Cardiac electrophysiology in heart failure patients is the result of complex interactions between local events, such as myocardial ischemia, fibrosis, and replacement of the normal myocardial syncytium coupled with functional modifications by cardiac control systems primarily arising from the autonomic nervous and renin-angiotensin-aldosterone systems (Chap.​ 35). Adverse tissue and architectural remodeling, characteristic of chronic heart failure, is not homogeneous, which has direct consequences on cardiac electrical properties. In addition to cardiac structural changes, remodeling of cardiac ion channel densities, structure, or function, coupled with alterations in cell-to-cell communication, significantly alters both activation and repolarization. This process, called “electrical remodeling,” represents the upstream process by which an arrhythmogenic substrate provides risk for lethal tachyarrhythmias (Fig. 7.2) [49–54] (Chap.​ 47).

Cardiac cell activation and conduction of the action potential through the myocardial syncytium depend on the availability of appropriate sodium current and cell-to-cell communication through the proper density and distribution of gap junctions [55–58]. Adverse remodeling associated with chronic cardiovascular disease and heart failure can alter activation and conduction by influencing sodium channel (I_Na) densities especially in areas of myocardial ischemia or infarction. I_Na function is also altered in heart failure by changes in cytoskeletal support of the channel [53, 58–63]. Conduction abnormalities can arise from altered I_Na or by functional abnormalities imposed by intracellular fibrosis or changes in cell size.

These aspects of electrical remodeling can result in a “fixed” arrhythmogenic substrate when changes in the ventricular myocardium permanently alter electrophysiologic characteristics in the area of change. Examples of fixed electrophysiologic abnormalities include fractionated activation across a “mottled” infarct created by surviving tissue interspersed among necrotic or fibrotic tissue [64–70]. Activation fronts encountering areas of patchy fibrosis or fatty necrosis either alter conduction impedance or allow conduction through the zone by way of surviving tissue that forms conduction channels that traverse the area of patchy necrosis. Impulses conducting through channels can exit from the zone of patchy conduction to encounter excitable tissue and give rise to triggers for reentrant arrhythmias. This combination of delayed activation, unidirectional block, and discontinuous conduction is thought to be the macroscopic mechanisms responsible for reentrant tachyarrhythmias.

Additional influences on activation electrophysiology include changes in anisotropy or cell-to-cell communication arising from altered gap junctions producing delayed conduction in the affected areas. Myocardial ischemia or left ventricular hypertrophy results in the downregulation of connexin 43 (Cx43), as well as a redistribution of this protein to the lateral aspects of the myocyte [71–74]. The stimuli for gap junction remodeling are not completely understood, but likely rely on neural and hormonal control of expression and distribution kinetics.

Activation alterations produce fractionated wave fronts that are detectable in heart failure patients at high sudden death risk [68, 69]. The mechanisms involved in establishing fixed changes in activation involve stimulation of fibrosis and fatty necrosis by angiotensin II, aldosterone, and ß-adrenergic receptor activation (Table 7.1). Therefore, neurohormonal intervention is a critical means to prevent permanent changes in the myocardium that produce a fixed substrate for arrhythmias. It is unclear if continued neurohormonal antagonism results in reversal of the electrophysiologic substrate for lethal arrhythmias once that substrate is established. What is clear, however, is that altered activation and conduction, especially when coupled with repolarization heterogeneity, are key components of the high-risk substrate [75, 76].

Prolonged repolarization is characteristic of ischemic heart disease and heart failure pathophysiology resulting in lengthening of the myocardial monophasic action potential [77–92]. Typically, changes in ventricular function, tissue, and electrical remodeling in heart failure are heterogeneous, which is especially true for repolarization abnormalities [78–89]. Repolarization heterogeneity can produce severe repolarization dispersion which is found in subjects at high risk for lethal arrhythmias [78]. Interestingly, lower-risk individuals seem to have much less repolarization heterogeneity compared to their high-risk counterparts. Why some individuals develop severe repolarization heterogeneity is complex, but likely relates to control system responses to injury, such as the degree of sympathetic activation following myocardial infarction. Abnormal repolarization can be detected in humans and animals at high sudden death risk in a variety of ways, including microvolt T-wave alternans [79, 80], increased QT interval dispersion, or heterogeneous ventricular repolarization by high-density mapping [78].

