of	 102	 (45%)	 evaluated	 first-and	 second	 degree	 relatives.6 In	 England,	
cardiogenetic	screening	of	relatives	of	57	SUD	victims	with	a	negative	autopsy	resulted	
in	a	diagnosis	in	46	of	184	(25%)	relatives.5	A	Canadian	study	reported	that	cardiogenetic	
screening	of	relatives	of	nine	patients	with	unexplained	cardiac	arrest	in	whom	a	disease	
causing	mutation	was	identified,	a	mutation	could	be	established	in	15	of	64	relatives	
(24%).9
The	relatively	low	detection	rate	of	inherited	diseases	among	the	families	of	(aborted)	
SCD	 and	SUD	 victims	in	 the	current	study	 can	 be	partly	explained	 by	the	fact	that	all	
young	victims	of	SCD	and	SUD	with	possible	inherited	diseases	were	included,	in	contrast	
to	former	studies	that	focused	on	(aborted)	SUD	victims.3-6,9 In the current study, three
cases	of	(aborted)	cardiac	death	due	to	myocardial	infarction	were	included,	in	whom	
normal	lipid	levels	prior	to	their	cardiac	arrest	were	measured.	As	such,	the	diagnosis	

118
                      Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young


familiar	 hypercholesterolemia	 was	 considered	 unlikely	 in	 these	 families.	 Another	
                          	                    	
reason	 for	 the	 relatively	 low	 detection	 rate	 of	 inherited	 diseases	 in	 our	 study	 is	 that	
                                                                         	
the	screening	that	was	performed	in	the	usual	care	was	often	not	performed	according	
                  	                                                                      	
to	 a	 systematic	 approach.	 Former	 studies	 were	 performed	 in	 tertiary	 referral	 centers	
                    	                                                            	         	
with	 an	 expertise	 on	 inherited	 cardiac	 diseases	 and	 diagnostic	 testing.	 In	 the	 current	
                    	
study	the	relatives	were	evaluated	primarily	by	a	cardiologist	who	consulted	a	clinical	
         	
geneticist	if	deemed	necessary.	In	only	one	case	the	diagnosis	was	confirmed	by	genetic	      	                 	
     	
testing,	 which	 is	 less	 than	 in	 former	 studies.	 Even	 when	 autopsy	 was	 performed	 in	
    	                                                                        	
victims	of	SCD	and	SUD	(that	included	microscopic	examination	in	all	cases)	a	(genetic)	                      	
diagnosis	could	not	always	be	established	(in	cases	of	autopsy-negative	sudden	death).	    	
                               	                                       	
In	cases	of	autopsy-negative	sudden	death,	the	lack	of	routine	use	of	exercise	testing	and	           	
                            	                                       	
pharmacological	testing	(e.g.	adrenaline,	ajmaline	and	flecainide),	reduced	the	chance	
of	 diagnosing	 primary	 arrhythmia	 syndromes	 like	 CPVT,	 LQTS	 and	 BS	 among	 families.	
                                           	              	 	                    	
Furthermore,	 as	 extensive	 genetic	 investigation	 might	 identify	 mutations	 associated	    	
with	for	example	CPVT	and	LQTS	a	lack	of	molecular	autopsy	in	our	study	consequentely	
  	
affected	the	yield	of	screening.	Recently,	a	standardized	autopsy	protocol	for	victims	of	              	
                                                                   	 	
SCD	has	been	published	to	improve	post-mortem	investigation	of	SCD	and	SUD	victims.22                     	
                                                 	
In	case	of	uncertainty,	review	of	the	findings	by	an	expert	in	cardiac	pathology	may	be	
                        	                             	                        	
useful,	as	exemplified	by	one	of	our	victims.	A	higher	diagnostic	yield	of	autopsies	in	the	
                                                                                 		 	
future	 is	 likely	 to	 translate	 into	 a	 higher	 percentage	 of	 identification	 of	 cardiogenetic	          	
              	         	                    	                                       	
abnormalities	 in	 first-degree	 relatives,	 although	 autopsy-negative	 sudden	 death	 will	
never	 be	 completely	 eliminated	 (e.g.	 in	 case	 of	 primary	 arrhythmia	 syndromes).	 The	
                                                                                       	
results	of	this	study,	together	with	the	rapid	developments	in	the	field	of	cardiogenetics,	                	
                                                                                                                    4.1
the	low	prevalence	of	inherited	cardiac	diseases	and	the	complexity	of	cardiogenetics,	                     	
                      	                            	                       	
support	 the	 notion	 that	 cardiogenetic	 screening	 of	 relatives	 should	 be	 performed	
                                                                                   	
in	 specialized	 centers	 that	 have	 cardiologists,	 clinical-geneticists	 and	 pathologists	
                          	                         	                       	
experienced	in	the	field	of	cardiogenetics.	A	close	collaboration	with	(satellite)	regional	
                                                                      		
hospitals	is	important	for	the	follow-up	of	persons	identified	with	an	inherited	cardiac	
disease.
                                 	                               	
The	study	has	some	limitations,	notably	the	relatively	small	number	(20)	of	(aborted)	SCD	
                	
and	SUD	victims	that	were	registered.	This	is	mainly	due	to	the	rare	nature	of	(aborted)	
                                                            	
SCD	and	SUD	in	the	young,	which	is	also	reflected	in	the	number	of	index	patients	in	                 	
                                                    	
previous	studies	(9,	43	and	57	respectively). 	Furthermore,	a	relatively	high	number	
                                                            5,6,9
                                                                                            	
          	                 		
of	victims	were	identified	by	reviewing	the	hospital	records,	because	information	on	all	           	
cardiac	arrests	(either	occurring	in-hospital	or	presented	at	the	emergency	department	
  	                                                     	
after	out-of-hospital	cardiac	arrest)	is	routinely	collected	including	clinical	outcome.	This	
                                    	    	
might	have	led	to	an	overestimation	of	the	autopsy	rate	and	the	number	of	first-degree	           	
       	                                                                                     	 	
relatives	 that	 were	 evaluated,	 because	 we	 expect	 that	 these	 investigations	 are	 more	


                                                                                                            119
Chapter 4.1


often	 initiated	 in	 an	 in-hospital	 setting.	 A	 prospective	 study	 is	 currently	 underway	 to	
further	investigate	the	autopsy	rates	and	the	amount	of	referred	first-degree	relatives	
with	inclusion	of	all	victims	that	died	in	an	out-of-hospital	setting.15
The	strength	of	the	current	study	is	that	the	results	represent	the	yield	of	cardiogenetic	
screening	in	routine	clinical	practice	without	prior	selection	of	SCD	and	SUD	cases.	In	
routine	 clinical	 practice	 it	 is	 often	 unclear	 whether	 screening	 of	 relatives	 is	 indicated	
because	 causes	 of	 death	 are	 often	 not	 well	 established	 or	 remain	 unclear.	 Common	
examples	are	young	victims	that	died	because	of	a	myocardial	infarction	or	SCD	victims	
in	whom	unspecified	left	ventricular	hypertrophy	was	found	with	autopsy.	
In	conclusion,	in	routine	clinical	practice,	first-degree	relatives	of	aborted	SCD	and	SUD	
victims	are	often	not	referred	for	cardiogenetic	screening.	If	referred,	screening	is	not	
performed	according	to	a	systematic	approach.	The	detection	rate	of	inherited	diseases	
in	relatives	of	(aborted)	SCD	and	SUD	victims	in	a	population	based	setting	is	substantial	
(14%	 (95%	 CI;	 3%-25%))	 but	 lower	 than	 expected	 based	 on	 previous	 studies.	 A	 less	
structured	and	extensive	screening	approach,	as	performed	in	the	current	usual	care,	
might	 explain	 this	 lower	 detection	 rate	 of	 inherited	 cardiac	 diseases	 among	 relatives.	
A	 centralized,	 expert	 setting	 for	 cardiogenetic	 screening	 of	 relatives	 of	 SCD	 and	 SUD	
victims	that	encompasses	a	close	collaboration	between	cardiologists,	geneticists,	and	
pathologists,	is	likely	to	lead	to	higher	detection	rates	of	inherited	cardiac	diseases.




120
                      Cardiogenetic screening of first-degree relatives after sudden cardiac death in the young


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(1)	 Vaartjes	I,	Hendrix	A,	Hertogh	EM,	Grobbe	DE,	Doevendans	PA,	Mosterd	et	al.	Sudden	death	
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(2)	 Wilde	 AA,	 van	 Langen	 IM,	 Mannens	 MM,	 Waalewijn	 RA,	 Maes	 A.	 Sudden	 death	 at	 young	
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     molecular	 basis	 of	 cardiac	 arrhythmias:	 impact	 on	 clinical	 management	 parts	 I	 and	 II.	
     Circulation 1999;99:518-528.
(11)	Williams	RR,	Hunt	SC,	Schumacher	MC,	Hegele	RA,	Leppert	MF,	Ludwig	EH	et	al.	Diagnosing	                          4.1
                                                                         	
     heterozygous	familial	hypercholesterolemia	using	new	practical	criteria	validated	by	molecular	
     genetics.	Am J Cardiol 1993;72:171-176.
            	
(12)	Drory	Y,	Turetz	Y,	Hiss	Y,	Lev	B,	Fisman	EZ,	Pines	A	et	al.	Sudden	unexpected	death	in	persons	
     less than 40 years of age. Am J Cardiol 1991;68:1388-1392.
                                                                                                                 	
(13)	Amital	 H,	 Glikson	 M,	 Burstein	 M,	 Afek	 A,	 Sinnreich	 R,	 Weiss	 Y	 et	 al.	 Clinical	 characteristics	
     of	 unexpected	 death	 among	 young	 enlisted	 military	 personnel:	 results	 of	 a	 three-decade	
                 	
     retrospective	surveillance.	Chest 2004;126:528-533.
(14)	Wisten	A,	Forsberg	H,	Krantz	P,	Messner	T.	Sudden	cardiac	death	in	15-35-year	olds	in	Sweden	
     during 1992-99. J Intern Med 2002;252:529-536.
                                                                                	
(15)	Hendrix	A.,	Werf	vd	C,	Bots	ML,	Birnie	E,	Smagt	van	der	JJ,	Borleffs	CJW	et	al.	Rationale	and	  	
                                                                  	                    	
     design	of	the	CAREFUL	study,	the	yield	of	cardiogenetic	screening	in	first	degree	relatives	of	     	
     sudden	cardiac	and	unexplained	death	victims	<45	years.	Neth Heart J 2010;18:286-290.
                                                     	
(16)	Carturan	E,	Tester	DJ,	Brost	BC,	Basso	C,	Thiene	G,	Ackerman	MJ.	Postmortem	genetic	testing	      	        	
                   	                      	                                                    	
     for	 conventional	 autopsy-negative	 sudden	 unexplained	 death:	 an	 evaluation	 of	 different	      	
                    	                                               	
     DNA	 extraction	 protocols	 and	 the	 feasibility	 of	 mutational	 analysis	 from	 archival	 paraffi       		n-
     embedded	heart	tissue.	Am J Clin Pathol 2008;129:391-397.
                         	
                                                                       	
(17)	Schwartz	PJ,	Moss	AJ,	Vincent	GM,	Crampton	RS.	Diagnostic	criteria	for	the	long	QT	syndrome.	
     An	update.	Circulation 1993;88:782-784.



                                                                                                               121
Chapter 4.1


(18)	Marcus	 FI,	 McKenna	 WJ,	 Sherrill	 D,	 Basso	 C,	 Bauce	 B,	 Bluemke	 DA,	 et	 al.	 Diagnosis	 of	
     arrhythmogenic	 right	 ventricular	 cardiomyopathy/dysplasia:	 proposed	 modification	 of	 the	
     Task Force Criteria. Eur Heart J 2010;31:806-814.
(19)	Wilde	 AA,	 Antzelevitch	 C,	 Borggrefe	 M,	 Brugada	 J,	 Brugada	 R,	 Brugada	 P	 et	 al.	 Proposed	
     diagnostic	criteria	for	the	Brugada	syndrome:	consensus	report.	Circulation 2002;106:2514-
     2519.
(20)	Survivors	of	out-of-hospital	cardiac	arrest	with	apparently	normal	heart.	Need	for	definition	
     and	standardized	clinical	evaluation.	Consensus	Statement	of	the	Joint	Steering	Committees	
     of	 the	 Unexplained	 Cardiac	 Arrest	 Registry	 of	 Europe	 and	 of	 the	 Idiopathic	 Ventricular	
     Fibrillation	Registry	of	the	United	States.	Circulation 1997;95:265-272.
(21)	Clinical	indications	for	genetic	testing	in	familial	sudden	cardiac	death	syndromes:	an	HRUK	
     position	statement.	Heart 2008;94:502-507.
(22)	Basso	C,	Burke	M,	Fornes	P,	Gallagher	PJ,	de	Gouveia	RH,	Sheppard	M	et	al.	Guidelines	for	
     autopsy	investigation	of	sudden	cardiac	death.	Virchows Arch 2008;452:11-18.




122
                                 Chapter	4.2

         Screening	for	familial	hypertrophic	
cardiomyopathy:	a	cost-effectiveness	analysis
Chapter 4.2


Abstract	
Background: Information	on	the	balance	between	the	beneficial	and	harmful	effects	of	
genetic	cascade	screening	for	hypertrophic	cardiomyopathy	(HCM)	is	scarce.	We	aimed	
to	 evaluate	 the	 potential	 benefits,	 harms	 and	 cost-effectiveness	 of	 genetic	 cascade	
screening	of	first-degree	relatives	of	HCM	mutation	carriers.

Methods: A	 decision	 analytical	 model	 was	 developed	 to	 compare	 genetic	 cascade	
screening	to	no	screening	in	first-degree	relatives	of	HCM	mutation	carriers.	Cohort	age	
of	the	relatives	was	taken	as	20	years	and	45	years.	Furthermore,	screening	was	evaluated	
for	relatives	of		victims	of	sudden	cardiac	death	(SCD)	in	whom	HCM	was	diagnosed	with	
post-mortem	investigation.	Univariable	and	probabilistic	sensitivity	analyses	addressed	
uncertainty	in	all	model	parameters.

Results:	 In	 20-year-old	 relatives,	 screening	 prevented	 almost	 half	 of	 the	 SCD	 events	
(6%	vs.	12%),	increased	life	expectancy	(44.0	vs.	42.7	years),	increased	quality-adjusted	
life-years	 (QALY)	 (30.2	 vs.	 29.9	 QALYs)	 but	 also	 increased	 costs	 (€13,218	 vs.	 €580	 per	
patient).	The	costs	of	screening	were	€44,657	per	QALY	gained.	Cost	of	screening	were	
>€150,000	 per	 QALY	 gained	 if	 age	 at	 screening	 was	 45	 years.	 The	 cost-effectiveness	
strongly	improved	when	screening	was	performed	in	relatives	of	SCD	victims	diagnosed	
with	HCM	(€17,901	per	QALY	in	20-year-old	relatives	and	€30,178	per	QALY	in	45-year-
old	relatives).

Conclusion:	Genetic	cascade	screening	for	HCM	and	cardiologic	follow-up	of	mutation	
carriers	 in	 first-degree	 relatives	 of	 a	 HCM	 mutation	 carrier	 appears	 to	 be	 more	 cost-
effective	 in	 20-year-old	 relatives	 than	 in	 45-year-old	 relatives.	 Screening	 of	 first-
degree	relatives	of	SCD	victims	in	whom	HCM	was	diagnosed	strongly	improved	cost-
effectiveness.	These	findings	are	crucial	for	the	development	of	guidelines	on	screening	
for HCM.




124
                          Screening for familial hypertrophic cardiomyopathy: a cost-effectiveness analysis


         	
Introduction
Hypertrophic	 cardiomyopathy	 (HCM)	 is	 a	 common	 inherited	 cardiac	 disease	 that	 is	
                                       	
characterized	by	unexplained	(left)	ventricular	hypertrophy.	Disease	prevalence	among	
                                                             	
adults	is	around	0.2%. 	HCM	can	be	caused	by	mutations	in	several	genes	among	which	
                             1,2

MYH7	and	MYBPC3	are	the	most	frequent.3	HCM	is	associated	with	an	absolute	risk	for	
sudden	cardiac	death	(SCD)	that	ranges	from	1%	to	6%	per	year	depending	on	the	number	
of	clinical	risk	factors	present.4,5	Clinical	risk	factors	associated	with	SCD	in	HCM	patients		
are:	a	family	history	of	premature	sudden	death,	unexplained	syncope,	non-sustained	
ventricular	tachycardia	at	24-hours	Holter	recording,	abnormal	blood	pressure	response	
                         	                 	
during	exercise	testing,	extreme	left	ventricular	hypertrophy	on	echocardiography	and	
                                               	                                            	
a	 previous	 cardiac	 arrest.4,6	 	 Implantation	 of	 an	 implantable	 cardioverter	 defibrillator	
                                   	 	                	                   	
(ICD)	has	shown	to	be	effective	in	the	prevention	of	SCD	for	patients	at	increased	risk	
for cardiac events.4,5,7,8	Consensus	documents	advise	ICD	therapy	for	every	patient	with	  	
HCM	with	either	a	previous	cardiac	arrest	or	with	two	of	the	other	clinical	risk	factors.	
                 	                   	                                    	
ICD	implantation	in	HCM	patients	with	one	clinical	risk	factor	is	still	being	discussed.4,5, 9
                  	                      	
Because	 relatives	 of	 HCM	 mutation	 carriers	 have	 an	 increased	 risk	 of	 carrying	 the	
                           	                                            	
inherited	predisposition	to	develop	HCM,	screening	of	these	relatives	is	currently	advised	
                                        	
to	enable	early	diagnosis	and	initiate	treatment	when	indicated.4 A	decision-analytical	          	
                                                                            	
model	based	on	the	available	evidence	can	help	to	decide	whether	first-degree	relatives	         	
                  	                          	
of	HCM	mutation	carriers	would	benefit	from	screening	in	terms	of	reducing	SCD	events	
               	 	
in	a	cost-effective	manner.	To	date,	only	one	study	is	available	that	examined	the	cost-
  	 	                        	                    	
effectiveness	of	genetic	versus	clinical	testing	strategies	in	children	(18-	to	22-year-old)	
          	                                            	      	                               	 	
of	 a	 patient	 with	 HCM.10	 In	 that	 study,	 genetic	 testing	 proved	 to	 be	 a	 cost-effective	
                                 	                              	 	
approach	in	the	prevention	of	SCD.	However,	the	cost-effectiveness	of	screening	of	older	
      	                          	
relatives	 of	 HCM	 mutation	 carriers	 was	 not	 assessed	 and	 also	 quality	 of	 life	 was	 not	
incorporated	in	the	analysis.	The	purpose	of	the	current	study	is	to	expand	the	evidence	                     4.2
             	                     	     	                       	 	                     	
by	 evaluating	 the	 potential	 benefits,	 harms	 and	 cost-effectiveness	 of	 genetic	 cascade	
                                                 	                	                    	
screening	as	compared	to	no	screening	in	first-degree	relatives	of	HCM	mutation	carriers	
    	                   	                           	
or	first-degree	relatives	of	sudden	death	victims	in	whom	HCM	was	diagnosed	with	post-
                    	 	
mortem	investigation.

