Non-channel drug targets in atrial fibrillation by cqe15118

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									           Atrial Fibrillation in Congestive Heart Failure

     Andreas Goette, MD, Otto-von-Guericke University, Magdeburg, Germany


Atrial fibrillation (AF) is the most common cardiac arrhythmia, with a prevalence of
2% in the general population (1-4). In addition to severe clinical symptoms like
palpitations, dizziness, dyspnea etc., AF is the single most important factor for
ischemic stroke in the population over 75 years of age (5). In about 90 % of cases AF
occurs in the presence of other cardiac diseases like hypertensive heart disease,
congestive heart failure or valve diseases (6). In only 10% AF develops in the
absence of cardiac abnormalities (“lone“ AF) (2, 3). AF therapy encompasses the
reduction of AF-related symptoms, prevention of thromboembolic complications, and
termination of the arrhythmia when appropriate. Restoration and maintenance of
sinus rhythm is achieved traditionally with channel blocking drugs like class IA, IC
and III antiarrhythmic drugs (7-11). Importantly, recent studies have demonstrated
that control of ventricular rate during AF (“rate control“) is not inferior to “rhythm
control“ in patients with AF (12, 13). Nevertheless, stroke prevention is of major
importance in both treatment strategies.
      A tremendous amount has been learned over the last decade about the
pathophysiology of AF. One of the most important pathophysiological mechanisms
called „electrical remodeling“ has shown that AF begets AF (14). In addition to AF-
induced alterations, recent studies have also demonstrated the importance of
preexisting structural abnormalities for the development of AF (15-20).


Atrial electrophysiology in CHF
Congestive heart failure (CHF) has a significant impact on atrial electrophysiology.
Recently, Sanders et al. (21) have analyzed twenty-one patients with symptomatic
CHF (left ventricular ejection fraction 25.5±6.0%) and 21 age-matched controls.
Patients with CHF demonstrated an increase in atrial ERPs with no change in the
heterogeneity of refractoriness, an increase of atrial conduction time along the low
lateral right atrium (LRA) and the distal coronary sinus (CS), prolongation of the P-



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wave duration and corrected sinus node recovery times, and greater number and
duration of double potentials along the crista terminalis. Electroanatomic mapping
demonstrated regional conduction slowing with a greater number of electrograms with
fractionation or double potentials, associated with areas of low voltage and electrical
silence (scar). Of note, patients with CHF demonstrated an increased propensity for
AF with single extrastimuli, and induced AF was more often sustained. Thus, the
increased propensity for AF in CHF might be explained by structural atrial changes,
abnormalities of conduction, sinus node dysfunction, and increased refractoriness in
the atria.
       Similar to these clinical data, the effects of CHF on atrial cellular
electrophysiology were characterized by Li et al. (22) in a canine model (Table 1).

                         Table 1


                         • Atrial APD are prolonged especially at fast rates
                           (reduced Ito,IKs currents,
                           upregulation of the Na/Ca exchanger)
                         • Hypertrophy of atrial myocytes
                         • Transient increase in apoptotic cell death
                         • Angiotensin II-dependent interstitial atrial fibrosis
                         • Increased likelihood for the occurrence of atrial fibrillation
                         • Atrial dilation and depressed contractile function, which
                           are related to some extent to the amount of fibrotic tissue
                         • Altered protein expression



                     Table 1: Impact of CHF on atrial pathophysiology
       They studied action potential (AP) properties and ionic currents in atrial
myocytes from dogs with CHF induced by ventricular pacing at 220 to 240 bpm for 5
weeks. Atrial myocytes from CHF dogs were hypertrophied. CHF significantly
reduced the density of L-type Ca2+ current (ICa) by ≅30%, of transient outward K+
current (Ito) by ≅50%, and of slow delayed rectifier current (IKs) by ≅30% without
altering their voltage dependencies or kinetics. Of note, CHF increased transient
inward Na+/Ca2+ exchanger (NCX) current by ≅45%. The AP duration of atrial
myocytes was not altered by CHF at slow rates but was increased at faster rates,
paralleling in vivo refractory changes. CHF created a substrate for AF, prolonging
mean AF duration from 8±4 to 535±82 seconds (P<0.01) (Figure 1).




