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									                  Reñaca XI International
                  Course of Cardiology



           Myocardial Viability:
            New Techniques
          Panithaya Chareonthaitawee, MD
                & Allan S. Jaffe, M.D.
                   Division of Cardiovascular Diseases
                                Mayo Clinic
                          Rochester, Minnesota
                             August 19, 2008
 *Dr. Jaffe is a consultant and receives research support from Siemens and
Beckman - Coulter. He is or has been a consultant to most of the major diagnostic
companies as well as Novartis and Hoffmann LaRoche.
Myocardial Viability Update
1. Clinical relevance
2. Noninvasive techniques
3. Diagnostic and prognostic literature
4. Limitations
5. What’s new
    72 year-old Woman

•   Diabetic
•   Heart failure NYHA class III
•   LVEF 26%
•   Moderately dilated LV
•   Multivessel coronary artery disease
•   Impaired renal function
•   History of TIA
72 year-old Woman
   Heart Failure
   What next?
• Medical therapy?
• Stress imaging?
• Viability imaging?
• Coronary angiography?
• Device therapy?
                              Cardiovascular                Systemic and
 Myocardial factors        non-myocardial factors           other factors
• Remote myocardium         • CAD extent/               • Renin-angiotensin-
                             endothelial function         aldosterone system
• Scar tissue
                            • Arrhythmias               • Sympathetic nervous
• Hibernating                                             system
 myocardium                 • Mitral valve function
                                                        • Vasodilators
• Ischemia/stunning         • Ventricular synchrony
                                                        • Natriuretic peptides
• Apoptosis                 • Diastolic function        • Cytokines
• Hypertrophy                                           • Diabetes mellitus and
                                                          metabolic syndrome
                                                        • Sleep apnea
                                                        • Renal disease
                                                        • Environmental
                                                        • Age


                              Ischemic
                          Heart Failure

     Chareonthaitawee P et al, J Am Coll Cardiol 2005;46:567-74.               CP1173554-2
                                         Duke Database
                               Medical therapy vs. CABG

                      100
10 year survival, %




                                          74%
                      75
                               65%                         62%
                                                 50%                         56%
                      50

                                                                    27%
                      25

                       0
                            Medical Surgical    Medical Surgical   Medical Surgical
                                EF >50%           EF 35-50%            EF <35%
                            Circulation 1992
                                                   SPECT MPI
Rate of Revascularization and Perfusion Results

                            30
    Revascularization (%)


                                        Large fixed perfusion defects
                                        Large reversible perfusion defects
                                        No or small perfusion defects
                            20
                                     P=0.161
                                                                                  13%

                            10


                            0
                                 0             1        2            3       4      5
                 No. at
                 risk                                        Years
               130         84                           75           66      46     27
                75         52                           42           32      15     10
               114       100                            85           71      41     25
W Miller et al: AHJ 147(4), 2004                                                        CP1314690-9
           Rationale for Viability Testing


Improve contractile function
Improve outcome                  ↑Periprocedural risk
Improve symptoms                 ++Co-morbidities
Reduce ischemic burden
Decrease arrhythmic potential
Decrease adverse remodeling




            Selection of appropriate patients
Types of Viable Myocardium
• Normal/remote myocardium
• Stunned myocardium
  • Contractile dysfunction from transient
      ischemia, followed by restoration of flow
  •   Likely will improve function with time
      (unless repetitive stunning)
• Hibernating myocardium
  • Chronic contractile dysfunction from
      persistently low flow
  •   May improve function with improvement
      of flow

  Chareonthaitawee P et al, J Am Coll Cardiol 2005;46:567-74.
     Dysfunctional
        Viable



Stunning       Hibernation




                         CP1275728-1
Viable Myocardium


                    Stunned



                    Hibernating
                        PET Viability
                        Scan Patterns
                    Contractility                  Perfusion   Metabolism
Normal                       N                        N            N


Stunning                                            -N             N-


Hibernation


Scar


   Schelbert et al, J Nucl Med 35 (Suppl), 1994.
Viability Imaging Techniques
            Nuclear
  • PET
  • SPECT
            Viability PET Study
• Traditionally the gold standard
• Two sets of resting images to detect viable
 and hibernating myocardium:
  • Perfusion image (usually with N-13 ammonia
       or rubidium-82)
   •   Glucose metabolic image (with F-18
       fluorodeoxyglucose = FDG)
                HO


          HO                           OH

           HO              18F
                 Myocyte FDG Uptake
          Normal Myocyte                                           Ischemic Myocyte