Methods
Model structure
                                                                     	
A	 Markov	 model	 was	 developed	 to	 evaluate	 health	 benefits	 and	 costs	 associated	
           	                            	                 	                   	
with	 genetic	 cascade	 screening	 in	 first-degree	 relatives	 of	 HCM	 mutation	 carriers.	 To	
account	for	variable	ICD	treatment	strategies	(depending	on	the	number	of	risk	factors	
                               	
present),	we	modeled	two	different	clinical	scenarios.	In	scenario	A	(which	is	considered	


                                                                                                       125
Chapter 4.2


the	 base-case	 scenario),	 every	 HCM	 patient	 with	 two	 or	 more	 clinical	 risk	 factors	
received	an	ICD.	All	other	HCM	patients	with	less	than	two	risk	factors,	received	yearly	
cardiologic	assessment	including	risk	stratification	(which	consists	of	electrocardiogram,	
echocardiography,	 Holter	 recording	 and	 exercise	 testing).	 In	 scenario	 B,	 every	 HCM	
patient	with	one	or	more	clinical	risk	factors	received	an	ICD.	Clinical	follow-up	of	HCM	
patients	without	clinical	risk	factors	consisted	of	yearly	cardiologic	assessment	with	risk	
stratification,	as	described	in	scenario	A.	
Additionally,	 we	 evaluated	 the	 cost-effectiveness	 of	 screening	 of	 asymptomatic	
first-degree	 relatives	 of	 SCD	 victims	 in	 whom	 HCM	 was	 diagnosed	 by	 post-mortem	
investigation.	In	this	latter	group,	at	least	one	risk	factor	was	present	(premature	sudden	
cardiac	death	of	a	first-degree	relative)	in	all	relatives.	
We	 chose	 20	 years	 and	 45	 years	 as	 cohort	 age	 for	 the	 relatives	 for	 all	 scenarios.	 All	
relatives	were	assumed	to	be	asymptomatic	and	had	not	previously	suffered	an	aborted	
cardiac	arrest	at	the	moment	of	initial	screening.	In	our	model,	time	cycles	of	one	year	
and	a	lifetime	timehorizon	were	used.	The	input	variables	and	transition	probabilities	
that	we	used	are	summarized	in	table	1a.	




126
                                    Screening for familial hypertrophic cardiomyopathy: a cost-effectiveness analysis


Table 1a.	Input	variables	used	in	the	model

Variable                                                            Base-case           Range                 	
                                                                                                     Distribution      References


ICD variables
                             	
			Probability	of	peri-operative	death	due	to	ICD                    0.7%             (0.4%-1.3%)       Beta               18, 19

             	
			implantation,	%
			Probability	of	successful	shock%                                 97.7%            (97.5%-97.9%)      Beta                18


			Annual	incidence	of	inappropriate	ICD	shock,	%                    9.5%            (7.3%-11.9%)       Beta                19


                                      	
			Annual	incidence	of	ICD	lead	infection,	%                         0.6%             (0.2%-1.4%)       Beta               5, 19


                                              	
			Probability	of	death	due	to	ICD	lead	infection,	%                  5%               (0%-17%)         Beta                17


			Annual	incidence	of	ICD	lead	failure,	%                           2.7%             (1.5%-4.4%)       Beta                 5


Mortality and event rates
                                        	
			Annual	incidence	of	cardiac	arrest	after	a	cardiac	arrest,	%     10.6%            (7.9%-13.5%)       Beta                 9


			Annual	incidence	of	cardiac	arrest,	no	risk	factors,	%            0.8%             (0.3%-1.6%)       Beta                21


			Annual	incidence	of	cardiac	arrest,	1	risk	factor,	%              1.4%             (0.5%-2.6%)       Beta                21


   Annual incidence of cardiac arrest, 2 or more risk                6.5%            (3.1%-10.9%)       Beta                21

			factors,	%
 Annual incidence of non-HCM death                                             	
                                                                    Age-specific	
                                                                             	
                                                                    population	
                                                                   mortality rates
 Annual incidence non-sudden HCM-related death                       0.7%	            (0.5%-0.9%)       Beta               20, 21


			Probability	of	death	during	cardiac	arrest,	%	(without	ICD)      91.2%            (89.9%-92.4%)      Beta                30


                                                   	
			Probability	of	severe	neurological	disability	after	cardiac		     5.9%            (2.0%-11.9%)       Beta                31

			arrest	%
HCM
			One	risk	factor,	%                                                33%              (28%-38%)         Beta                21


			Two	risk	factors,	%                                               12%               (9%-15%)         Beta                21


                               	
			Annual	probability	of	detecting	a	new	risk	factor,	%               2%               (1%-3%)          Beta               EO
			Annual	incidence	of	HCM	(phenotype)	development,	%                1.5%              (1%-2%)          Beta               14-16


Utilities
  HCM	mutation	carrier
           	                                                           1                                                    23               4.2
          	
			HCM	patients	without	ICD                                          0.92             (0.83-0.98)       Beta            24
                                                                                                                          ,	Eurocol	
                                                                                                                       instrument
          	
			HCM	patients	with	ICD                                             0.92             (0.83-0.98)       Beta        Eurocol	instrument
           	
			HCM	patients,	survived	cardiac	arrest	without	                    0.89             (0.82-0.97)       Beta        Eurocol	instrument
			neurological	disability	
           	
			HCM	patients,	survived	cardiac	arrest	with	severe	                0.41             (0.33-0.48)    Triangular             32

			neurological	disability
Disutilities
                	
			ICD	implantation	or	replacement,	days	                              3                  1-7           Beta               22, 25


               	
			Hospitalization	because	of	cardiac	arrest,	days                    10                 5-17           Beta               EO
			ICD	shock	(appropriate),	days                                       1                  0-4           Beta               EO
			ICD	shock	(inappropriate),	days	                                    1                  0-4           Beta               EO
              	
			Lead	infection,	days                                               14                 6-25           Beta               EO

                                  	
ICD	=	implantable	cardioverter	defibrillator,	HCM	=	hypertrophic	cardiomyopathy,	EO	=	expert	opinion


                                                                                                                                       127
Chapter 4.2


In	the	model,	seven	health	states	were	defined;	1)	HCM	mutation	carrier	without	HCM	
phenotype;	2)	HCM	phenotype	without	any	risk	factors;	3)	HCM	phenotype	with	one	
risk	factor;	4)	HCM	phenotype	with	two	or	more	risk	factors;	5)	HCM	phenotype	with	
previous	cardiac	arrest;	6)	HCM	phenotype	with	severe	neurological	disability	due	to	a	
previous	cardiac	arrest,	and	7)	death.	A	schematic	overview	of	the	model	is	presented	
in	figure	1.

Figure 1.	Simplified	overview	of	the	decision	model	comparing	genetic	cascade	screening	for	HCM	
to	no	screening	in	first-degree	relatives	of	HCM	mutation	carriers,	with	ICD	implantation	in	HCM	
patients	with	two	or	more	risk	factors	(scenario	A)

                                                                                  No HCM phenotype

                                                                                  HCM 0 RF     no therapy

                                                                                  HCM 1 RF     no therapy

                                                                                  HCM 2 RF     ICD therapy
                                                       Mutation carrier 
                                                                                  Aborted SCD with severe disability
                                                       cardiologic evaluation
                                                                                  Aborted SCD  ICD therapy
                            Cascade genetic
                            testing of relatives                                  Death


Mutation carrier                                       No mutation carrier


                              No Screening

HCM	 =	 hypertrophic	 cardiomyopathy,	 RF	 =	 risk	 factors,	 ICD	 =	 implantable	 cardioverter	 defibrillator,	 SCD	 =	
sudden cardiac death


Genetic cascade screening of the first-degree relatives
To	evaluate	the	most	effective	approach,	we	presumed	that	the	mutant	gene	in	the	HCM	
mutation	carrier	(or	SCD	victim)	shows	an	autosomal	dominant	pattern	of	inheritance	
(without	being	a	‘de	novo’	mutation).	As	such,	first-degree	relatives	of	probands	have	a	
50%	risk	of	being	carrier	of	the	same	mutation.11	When	a	mutation	is	found	in	a	relative,	
the	 genetic	 screening	 can	 be	 extended	 to	 the	 connecting	 branch	 of	 the	 pedigree.12
Consequently,	absence	of	the	mutation	rules	out	the	presence	of	the	disease,	and	no	
further	investigation	of	the	connecting	branch	of	the	pedigree	is	needed.	The	sensitivity	
and	 specificity	 of	 genetic	 testing	 of	 a	 known	 mutation	 is	 approaching	 100%.12 We
assumed	that	one	proband	has	on	average	two	children	and	one	sibling.	Furthermore,	
we	presumed	that	in	55%	of	the	probands	a	mutation	can	be	identified	when	testing	
for	the	most	commonly	involved	genes	(MYH7,	MYBPC3)	and	that	the	acceptation	rate	
for	genetic	screening	of	relatives	was	50%.3,10	In	case	a	mutation	is	present	in	a	relative,	
cardiologic	 examination	 (including	 an	 electrocardiogram	 and	 echocardiography)	 and	


128
                          Screening for familial hypertrophic cardiomyopathy: a cost-effectiveness analysis


          	
diagnostic	follow-up	is	indicated	to	assess	the	phenotypic	expression	of	HCM.4 Based on
                                            	
the	literature,	we	assumed	that	in	mutation	carriers	aged	20	and	45	years,	the	expression	
                                                        	
of	the	HCM	phenotype	is	20%	and	45%	respectively13,	and	that	cardiologic	examination	          	
                	
of	 HCM	 mutation	 carriers	 (every	 year)	 would	 lead	 to	 the	 clinical	 diagnosis	 of	 HCM	 in	
                    	                                        	
1.5%	 of	 the	 mutation	 carriers	 per	 year.3,14-16	 In	 patients	 with	 the	 HCM	 phenotype,	 we	
                                      		 	                                 		 	
assumed	that	the	annual	risk	stratification	would	lead	to	identification	of	one	new	risk	
                       	
factor	in	2%	of	the	patients	each	year	based	on	expert	opinion	(cardiologist).	

Treatment
                                                         	                  	
According	 to	 the	 current	 guidelines,	 prophylactic	 ICD	 implantation	 is	 indicated	 in	
subjects	with	the	HCM	phenotype	and	two	or	more	risk	factors	for	SCD	(scenario	A).4
         	           	                     	
In	addition,	we	estimated	health	benefits	and	costs	when	an	ICD	was	implanted	in	HCM	
    	
patients	with	one	or	more	risk	factors	(scenario	B)	since	this	treatment	strategy	is	still	        	
                                                                                          	
being	 discussed.5,9	 Medical	 treatment	 (such	 as	 amiodarone	 therapy)	 was	 left	 out	 of	
           	                 	                                   	                   	
consideration,	because	little	is	known	about	the	beneficial	and	adverse	effects	of	this	
                                               	
long-term	medical	treatment	in	young	patients.4	Data	on	ICD	therapy	and	complications	         	
were	 based	 on	 former	 studies	 on	 ICD	 therapy.    5,17-19
                                                                                        	
                                                              	 We	 assumed	 that	 patients	 who	
survived	 a	 cardiac	 arrest	 would	 receive	 an	 ICD	 because	 of	 their	 high	 risk	 for	 sudden	
                     	         	                                                             	
death	 with	 exception	 of	 patients	 that	 became	 severely	 neurological	 disabled	 after	 an	
                                                         	
aborted	cardiac	arrest.	Furthermore,	the	assumption	was	made	that	all	ICD	infections	          	
                                                              	
were	 treated	 by	 ICD	 replacement	 and	 that	 ICD	 battery	 replacement	 was	 performed	
       	                                         	
every	five	years.5,17	The	following	complications	of	ICD	therapy	were	incorporated	in	the	
                                             	                                	
model:	inappropriate	shock,	peri-operative	death	with	ICD	implantation,	ICD	infection	           	
and ICD lead failure.

Mortality and event rates
                                                                                                              4.2
                        	                                              	
Age-	 and	 sex-specific	 mortality	 rates	 of	 the	 general	 population	 were	 extracted	 from	
   	                        	
national	 life	 tables	 (http://statline.cbs.nl).	 The	 annual	 incidence	 of	 non-sudden	 HCM-
related	death	(e.g.	due	to	heart	failure)	was	assumed	to	be	0.7%.20-22 The annual event
                                               	
(SCD	 or	 cardiac	 arrest)	 rate	 of	 HCM	 patients	 with	 no	 risk	 factors	 was	 assumed	 to	 be	
                   	
0.8%	and	for	patients	with	one	risk	factor	1.4%.21	For	the	high-risk	group	(≥2	risk	factors)	
                           	
the	event	rate	was	estimated	to	be	6.5%	and	for	survivors	of	a	cardiac	arrest	10.6%.9, 21
                                                                 	            	
We	assumed	that	SCD	event	rates	were	constant	over	time.20	In	patients	with	a	severe	
                              	
neurological	disability	after	an	aborted	SCD,	the	mortality	rate	was	assumed	to	be	twice	
as	high	compared	to	the	mortality	rates	in	the	general	population.     	




                                                                                                       129
Chapter 4.2


Health outcome
Health	 outcomes	 of	 interest	 were	 the	 number	 of	 prevented	 SCD	 cases	 and	 quality-
adjusted	 life-years	 (QALYs).	 QALYs	 were	 calculated	 by	 multiplying	 the	 time	 a	 person	
remained	in	a	certain	health	state	by	the	utility	associated	with	that	particular	health	
state	(values	ranging	from	1	for	perfect	health	to	0	for	death)	and	subsequent	summing	
up	over	all	health	states.	
Utilities	associated	with	the	different	health	states	were	derived	from	the	literature22-25
or	estimated	with	the	EuroQol	instrument	(www.euroqol.org).	

Costs
We	conducted	our	cost-effectiveness	analysis	from	the	perspective	of	the	health	care	
payer.	 Direct	 costs	 of	 screening	 and	 treatment	 were	 based	 on	 rates	 from	 the	 Dutch	
Healthcare	 Authority,	 updated	 to	 2010	 Euros	 with	 the	 Dutch	 consumer	 price	 indices	
(http://statline.cbs.nl)	and	presented	in	table	1b.	Indirect	costs	concerning	the	inability	
to	work	were	not	incorporated	in	the	analysis.	




130
                                    Screening for familial hypertrophic cardiomyopathy: a cost-effectiveness analysis


Table 1b.	Cost	estimates	(2010	Euros)	used	in	the	model
                  	

Cost estimates                                              Euros           Range                  	
                                                                                          Distribution   References


                                		 	
		Costs	cardiological	risk	stratification	in	HCM	            348                            Gamma          DHA
      	
   patients	without	ICD				(every	year)
        -                 	                        	
              visit	outpatient	clinic		(control	patient)     20             (12-30)
        -     electrocardiogram                              55             (42-70)
        -     echocardiography                               66             (51-83)
        -                   	
              exercise	testing,	                             76             (60-94)
        -     24 hours, holter recording                     131           (109-154)
                             	
Costs	cardiological	examination	in	HCM	mutation	   	         162                            Gamma          DHA
carriers	without	phenotype	(every	year)
       -                 	             	
             visit	outpatient	clinic	(first	visit)           41             (29-54)
       -     electrocardiogram                               55             (42-70)
       -     echocardiography                                66             (51-83)
               		 	        	
Cost	risk	stratification	after	diagnosis	HCM	                227                            Gamma          DHA
phenotype
       -                   	
              visit	outpatient	clinic	(control	visit)        20             (12-30)
       -                     	
              exercise	testing                               76             (60-94)
       -      24 hours, holter monitoring                    131           (109-154)
     	      	                      	
Genetic	testing	for	a	single	mutation                       2,410        (2,316-2,507)      Gamma          DHA
      -                            	        	
              with	two	visits	genetic	outpatient	clinic	    1,674
              (including	one	complex	visit)
      -             	
              genetic	test                                   736
Cost	for	identifying	disease	causing	mutation	in	the	
              	                           	                 2,900        (2,795-3,007)
                                   	        	
proband (including	one	visit	genetic	outpatient	clinic	
(complex))
             	      	
ICD	implantation	+	first	control	visit                     28,030                           Gamma          DHA
      -                    	
            ICD	implantation	                              27,803       (27,478-28,130)
      -     Control visit                                    20             (12-30)
      -     1	day	in-hospital                               207            (179-236)
                          	
ICD	lead	replacement	+	first	control	visit                 28,030                           Gamma          DHA
      -      ICD	lead	replacement                          27,803       (27,478-28,130)
      -      Control visit                                   20             	(12-30)
      -      1	day	in-hospital                              207            (179-236)
                	      	
Cost	lead	infection	+	first	control	visit                  30,719                           Gamma          DHA
       -     14	days	in-hospital	                          2,896         (2,513-3,303)
       -     ICD	replacement                               27,803       (27,478-28,130)
       -     Control visit                                   20             (12-30)
                	
Costs	ICD	battery	replacement	(which	occurs	every	5	       28,030                           Gamma          DHA
years)	+	first	control	visit
          	                                                                                                             4.2
       -       ICD	replacement                             27,803       (27,478-28,130)
       -       Control visit                                 20             (12-30)
       -       1	day	in-hospital                            207            (179-236)
Control	visit	ICD	(which	occurs	every	6	months)              38             (27-51)         Gamma          DHA

       	     	
Evaluation	after	ICD	shock	(appropriate	or	                  38             (27-51)         Gamma          DHA
inappropriate)
            	     	
Hospitalization	after	cardiac	arrest                        6,989                           Gamma          DHA
      -       3 days at intensive care                      5,541        (5,290-5,799)
      -       7 days regular care                           1,448        (1,256-1,651)
Costs	per	year,	severe	neurological	disability             21,089       (21,089-21,662)    Gamma           DHA

                                      	
ICD	 =	 implantable	 cardioverter	 defibrillator,	 HCM	 =	 hypertrophic	 cardiomyopathy,	 DHA	 =	 Dutch	 Healthcare	
Authority




                                                                                                                 131
Chapter 4.2


Analysis
Expected	 life-years,	 QALYs	 and	 costs	 were	 calculated	 for	 each	 screening	 scenario	
separately.	Costs	were	discounted	with	4%	and	health	benefits	with	1.5%.26 Incremental
cost-effectiveness	ratios	were	calculated	by	dividing	the	additional	costs	by	the	additional	
number	of	QALYs	due	to	screening.	We	performed	univariable	and	probabilistic	sensitivity	
analyses	by	varying	all	model	parameters	within	ranges	specified	in	table	1a	and	table	
1b.	All	analyses	were	conducted	in	TreeAge	(TreeAge	Pro	Suite	2009,	Williamston,	VA).	

