58. Heart Failure and Sudden Death 875
Mechanisms of Sudden Death inHeart Failure
Arrhythmogenic Substrates Predisposing toSudden Death
Abnormalities in Cellular Electrophysiology
Prolongation of the ventricular action potentialhas been well documented in both animal modelsand humans in heart failure. Downregulation of ionic currents
has been observedfrom animal or human studies. Despite prolonga-tion of action potential duration and increaseddispersion of repolarization, these changes con-tribute only in part to the genesis of malignantventricular tachyarrhythmias leading to suddencardiac death.
In heart failure, altered calciumhandling not only affects ventricular mechanics,but also affects electrophysiological properties.The
density has been reported to beunchanged,
was decreased incardiac hypertrophy and severe heart failure pri-marily from Ca-mediated inactivation of the
Spontaneous calcium release from thesarcoplasmic reticulum results in enhanced Na–Ca exchanger current, which likely contributes tothe genesis of delayed afterdepolarization (DAD)and DAD-mediated ventricular arrhythmias.
Gap junctions are composed of intercellular chan-nels that permit the transfer of electrical currentbetween neighboring cells. Connexin43 is a prin-cipal gap junction protein in the ventricle, playinga critical role in impulse propagation and electri-cal synchronization between myocytes. To deter-mine transmural connexin43 expression andits relationship to electrophysiological function,Poelzing and Rosenbaum
performed a high-resolution transmural optical mapping of the art-erially perfused canine preparation to measurethe conduction velocity and transmural changesof action potential duration in a pacing-inducedheart failure model. The absolute connexin43expression in failing myocardium, quantiﬁed by confocal immunoﬂuorescence, was uniformly reduced by 40%, compared with control. Reducedconnexin43 expression in heart failure was associ-ated with a signiﬁcant reduction in intercellularcoupling between transmural muscular layerscorrelated with reduced conduction velocity. Theaction potential duration dispersion was greatestin failing myocardium and the largest transmuralaction potential duration gradient was consist-ently found in regions exhibiting lowest con-nexin43 expression. These ﬁndings led to theconclusion that reduced connexin43 expressionproduced uncoupling between transmural musclelayers resulting in a slow conduction and markeddispersion of repolarization between the epicar-dial and deeper myocardial layers, contributing toan arrhythmia substrate in failing myocardium.
Nerve Spouting and Sympathetic Nerve Activity
Excessive sympathetic activation is one of themechanisms contributing to the increased mortal-ity and sudden death in heart failure. Ventriculararrhythmia associated with sympathetic activity isoften seen in patients with ischemic cardiomyopa-thy owing to prior myocardial infarction (MI).Following myocardial injury, peripheral nervesundergo Wallerian degeneration, which may befollowed by neurilemma cell proliferation andaxonal regeneration (nerve sprouting), resultingin sympathetic hyperinnervation.
Nerve sprout-ing activity and sympathetic innervation after MIhave been investigated from several experiementalconditions. Meiri used computerized morphome-try to quantify the density of nerve ﬁbers that wereimmunopositive for growth-associated protein 43(GAP43) or tyrosine hydroxylase (TH) in a mousemodel.
GAP43 is a protein associated with theaxonal growth cone and is upregulated duringnerve sprouting. The density of GAP43-positivenerve ﬁbers is a measurement of nerve sproutingactivity. In contrast, TH is a measurement of stablesympathetic innervations in the myocardium.There was an acute increase in GAP43 immunore-active nerve ﬁber density within 3 h, which per-sisted for 1 week after MI, so was TH-positivenerve ﬁber density.
The magnitude of the increasein TH-positive nerve ﬁber density, as compared tocontrols, appeared to be greater in the periinfarctarea than in the remote area. In a large animalstudy, Zhou
created MI in dogs by either ligatingthe coronary artery or by intracoronary ballooninﬂation. Consistent with ﬁndings in the mousemodel of MI, GAP43-positive nerve numbers