                                                                               Glucose 6-phosphatase
                 Glucose 6-phosphatase


  FDG
                          X
                                                             FDG
                                                            FDG          FDG
                                                                             FDG
                                                                                           X        FDG-6-P
             FDG                    FDG-6-P
                                                            FDG        FDG
FFA        FFA
                                                           FDG         FDG
FFA        FFA
                                                           FDG         FDG                                  Glycolytic
                                              Glycolytic
FFA        FFA
                      Hexokinase              Pathway      FDG         FDG          Hexokinase              Pathway
FFA        FFA
                                                           FDG         FDG
FFA        FFA
                                                           FFA         FFA
FFA        FFA                                                                                        G6P
   D-          D-                    G6P                        D-         D-
Glucose     Glucose                                          Glucose    Glucose
                                                                                   Glucose 6-phosphatase
                   Glucose 6-phosphatase
    72 year-old Woman

•   Diabetic
•   Heart failure NYHA class III
•   LVEF 26%
•   Moderately dilated LV
•   Multivessel coronary artery disease
•   Impaired renal function
•   History of TIA
                72 year-old Woman
                 SPECT Sestamibi

SA     Stress     Rest         Stress     Rest


Apex                     HLA




Mid


                         VLA
Base

                          Gated SPECT LVEF = 27%
             76 year-old Woman
                Viability PET

SA     NH3      FDG             NH3   FDG

Apex
                       HLA


Mid



                       VLA
Base
         72 year old female
Before CABG – LVEF = 26%




After CABG – LVEF = 45%
                      Nuclear and Echo
         Prediction of Contractile Recovery
                                                               Sensitivity
                                                               Specificity
        100
                                                              93
         80                86           88
                 81   80                            81
         60                                              66
                                59
    %                                          50
                                                                   58
         40

         20

          0
                  DE        TI-RR        TI-RI      MIBI       PET
Studies (no.)       32        22              11      20        20
Patients (no.)   1,090       557             301     488       598

          Bax et al Curr Prob Cardiol 2001                              CP1173554-4
           Contractile Recovery
           in Akinetic Segments
                                                      PPV

    100                    94                         NPV
                80
    80                                    73        n = 156

    60
                                               41
%




    40
    20
      0
                     PET                   Echo
                     Multivessel CAD
                   mean LVEF = 25±7%
             MUGA pre and 6 months post CABG
                    n = 453 segments

    Pagano et al. Heart 1998;79:281-88.
                             PET Viability
                Improved symptoms of CHF
              200

                        r=0.87,
                        SEE=10.8
Improvement




                        P<0.001
    (%)




              100



                                                           Multivessel CAD
                                                           Mean LVEF = 28±6%

               0
                    0           20              40         60        80
                             18% Extent mismatch (%LV)
          Di Carli M et al, Circulation 1995;92:3436-44.                  CP1116396-4
                           PET and Prognosis
                                LVEF = 25±6%
                                   n=73
                      (+)PET viable                                      (-)PET Viable

100100      88   88   88   88   88   88   88   88 100100       94   94    94   94   94   94   94    94
   100                                               100       97   97
 80                                                 80                    92   92   92
            81                                                                           82   82    82
                 75
 60                                                 60

 40                   50   50   50   50   50   50 40
                                                                                          Revasc (43)
 20       p = 0.03                                  20       p = 0.79                     Med Rx (50)
  0                                                 0
      0     4    8    12   16   20   24   28   32        0     4    8     12   16   20   24   28    32

                                 Months of Follow-up


            Di Carli et al Am J Cardiol 1994
      Nuclear/Echo and Prognosis
 Meta-Analysis of 24 Studies – 3,088 Patients
                           -79.6%
                           2 =147       Revascularization
          20              P<0.0001       Medical therapy

                                 16.0
          15                                  23.0%
                                              2 =1.43
Death                                         P=0.23
 rate     10
(%/yr)                                  7.7
                                                       6.2
           5         3.2