Results
Screening first-degree relatives of HCM mutation carriers
Overall,	about	60%	of	all	mutation	carriers	developed	HCM	during	their	lifespan.	Genetic	
cascade	 screening	 of	 first-degree	 relatives	 of	 HCM	 mutation	 carriers	 and	 cardiologic	
follow-up	of	mutation	carriers	reduced	the	risk	of	HCM-related	SCD	from	12%	(without	
screening)	to	6%	in	scenario	A	and	to	2%	in	scenario	B	(table	2).	
For	45-year-old	relatives	of	HCM	mutation	carriers,	the	lifetime	HCM-related	SCD	risk	
was	reduced	with	screening	from	10%	to	5%	in	scenario	A	and	to	2%	in	scenario	B.	Over	a	
lifespan,	an	ICD	was	predicted	to	be	implanted	in	9%	of	all	20-year-old	screened	relatives	
in	scenario	A,	in	20%	of	the	screened	relatives	in	scenario	B	and	in	1%	of	relatives	in	whom	
no	genetic	cascade	screening	was	performed	but	who	survived	a	cardiac	arrest	(table	2).	
The	occurrence	of	complications	due	to	ICD	therapy	was	related	to	the	proportion	of	
relatives	who	received	ICD	treatment.	In	scenario	A,	lead	infection	occurred	in	4%	of	all	
20-year-old	relatives	with	the	HCM	phenotype,	lead	failure	in	13%	of	these	relatives	and	
inappropriate	shocks	in	25%	of	these	relatives.

Health outcomes
Both	screening	scenarios	A	and	B	resulted	in	an	increased	life	expectancy	and	in	a	higher	
number	 of	 quality-adjusted	 life-years	 (QALY)	 compared	 to	 no	 screening.	 In	 general,	
scenario	B	provided	the	highest	QALY	gain.	For	20-year-old	relatives	of	HCM	mutation	
carriers,	screening	resulted	in	a	net	health	benefit	of	0.3	QALY	for	scenario	A	and	0.7	
QALY	for	scenario	B	(table	2).	The	magnitude	of	the	health	benefit	decreased	with	age,	
but	was	still	present	for	scenario	B	in	relatives	aged	45	years	(net	health	benefit	of	0.1	
QALY	and	0.3	QALY,	respectively).




132
      Table 2. Expected	number	of	implanted	ICDs,	cardiac	arrests,	sudden	cardiac	death	cases,	life	expectancy	(years),	quality-adjusted-life-years	and	costs	by	screening	
                               	                	                	                 	               	                	                                 	
      strategy	based	on	simulations	of	500,000	first-degree	relatives	of	HCM	mutation	carriers	or	first-degree	relatives	of	sudden	cardiac	death	victims	with	HCM

      Age             Scenario                       	               	
                                         ICD	indication	 ICD	indication	 Cardiac              SCD events          Life    Mean	QALYs Mean costs Incremental
                                                   	
                                            at	initial	       over a       arrest                (%)          expectancy	            per	person,	 costs	per	
                                         screening	(%)         	
                                                          lifetime	(%)   events	(%)                             (years)                   €         QALY

                        	              	
      First-degree	relatives	of	HCM	patients

      20 years        screening A              1%                 9%              13%              6%             44.0            30.2           13,218          44,657
                      screening B              5%                20%              13%              2%             44.8            30.6           22,050          32,530
                      no screening             0%                 1%              13%             12%             42.7            29.9             580

      45 years        screening A              3%                 9%              11%              5%             27.3            21.1           13,548         174,811
                      screening B             10%                20%              11%              2%             27.7            21.4           23,546          68,665
                      no screening             0%                 1%              11%             10%             26.5            21.1             612

                        	               	
      First-degree	relatives	of	SCD	victims


      20 years        screening A              3%                16%              17%              5%             44.1            30.2           18,348          17,901
                      screening B             10%                29%              17%              0%             45.3            30.8           31,796          19,729
                      no screening             0%                 1%              17%             15%             41.6            29.2             841

      45 years        screening A              6%                16%              15%              5%             27.2            21.1           19,417          30,178
                      screening B             23%                32%              15%              0%             27.9            21.5           34,884          32,074
                      no screening             0%                 1%              15%             14%             25.7            20.5             918
                                            	                                                                                                  	
      In	screening	scenario	A,	every	HCM	patient	with	two	or	more	clinical	risk	factors	received	an	ICD.	In	screening	scenario	B,	every	HCM	patient	with	one	or	more	clinical	
      risk factors received an ICD
                                                                                                                                                                                 Screening for familial hypertrophic cardiomyopathy: a cost-effectiveness analysis




133
                                                         4.2
Chapter 4.2


Cost-effectiveness analyses
The	 expected	 costs	 for	 relatives	 undergoing	 the	 different	 screening	 scenarios	 are	
presented	 in	 table	 2.	 Overall,	 screening	 scenario	 B	 was	 almost	 twice	 as	 expensive	 as	
compared	to	screening	scenario	A	in	absolute	terms	(i.e.	not	taken	into	account	QALYs).	
For	20-year-old	relatives	of	HCM	mutation	carriers,	screening	scenario	A	was	associated	
with	additional	lifetime	costs	of	€12,638,	resulting	in	an	incremental	cost-effectiveness	
ratio	 (ICER)	 of	 €44,657	 per	 QALY	 gained	 compared	 to	 no	 screening.	 Compared	 to	 no	
screening,	scenario	B	was	associated	with	additional	lifetime	costs	of	€21,470,	resulting	
in	an	ICER	of	€32,530	per	QALY	gained.	For	45-year-old	relatives,	the	ICERs	were	much	
higher	(€174,811	per	QALY	gained	for	screening	scenario	A	and	€68,665	per	QALY	gained	
for	screening	scenario	B).

Sensitivity analyses
The	results	of	the	sensitivity	analyses	suggest	that	model	results	are	robust	to	the	values	
of	most	parameters.	However,	the	results	are	most	sensitive	to	the	utility	of	HCM	patients	
without	 an	 ICD	 implantation,	 the	 event	 rate	 among	 HCM	 patients	 with	 two	 or	 more	
clinical	risk	factors,	and	the	probability	of	detecting	a	new	clinical	risk	factor	(table	3).	

Table 3. Univariable	sensitivity	analyses

Assumption                                             QALY	gain          Additional	        Incremental	cost	per	
                                                                           costs	(€)            QALY	(€/QALY)
Base-case scenario*                                     0.28              12,638                  44,657
Utility	of	HCM	(asymptomatic	patient)	
without	ICD	(base-case,	0.92)
 0.83                                                   -0.08              12,629                      NA
   0.98                                                 0.53               12,625                    23,731
Annual incidence of SCD among HCM
patients	with	≥	2	clinical	risk	factors	
(base-case,	6.4%)
			3.0%                                                 0.01               12,782                   913,000
			11.4%                                                0.47               12,508                    26,841
Probability	of	detecting	new	clinical	
risk factors
(base-case,	2%)
			1%                                                   0.11               11,337                   107,971
			3%                                                   0.45               13,882                    30,849
QALY	 =	 quality-adjusted	 life-years,	 NA	 =	 not	 applicable,	 ICD	 =	 implantable	 cardioverter	 defibrillator,	 HCM	 =	
hypertrophic	cardiomyopathy	*	Genetic	screening	for	HCM	in	20-year-old	relatives	of	HCM	mutation	carriers	
in	which	every	relative	with	HCM	and	with	two	or	more	risk	factors	received	an	ICD




134
                                               Screening for familial hypertrophic cardiomyopathy: a cost-effectiveness analysis


                                              	        	                       	
Figure	2a	depicts	the	results	of	a	probabilistic	sensitivity	analysis	for	genetic	screening	of	
                         	                    	
HCM	in	20-year-old	relatives	of	HCM	mutation	carriers.	Hence,	when	considering	a	cost-
  	 	                                                                         	
effectiveness	threshold	of	€20,000	per	QALY	gained,	a	threshold	that	is	often	used	in	the	
Netherlands,27	there	was	a	2%	probability	that	screening	scenario	A	was	cost-effective		 	
compared	to	no	screening.	

Figure 2a. Results	of	the	probabilistic	sensitivity	analysis	for	genetic	screening	for	HCM	in	20-year-
                                      	        	                      	
          	                    	                                                	
old	 relatives	 of	 HCM	 mutation	 carriers.	 Each	 dot	 represents	 one	 iteration	 of	 the	 model.	 The	
y-axis	represents	incremental	costs	of	screening	compared	to	no	screening.	The	x-axis	represents	
net	 quality-adjusted	 life-years	 (QALYs)	 with	 screening	 compared	 to	 no	 screening.	 The	 diagonal	
                                                                                          	
lines	represent	costs	per	QALY	gained	of	€20,000,	which	is	a	threshold	that	is	often	used	in	the	
                                                           	 	
Netherlands	for	which	treatment	is	considered	cost-effective26
                            30,000



                            25,000


                            20,000
Incremental costs (€)




                            15,000


                            10,000

                                                           screening scenario A
                                5,000
                                                           screening scenario B
                                                           CE threshold (20,000 €/QALY)
                                    0
                        -0.50        0.00    0.50       1.00        1.50          2.00
                                            Incremental QALYs
                                                                                                                                   4.2

        	     	                                                      	
In	addition,	figure	2b	shows	the	probability	that	screening	of	relatives	and	cardiologic	
                    	                    	 	
follow-up	of	mutation	carriers	is	cost-effective	for	other	thresholds	that	might	be	used	
                      	 	
to	determine	cost-effectiveness.




                                                                                                                            135
Chapter 4.2


Figure 2b. Cost-effectiveness	acceptability	curve	for	20-year-old	relatives,	for	scenario	A	and	B.	
The	y-axis	represents	the	probability	that	the	costs	per	QALY	gained	is	less	than	or	equal	to	the	
values listed on the x-axis
                   100%

                   90%

                   80%

                   70%

                   60%
% Cost-effective




                   50%

                   40%

                   30%                                                      screening scenario A
                                                                            screening scenario B
                   20%

                   10%

                    0%
                          0   20,000   40,000     60,000       80,000   100,000     120,000
                                            CE threshold (€/QALY)




Screening relatives of SCD victims in whom HCM was diagnosed
The	incidence	of	a	cardiac	arrest	is	higher	in	relatives	of	SCD	victims	in	whom	HCM	was	
diagnosed	compared	to	relatives	of	HCM	mutation	carriers,	because	all	relatives	of	SCD	
victims	carry	at	least	one	risk	factor	(a	positive	family	history	for	SCD).	In	20-year-old	
relatives,	the	predicted	probability	of	SCD	during	the	remaining	lifespan	was	about	15%	
without	 screening,	 decreased	 to	 5%	 in	 scenario	 A	 and	 approached	 zero	 in	 scenario	 B	
(since	all	relatives	with	the	HCM	phenotype	receive	an	ICD	and	are	therefore	protected	
for	SCD)	(table	2).	
For	 20-year-old	 relatives	 of	 SCD	 victims,	 screening	 scenario	 A	 was	 associated	 with	
additional	lifetime	costs	of	€17,507	and	a	gain	of	1.0	QALYs	compared	to	no	screening,	
resulting	in	an	incremental	cost-effectiveness	ratio	(ICER)	of	€17,901	per	QALY	gained.	
Screening	scenario	B	was	associated	with	additional	costs	of	€30,955	and	a	gain	of	1.6	
QALYs,	resulting	in	an	ICER	of	€19,729	per	QALY	gained.	For	45-year-old	relatives,	the	
ICERs	were	higher	(€30,178	per	QALY	gained	for	screening	scenario	A	and	€30,074	per	
QALY	gained	for	screening	scenario	B)	(table	2).	




136
                            Screening for familial hypertrophic cardiomyopathy: a cost-effectiveness analysis


Discussion
                   	 	                                           	
This	 cost-effectiveness	 analysis	 shows	 that	 genetic	 cascade	 screening	 for	 HCM	 and	
                                    	                               	 	
cardiologic	follow-up	of	mutation	carriers	is	more	cost-effective	in	younger	first-degree	  	
        	                         	                      	                 	
relatives	compared	to	older	first-degree	relatives	of	HCM	mutation	carriers.	Screening	
      	                   	              	
of	first-degree	relatives	of	SCD	victims,	in	whom	HCM	was	diagnosed,	strongly	improves	
            	 	
cost-effectiveness.	
                                              	 	                      	            	
Recently,	 a	 few	 decision	 and	 cost-effectiveness	 studies	 attempted	 to	 find	 the	 most	
      	
optimal	strategies	of	familial	screening	for	HCM	and	treatment	to	prevent	SCD.10,22,28 To
                                                                    	 	
our	knowledge,	only	one	study	has	evaluated	the	cost-effectiveness	of	genetic	cascade	        	
                                            	                	
screening	 in	 18-	 to	 22-year-old	 relatives	 of	 a	 patient	 with	 HCM. 	 This	 study	 reported	
                                                                            10

             	 	            	           	
a	cost-effectiveness	ratio	of	genetic	cascade	screening	followed	by	ICD	implantation	in	             	
              	
HCM	patients	with	two	or	more	risk	factors	of	€16,185	per	discounted	life-year	saved	
                                                                               	
(i.e.	 no	 adjustment	 for	 quality	 of	 life	 was	 made).	 Our	 model	 confirms	 this	 result	 and	
                                                                 	     	                   	 	
indicates	that	taking	into	account	quality	of	life	estimates	affects	the	cost-effectiveness	
    	
ratio.
The	strength	of	the	current	study	is	that	it	expands	the	evidence	by	modelling	the	cost-
   	 	                                          	
effectiveness	of	screening	of	older	relatives	(aged	45	years)	of	HCM	mutation	carriers	   	
                                	                   	
and	the	screening	of	relatives	of	SCD	victims	in	whom	HCM	was	diagnosed.	Also,	the	
            	 	                          	             	
cost-effectiveness	of	ICD	implantation	in	relatives	with	either	one	or	two	risk	factors	was	
                                                                  	                   	
assessed	which	provides	clinically	relevant	information	on	costs,	complications	and	life-
                                                           	
years	saved	for	both	treatment	scenarios.	Additionally,	quality	of	life	was	incorporated	
in	our	model.	We	believe	that	quality	of	life	is	an	important	factor	in	cost-effectiveness		 	
                                              	         	
analyses	 of	 screening	 of	 asymptomatic	 relatives,	 because	 screening	 might	 impact	 on	
                                       	         	
quality	 of	 life	 when	 asymptomatic	 relatives	 become	 aware	 of	 their	 illness	 and	 when	
                              	                                              	
considering	the	complications	that	might	be	caused	by	prophylactic	ICD	treatment.	
                                  	                                                     	
Our	 study	 has	 certain	 limitations.	 First,	 our	 model	 provides	 only	 information	 on	 cost-              4.2
   	 	                                               	       	                                 	
effectiveness	 of	 screening	 of	 asymptomatic	 relatives.	 Yet,	 it	 seems	 unrealistic	 that	 all	
        	                                                                  	
relatives	 with	 HCM	 phenotype	 expression	 remain	 asymptomatic	 over	 their	 lifespan.	
                  	
Some	 relatives	 in	 the	 non-screening	 strategy,	 upon	 developing	 symptoms,	 will	 be	
                                                                      	                          	
referred	 to	 a	 cardiologist	 and	 will	 receive	 further	 diagnostic	 follow-up.	 Relatives	 with	
HCM	and	two	or	more	risk	factors	will	also	receive	ICD	therapy,	which	might	attenuate	             	
                	       	                          	
the	 beneficial	 effects	 of	 pre-symptomatic	 screening	 as	 compared	 to	 no	 screening.	
                      	                                        	
Second,	we	estimated	the	individual	health	benefits	and	costs	associated	with	genetic	                   	
                    	             	                        	
screening	of	first-degree	relatives	of	HCM	mutation	carriers.	However,	once	a	causative	               	
          	                   		              	                                        	
mutation	 has	 been	 identified	 in	 relatives	 of	 a	 proband,	 further	 examination	 of	 other	
family	members	(including	younger	or	older	subjects)	might	be	indicated.	Therefore,	the	
            	 	
cost-effectiveness	of	screening	might	also	depend	on	the	screening	of	the	connecting	                  	
branch	of	the	pedigree	(and	the	age	of	these	family	members).