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                             Figure 1




                                                 APD                     Angiotensin II
                              Ion-Channels                   Ca2+                AT-1 Receptor




                                                     Na+
                                                               MAP Kinases
                             Afterdepolarizations                         Differentiation
                             Triggered arrhythmias         Hypertrophy      (ERK1/2)
                                                            (ERK1/2)
                                                                         Apoptosis
                                                                         (JNK,p38)



                     Figure 1: Molecular effects of CHF on atrial myocytes


      However, the relative importance of ionic versus structural remodeling in CHF-
related atrial fibrillation (AF) is controversial. Cha et al. (23) measured hemodynamic
and echocardiographic parameters, mean duration of burst pacing–induced AF
(DAF), and atrial-myocyte ionic currents in dogs with CHF induced by 2-week
ventricular tachypacing (240 bpm), CHF dogs allowed to recover without pacing for 4
weeks (REC), and unpaced controls. Atrial ionic currents changed during pacing as
previously described (22). In REC, all ionic current densities returned to control
values. DAF increased in CHF (1132±207 versus 14.3±8.8 seconds, control) and
remained increased with REC (1014±252 seconds). Atrial fibrous tissue content also
increased in CHF (2.1±0.2% for control versus 10.2±0.7% for CHF, P<0.01), with no
recovery observed in REC (9.4±0.8%, P<0.01 versus control, P=NS versus CHF).
Thus, with reversal of CHF, there is complete recovery of ionic remodeling, but the
prolonged-AF substrate and structural remodeling remain. This suggests that
structural, not ionic, remodeling is the primary contributor to AF maintenance in
experimental CHF.


Angiotensin II and AF
Furberg et al. (6) showed that about 90% of patients with AF have clinical or
subclinical cardiovascular diseases, which may alter cardiac pressure and volume
load. Myocardial stretch is a potent stimulus, which increases local angiotensin II
levels (24-26). Thus, preexisting cardiac diseases are likely to induce an activation of
the atrial angiotensin II system resulting in proliferation of fibroblasts, interstitial


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accumulation of collagen, and myocardial hypertrophy (18,27). Li et al. (20) have
shown that atrial fibrillation is promoted by atrial fibrosis in congestive heart failure.
Fibrosis isolates groups of atrial myocytes as well as individual myocytes. It also
impairs cell-to-cell coupling causing inhomogeneities in intra- and interatrial
conduction, which in summary favours the inducibility of prolonged episodes of AF. In
that heart failure model, the development of atrial fibrosis was associated with
increased atrial angiotensin II levels (28). In addition, the expression of extracellular-
signal regulated kinases (ERK-1, ERK-2) and their degree of activation (e.g.
phosphorylation) was increased. Interestingly, expression of stress-responsive
kinases (p38 MAP kinase and JNK) that are known to induce apoptosis was
increased transiently in parallel to the numbers of apoptotic atrial cells (28). If AF
occurs in the presence of preexisting fibrosis, the arrhythmia itself increases the
amount of collagen accumulation, and thereby, initiates a vicious circle. In particular,
patients with permanent AF show severe alterations in tissue architecture (18,29). In
summary, activation of the atrial angiotensin II system induces apoptosis, severe
morphologic interstitial changes, and myocardial hypertrophy (Figure 1). Thereby,
conduction velocity is reduced and conduction heterogeneities occur (19,20,28,30-
32).
       Importantly, enalapril therapy has been shown to reduce the occurrence of AF
in patients with left ventricular dysfunction (SOLVD Trials). Vermes et al. (33) have
analyzed data from 391 patients (186 were on enalapril) included in the SOLVD trials.
They found during a 5-year follow-up that AF occurred in 5.4% in the enalapril group
compared to 24% in the placebo group (p<0.0001). A reduced recurrence rate after
cardioversion of persistent AF was also observed after pre-treatment with ACE
inhibitors (34).