           0
 Allman et al JACC 2002
                           Viable       Nonviable            CP1173554-5
Viability Imaging Techniques
      Limitations of Past Literature
 •   No randomized trial available
 •   Small sample sizes
 •   Referral and selection biases
 •   Variation of patient characteristics between and within cohorts
 •   Technique under investigation served as gold standard for contractile
     measurements
 •   Varied protocols, even among the same technique
 •   Arbitrary definition/criterion for viability
 •   No evaluation of graft/vessel patency at time of postrevascularization
     functional assessment
 •   No assessment of impact of peri-procedural cardiac events
 •   Limited follow-up
 •   Unknown duration of dysfunctional but viable myocardium prior to
     revascularization
 •   Unknown severity of LV remodeling prior to revascularization
 •   Lack of information about subendocardial scar
 •   Frequent exclusion of patients who did not undergo revascularization
 •   Frequent exclusion of patients who died undergoing revascularization
     Adapted from Chareonthaitawee P et al, J Am Coll Cardiol 2005;46:567-74.
Myocardial Viability Update
1. Clinical relevance
2. Noninvasive techniques
3. Diagnostic and prognostic literature
4. Limitations
5. What’s new
  Myocardial Viability Update
        What’s New?
• PARR-2
• MRI delayed hyperenhancement and
 prognosis
• CT delayed enhancement for viability
• Prediction of CRT response
Viability Imaging Techniques
      Limitations of Past Literature
 •   No randomized trial available
 •   Small sample sizes
 •   Referral and selection biases
 •   Variation of patient characteristics between and within cohorts
 •   Technique under investigation served as gold standard for contractile
     measurements
 •   Varied protocols, even among the same technique
 •   Arbitrary definition/criterion for viability
 •   No evaluation of graft/vessel patency at time of postrevascularization
     functional assessment
 •   No assessment of impact of peri-procedural cardiac events
 •   Limited follow-up
 •   Unknown duration of dysfunctional but viable myocardium prior to
     revascularization
 •   Unknown severity of LV remodeling prior to revascularization
 •   Lack of information about subendocardial scar
 •   Frequent exclusion of patients who did not undergo revascularization
 •   Frequent exclusion of patients who died undergoing revascularization
     Adapted from Chareonthaitawee P et al, J Am Coll Cardiol 2005;46:567-74.
                PARR-2
   PET-guided Therapy vs Standard Care
         1.0


         0.8
                                                    PET arm

 Event- 0.6                                       Standard arm
  free
survival 0.4
                                                430 patients
         0.2
                                                p = 0.046

         0.0
               0           100            200      300
                                     Days
        Beanlands R et al. JACC 2007;13:2007.
                                                               CP1275728-8
             PARR-2
PET-guided Therapy vs Standard Care
         1.0

                                                     ADHERE arm
         0.8


 Event- 0.6                                          Standard arm
  free
survival 0.4
                                                      p = 0.019
         0.2


         0.0
               0   50    100    150    200     250     300   350    400
                                      Days
       Beanlands R et al: JACC 50:2002, 2007                        CP1314974-1
  Myocardial Viability Update
        What’s New?
• PARR-2
• MRI delayed hyperenhancement and
 prognosis
• CT delayed enhancement for viability
• Prediction of CRT response
       Viability Imaging
MRI Delayed Hyperenhancement


           RV

      RA        LV

                                       LA
           LA
                                  LV




  Courtesy of Dr. Thomas Gerber
   MRI Delayed Hyperenhancement
            Mechanism

            Normal Myocardium
   Gad                                   Infarcted Myocardium
injection



                                        Ischemic Myocardium




               First-Pass                        Delayed      time
                                               Enhancement


        Courtesy of Dr. Thomas Gerber
MRI Delayed Hyperenhancement
                                     Mechanism
             Na                 Na                   Na                       Na                  Na
                                                                                                                 Gd
     Na                                    Gd                                                Gd    Na
                                                                                                                           Na
                                     Na                                            Na
         K                                 Na
                  K                             Gd        Na    Gd
Gd                         Gd                                                                          Gd

                                      Gd              Na
     K        K        K                                            Gd   Na             Na                            Na
                                           Na         Gd
                                                                                                  Na
Na                                              Na             Gd
                                                                              Gd        Gd
          K        K                 Gd
Gd
                                                 Gd             Na
                                                                                                            Gd
                                                          Gd
     K        K        K
                                      Gd                       Na
                                           Na         Na
                                                                         Gd



intact cell membrane ruptured cell membrane                                           collagen matrix
(viable myocardium)     (acute infarction)                                          (chronic infarction)

                  Courtesy of Dr. Ray Kim
                    PET vs ceCMR
               Diagnostic Accuracy
                                                                         Sensitivity
                                                       97
    100                                                                  Specificity
                  87
    80                       76
                                                                    68
    60
%




    40

    20

      0
                       PET                                  ceCMR


                                  n = 29 patients
                                  Mean LVEF = 32±10%



          Adapted from Kühl et al. Eur Heart J 2006;27:846-53.
           PET vs ceMRI
         Viable Myocardium

                               Pre-revasc
                               LVEF 25%




                               Post-revasc
                               LVEF 45%




Adapted from Kühl et al. Eur Heart J 2006;27:846-53.
MRI Transmural Extent of Hyperenhancement
         and Functional Recovery
                                  100
    Contractile Improvement (%)

                                                                     n=41 patients
                                        256/329
                                  80                                 804 segments
                                                  109/183            P<0.001
                                  60
                                                            46/110
                                  40