                                                                                                         137
Chapter 4.2


Sensitivity	analysis	shows	that	an	increase	in	the	SCD	rate	among	HCM	patients	at	high	risk	
(e.g.	in	HCM	patients	with	a	malignant	causative	mutation	or	a	double	mutation)	results	
in	a	substantial	improvement	of	cost-effectiveness.	The	results	of	our	model	were	also	
sensitive	to	the	utility	of	HCM	patients	without	ICD	treatment	and	the	SCD	rate	among	
HCM	patients	with	two	or	more	clinical	risk	factors.	A	slight	increase	in	the	utility	of	HCM	
patients	resulted	in	considerably	favourable	cost-effectiveness	ratios.	Further	research	
on	these	model	variables	is	therefore	needed.	The	threshold	used	for	cost-effectiveness	
is	arbitrary	and	differs	between	countries	and	for	different	diseases.	In	the	Netherlands,	
a	 threshold	 of	 €20,000	 per	 QALY	 is	 commonly	 used.27	 In	 addition,	 recommendations	
produced	 by	 the	 Dutch	 Council	 for	 Public	 Health	 and	 Health	 Care	 to	 the	 Minister	 of	
Health,	Welfare	and	Sport	(2006),	suggested	a	ceiling	threshold	of	€80,000	per	QALY	per	
year,	when	considering	an	severe	illnesses	with	a	high	impact	on	quality	of	life.29,29 Based
on	this	 recommendation,	 screening	of	20-year-old	 relatives	of	HCM	mutation	carriers	
and	45-year-old	relatives	of	a	SCD	victim	with	established	HCM	might	also	be	considered	
cost-effective	 as	 is	 screening	 of	 20-year-old	 relatives	 of	 a	 SCD	 victim	 with	 established	
HCM.	Furthermore,	we	expect	that	the	cost-effectiveness	will	improve	over	time	because	
new	 developments	 and	 improvement	 of	 screening	 strategies	 will	 lead	 to	 a	 decline	 in	
costs	related	to	screening	and	ICD	therapy	and	to	a	higher	effectiveness	of	screening.	
Future	studies	on	the	risk	stratification	of	HCM	mutation	carriers	and	HCM	patients	are	
needed	to	improve	the	cost-effectiveness	of	screening	of	first-degree	relatives.	To	study	
risk	 factors	 (including	 genetic	 factors)	 associated	 with	 SCD,	 large	 databases	 with	 long	
term	follow-up	of	HCM	mutation	carriers	and	HCM	patients	are	warranted.
In	conclusion,	genetic	cascade	screening	for	HCM	and	cardiologic	follow-up	of	mutation	
carriers	appeared	to	be	more	cost-effective	in	20-year-old	relatives	than	in	45-year-old	
relatives	of	HCM	mutation	carriers.	Screening	of	first-degree	relatives	of	SCD	victims	in	
whom	HCM	was	diagnosed	strongly	improved	cost-effectiveness.	Our	results	are	relevant	
for	the	development	of	future	guidelines	concerning	the	genetic	cascade	screening	and	
cardiologic	follow-up	for	HCM.




138
                             Screening for familial hypertrophic cardiomyopathy: a cost-effectiveness analysis


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     Committee	for	Practice	Guidelines.	J Am Coll Cardiol 2003;42:1687-1713.
               	             	
(5)	 Syska	P,	Przybylski	A,	Chojnowska	L,	Lewandowski	M,	Sterliński	M,	Maciag	A	et	al.	Implantable	
                          	                 	
     Cardioverter-Defibrillator	 in	 Patients	 With	 Hypertrophic	 Cardiomyopathy:	 Effi             		cacy	 and	
     Complications	of	the	Therapy	in	Long-Term	Follow-up.	J Cardiovasc Electrophysiol 2010;21:883-
                 	
     889.
             	                                                                     	                     		 	
(6)	 Christiaans	I,	van	Engelen	K,	van	Langen	IM,	Birnie	E,	Bonsel	GJ,	Elliott	PM	et	al.	Risk	stratification	
                                                                                        	
     for	 sudden	 cardiac	 death	 in	 hypertrophic	 cardiomyopathy:	 systematic	 review	 of	 clinical	 risk	
     markers. Europace 2010;12:313-321.
                                                                   	
(7)	 Maron	BJ.	Hypertrophic	cardiomyopathy:	a	systematic	review.	JAMA 2002;287:1308-1320.
(8)	 Zipes	DP,	Camm	AJ,	Borggrefe	M,	Buxton	AE,	Chaitman	B,	Fromer	M	et	al.	ACC/AHA/ESC	2006	
                                              	
     guidelines	 for	 management	 of	 patients	 with	 ventricular	 arrhythmias	 and	 the	 prevention	 of	  	
     sudden	cardiac	death:	a	report	of	the	American	College	of	Cardiology/American	Heart	Association	          	
                                                                           	              	
     Task	Force	and	the	European	Society	of	Cardiology	Committee	for	Practice	Guidelines	(Writing	             	
               	                                                          	
     Committee	to	Develop	Guidelines	for	Management	of	Patients	With	Ventricular	Arrhythmias	
     and	the	Prevention	of	Sudden	Cardiac	Death).	J Am Coll Cardiol 2006;48:e247-e346.
                        	
(9)	 Maron	BJ,	Spirito	P,	Shen	WK,	Haas	TS,	Formisano	F,	Link	MS	et	al.	Implantable	cardioverter-
         	                         	
     defibrillators	and	prevention	of	sudden	cardiac	death	in	hypertrophic	cardiomyopathy.	JAMA
     2007;298:405-412.
                                                                                            	
(10)	Wordsworth	S,	Leal	J,	Blair	E,	Legood	R,	Thomson	K,	Seller	A	et	al.	DNA	testing	for	hypertrophic	
     cardiomyopathy:	a	cost-effectiveness	model.	Eur Heart J 2010;31:926-935.
                                   	 	                                                                              4.2
(11)	Maron	BJ,	Nichols	PF	3rd,	Pickle	LW,	Wesley	YE,	Mulvihill	JJ.	Patterns	of	inheritance	in	hypertrophic	
                                                                            	
     cardiomyopathy:	assessment	by	M-mode	and	two-dimensional	echocardiography.	Am J Cardiol
     1984;53:1087-1094.
                      	                	      	
(12)	Clinical	 indications	 for	 genetic	 testing	 in	 familial	 sudden	 cardiac	 death	 syndromes:	 an	 HRUK	
           	
     position	statement.	Heart 2008;94:502-507.
(13)	McKenna	WJ,	Spirito	P,	Desnos	M,	Dubourg	O,	Komajda	M.	Experience	from	clinical	genetics	in	            	
                                                                      	
     hypertrophic	cardiomyopathy:	proposal	for	new	diagnostic	criteria	in	adult	members	of	affected	       	
     families. Heart 1997;77:130-132.
             	
(14)	Christiaans	I,	Birnie	E,	van	Langen	IM,	van	Spaendonck-Zwarts	KY,	van	Tintelen	JP,	van	den	Berg	
                                        		 	
     MP	et	al.	The	yield	of	risk	stratification	for	sudden	cardiac	death	in	hypertrophic	cardiomyopathy	
     myosin-binding	 protein	 C	 gene	 mutation	 carriers:	 focus	 on	 predictive	 screening.	 Eur Heart J
                                                  	                                  	
     2010;31:842-848.
                                     	                                                        		 	
(15)	Michels	M,	Soliman	OI,	Phefferkorn	J	et	al.	Disease	penetrance	and	risk	stratification	for	sudden	
     cardiac	 death	 in	 asymptomatic	 hypertrophic	 cardiomyopathy	 mutation	 carriers.	 Eur Heart J
                                          	                                            	
     2009;30:2593-2598.


                                                                                                            139
Chapter 4.2


(16)	Niimura	H,	Bachinski	LL,	Sangwatanaroj	S,	Watkins H, Chudley	AE, McKenna	W,	et	al.	Mutations	
     in	 the	 gene	 for	 cardiac	 myosin-binding	 protein	 C	 and	 late-onset	 familial	 hypertrophic	
     cardiomyopathy.	N Engl J Med 1998;338:1248-1257.
(17)	Mela	T,	McGovern	BA,	Garan	H,	Vlahakes	GJ, Torchiana DF, Ruskin	J	et	al.	Long-term	infection	
     rates	associated	with	the	pectoral	versus	abdominal	approach	to	cardioverter-	defibrillator	
     implants.	Am J Cardiol 2001;88:750-753.
(18)	Zipes	 DP,	 Roberts	 D.	 Results	 of	 the	 international	 study	 of	 the	 implantable	 pacemaker	
     cardioverter-defibrillator.	 A	 comparison	 of	 epicardial	 and	 endocardial	 lead	 systems.The	
     Pacemaker-Cardioverter-Defibrillator	Investigators.	Circulation 1995;92:59-65.
(19)	Begley	 DA,	 Mohiddin	 SA,	 Tripodi	 D,	 Winkler	 JB,	 Fananapazir	 L.	 Efficacy	 of	 implantable	
     cardioverter	 defibrillator	 therapy	 for	 primary	 and	 secondary	 prevention	 of	 sudden	 cardiac	
     death	in	hypertrophic	cardiomyopathy.	Pacing Clin Electrophysiol 2003;26:1887-1896.
(20)	Maron	 BJ,	 Olivotto	 I,	 Spirito	 P,	 Casey	 SA,	 Bellone	 P,	 Gohman	 TE	 et	 al.	 Epidemiology	 of	
     hypertrophic	 cardiomyopathy-related	 death:	 revisited	 in	 a	 large	 non-referral-based	 patient	
     population.	Circulation 2000;102:858-864.
(21)	Elliott	 PM,	 Poloniecki	 J,	 Dickie	 S,	 Sharma	 S,	 Monserrat	 L,	 Varnava	 A	 et	 al.	 Sudden	 death	
     in	 hypertrophic	 cardiomyopathy:	 identification	 of	 high	 risk	 patients.	 J Am Coll Cardiol
     2000;36:2212-2218.
(22)	You	JJ,	Woo	A,	Ko	DT,	Cameron	DA,	Mihailovic	A,	Krahn	M.	Life	expectancy	gains	and	cost-
     effectiveness	of	implantable	cardioverter/defibrillators	for	the	primary	prevention	of	sudden	
     cardiac	death	in	patients	with	hypertrophic	cardiomyopathy.	Am Heart J 2007;154:899-907.
(23)	Christiaans	 I,	 van	 Langen	 IM,	 Birnie	 E,	 Bonsel	 GJ,	 Wilde	 AA,	 Smets	 EM.	 Quality	 of	 life	 and	
     psychological	 distress	 in	 hypertrophic	 cardiomyopathy	 mutation	 carriers:	 a	 cross-sectional	
     cohort study. Am J Med Genet A 2009;149A:602-612.
(24)	Cox	S,	O’Donoghue	AC,	McKenna	WJ,	Steptoe	A.	Health	related	quality	of	life	and	psychological	
     wellbeing	in	patients	with	hypertrophic	cardiomyopathy.	Heart 1997;78:182-187
(25)	Sanders	 GD,	 Hlatky	 MA,	 Owens	 DK.	 Cost-effectiveness	 of	 implantable	 cardioverter-
     defibrillators.	N Engl J Med 2005;353:1471-1480.
(26)	Rutten	FFH,	Rodenburg-van	Dieten	HEM,	Herings	RMC,	van	Hout	BA,	Krabbe	PFM,	van	Loon	J	
     et	al.	Guidelines	for	farmaco-economic	research,	an	updated	version	(In	Dutch)	Diemen,	the	
     Netherlands: Health Care Insurance Board. 2006.
(27)	Pomp	M,	Brouwer	WBF,	Rutten	FFH.	QALY-time.	New	medical	technology,	cost-effectiveness	
     and guidelines. The Hague, The Netherlands: Central Planning Bureau. 2007.
(28)	Goldenberg	 I,	 Moss	 AJ,	 Maron	 BJ,	 Dick	 AW,	 Zareba	 W.	 Cost-effectiveness	 of	 implanted	
     defibrillators	 in	 young	 people	 with	 inherited	 cardiac	 arrhythmias.	 Ann Noninvasive
     Electrocardiol 2005;10:67-83.
(29)	Sensible	and	sustainable	care.	Recommendations	produced	by	the	Council	for	Public	Health	
     and	Health	Care	to	the	Minister	of	Health,	Welfare	and	Sport.	2006	                 	
(30)	Stiell	IG,	Wells	GA,	DeMaio	VJ,	Spaite	DW,	Field	BJ	3rd,	Munkley	DP	et	al.	Modifiable	factors	
     associated	 with	 improved	 cardiac	 arrest	 survival	 in	 a	 multicenter	 basic	 life	 support/
     defibrillation	system:	OPALS	Study	Phase	I	results.	Ontario	Prehospital	Advanced	Life	Support.	
     Ann Emerg Med 1999;33:44-50.
(31)	Bunch	 TJ,	 White	 RD,	 Gersh	 BJ,	 Meverden	 RA,	 Hodge	 DO,	 Ballman	 KV	 et	 al.	 Long-term	
     outcomes	of	out-of-hospital	cardiac	arrest	after	successful	early	defibrillation.	N Engl J Med
     2003;348:2626-2633.
(32)	Post	PN,	Stiggelbout	AM,	Wakker	PP.	The	utility	of	health	states	after	stroke:	a		
     systematic	review	of	the	literature.	Stroke 2001;32:1425-1429.




140
Chapter       5
 General	discussion	
Chapter 5


Case	report	
A	38-year-old	man	was	found,	lying	unconsciously	on	the	floor	of	the	living	room,	by	his	
wife	who	returned	from	work.	The	television	was	switched	on	and	a	cup	of	cold	coffee	
stood	on	the	table.	She	immediately	called	the	emergency	medical	services	and	warned	
the	general	practitioner	on	call.	They	arrived	to	conclude	that	her	husband	had	already	
died.	He	had	no	relevant	past	medical	history,	was	not	using	any	medication	and	had	
given	 up	 smoking	 10	 years	 ago.	 He	 exercised	 regularly	 and	 occasionally	 drank	 a	 glass	
of	wine.	He	had	complained	sporadically	about	spells	of	‘dizziness’,	without	having	any	
other	complaints.	His	father	died	suddenly	from	a	‘heart	attack’,	at	the	age	of	forty,	but	
no	autopsy	had	been	performed.	Their	two	teenage	children	have	no	known	(cardiac)	
disease.
Because	 of	 the	 unexpected	 and	 unexplained	 death,	 the	 coroner	 was	 contacted	 to	
exclude	a	non-natural	cause	of	death.	After	an	elaborate	inspection	of	the	corpse	and	
the	circumstances	of	death,	the	coroner	concluded	a	natural	cause	of	death	and	filled	
out	the	death	declaration	forms.	The	possibility	of	a	clinical	autopsy	was	discussed	with	
the	relatives,	but	no	permission	for	autopsy	was	obtained.	

This	case	report	exemplifies	a	common	scenario	following	a	sudden	death	in	the	young	
and	 raises	 several	 questions	 including;	 how	 often	 does	 sudden	 death	 in	 the	 young	
occur?	What	is	the	most	probable	cause	of	death?	What	is	the	probability	that	inherited	
cardiac	 diseases	 underlie	 the	 sudden	 death	 of	 a	 young	 person?	 Should	 autopsy	 have	
been	performed?	What	are	the	possible	consequences	for	surviving	relatives?	
The	purpose	of	this	thesis	was	to	provide	information	on	the	incidence	and	causes	of	
sudden	 cardiac	 death	 (SCD)	 and	 sudden	 unexplained	 death	 (SUD)	 in	 the	 young	 (1-44	
years)	in	the	Netherlands	and	to	estimate	the	proportion	of	inherited	cardiac	diseases.	
Furthermore,	we	set	out	to	determine	the	autopsy	rate	in	young	sudden	death	victims	
and	to	study	the	yield	of	cardiogenetic	screening	of	first-degree	relatives	in	the	usual	care	
to	identify	inherited	cardiac	diseases.	Finally,	the	cost-effectiveness	of	genetic	cascade	
screening,	cardiologic	follow-up	and	treatment	of	relatives	of	patients	with	hypertrophic	
cardiomyopathy	(HCM)	was	evaluated.

Overview	of	thesis	results
The	main	results	of	the	studies	described	in	this	thesis	are:
    - In	 the	 Netherlands,	 SCD	 (including	 SUD)	 accounts	 for	 approximately	 500	
        deaths	per	year	in	subjects	aged	1-44	years,	with	more	than	70%	of	the	deaths	
        occurring in those aged 30-44 years.
    - An	inherited	cardiac	disease	(including	atherosclerotic	coronary	artery	disease)	


142
                                                                                    General discussion


          was	suspected	or	could	not	be	excluded	in	the	majority	(79%)	of	sudden	death	
              	
          victims	aged	1-44	years.	
     -    In	the	Netherlands,	autopsy	is	performed	in	approximately	35%	of	the	sudden	
                     	
          death	victims	aged	1-44	years	with	an	unexplained,	cardiac	and	natural	non-
          cardiac cause of death.
     -                               	                     	                        	
          The	yield	of	cardiogenetic	screening	of	relatives	of	unselected	victims	of	SCD	
          and	 SUD	 aged	 1-40	 years	 in	 a	 regional	 hospital	 was	 14%	 (95%	 CI;	 3%-25%),	
          which	is	lower	than	expected	based	on	former	studies	that	were	performed	in	
              	
          tertiary	referral	hospitals.	
     -                  	                     	          	
          Cardiogenetic	screening	of	relatives	of	patients	with	HCM	prevents	half	of	the	
                                  	
          SCD	 events	 over	 lifetime,	 increases	 quality-adjusted	 life-years	 but	 also	 costs	
          that	are	related	to	screening,	follow-up	and	treatment.
     -                  	                                      	 	
          Cardiogenetic	screening	for	HCM	is	more	cost-effective	in	20-year-old	relatives	   	
          as	compared	to	45-year-old	relatives. 	
     -                 	 	                                                               	
          The	 cost-effectiveness	 increases	 when	 screening	 is	 performed	 in	 relatives	 of	
                   	
          SCD	victims	in	whom	HCM	has	been	diagnosed	with	autopsy.	

            	                                                                           	 	
The	implications	of	the	studies	described	in	this	thesis	relate	to	post-mortem	investigation	
                               	                  	                   	                 	
of	 young	 sudden	 death	 victims,	 cardiogenetic	 screening	 of	 first-degree	 relatives	 of	
                   	                 	 	                               	                	
sudden	 death	 victims,	 the	 cost-effectiveness	 of	 screening	 of	 first-degree	 relatives	 of	
    	                                                                   	
patients	with	inherited	cardiac	disease	and	the	need	for	registration	of	(causes	of	death	
                             	
in)	young	sudden	death	victims.