Catecholamines and AF
CHF is accompanied by elevated systemic and local catecholamine levels.
Endogenous catecholamines, norepinephrine and epinephrine, are released by
postganglionic nerve terminals. After interaction with membrane bound (heptahelical)
receptors, they activate several intracellular signalling cascades (35,36,37).
Sympathetic hyperinnervation, nerve sprouting and a heterogeneous increase in


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atrial sympathetic stimulation have been demonstrated in AF models (38,39). These
findings underline the well-known profibrillatory effect of catecholamines (35,40). β-
blockade is recognized to reduce the recurrence of adrenergically-mediated AF, for
example after cardiothoracic surgery (41). Beta-adrenoreceptor antagonists (β-
blockers) have also a well established efficacy for controlling ventricular rate during
AF, by slowing atrioventricular conduction. However, evidence is accumulating
showing that β- blockade may also exert anti-arrhythmic actions in other groups of
patients with AF (42).
   The electrophysiologic effects of chronic β-blockade have recently been assessed
by Workman et al. (43). In atrial cells from patients treated chronically with β-
blockers, the APD90 and ERP (75 beats/min stimulation) were significantly longer
than in cells from non-β-blocked patients. These cells also displayed a significantly
reduced action potential phase 1 velocity (22±3 vs. 34±3 V/s). Chronic β-blockade
was associated with a significant reduction in the heart rate (58±3 vs. 69±5
beats/min) and in the density of ITO. These data suggest that the anti-fibrillatory action
of β-blockers is due to prolonging atrial refractoriness, and thus lengthening the
minimum path length required for re-entry. Thus, β-blockers may especially be
effective in CHF patients, who present with elevated catecholamine levels.


Conclusions
In the recent years, much has been learned about the pathophysiology and molecular
biology of AF. Especially the introduction of proteome analysis may help to identified
altered levels of proteins localised in atrial myocardium in patients with
cardiomyopathies. High resolution two-dimensional electrophoresis (2-DE) and
computer-assisted image analysis were already used to screen patients suffering
from dilated cardiomyopathy (DCM) versus control patients for quantitative and
qualitative differences in their atrial protein expression (Figure 2) (44).
                             Figure 2




                                Matrixmetalloproteinase (MMP)-7                       Angiotensin II
                                                                             AT1-Receptor


                                                  impaired ATP metabolism          MAP Kinases
                             Altered expression
                            of contractile proteins                           Hypertrophy          Fibrosis
                                                                               (ERK1/2)            (ERK1/2)

                                                                                                  Apoptosis
                                                                         Heat shock proteins
                                                                                                  (JNK,p38)

                                                          glycogen          Protein degradation
                            control         CHF           accumulation


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   Figure 2: Impact of dilated cardiomyopathy on mechanical atrial function and protein expression.


        Thus, a better understanding of the underlying pathophysiology of AF in the
presence of CHF might be promising to determine novel antiarrhythmic approach to
maintain sinus rhythm. The most promising agents are ACE inhibitors and
angiotensin II receptor blocking drugs, First clinical trails already support this novel
therapeutic concept. Nevertheless, the combination of ACE inhibitors with β-blockers
might be markedly effective in patients with CHF. Future studies will also have to
determine       the    impact       of    resynchronization         therapy       on     structural    and
electrophysiologic alterations at the atrial level. Of note, most animal CHF models are
based on rapid right ventricular pacing, which induces a left bundle branch block
throughout the pacing period. Thus, most available experimental data from CHF
models encompass already the characterization of ventricular dyssynchrony on atrial
pathophysiology.




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