                                  20                                 13/124
                                                                                1/58
                                   0
                                          0%      1-25%     26-50%   51-75%   76-100%
                                    Transmural Extent of Hyperenhancement
           Kim et al NEJM 2000
MRI Transmural Extent of Hyperenhancement
         and Functional Recovery
                                  100
    Contractile Improvement (%)

                                                               n=19 patients
                                  80              23/32        396 segments
                                        39/60
                                                               P<0.0001
                                  60

                                                           29/67
                                  40
                                                                    27/122
                                  20

                                   0
                                        0-25%    26-50%   51-75%   76-100%
                                    Transmural Extent of Hyperenhancement
           Barclay et al: Cardiology 2007;108:217
MRI Transmural Extent of Hyperenhancement
         Predictive Value of >50%
       100
                                                  n=19 patients
                          82
         80                                       396 segments

         60                                         54
   %




         40

         20

          0
                     Sensitivity                Specificity

       Barclay et al: Cardiology 2007;108:217
    MRI Peri-infarction and Prognosis

             1.0                                    Without late gadolinium


             0.8


             0.6
Event-free                                          With late gadolinium
 survival
             0.4

                       n=144 patients
             0.2       P=0.03

             0.0
                   0     100   200      300   400    500    600    700     800
                                     Follow-up (days)
       Yan et al: Circulation 2006;114:32                                   CP1322903-1
  Myocardial Viability Update
        What’s New?
• PARR-2
• MRI delayed hyperenhancement and
 prognosis
• CT delayed enhancement for viability
• Prediction of CRT response
64-slice CT with Contrast Injection
       Delayed Enhancement
                        n=6 pigs




    Baks et al AJR:188, 2007
    CT Infarct Size Correlates
   with Pathologic Infarct Size
          50
                   n=6 pigs
                   r2=0.92
          40       y=1x + 0.01

Infarct   30
 size,
MDCT
  (%)     20


          10


           0
               0          10      20           30   40         50
                     Infarct size, histochemical imaging (%)
     Baks et al: AJR 188:W135, February 2007                   CP1322903-3
      64-slice CT
 Following Primary PCI
                   n=36 patients




Habis et al. JACC 2007;49:1178-85.
64-slice CT Delayed Enhancement
 vs. Low-Dose Dobutamine Echo
    100                   98
                                                94        n=36
    90


    80
%




    70


    60


    50
                     Sensitivity            Specificity

          Habis et al: JACC 2007;49:1178.
  Myocardial Viability Update
        What’s New?
• PARR-2
• MRI delayed hyperenhancement and
 prognosis
• CT delayed enhancement for viability
• Prediction of CRT response
      CRT Response


           30%


                     Responder
                     Nonresponder




70%
SPECT Predicts LVEF Response to CRT

                      90              82.1
                                                               n=50
                      80
 %Pts with Positive




                                                               Mean LVEF=20%
  Echo Response



                      70
                                                               P=0.00004
                      60
                      50
                      40
                      30                                            22.7
                      20
                      10
                      0
                                     <27                            ≥27
                                               Global Scar Burden


                      Adelstein E et al. AHJ 2007;153:110
                  SPECT Scar and CRT Response
                   30

                                                         n=51 pts
                   20                                    mean LVEF=22%
Absolute change




                                                         r=0.63, P<0.001
  in LVEF (%)




                   10


                    0


                  -10

                           0            10          20       30            40
                                      Total scar score
                  Ypenburg et al: EHJ 28:33, 2007
                                                                            CP1315140-5
       PET and CRT Response

25.0                                  23.8


20.0                                           Responders
                                               Nonresponders
15.0                           13.6


10.0
                 7.2

 5.0       4.0


 0.0
        Scar Segments       Total Scar Score


 Feng D et al. ASNC 2007.
          MRI and CRT Response
         20

         15                                           r=0.480
                                                      P=0.02
         10

Change    5
 in EF
  (%)     0

          -5

         -10

         -15
               0   10     20      30     40      50     60      70
                                Total scar (%)

     White. JACC 2006;48:1953                                   CP1322903-2
            Summary
• Literature limitations
• Consider viability testing in
 moderate-to-severe ischemic LV
 systolic dysfunction
• Consider revascularization if
 significant amount of dysfunctional
 but viable myocardium present
            Summary
• Many old and new techniques
• Choice of technique depends on
 many factors
  • Local expertise
  • Availability
  • Diagnostic and prognostic literature
  • Cost
  • Body habitus
  • Severity of LV systolic dysfunction
  • Heart rate and rhythm
  • Metallic devices/pacemakers/ICDs

								
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