                  	 	                               	
Post-mortem	investigation	of	young	sudden	death	victims
                                           	
Autopsy	 in	 young	 sudden	 death	 victims	 is	 important	 to	 establish	 the	 cause	 of	 death	
                                                                                       	
(as	 described	 in	 chapter	 3.3	 and	 3.4	 of	 this	 thesis)	 and	 might	 be	 a	 starting	 point	 for	
           		 	                                                          	
the	identification	of	inherited	cardiac	diseases	in	surviving	relatives.1	Based	on	autopsy	
                	                            	
results,	 relatives	 of	 sudden	 death	 victims	 can	 be	 reassured	 (e.g.	 when	 a	 myocarditis	   	
                                                            	
is	diagnosed)	or	can	be	referred	for	(cardio-)genetic	screening.	In	the	Netherlands,	in	                  5
contrast	to	several	other	countries	(e.g.	Sweden,		Norway	and	England),	autopsy	is	only	
                                                        	
performed	 in	 a	 minority	 of	 	 sudden	 death	 victims	 (approximately	 35%	 of	 the	 sudden	
death	cases	undergo	autopsy	in	the	Netherlands	(chapter	3.3)).2,3	The	most	important	
barriers	to	request	an	autopsy	are	a	lack	of	awareness	of	inherited	(cardiac)	diseases	
              	                                	
among	relatives	and	physicians,	the	emotional	turmoil	following	the	sudden	unexpected	
                                    	                         	
death	of	a	young	person	and	financial	as	well	logistic	problems	to	arrange	an	autopsy	
(see	chapter	3.4).   4,5

                                                              	
With	 approximately	 70%	 of	 the	 sudden	 death	 victims	 aged	 1-44	 years	 dying	 out-of-
                                        		                      	
hospital	(chapter	3.4),	general	practitioners	(and	sometimes	coroners)	play	a	central	role	

                                                                                                  143
Chapter 5


in	 informing	 relatives	 about	 the	 possibility	 of	 an	 underlying	 inherited	 cardiac	 disease	
and	 the	 importance	 of	 autopsy	 to	 detect	 or	 exclude	 inherited	 (cardiac)	 diseases.	 As	
sudden	 death	 in	 the	 young	 is	 extremely	 rare	 and	 the	 overall	 prevalence	 of	 inherited	
cardiac	diseases	is	low,	physicians	might	be	unaware	of	the	increased	risk	that	relatives	
of	young	sudden	death	victims	have	to	be	carrier	of	an	inherited	cardiac	disease.	The	
CAREFUL	 study	 was	 designed	 to	 create	 awareness	 for	 inherited	 cardiac	 diseases	 and	
to	stimulate	the	performance	of	autopsy	and	the	referral	of	relatives	(when	indicated)	
by	 two	 different	 approaches,	 as	 described	 in	 chapter	 2.2.	 Results	 of	 these	 strategies	
will	become	available	after	completion	of	the	data	collection	of	the	CAREFUL	study	in	
2011.	By	emphasizing	the	potential	consequences	for	the	surviving	relatives,	emotional	
barriers	may	be	overcome	and	relatives	might	be	more	inclined	to	allow	for	an	autopsy.
Reimbursement	of	the	costs	for	transportation	of	the	body	to	a	hospital	and	performance	
of	an	autopsy	is	currently	not	well	organized.	In	daily	practice	–when	a	clinical	autopsy	
is	 arranged	 -	 the	 family	 will	 incur	 the	 costs	 for	 transportation	 of	 the	 corpse	 and	 the	
pathology	 department	 (or	 the	 hospital)	 is	 usually	 not	 reimbursed	 for	 the	 costs	 of	
performing	a	laborious	post-mortem	investigation.	The	‘College	voor	Zorgverzekeringen’	
states	in	an	additional	document	on	reimbursement	of	healthcare	costs	2007,	that	costs	
of	 diagnostic	 tests	 that	 are	 initiated	 post-mortem	 (e.g.	 autopsy	 and	 genetic	 testing)	
might	be	paid	by	the	health	care	insurance	of	one	of	the	relatives	when	these	diagnostic	
tests	 are	 relevant	 for	 surviving	 relatives	 (e.g.	 inherited	 diseases	 are	 considered).	 As	 a	
straightforward	 procedure	 having	 these	 costs	 covered	 by	 the	 health	 care	 insurance	
companies	of	the	surviving	relatives	is	lacking,	it	appears	prudent	that	the	health	care	
insurances	 of	 sudden	 death	 victims	 (aged	 1-44	 years)	 reimburse	 the	 costs	 related	 to	
post-mortem	investigation.6

Cardiogenetic	screening	of	first-degree	relatives	of	young	sudden	
death	victims
The	 results	 of	 this	 thesis	 support	 the	 notion	 (as	 described	 in	 chapter	 two)	 that	
cardiogenetic	screening	of	relatives	of	SCD	victims	in	whom	an	inherited	cardiac	disease	is	
detected	or	in	whom	the	cause	of	death	remains	unexplained	(with	or	without	autopsy),	
seems	 an	 effective	 approach	 to	 prevent	 future	 SCD	 cases	 in	 the	 population.	 Many	
inherited	cardiac	diseases	have	an	autosomal	dominant	pattern	of	inheritance7 and in
22-53%	of	the	relatives	of	SUD	victims	an	inherited	cardiac	disease	can	be	established	
with	elaborate	cardiogenetic	screening.8-11	Furthermore,	a	positive	family	history	of	SCD	
increases	the	risk	of	SCD	in	patients	with	(inherited)	cardiac	diseases.12-15
Several	 aspects	 need	 consideration.	 Awareness	 of	 both	 medical	 professionals	 (e.g.	
general	practitioners,	cardiologists,	pathologists	and	coroners)	and	the	lay	public	of	the	
importance	of	cardiogenetic	screening	of	relatives	of	young	sudden	death	victims	should	

144
                                                                                    General discussion


                                	
be	 raised	 (www.cardiogenetica.nl).	 Because	 the	 prevalence	 of	 most	 inherited	 cardiac	
                                        	                       	
diseases	 is	 low	 and	 the	 cardiogenetic	 screening	 of	 relatives	 might	 be	 very	 complex,	
     	                                                                   		
relatives	should	preferably	be	referred	(by	their	own	general	practitioner)	to	one	of	the	
              	
cardiogenetic	clinics,	currently	located	in	each	of	eight	university	hospitals	and	in	a	few	
                                                                             	
(satellite)	non-university	hospitals	in	the	Netherlands.	To	inform	relatives	upfront	about	
                                                        	                      	
the	 advantages	 and	 disadvantages	 of	 cardiogenetic	 screening,	 genetic	 counseling	 by	
                                                                            	
experienced	professionals	in	that	area	needs	to	precede	cardiogenetic	screening.	

       	 	                              	          	
Cost-effectiveness	of	screening	of	relatives	of	patients	with	an	
inherited cardiac disease
                                                                       	
Although	 the	 yield	 of	 screening,	 in	 terms	 of	 the	 detection	 of	 inherited	 diseases,	 has	
                 	               	                 	                     	            	
been	investigated	for	relatives	of	SUD	victims	and	for	relatives	of	patients	(or	sudden	
              	
death	victims)	with	inherited	cardiac	diseases,        7-11,16
                                                                                        	 	
                                                                	studies	on	the	cost-effectiveness	of	
                         	                                                                	 	
screening	 of	 relatives	 with	 the	 aim	 to	 prevent	 SCD	 are	 scarce.	 The	 cost-effectiveness	
                             	         	                                 	
of	 screening	 of	 relatives	 of	 patients	 (or	 sudden	 death	 victims)	 with	 inherited	 cardiac	
                                                                                    	
disease	to	prevent	SCD	depends	mainly	on	the	following	characteristics	related	to	the	
inherited	cardiac	disease	and	the	available	treatment:
                                                                                  	
1. The	probability	of	diagnosing	an	inherited	cardiac	disease	in	a	first-degree	relative	         	
                                 	                                               	
      of	a	sudden	death	victim.	This	relates	to	the	probability	of	identifying	the	causative	     	
               	                   	                 	               	
      mutation	in	the	index	patient	or	in	the	affected	relative,	disease	penetrance	and	the	
      mode of inheritance of the inherited disease
2. The	natural	course	of	disease	(annual	mortality	rate),	and	mortality	rate	with	the	
                                           	
      presence	(or	absence)	of	additional	risk	factors
                           	                                               	
3. SCD	risk	reduction	achieved	though	treatment	(proportion	of	sudden	deaths	that	
                                                   	                                      	
      can	 be	 prevented	 by	 pre-symptomatic	 screening	 and	 treatment	 of	 first-degree	
           	
      relatives)
                     	               	
4. Complications	of	diagnostic	procedures	and	treatment
5. Costs	associated	with	diagnosis,	clinical	follow-up	and	treatment
                         	
These	characteristics	are	largely	available	for	HCM	in	the	published	literature.	Chapter	4.2	
                                                                                                         5
                             	 	                              	            	
described	the	cost-effectiveness	of	screening	relatives	of	patients	with	HCM.	Screening	
      	                              	
relatives	of	sudden	 death	victims	in	whom	HCM	is	diagnosed	 with	autopsy,	increases	
                	 	                              	
the	cost-effectiveness	because	these	relatives	are	at	an	increased	risk	for	sudden	death	
             	
(and	relatively	more	deaths	can	be	prevented	by	screening).	Unfortunately,	information	          	
on	the	natural	course	of	disease	and	risk	factors	associated	with	increased	SCD	rates	is	
scarce	for	most	other	inherited	cardiac	diseases	and	lacks	precision.	The	exact	increase	
                                         	                  	
in	risk	of	premature	death	in	relatives	of	SCD	victims	remains	to	be	elucidated.	Several	
                   	
studies	 investigated	 whether	 a	 family	 history	 for	 SCD	 can	 predict	 premature	 death	 in	
 	                     	
first-degree	relatives	(with	or	without	underlying	diseases).12-15	However,	these	studies	

                                                                                                  145
Chapter 5


are	 often	 underpowered	 because	 SCD	 in	 the	 young	 is	 extremely	 rare	 and	 therefore	
the	 estimated	 risks	 lack	 precision.	 Linkage	 of	 databases	 with	 the	 aim	 to	 create	 large	
registries	 of	 patients	 with	 inherited	 cardiac	 diseases	 will	 provide	 the	 opportunity	 to	
study	 mortality	 rates	 and	 risk	 factors	 associated	 with	 SCD.	 A	 Dutch	 example	 of	 such	
a	 registry	 is	 the	 GENCOR	 (GENetic	 CORvitia)	 database	 (www.gencor.nl).	 The	 GENCOR	
database	is	a	national	registry	of	patients	and	families	with	inherited	cardiac	diseases	in	
the	Netherlands.	The	purpose	of	this	database	is	to	register	patients	that	were	diagnosed	
with	 primary	 arrhythmia	 syndromes	 or	 cardiomyopathies	 and	 in	 whom	 a	 causative	
mutation	has	been	identified.	However,	except	from	registering	patients	with	inherited	
cardiac	diseases	also	comprehensive	short	term	and	long	term	follow-up	is	needed	to	
collect	information	on	risk	factors	and	the	associated	risks	of	suffering	from	an	event	in	
the	future.	Several	other	(international)	initiatives	have	been	launched	to	link	databases	
of	patients	with	inherited	cardiac	diseases;	for	example	for	patients	with	the	Brugada	
syndrome	and	patients	with	arrhythmogenic	right	ventricular	cardiomyopathy.17,18
Accumulation	 of	 information	 derived	 from	 these	 registries	 enables	 future	 studies	 on	
the	 benefits,	 harms	 and	 cost-effectiveness	 of	 cardiogenetic	 screening	 of	 relatives	 of	
patients	or	sudden	death	victims	in	whom	an	inherited	disease	is	diagnosed.	Based	on	
this	information	guidelines	concerning	preventive	cardiogenetic	screening	of	relatives	of	
sudden	death	victims	can	be	developed	or	adapted.

Registration	of	SCD	victims:	population	based	data	versus	national	
death	certificate	data
Based	on	the	CAREFUL	study,	we	estimated	that	in	the	Netherlands	307	SCD	cases	occur	
annually	in	persons	aged	1-39	years.	This	is	figure	is	twice	as	high	as	the	estimate	(150	
SCD	 cases	 annually)	 obtained	 by	 using	 national	 death	 certificate	 data	 from	 Statistics	
Netherlands	(chapter	3.1).	The	observed	difference	relates	to	the	methods	and	definitions	
that	were	used	to	identify	SCD	cases.	In	the	first	place,	the	sudden	death	victims	that	
died	in	the	emergency	department	were	excluded	from	the	national	death	certificate	
data	 analysis,	 as	 it	 is	 impossible	 to	 distinguish	 patients	 that	 died	 at	 the	 emergency	
department	 from	 the	 in-hospital	 deaths.	 Secondly,	 only	 the	 ICD	 codes	 corresponding	
with	the	most	common	causes	of	sudden	death	based	on	a	review	of	clinico-pathologic	
studies	 were	 used.	 As	 a	 result	 (less)	 relevant	 ICD	 codes	 to	 identify	 cases	 of	 sudden	
death	may	have	been	missed.	In	the	third	place,	misclassification	of	the	causes	of	death	
might	 have	 led	 to	 an	 underestimation	 of	 the	 SCD	 incidence	 (as	 described	 in	 chapter	
3.3).19,20	The	higher	SCD	incidence	found	in	the	CAREFUL	study	can	be	attributed	to	the	
comprehensive	population	based	collection	of	data	and	more	lenient	inclusion	criteria	
for	sudden	death	victims	as	compared	to	former	studies.3,21,22
To	 study	 trends	 over	 time,	 autopsy	 rates	 and	 effects	 of	 pre-symtomatic	 cardiogenetic	

146
                                                                         General discussion


screening of individuals at risk for inherited cardiac diseases, an accurate surveillance
tool	is	needed.	As	the	CAREFUL	study	has	demonstrated	to	provide	accurate	data	on	the	
incidence	and	causes	of	SCD	(and	non-SCD)	in	the	young	in	the	Netherlands,	extension	
                                   	               	                            	
of	this	CAREFUL	database	to	a	nationwide	population	based	registry	of	SCD	victims	(and	
                                                                    	
the	causes	of	death)	would	provide	the	needed	valuable	information	on	incidence	and	
                                                                       	
causes	of	SCD	due	to	rare	inherited	cardiac	diseases		(caused	by	different	pathogenic	
       	                                                 	
mutations).	Linkage	with	other	databases	(e.g.	the	national	hospital	discharge	register,	
              		                                           	
general	 practitioner	 based	 databases	 or	 pharmaceutical	 databases),	 enables	 the	
       	 	
investigation	of	factors	that	might	be	associated	with	sudden	death	in	the	young,	like	
         	                                   	
medication	use,	the	presence	of	comorbidities,	socio-economical	status	(as	described	in	
                                                                  	
chapter	3.2),	race,	drug	abuse	and	alcohol	abuse.	This	information	is	a	prerequisite	to	
develop	accurate	measures	to	prevent	SCD	in	the	young.




                                                                                              5




                                                                                       147
Chapter 5


References
(1)	 Basso	C,	Burke	M,	Fornes	P,	Gallagher	PJ, de	Gouveia	RH, Sheppard	M	et	al.	Guidelines	for	
     autopsy	investigation	of	sudden	cardiac	death.	Virchows Arch 2008;452:11-18.
(2)	 Saukko	P.	Medicolegal	investigative	system	and	sudden	death	in	Scandinavia.	Nihon Hoigaku
     Zasshi 1995;49:458-465.
(3)	 Wisten	A,	Forsberg	H,	Krantz	P,	Messner	T.	Sudden	cardiac	death	in	15-35-year	olds	in	Sweden	
     during 1992-99. J Intern Med 2002;252:529-536.
(4)	 van	Zwieten.Sparen	voor	obductie.	Medisch Contact 2006;61:1418-1419
(5)	 Oppewal	F,	Meyboom-de	JB.	Issues	involved	in	Dutch	general	practitioners’	failure	to	request	
     autopsy:	report	from	three	focus	groups.	Ned Tijdschr Geneeskd 2003;147:1315-1318.
(6)	 Borleffs	 CJW,	 A.A.M.	 Wilde,	 M.L.	 Bots,	 E.	 Kruyt,	 A.	 Mosterd.	 Obductie	 redt	 levens,	
     onwetendheid	 over	 erfelijke	 hartafwijking	 maakt	 onnodig	 slachtoffers.	 Medisch Contact
     2007; 45:1851-1853
(7)	 Priori	 SG,	 Barhanin	 J,	 Hauer	 RN,	 Haverkamp	 W,	 Jongsma	 HJ,	 Kleber	 AG	 et	 al.	 Genetic	 and	
     molecular	 basis	 of	 cardiac	 arrhythmias:	 impact	 on	 clinical	 management	 parts	 I	 and	 II.	
     Circulation 1999;99:518-528.
(8)	 Behr	E,	Wood	DA,	Wright	M,	Syrris	P,	Sheppard	MN,	Casey	A	et	al.	Cardiological	assessment	of	
     first-degree	relatives	in	sudden	arrhythmic	death	syndrome.	Lancet 2003;362:1457-1459.
(9)	 Behr	ER,	Dalageorgou	C,	Christiansen	M,	Syrris,	Hughes	S,	Tome	Esteban	MT	et	al.	Sudden	
     arrhythmic	 death	 syndrome:	 familial	 evaluation	 identifies	 inheritable	 heart	 disease	 in	 the	
     majority	of	families.	Eur Heart J 2008;29:1670-1680.
(10)	van	der	Werf	C,	Hofman	N,	Tan	HL,	van	Dessel	PF,	Alders	M,	van	der	Wal	AC	et	al.	Diagnostic	
     yield	in	sudden	unexplained	death	and	aborted	cardiac	arrest	in	the	young:	The	experience	of	
     a	tertiary	referral	center	in	The	Netherlands.	Heart Rhythm 2010;7:1383-1389.
(11)	Hofman	N,	Tan	HL,	Alders	M,	van	Langen	IM,	Wilde	AA.	Active	cascade	screening	in	primary	
     inherited	arrhythmia	syndromes:	does	it	lead	to	prophylactic	treatment?	J Am Coll Cardiol
     2010;55:2570-2576.
(12)	Kaikkonen	 KS,	 Kortelainen	 ML,	 Linna	 E,	 Huikuri	 HV.	 Family	 history	 and	 the	 risk	 of	 sudden	
     cardiac	death	as	a	manifestation	of	an	acute	coronary	event.	Circulation 2006;114:1462-1467.
(13)	Elliott	 PM,	 Poloniecki	 J,	 Dickie	 S,	 Sharma	 S,	 Monserrat	 L,	 Varnava	 A	 et	 al.	 Sudden	 death	
     in	 hypertrophic	 cardiomyopathy:	 identification	 of	 high	 risk	 patients.	 J Am Coll Cardiol
     2000;36:2212-2218.
(14)	Dekker	LR,	Bezzina	CR,	Henriques	JP,	Tanck MW, Koch	KT, Alings MW et al. Familial sudden
     death	is	an	important	risk	factor	for	primary	ventricular	fibrillation:	a	case-control	study	in	
     acute	myocardial	infarction	patients.	Circulation 2006;114:1140-1145.
(15)	Maki	S,	Ikeda	H,	Muro	A,	Yoshida	N,	Shibata	A,	Koga	Y	et	al.	Predictors	of	sudden	cardiac	death	
     in	hypertrophic	cardiomyopathy.	Am J Cardiol 1998;82:774-778.
(16)	Krahn	 AD,	 Healey	 JS,	 Chauhan	 V,	 Birnie	 DH,	 Simpson	 CS,	 Champagne	 et	 al.	 Systematic	
     assessment	 of	 patients	 with	 unexplained	 cardiac	 arrest:	 Cardiac	 Arrest	 Survivors	 With	
     Preserved	Ejection	Fraction	Registry	(CASPER).	Circulation 2009;120:278-285.
(17)	Probst	 V,	 Veltmann	 C,	 Eckardt	 L,	 Meregalli	 PG, Gaita	 F, Tan HL	 et	 al.	 Long-term	 prognosis	
     of	patients	diagnosed	with	Brugada	syndrome:	Results	from	the	FINGER	Brugada	Syndrome	
     Registry.	Circulation 2010;121:635-643.
(18)	Corrado	D,	Fontaine	G,	Marcus	FI,	McKenna	WJ,	Nava	A,	Thiene	G	et	al.	Arrhythmogenic	right	
     ventricular	dysplasia/cardiomyopathy:	need	for	an	international	registry.	European	Society	of	
     Cardiology	and	the	Scientific	Council	on	Cardiomyopathies	of	the	World	Heart	Federation.	J
     Cardiovasc Electrophysiol 2000;11:827-832.


148
                                                                                            General discussion


                                                                                    	                   		
(19)	Iribarren	 C,	 Crow	 RS,	 Hannan	 PJ,	 Jacobs	 DR,	 Jr.,	 Luepker	 RV.	 Validation	 of	 death	 certificate	
     diagnosis	of	out-of-hospital	sudden	cardiac	death.	Am J Cardiol 1998;82:50-53.
(20)	Fox	 CS,	 Evans	 JC,	 Larson	 MG,	 Lloyd-Jones	 DM,	 O’Donnell	 CJ,	Sorlie	 PD	 et	 al.	 A	comparison	
                     		
     of	death	certificate	out-of-hospital	coronary	heart	disease	death	with	physician-adjudicated	
     sudden cardiac death. Am J Cardiol 2005;95:856-859.
(21)	Vaartjes	 I,	 Hendrix	 A,	 Hertogh	 EM,	 Grobbee	 DE,	 Doevendans	 PA,	 Mosterd	 A	 et	 al.	 Sudden	
     death	in	persons	younger	than	40	years	of	age:	incidence	and	causes.	Eur J Cardiovasc Prev
     Rehabil 2009;16:592-596.
             	
(22)	Morentin	 B,	 Suarez-Mier	 MP,	 Aguilera	 B.	 Sudden	 unexplained	 death	 among	 persons	 1-35	
     years old. Forensic Sci Int 2003;135:213-217.




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                                                                                                           149
         Chapter	6

          Summary
      Samenvatting
        Dankwoord
  Curriculum	Vitae
List	of	publications
Chapter 6


Sudden	 cardiac	 death	 (SCD)	 and	 sudden	 unexplained	 death	 (SUD)	 in	 the	 young	 (1-44	
years)	is	rare	and	accounts	for	approximately	500	deaths	per	year	in	the	Netherlands.	
More	than	70%	of	these	deaths	occur	in	those	aged	30-44	years.	Inherited	cardiac	diseases	
often	underlie	a	SCD	or	SUD	in	the	young.	Inherited	cardiac	diseases	can	be	subdivided	
into	three	main	categories:	cardiomyopathies	(e.g.	hypertrophic	cardiomyopathy	(HCM)),	
premature	atherosclerosis	(e.g.	familial	hypercholesterolemia),	and	primary	arrhythmia	
syndromes	 (e.g.	 long-QT	 syndrome).	 Relatives	 of	 young	 SCD	 and	 SUD	 victims	 have	
an	 increased	 risk	 of	 carrying	 the	 inherited	 predisposition	 to	 develop	 cardiac	 disease.
Early	detection	of	inherited	cardiac	diseases	in	families	offers	opportunities	to	prevent	
SCD	 through	 treatment	 which	 may	 include	 lifestyle	 modifications,	 pharmacological	
treatment	 and	 implantation	 of	 a	 pacemaker	 or	 implantable	 cardioverter	 defibrillator	
(ICD).	 As	 sudden	 cardiac	 arrest	 in	 the	 young	 is	 often	 the	 first	 ‘symptom’	 of	 inherited	
cardiac	disease,	early	identification	is	difficult	in	apparently	healthy	young	individuals.
Post-mortem	investigation	of	sudden	death	victims	might	be	an	important	diagnostic	tool	
to detect inherited cardiac diseases among families. When an inherited cardiac disease
is	 diagnosed	 or	 suspected	 based	 on	 autopsy	 findings,	 pre-symptomatic	 cardiogenetic	
screening	 of	 first-degree	 relatives	 of	 SCD	 and	 SUD	 victims	 to	 detect	 inherited	 cardiac	
diseases	might	be	indicated.	
Chapter 1	 provides	 the	 general	 introduction	 of	 the	 thesis.	 Chapter 2.1	 provides	 an	
overview	of	the	definitions	and	the	background	of	SCD	in	the	young.	Also	the	current	
view	on	the	optimal	care	after	the	sudden	death	of	a	young	person	is	described.	
In Chapter 2.2	 we	 described	 the	 rationale	 and	 design	 of	 the	 CAREFUL	 (The	 yield	 of	
cardiogenetic	 screening in first-degree	 relatives	 of	 sudden	 cardiac	 and	 unexplained
death	victims	<45	year) study.	One	of	the	purposes	of	the	CAREFUL	study	is	to	provide	
population	based	data	on	the	incidence	and	causes	of	SCD	and	SUD	in	the	young	(1-44	
years).	 The	 CAREFUL	 study	 is	 a	 population	 based	 follow-up	 study	 carried	 out	 in	 four	
regions	 of	 the	 Netherlands	 that	 comprise	 28%	 of	 the	 Dutch	 population	 (1-44	 years).	
Sudden	 death	 victims	 aged	 1-44	 years	 are	 registered	 by	 systematically	 reviewing	
resuscitation	records	and	death	declaration	certificates.	Autopsy	results	are	collected	for	
all	victims	on	whom	autopsy	had	been	performed.	We	expect	that	the	CAREFUL	study	
will	help	to	set	a	new	standard	of	care	in	the	screening	of	young	sudden	death	victims	
and	 their	 relatives	 to	 identify	 the	 presence	 of	 inherited	 cardiac	 diseases,	 in	 order	 to	
prevent	sudden	death.	
In chapter 3.1 we	 described	 the	 incidence	 and	 causes	 of	 SCD	 in	 the	 Netherlands	 by	
using	death	certificate	data	of	out-of-hospital	deaths	recorded	by	Statistics	Netherlands.	
To	 define	 sudden	 death,	 International	 Classification	 of	 Diseases	 codes	 were	 selected	
based	 on	 a	 systematic	 review	 of	 the	 literature	assessing	 the	 most	 common	 causes	 of	
(natural)	sudden	death	in	the	young.	We	found	an	incidence	of	sudden	death	in	persons	


152
                                                                                           Summary


1-39	years	of	2.1	(95%	CI;	2.0-2.2)	per	100,000	person-years.	The	incidence	was	higher	
for	men	than	for	women	and	increased	by	age.	The	majority	of	sudden	deaths	were	of	
                         	
cardiac	origin	and	often	treatable	causes	were	underlying	a	sudden	death	in	the	young.	
In chapter 3.2 we	described	the regional	differences	in	the	incidence	of	SCD	in	young	
                                                      	
                                              	
individuals	 (<40	 years)	 and	 the	 association	 of	 the	 SCD	 incidence	 and	 socio-economic	
                                                          		
status	(SES).	SCD	cases	<40	years	old	were	identified	in	12	provinces	of	the	Netherlands	
                        		                          	 	
by	using	death	certificates	recorded	by	Statistics	Netherlands.	Regional	SCD	incidence	
was	assessed	for	two	age	categories;	1-29	years	and	30-39	years.	We	found	that	between	
               	 	            	         	
regions	 statistically	 significant	 differences	 exits	 in	 SCD	 incidence	 in	 young	 individuals.	
           	                                                     	    	
The	nationwide	incidence	of	SCD	increased	substantially	after	30	years	of	age	and	was	
inversely	related	to	SES	in	men	aged	30-39	years.	This	might	be	due	to	the	increasing	
percentage	of	deaths	due	to	coronary	artery	disease	with	age.	
In chapter 3.3	the	data	of	the	first	study	year	(June	2008-June	2009)	of	the	CAREFUL	
                                      	
                                                                         	
study	are	presented.	In	this	study	we	determined	the	population	based	incidence	and	
causes	of	(presumed)	natural	sudden	death.	During	one	year,	175	sudden	death	cases	
were	registered;	the	mean	age	was	34	years	(range	1-44)	and	70%	of	the	victims	were	      	
male.	The	incidence	of	sudden	death	and	SCD	was	6.8	(95%	CI;	5.8-7.8)	and	5.5	(95%	CI;	
                                               	
4.6-6.4)	per	100,000	person-years	respectively,	which	was	twofold	higher	than	previously	
   	                                    		                    	 	
estimated	by	using	the	death	certificate	data	of	Statistics	Netherlands	(see	chapter	3.1).	
An	 inherited	 cardiac	 disease	 was	 suspected,	 or	 could	 not	 be	 excluded,	 in	 79%	 of	 all	
                      	
sudden	 death	 victims.	 Because	 inherited	 cardiac	 diseases	 predominate	 as	 underlying	
                                                    	               	               	
cause	 of	 death	 in	 young	 sudden	 death	 victims,	 systematic	 cardiogenetic	 screening	 of	
       	                                    	
relatives	of	young	sudden	death	victims	might	be	useful	to	prevent	SCD.	
In chapter 3.4,	we	described	the	clinical	autopsy	rate	among	young	sudden	death	victims	         	
(1-44	years)	and	the	factors	that	relate	to	the	performance	of	a	clinical	autopsy.	Sudden	
             	                		
death	victims	were	identified	over	a	two	year	period	(2006-2008)	in	the	four	CAREFUL	
                                                  	          		
study	regions	by	reviewing	death	declaration	certificates	of	the	public	health	services.	
The	autopsy	rate	in	these	cases	was	determined.	The	search	yielded	224	sudden	death	
     	
victims.	The	mean	age	of	death	was	34	years	(range	1-44)	and	52	(23%)	were	women.	
                                                                      	
Clinical	 autopsy	 was	 performed	 in	 48	 sudden	 death	 victims	 (21%).	 Autopsies	 were	
         	               	                       	
significantly	more	often	performed	in	victims	who	had	been	resuscitated	(adjusted	OR	
                                          	                                  	
3.67	(95%	CI;	1.46-9.25))	and	in	victims	without	relevant	comorbidities	(adjusted	OR	3.13	
(95%	CI;	1.44-6.79)).	As	a	clinical	autopsy	is	currently	performed	in	a	minority	of	young	              6
                    	
sudden	death	victims	in	the	Netherlands,	inherited	cardiac	diseases	remain	undetected.	
We	expect	that	the	autopsy	rate	will	increase	not	only	by	emphasizing	the	importance	
of	autopsy	among	physicians,	coroners	and	the	lay	public,	but	also	by	improvement	of	
         	                                       	      	
logistics	and	the	removal	of	currently	existing	financial	barriers.	
In Chapter 4.1	we	described	the	yield	of	cardiogenetic	screening	of	first-degree	relatives	
                                                               	               	                	


                                                                                                153
Chapter 6


of	young	SCD	and	SUD	victims	in	a	population	based	setting.	Most	former	studies	that	
investigated	 the	 yield	 of	 screening	 in	 first-degree	 relatives	 of	 sudden	 death	 victims	
were	carried	out	in	tertiary	referral	centers	and	were	based	on	a	selected	population	
of	SUD	victims.	We	searched	for	SCD	and	SUD	victims	(1-40	years)	that	died	between	
2000 and 2006 in the region adhering to the Meander Medical Center in Amersfoort, the
Netherlands.	Information	on	autopsy	results	and	cardiogenetic	screening	of	the	victims’	
first-degree	relatives	was	collected.	Relatives	were	invited	for	additional	cardiogenetic	
screening	when	this	had	not	yet	been	performed	in	routine	clinical	practice.	The	search	
led	to	16	cases	of	SCD	and	SUD	and	four	cases	of	aborted	sudden	death.	The	cardiogenetic	
screening	of	37	relatives	of	12	victims	led	to	a	diagnosis	of	Brugada	syndrome	in	three	
relatives	and	a	high	probability	of	arrhythmogenic	right	ventricular	cardiomyopathy	in	
two	relatives.	The	total	yield	of	screening	of	these	surviving	first-degree	relatives	was	
14%	(95%	confidence	interval;	3%-25%),	which	is	substantial	but	lower	than	expected	
based	 on	 previous	 studies.	 A	 less	 structured	 and	 extensive	 screening	 approach,	 as	
performed	in	the	usual	care,	might	explain	this	lower	detection	rate	of	inherited	cardiac	
diseases	 among	 relatives.	 A	 centralized,	 expert	 setting	 for	 cardiogenetic	 screening	 of	
relatives	 of	 SCD	 and	 SUD	 victims	 that	 encompasses	 a	 close	 collaboration	 between	
cardiologists,	geneticists,	and	pathologists,	is	likely	to	lead	to	higher	detection	rates	of	
inherited cardiac diseases.
In chapter 4.2 we	 evaluated	 the	 potential	 benefits,	 harms	 and	 cost-effectiveness	 of	
genetic	cascade	screening	for	HCM	and	the	cardiologic	follow-up	of	mutation	carriers.	
A	 decision	 analytical	 model	 was	 developed	 to	 compare	 genetic	 cascade	 screening	 to	
no	screening	in	first-degree	relatives	of	a	HCM	patient.	Cohort	age	of	the	first-degree	
relatives	was	taken	as	20	years	and	45	years.	Furthermore,	screening	was	evaluated	for	
relatives	of	a	victim	of	SCD	in	whom	HCM	was	diagnosed	with	post-mortem	investigation.	
In	20-year-old	relatives,	screening	prevented	almost	half	of	the	SCD	events	(6%	vs.12%),	
increased	 life	 expectancy	 (44.0	 vs.	 42.7	 years),	 increased	 quality-adjusted	 life-years	
(QALY)	 (30.2	 vs.	 29.9	 QALYs)	 but	 also	 increased	 costs	 (€13,218	 vs.	 €580	 per	 patient).	
Genetic	 cascade	 screening	 for	 HCM	 and	 cardiologic	 follow-up	 of	 mutation	 carriers	 in	
first-degree	relatives	of	a	HCM	mutation	carrier	appeared	to	be	more	cost-effective	in	
20-year-old	relatives	than	in	45-year-old	relatives.	Screening	of	first-degree	relatives	of	
SCD	victims	in	whom	HCM	was	diagnosed	strongly	improved	cost-effectiveness.	These	
results	 are	 relevant	 for	 the	 development	 of	 future	 guidelines	 concerning	 the	 genetic	
cascade screening for HCM.
In the general discussion we	discussed	strategies	to	improve	the	usual	care	after	the	
sudden	 death	 of	 a	 young	 person,	 particularly	 in	 relation	 to	 identification	 of	 inherited	
cardiac	 diseases.	 Registries	 of	 patients	 with	 inherited	 cardiac	 diseases	 enable	 future	
studies	 on	 the	 benefits,	 harms	 and	 cost-effectiveness	 of	 cardiogenetic	 screening	


154
                                                                                        Summary


         	                              	
of	 relatives	 of	 sudden	 death	 victims	 with	 inherited	 cardiac	 diseases.	 Based	 on	 this	
           	                              	               	
information,	 guidelines	 on	 preventive	 cardiogenetic	 screening	 can	 be	 developed	 or	
                     	
adapted.	 The	 initial	 results	 of	 the	 CAREFUL	 study	 demonstrate	 the	 value	 of	 accurate	
           	
information	 on	 the	 incidence	 and	 causes	 of	 SCD	 (and	 non-SCD)	 in	 the	 young	 in	 the	
Netherlands.	 With	 the	 CAREFUL	 study	 we	 found	 that	 the	 incidence	 of	 SCD	 in	 the	
                                                	
young	is	twofold	higher	than	previously	estimated.	Extension	of	the	CAREFUL	database	
          	                 	                                	
to	 a	 nationwide	 population	 based	 registry	 of	 SCD	 victims,	 and	 the	 linkage	 with	 other	
                                 		 	
databases,	enables	the	identification	of	risk	factors	associated	with	sudden	death	in	the	
                       	
young.	This	information	is	a	prerequisite	to	develop	accurate	measures	to	prevent	SCD	
in the young.




                                                                                                     6




                                                                                              155
          Summary
      Samenvatting
        Dankwoord
  Curriculum	Vitae
List	of	publications
Chapter 6


In	Nederland	overlijden	jaarlijks	ongeveer	500	mensen	op	jonge	leeftijd	(1-44	jaar)	aan	
een	 plotselinge,	 onverklaarde	 of	 cardiale	 dood.	 Het	 merendeel	 van	 deze	 slachtoffers	
(70%)	is	tussen	de	30	en	44	jaar	oud.	Erfelijke	hartziekten	zijn	vaak	de	onderliggende	
oorzaak	 van	 plotseling	 overlijden	 op	 jonge	 leeftijd.	 Erfelijke	 hartziekten	 kunnen	
worden	 onderverdeeld	 in	 drie	 groepen;	 erfelijke	 ziekten	 waarbij	 de	 hartspier	 is	
aangedaan	 (cardiomyopathieën),	 vroegtijdige	 slagaderverkalking	 door	 bijvoorbeeld	
een	 familiair	 verhoogd	 cholesterolgehalte	 en	 	 elektrische	 hartziekten	 (waarbij	 soms	
fatale	 hartritmestoornissen	 kunnen	 optreden).	 Familieleden	 van	 slachtoffers	 van	
plotseling	overlijden	hebben	een	verhoogd	risico	om	een	erfelijke	hartziekte	te	hebben.	
Vroegtijdige	 diagnostiek	 en	 behandeling	 kan	 plotseling	 overlijden	 op	 jonge	 leeftijd	
voorkomen.	 Vaak	 hebben	 mensen	 die	 plotseling	 overlijden	 niet	 eerder	 hartklachten	
gehad	 en	 is	 een	 hartstilstand	 het	 eerste	 ‘symptoom’	 van	 de	 ziekte.	 Daarom	 is	 het	
wenselijk	 erfelijke	 hartziekten	 zo	 vroeg	 mogelijk	 op	 te	 sporen.	 Het	 uitvoeren	 van	 een	
obductie	 en	 genetisch	 onderzoek	 na	 een	 plotseling	 overlijden	 op	 jonge	 leeftijd	 kan	
bijdragen	 aan	 de	 opsporing	 van	 erfelijke	 hartziekten	 binnen	 families.	 Wanneer	 bij	 de	
overledene	een	erfelijke	hartziekte	wordt	vastgesteld,	kunnen	familieleden	op	dezelfde	
ziekte	worden	onderzocht	door	middel	van	cardiologisch	en	genetisch	onderzoek.
In Hoofdstuk 1 van	het	proefschrift	wordt	een	kort	overzicht	gegeven	van	de	doelstellingen	
en	de	inhoud	van	het	proefschrift.	
Een	 uitgebreide	 inleiding	 wordt	 gegeven	 in	 hoofdstuk 2.1.	 Daarnaast	 worden	 ook	 de	
definities	die	betrekking	hebben	op	een	plotseling	overlijden	op	jonge	leeftijd	besproken	
en	 wordt	 ingegaan	 op	 de	 huidige	 inzichten	 met	 betrekking	 tot	 het	 post-mortem	
onderzoek	bij	de	overledene	en	de	cardiogenetische	screening	van	familieleden.
In hoofdstuk 2.2 worden	de	achtergronden	en	de	opzet	van	het	CAREFUL	(The	yield	of	
cardiogenetic	screening in first-degree	relatives	of	sudden	cardiac	and	unexplained death
victims	<45	years)	onderzoek	beschreven.	Eén	van	de	doelstellingen	van	het	CAREFUL	
onderzoek	 is	 om	 gegevens	 te	 verzamelen	 over	 de	 incidentie	 (het	 aantal	 gevallen	 per	
tijdseenheid,	 bijvoorbeeld	 gedurende	 een	 jaar)	 en	 van	 de	 oorzaken	 van	 plotseling	
overlijden	op	jonge	leeftijd	in	Nederland.	Het	CAREFUL	onderzoek	wordt	uitgevoerd	in	
vier	 regio’s	 in	 Nederland,	 die	 in	 totaal	 28%	 van	 de	 Nederlandse	 bevolking	 omvatten.	
Gegevens	van	slachtoffers	van	plotseling	overlijden	(1-44	jaar)	worden	verzameld	door	
ritverslagen	 van	 de	 ambulancediensten	 en	 lijkschouwverslagen	 van	 de	 gemeentelijk	
lijkschouwers	 systematisch	 te	 doorzoeken.	 Van	 alle	 slachtoffers	 wordt	 nagegaan	 of	 er	
een	 obductie	 heeft	 plaatsgevonden	 en	 zo	 ja,	 wat	 de	 bevindingen	 bij	 obductie	 waren.	
De	verwachting	is	dat	het	CAREFUL	onderzoek	meer	inzicht	zal	geven	in	de	incidentie	
en	oorzaken	van	plotseling	overlijden	op	jonge	leeftijd.	We	hopen	dat	deze	informatie	
gebruikt	kan	worden	om	in	de	toekomst	erfelijke	hartziekten	bij	familieleden	beter	te	
kunnen	opsporen	en	(indien	nodig)	tijdig	te	behandelen.


158
                                                                                      Samenvatting


In Hoofdstuk 3.1 schatten	 we	 de	 incidentie	 en	 oorzaken van	 plotseling	 overlijden	
                            	                      	
                  	
op	 jonge	 leeftijd	 in	 Nederland	 met	 behulp	 van	 overlijdensverklaringen,	 die	 staan	
geregistreerd	in	het	doodsoorzakenregister	van	het	Centraal	Bureau	voor	de	Statistiek	       	 	
(CBS).	 Veelvoorkomende	 oorzaken	 van	 plotseling	 overlijden	 werden	 aan	 de	 hand	 van	
een	literatuuronderzoek	in	kaart	gebracht.	Op	basis	van	deze	oorzaken	en	met	behulp	
                                 	                                    		
van	codes	werden	de	slachtoffers	van	plotselinge	dood	geïdentificeerd	uit	de	registratie	          	
                            	
van	het	CBS.	De	incidentie	van	plotseling	overlijden	van	personen	van	1-39	jaar	was	2,1	
per	100.000	personen	per	jaar.	Plotseling	overlijden	kwam	vaker	voor	bij	mannen	dan	bij	
                                   	                                                	
vrouwen	en	nam	toe	met	de	leeftijd.	Het	grootste	gedeelte	van	de	slachtoffers	overleed	
                                                     	
aan	een	aandoening	van	het	hart.	De	incidentie	van	plotselinge	hartdood	was	1.6	per	
100.000	personen	per	jaar.	
In hoofdstuk 3.2	worden	de	regionale	verschillen	in	incidentie	van	plotselinge	hartdood	
                                                                    	
                                              	
bij	jonge	personen	(1-39	jaar)	en	de	relatie	met	sociaal-economische	status	beschreven.	
Uit	elke	provincie	in	Nederland	werden	gevallen	van	plotselinge	hartdood	op	jonge	leeftijd	    	
                      		
(1-39	jaar)	geïdentificeerd	met	behulp	van	het	doodsoorzakenregister	van	het	CBS	(zie	
hoofdstuk 3.1).	Regionale	incidentieschatti
                                       	        		ngen	werden	gedaan	voor	subgroepen	van	
1-29	jaar	en	van	30-39	jaar.	Er	werden	regionale	verschillen	gevonden	in	de	incidentie	            	
                                            	                 	
van	plotselinge	hartdood	op	jonge	leeftijd	in	beide	leeftijdsgroepen.	Bij	mannen	tussen	
de	30	en	39	jaar	was	een	lage	sociaal-economische	status	gerelateerd	aan	een	relatief	           	
                	
hoge	incidentie	van	plotseling	overlijden.	Dit	kan	mogelijk	verklaard	worden	door	een	
                                   	
toename	van	het	aantal	slachtoffers	van	plotseling	overlijden	door	slagaderverkalking,	
voornamelijk	bij	mannen	na	het	30ste	levensjaar.	
In hoofdstuk 3.3	worden	de	eerste	resultaten	van	het	CAREFUL	onderzoek	beschreven.	
                                                               	
Op	 basis	 van	 de	 eerste	 gegevens,	 werden	 de	 incidentie	 en	 oorzaken	 van	 (natuurlijk)	
plotseling	overlijden	van	jonge	personen	(1-44	jaar)	in	Nederland	onderzocht.	Tijdens	
het	 eerste	 studiejaar	 werden	 175	 gevallen	 van	 plotselinge	 dood	 geregistreerd;	 de	
                    	                                          	
gemiddelde	leeftijd	was	34	jaar	en	70%	van	de	slachtoffers	was	man.	De	incidentie	van	     	
                                                                             	
plotselinge	dood	was	6,8	per	100.000	personen	per	jaar	en	de	incidentie	van	plotselinge	
hartdood	was	5,5	per	100.000	personen	per	jaar.	Op	basis	van	deze	resultaten,	blijkt	de	
         	                                                                         	
incidentie	van	plotseling	overlijden	twee	keer	zo	hoog	als	eerdere	incidentieschatti      		ngen	
op	basis	van	het	doodsoorzakenregister	van	het	CBS	aangaven	(zie	hoofdstuk 3.1).	Een	
erfelijke	 hartziekte	 was	 waarschijnlijk	 of	 kon	 niet	 worden	 uitgesloten	 in	 79%	 van	 alle	
gevallen	van	plotseling	overlijden.                                                                    6
In hoofdstuk 3.4	wordt	het	obductie	percentage	van	slachtoffers	van	plotseling	overlijden	
                                     	                            	
(1-44	jaar)	in	Nederland	en	de	factoren	die	samenhangen	met	het	uitvoeren	van	een	
                    	
klinische	 obductie	 beschreven.	 Aangezien	 erfelijke	 hartziekten	 vaak	 de	 onderliggende	
                                                          	
oorzaak	 zijn	 van	 het	 overlijden,	 kan	 een	 obductie	 bijdragen	 aan	 de	 opsporing	 van	
erfelijke	hartziekten	bij	familieleden.	Gegevens	voor	het	onderzoek	werden	verkregen	


                                                                                               159
Chapter 6


gedurende	twee	jaar	voorafgaande	aan	het	CAREFUL	onderzoek	(2006-2008)	in	de	vier	
onderzoeksregio’s	 van	 de	 CAREFUL	 studie.	 Er	 werden	 224	 slachtoffers	 van	 plotseling	
overlijden	geregistreerd.	De	gemiddelde	leeftijd	van	overlijden	was	34	jaar	en	77%	van	
de	slachtoffers	was	man.	Bij	een	minderheid	(21%)	van	de	slachtoffers	werd	een	klinische	
obductie	uitgevoerd.	Bij	slachtoffers	met	een	blanco	medische	voorgeschiedenis	of	bij	
wie	 een	 reanimatie	 had	 plaatsgevonden,	 werd	 vaker	 een	 obductie	 verricht.	 Door	 het	
belang	van	obducties	te	benadrukken	onder	huisartsen	en	gemeentelijk	lijkschouwers,	
de	logistieke	structuur	te	verbeteren	en	de	obducties	te	vergoeden	(wat	tot	op	heden	
niet	het	geval	is)	zal	naar	verwachting	het	aantal	obducties	toenemen.	Hierdoor	zullen	
in	de	toekomst	naar	verwachting	meer	erfelijke	hartziekten	worden	gediagnosticeerd	bij	
slachtoffers	 van	 plotseling	 overlijden	 en	 kunnen	 familieleden	 op	 dezelfde	 aandoening	
worden	onderzocht	(en	indien	nodig)	worden	behandeld.	
In hoofdstuk 4.1	 wordt	 de	 cardiogenetische	 screening	 van	 familieleden	 van	 jonge	
slachtoffers	 van	 plotseling	 overlijden	 in	 een	 regionaal	 ziekenhuis	 beschreven.	
Eerdere	 onderzoeken	 naar	 het	 opsporen	 van	 erfelijke	 hartziekten	 met	 behulp	 van	
cardiogenetische	 screening	 bij	 familieleden	 werden	 uitgevoerd	 in	 academische	
ziekenhuizen,	waarbij	alleen	de	familieleden	van	slachtoffers	van	plotseling	onverklaard	
overlijden	werden	geselecteerd.	Voor	het	onderzoek	dat	is	beschreven	in	hoofdstuk	4.1,	
werden	de	gegevens	verzameld	van	slachtoffers	van	plotseling	onverklaard	en	cardiaal	
overlijden	die	plaatsvonden	tussen	2000-2006	in	het	adherentiegebied	van	het	Meander	
Medisch	 Centrum	 in	 Amersfoort.	 Resultaten	 van	 post-mortem	 onderzoek	 en	 van	
cardiogenetische	 screening	 van	 eerstegraads	 familieleden	 (indien	 uitgevoerd)	 werden	
verzameld.	Familieleden	van	slachtoffers	van	plotseling	overlijden	werden	uitgenodigd	
voor	 aanvullend	 cardiogenetisch	 onderzoek,	 wanneer	 dit	 nog	 niet	 was	 gedaan.	 In	
totaal	werden	16	gevallen	van	plotselinge	hartdood	en	plotselinge	onverklaarde	dood	
geregistreerd	 en	 daarnaast	 nog	 vier	 patiënten	 die	 succesvol	 werden	 gereanimeerd	
na	 een	 hartstilstand.	 De	 cardiogenetische	 screening	 van	 in	 totaal	 37	 familieleden	 van	
12	 slachtoffers	 leidde	 tot	 de	 diagnose	 Brugada	 syndroom	 bij	 drie	 familieleden	 en	 tot	
de	 waarschijnlijke	 diagnose	 aritmogene	 rechterkamer	 cardiomyopathie	 bij	 twee	
familieleden.	In	totaal	kon	er	bij	14%	van	de	gescreende	familieleden	een	(waarschijnlijk)	
erfelijke	hartziekte	worden	vastgesteld,	wat	een	aanzienlijk	percentage	is,	maar	lager	dan	
verwacht	op	basis	van	eerdere	onderzoeken.	Uit	het	onderzoek	bleek	dat	in	de	reguliere	
zorg	 de	 eerstegraads	 familieleden	 vaak	 niet	 werden	 verwezen	 voor	 cardiogenetisch	
onderzoek	 en	 dat	 de	 cardiogenetische	 screening	 niet	 altijd	 op	 een	 gestructureerde	
manier	 werd	 uitgevoerd.	 Dit	 zou	 het	 lage	 percentage	 van	 gediagnosticeerde	 erfelijke	
hartziekten	 bij	 de	 onderzochte	 familieleden	 kunnen	 verklaren.	 Het	 screenen	 van	
familieleden	 in	 gespecialiseerde	 centra,	 waarbij	 er	 een	 nauwe	 samenwerking	 bestaat	
tussen	de	klinische	genetica,	de	cardiologie	en	de	pathologie,	zal	mogelijk	lijden	tot	een	


160
                                                                                     Samenvatting


verhoging	van	het	percentage	erfelijke	hartziekten	dat	wordt	gevonden	bij	familieleden.	
In hoofdstuk 4.2 wordt	 een	 onderzoek	 beschreven	 naar	 de	 mogelijke	 voordelen,	
                              	 	                           	
nadelen	 en	 de	 kosten-effectiviteit	 van	 cardiogenetische	 screening	 op	 hypertrofische	  	
cardiomyopathie	(HCM)	ter	voorkoming	van	plotseling	overlijden.	Een	analytisch	model	   	
                                        	
werd	ontwikkeld	om	cardiogenetische	screening	te	vergelijken	met	het	niet-screenen	van	
                                                                          	
eerstegraads	familieleden	(van	20	jaar	en	van	45	jaar)	van	een	patiënt	met	HCM.	De	kosten-
   	 	                          	
effectiviteit	van	cardiogenetische	screening	werd	ook	onderzocht	voor	familieleden	van	
          	                                                                   	
slachtoffers	van	plotselinge	hartdood	waarbij	HCM	werd	gediagnosticeerd	met	behulp	
van	post-mortem	onderzoek.	De	resultaten	van	het	onderzoek	lieten	zien	dat	bij	20-jarige	
                                     	                          	
familieleden	 door	 cardiogenetische	 screening	 de	 helft	 van	 de	 plotselinge	 hartdoden	
                                                                        	
kon	worden	voorkomen	(6%	versus	12%),	de	levensverwachting	toe	nam	(44,0	versus	
42,7	 jaren),	 de	 voor	 kwaliteit	 van	 leven	 gecorrigeerde	 gewonnen	 levensjaren	 (QALYs)	
toenamen	(30,2	versus	29,0	QALYs)	en	dat	de	totale	kosten	toenamen	(	€13.218	versus	
                  	                        	                                           	
€	 580)	 per	 patiënt.	 Het	 cardiogenetisch	 screenen	 van	 familieleden	 van	 patiënten	 met	
                         	 	
HCM,	bleek	kosten-effectiever	te	zijn	voor	jonge	familieleden	(20	jaar)	dan	voor	oudere	
                                           	 	
familieleden	 (45	 jaar).	 De	 kosten-effectiviteit	 nam	 toe	 wanneer	 familieleden	 van	 een	
          	                                                              	
slachtoffer	 van	 plotseling	 overlijden	 (door	 HCM)	 cardiogenetisch	 werden	 onderzocht.	
                                       	 	
Onderzoeken	naar	de	kosten-effectiviteit	van	screening	op	erfelijke	hartziekten	dragen	
                                              	
bij	 aan	 het	 ontwikkelen	 van	 preventieve	 maatregelen	 om	 plotselinge	 dood	 op	 jonge	
     	
leeftijd	te	kunnen	voorkomen.
In de discussie	worden	strategieën	beschreven	om	de	reguliere	zorg	na	een	plotseling	
                            	
overlijden	op	jonge	leeftijd	te	verbeteren,	zodat	in	de	toekomst	meer	erfelijke	hartziekten	
        	                                                                   	          	
vroegtijdig	 kunnen	 worden	 opgespoord	 en	 behandeld.	 Registratie	 van	 patiënten	 met	
                                                                                    	
erfelijke	 hartziekten	 en	 de	 verzameling	 van	 gegevens,	 maakt	 toekomstig	 onderzoek	
                                                     	 	                          	
naar	de	voordelen,	de	nadelen	en	de	kosten-effectiviteit	van	cardiogenetische	screening	
                                           	
mogelijk.	Op	basis	van	deze	informatie	kunnen	richtlijnen	worden	ontwikkeld	of	worden	
                          	                                               	
aangepast	ter	preventie	van	plotseling	overlijden	op	jonge	leeftijd.	De	eerste	resultaten	
van	het	CAREFUL	onderzoek	laten	zien	dat	nauwkeurige	gegevensverzameling	belangrijk	
                    	                        	
is	 voor	 het	 schatten	 van	 de	 incidentie	 en	 voor	 het	 in	 kaart	 brengen	 van	 de	 oorzaken	
                                                 	
van	 plotselinge	 (hart)dood	 op	 jonge	 leeftijd.	 Zo	 laten	 de	 resultaten	 van	 het	 CAREFUL	
                                    	
onderzoek	zien	dat	de	incidentie	van	plotselinge	hartdood	twee	keer	zo	hoog	is	als	werd	
geschat	op	basis	van	eerdere	onderzoeken.	Uitbreiding	van	de	CAREFUL	registratie	naar	      	
een	landelijke	registratie	maakt	onderzoek	naar	risicofactoren,	die	zijn	gerelateerd	aan	
                            	                                                                         6
                                               	
een	plotseling	overlijden	op	jonge	leeftijd	mogelijk.	Op	basis	van	deze	informatie	kunnen		
                                                                               	
maatregelen	worden	genomen	om	plotseling	overlijden	op	jonge	leeftijd	te	voorkomen.




                                                                                              161
          Summary
      Samenvatting
        Dankwoord
  Curriculum	Vitae
List	of	publications
Chapter 6


Het	 schrijven	 van	 dit	 proefschrift	 heb	 ik	 te	 danken	 aan	 veel	 mensen	 met	 wie	 ik	 heb	
samengewerkt,	 die	 me	 hebben	 geholpen	 en	 voor	 de	 nodige	 ontspanning	 hebben	
gezorgd.	Een	aantal	van	deze	mensen	zou	ik	graag	in	het	bijzonder	willen	bedanken.

Beste	Prof.	dr.	P.A.F.M.	Doevendans,	hartelijk	dank	voor	uw	hulp	en	het	vertrouwen	bij	
de	uitvoering	van	dit	onderzoek.	Het	was	fijn	dat	u	vanaf	de	zijlijn	meekeek	en	dat	ik	bij	
u	terecht	kon	met	problemen	of	inhoudelijke	vragen.	Beste	Prof.	Dr.	A.A.M	Wilde,	graag	
wil	 ik	 u	 bedanken	 voor	 de	 steun	 en	 vrijheid	 voor	 het	 uitvoeren	 van	 dit	 onderzoek	 en	
voor	de	inhoudelijke	en	kritische	commentaren	op	de	stukken.	Prof.	dr.	M.L.	Bots,	beste	
Michiel,	ik	vond	het	erg	fijn	om	met	je	samen	te	mogen	werken.	Ik	heb	bewondering	
voor	je	‘helikopterview’	waardoor	je	altijd	weer	de	vinger	op	de	zere	plek	wist	te	leggen.	
We	 waren	 het	 aanvankelijk	 niet	 altijd	 eens,	 maar	 uiteindelijk	 toch	 vaak	 weer	 wel.	 Je	
laagdrempelige	 begeleiding,	 vertrouwen	 en	 eerlijkheid	 hebben	 mij	 tot	 de	 eindstreep	
gebracht.	Heel	erg	veel	dank	hiervoor.	Dr.	A.	Mosterd,	beste	Arend,	wij	kennen	elkaar	al	
uit	de	kliniek	in	Amersfoort	en	dankzij	jou	ben	ik	betrokken	geraakt	bij	dit	onderzoek.	Ik	
ben	erg	blij	en	dankbaar	dat	ik	deze	kans	heb	gekregen.	Bedankt	voor	je	engelengeduld	en	
voor	je	inhoudelijke	zeer	gedetailleerde	commentaar	op	de	stukken.	Jouw	enthousiasme	
voor	 het	 onderzoek	 en	 de	 kliniek	 waren	 een	 belangrijke	 motiverende	 factor	 voor	 de	
afronding	van	dit	onderzoek.	

Graag	wil	ik	leescommissie	van	dit	proefschrift	bestaande	uit	Prof.	dr.	R.N.	Hauer,	Prof.	dr.	
N.J.	de	Wit,	Dr.	A.C.	van	der	Wal,	Prof.	dr.	M.P.	van	den	Berg	en	Prof.	dr.	E.R.	Behr	danken	
voor	het	lezen	en	beoordelen	van	mijn	proefschrift.	Prof.	dr.	Behr,	thank	you	for	your	
willingness	to	read	and	assess	my	thesis.

De	 leden	 van	 de	 CAREFUL-projectgroep,	 de	 betrokken	 medewerkers	 van	 de	 GGD’s	
en	ambulancediensten	en	de	onderzoekers	van	de	ARREST	studie,	zou	ik	graag	willen	
bedanken	voor	hun	hulp	bij	het	opzetten	en	uitvoeren	van	het	CAREFUL	onderzoek	en	
voor	hun	belangrijke	bijdrage	aan	dit	proefschrift.	
In	 het	 bijzonder	 zou	 ik	 nog	 een	 aantal	 mensen	 willen	 noemen	 met	 wie	 ik	 veel	 heb	
samengewerkt;	Prof.	dr.	I.M.	van	Langen,	beste	Irene,	bedankt	voor	al	je	hulp	en	steun	bij	
het	opzetten	van	de	CAREFUL	studie	en	voor	je	gedetailleerde	commentaren	en	inzichten	
op	het	gebied	van	de	cardiogenetica.	Ik	heb	er	veel	van	geleerd!	Dr.	A.	Vink,	beste	Aryan,	
je	hulp	en	kennis	op	het	gebied	van	de	pathologie	waren	essentieel	voor	de	voltooiing	
van	dit	proefschrift.	Ik	vond	het	erg	prettig	om	met	je	samen	te	werken	en	hoop	dat	er	
in	de	toekomst	nog	meer	mogelijkheden	komen	om	samen	onderzoek	te	kunnen	doen.	
Dr.	E.	Birnie,	beste	Erwin,	hartelijk	dank	voor	je	kritische	inbreng	tijdens	het	opzetten	en	
uitvoeren	van	het	onderzoek.	Drs.	J.J.	van	der	Smagt,	beste	Jasper,	bedankt	voor	de	fijne	


164
                                                                                      Dankwoord


                                                                       	
samenwerking	en	ik	hoop	dat	je	ook	in	de	toekomst	bij	de	cardiogenetica	betrokken	zult	
                                                 	
blijven.	Beste	Drs.	C.	van	der	Werf,	beste	Christiaan,	wij	kennen	elkaar	al	uit	Nicaragua,	
waar	we	in	het	HEODRA	ziekenhuis	in	Leon	onze	echte	‘onderzoeksvuurdoop’	hebben	
                 	                                                       	
gehad.	Het	was	fijn	dat	we	samen	het	CAREFUL	onderzoek	konden	opzetten	en	uitvoeren	
              	
en	dat	we	altijd	alle	grote	(en	kleine)	dingen	konden	overleggen.	Chris,	bedankt	voor	
                                		ng	van	het	onderzoek.
alles	en	succes	met	de	voortzetti

                                                	                              	
Ook	zou	ik	graag	alle	co-auteurs	van	de	artikelen	waarop	dit	proefschrift	is	gebaseerd	
willen	bedanken	voor	al	hun	inbreng,	kennis	en	kunde.	De	rood	gekleurde	stukken	tekst,	
                   	                                             	
opmerkingen,	kritische	commentaren	en	nog	veel	meer	kritische	commentaren	hebben	
de	stukken	absoluut	verbeterd.
                                                               	
Dr.	J.P.	Greving,	beste	Jacoba,	heel	erg	bedankt	voor	de	fijne	samenwerking.	Door	jou	
                     	 	
werd	 de	 kosten-effectiviteit	 analyse	 een	interessant	 en	 leerzaam	 project	 (ik	 zou	 er	zo	
weer	aan	beginnen!).	Dr.	I.	Vaartjes,	beste	Ilonca,	het	was	pretti  		g	en	gezellig	om	met	je	
samen	te	werken.	Bedankt	voor	al	je	hulp	en	handige	tips!	 	

                                                                  	
Ook	 de	 collega’s	 van	 de	 cardiologie	 en	 de	 klinische	 genetica	 zou	 ik	 graag	 willen	
bedanken	voor	hun	nutti  		ge	feedback	op	studies,	en	voor	de	leerzame	besprekingen	en	
onderwijsmomenten.

Beste cardiologen uit Amersfoort; als 5e	jaars	co-assistent	(en	daarna)	is	in	Amersfoort	
                             	                                          	
de	basis	voor	dit	proefschrift	gelegd.	Ik	zal	de	gezellige	en	leerzame	tijd	op	‘de	berg’	niet	
snel	vergeten.	Heel	erg	bedankt	voor	alles.

Heini	Meegdes,	Tamara	Rietveld	en	Coby	van	Rijn	hartelijk	dank	voor	jullie	hulp	bij	het	
organiseren	en	regelen	van	afspraken	en	heel	veel	andere	dingen!

Lieve	Marieke,	Margriet,	Madeleine,	Jaap,	Corinne,	Sanne,	Marjolein,	Ilonca,	Gerrie-Cor,	
Anne,	Maud,	Caroline	en	alle	andere	(oud)	collega	promovendi	van	het	Julius	Centrum.	
                                                                      	            		e,	op	
Bedankt	voor	alle	gezelligheid	de	laatste	jaren;	in	de	wandelgangen,	tijdens	de	koffi
                                	
congressen	en	alle	overige	locaties	buiten	het	Julius...

Een	dag	niet	scherp	was	een	dag	niet	geleefd	in	kamertje	4.143.	Lieve	Lennie,	Susanne,	             6
                	                                  	         	
Roderick,	Martijn,	Bauke,	Florianne,	Miriam	en	Eefje;	ontzettend	bedankt	voor	de	leuke	
 	                                                                  	
tijd	met	natuurlijk	als	hoogtepunt	ons	zeildagje	J.	Bauke	en	Martijn,	met	jullie	op	de	
       	                	
schrijfkamer	was	ik	altijd	op	de	hoogte	van	het	laatste	voetbalnieuws	en	verzekerd	van	
           		e.	Bedankt	voor	alle	support	en	gezelligheid.	Len	en	Suus,	dames	van	‘de	
lekkere	koffi
Interne’	en	mijn	paranimfen!	Fijn	dat	jullie	me	willen	bijstaan	op	de	‘grote	dag’.	Ik	heb	


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Chapter 6


het	met	jullie	aan	eilandje	twee	ontzettend	naar	mijn	zin	gehad	en	kijk	mede	dankzij	
jullie	terug	op	een	hele	mooie	tijd.	Ik	zal	jullie	allemaal	heel	erg	missen

                                                                                                     	
Lieve	 Hilde,	 Hinke	 en	 Jertske,	 jullie	 houden	 het	 al	 sinds	 de	 kleuterschool	 met	 mij	 uit!	
Ondanks	dat	we	allemaal	wat	anders	zijn	gaan	doen,	zijn	jullie	niet	weg	te	denken	uit	
mijn	leven.	Hil,	bedankt	voor	je	eerlijke	feedback	op	van	alles	en	nog	wat.	Met	jou	kan	ik	
lachen	en	ruzie	maken.	Ik	ben	dol	op	je.

Lieve	 Alma,	 Maaike,	 Charles,	 Arco,	 Marleen,	 Sophie	 en	 Masja,	 bedankt	 voor	 al	 jullie	
support,	hulp	en	gezelligheid	gedurende	de	studiejaren	en	daarna!	Ik	ben	gezegend	met	
vrienden	als	jullie.	Charles,	behalve	een	goede	vriend,	was	je	de	laatste	jaren	ook	collega,	
studiegenoot,	redder	in	nood	en	natuurlijk	mijn	zonnetje	op	het	Julius.	Ik	zal	je	missen.

Lieve	oma,	98	jaar	en	de	meest	eigenwijze	persoon	op	aarde!	Ik	vind	het	heerlijk	om	bij	
u	te	zijn	en	ik	hoop	dat	er	nog	veel	dagen	volgen	voor	de	open	haard	en	met	ijs	op	het	
Diep.	

Als	laatste	wil	ik	mijn	ouders,	broer,	zus,	zwager	en	neefjes	bedanken	voor	hun	eindeloze	
steun,	 liefde,	 interesse,	 hulp,	 gezelligheid	 en	 natuurlijk	 voor	 alle	 gevraagde	 en	 (met	
uitzondering)	ongevraagde	adviezen.	Met	zo’n	hechte	en	warme	familie	kun	je	alles	aan!!	
Lieve	Mariek,	Erik,	Lars,	Stijn,	Rick,	pap	en	mam,	dank	jullie	wel.




166
          Summary
      Samenvatting
        Dankwoord
  Curriculum Vitae
List	of	publications
                                                                                   Curriculum Vitae


                                                                 	          	
Anneke	Hendrix	was	born	on	December	23th 1980	in	Maartensdijk.	After	graduating	from	
                                     	
the	Ulenhofcollege	(Atheneum)	in	Doetinchem	in	1999,	she	started	medical	school	at	
Utrecht	University.	

During	her	study	she	did	internships	in	gynaecology	and	internal	medicine	at	the	HEODRA	
hospital	in	Leon,	Nicaragua.	She	completed	her	study	with	an	internship	cardiology	in	the	
Meander	Medical	Center	in	Amersfoort	and	graduated	from	medical	school	in	December	
         	           	
2006.	After	graduation	she	worked	as	a	resident	in	cardiology	in	the	Meander	Medical	
Center	(Dr.	P.J.	Senden).

In	2007	she	began	her	PhD	project	on	‘Sudden	cardiac	death	in	the	young:	incidence	and	
consequences’	as	described	in	this	thesis.	The	project	was	directed	by	the	Interuniversity	
                   	
Cardiology	Institute	of	the	Netherlands.	She	conducted	her	research	project	at	the	Julius	
Center	for	Health	Sciences	and	Primary	Care	of	the	Utrecht	University	Medical	Center	
and	was	supervised	by	Prof.	dr.	P.A.F.M.	Doevendans,	Prof.	dr.	M.L.	Bots,	Prof.	dr.	A.A.M.	
Wilde	(Academic	Medical	Center,	Amsterdam)	and	Dr.	A.	Mosterd.	In	2010	she	obtained	
a	Master	of	Science	degree	in	clinical	epidemiology	at	Utrecht	University.	In	2011	she	
will	 start	 as	 a	 resident	 in	 cardiology	 in	 the	 Utrecht	 University	 Medical	 Center	 under	
supervision	of	Dr.	J.H.	Kirkels	and	Prof.	dr.	P.A.F.M.	Doevendans.




                                                                                                      6




                                                                                               169
          Summary
      Samenvatting
         Dankwoord
   Curriculum	Vitae
List of publications
                                                                             List of publications


                	
List	of	publications	related	to	this	thesis
   §                                                                               	
       Sudden	cardiac	death	in	the	young:	epidemiology	and	cardiogenetic	evaluation	       	
                	                     	
       of	 victims	 and	 their	 relatives.	 Hendrix A, Bots ML, Mosterd A. Clinical
                     	
       cardiogenetics,	from	basic	science	to	clinical	medicine.	Edited	by	H.F.	Baars,	J.J.	
       van der Smagt, P.A.F.M. Doevendans. 2011; 403-412.
   §        	
       Rationale	and	design	of	the	CAREFUL	study.	Hendrix A, van der Werf C, Bots
                                               	
       ML,	Birnie	E,	van	der	Smagt	JJ,	Borleffs	CJW,	Vink	A,	van	Weert	HC,	Doevendans	
       PAFM,	Wilde	AAM,	Mosterd	A,	van	Langen	IM,	on	behalf	of	the	CAREFUL	study	
       group.	Neth Heart J 2010;18:286-290
   §   Sudden	death	in	persons	younger	than	40	years:	incidence	and	causes.	Vaartjes	
       I, Hendrix A,	Hertog	EM,	Grobbee	DE,	Doevendans	PAFM,	Mosterd	A,	Bots	ML.	
       Eur J Cardiovasc Prev Rehabil 2009;16:592-596.
   §                 	
       Regional	differences	in	incidence	of	sudden	cardiac	death	in	the	young.	Hendrix
       A,	Vaartjes	I,	Mosterd	A,	Reitsma	JB,	Doevendans	PAFM,	Grobbee	DE,	Bots	ML.	
       Neth J Med. 2010; 68:274-279
   §                                                             	
       Incidence	and	causes	of	sudden	death	in	the	young;	first	results	of	the	CAREFUL	
       study. Hendrix A,	 van	 der	 Werf	 C,	 Birnie	 E,	 Bots	 ML,	 Doevendans	 PAFM,	 van	
       der	Smagt	JJ,	Vink	A,	van	Weert	HC,	Wilde	AAM,	Mosterd	A,	van	Langen	IM,	on	
       behalf	of	the	CAREFUL	study	group.	Submitted.	  	
   §                                     	                                        	
       Plotselinge	dood	op	jonge	leeftijd	(1-44	jaar)	in	Nederland:	obductiepercentage	
       en	kenmerken	die	samenhangen	met	het	verrichten	van	een	klinische	obductie.	          	
       Geurts	 S,	 Hendrix A,	 van	 der	 Werf	 C,	 Bots	 ML,	 Vink	 A,	 Birnie	 E,	 Doevendans	
       PAFM,	Wilde	AAM,	van	Langen	IM,	Mosterd	A.	Submitted.	       	
   §                  	        	        	                  	      	
       Cardiogenetic	 evaluation	 of	 first-degree	 relatives	 after	 sudden	 cardiac	 death	
                                  	                                            	
       in	 the	 young:	 a	 population	 based	 approach.	 Hendrix A,	 Borleffs	 CJW,	 Vink	 A,	
       Doevendans	 PAFM,	 Wilde	 AAM,	 van	 Langen	 IM,	 van	 der	 Smagt	 JJ,	 Bots	 ML,	
       Mosterd A. Europace 2011.	In	press.	
   §                                                                                 	 	
       Screening	 for	 familial	 hypertrophic	 cardiomyopathy:	 a	 cost-effectiveness	
       analysis. Hendrix A,	Mosterd	A,	Doevendans	PAFM,	Post	JG,	Bots	ML,	Greving	
                   	
       JP.	Submitted.


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