Prolongation of action potential duration may have an adaptive purpose. When the repolarization phase of cardiac tissue prolongs, it increases the likelihood that a reentrant wave front may encounter refractory tissue, which would serve to terminate the circuit. With this effect, repolarization prolongation has the potential to be antiarrhythmic, but the prolongation must be global and homogeneous for the effect to prevent an unstable ventricular electrophysiologic environment. These conditions are seldom encountered when adverse ventricular remodeling occurs.

Prolonged repolarization in heart failure arises because of changes in expression of functional ion channels responsible for the plateau and rapid repolarization of the monophasic action potential [83–93]. Repolarization abnormalities that contribute to the arrhythmogenic substrate arise from both acute changes in autonomic control [90] and from ion channel remodeling in the presence of left ventricular hypertrophy or stretch. Most consistently, the downregulation of the transient outward potassium channel, I_to, which contributes to the plateau phase of the monophasic action potential, is encountered in cells from most etiologies of heart failure. Other potassium channel abnormalities that occur in heart failure include reduced delayed rectifier (I_K) current density, coupled with faster deactivation kinetics and slow activation properties, which result in prolongation of the rapid repolarization phase of the monophasic action potential. Left ventricular hypertrophy results in a significant downregulation of the inward rectifying potassium channel, I_Ks, which becomes the predominant channel responsible for myocyte repolarization in states of sympathetic activation. Along with changes associated with hypertrophy, cytoskeletal support protein remodeling also influences potassium channel function [93]. When regional tissue remodeling is present, with areas of compensatory hypertrophy, the resulting heterogeneous repolarization kinetics increase the risk for spontaneous ventricular tachyarrhythmias (Chaps.​ 46 and 47).

Global prolongation of ventricular repolarization in patients with heart failure arises from multiple mechanisms [76], which include potassium channel dysfunction, as well as abnormalities in calcium homeostasis [94–100]. It must be recognized that calcium handling is a key component that gives rise to decreased force of contraction, but abnormalities in calcium kinetics also have direct electrophysiologic ramifications [94]. Cells from failing ventricles exhibit a decrease in calcium transient amplitude and its rate of decay. Heterogeneity of calcium transient amplitude and delay when comparing endocardial, mid-myocardial, and epicardial regions, as well as global changes associated with regional heterogeneity and ischemia in the failing heart, very likely contribute to ventricular electrophysiologic instability [96]. Further alterations in the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a), phospholamban, and the sodium-calcium exchanger proteins are described in the failing ventricle and can alter the intracellular calcium concentration [97]. This is associated with ryanodine receptor defects, which when combined with other alterations in calcium homeostasis increases the risk for calcium-dependent afterdepolarizations (Chap.​ 4). Afterdepolarizations are key elements that form the basis for triggered arrhythmias and sustained polymorphic ventricular tachycardia.

Heterogeneous ventricular repolarization kinetics that result in regional and global prolongation are induced by both acute and chronic changes in neural and hormonal control of the heart. Therefore, substrate changes resulting in fixed repolarization abnormalities can potentially be prevented by neurohormonal intervention, such as aldosterone antagonism or beta-blockade, when applied early in the adverse remodeling process. Chronic neurohormonal intervention also provides benefit by preventing functional or momentary abnormalities in repolarization induced by acute neural activation in response to further injury or physiologic needs.

The development of permanent (fixed) electrophysiologic substrates can be prevented by early use of neurohormonal interventions including angiotensin-converting enzyme (ACE) inhibitors [101], aldosterone antagonism [102], or antiadrenergic intervention with beta-blockers [103–108] (Table 7.1). Although the direct mechanisms involved in neurohormonal induced electrical remodeling are not fully characterized, general conclusions can be drawn from clinical trial observations. For example, ACE inhibitor therapy reduces mortality primarily by preventing pump failure deaths presumably by inhibiting progressive architectural changes leading to inefficient left ventricular function [109–115]. However, if applied following myocardial infarction (without the requirement for heart failure), ACE inhibitors seem to reduce the incidence of sudden death by as much as 20 % demonstrated by meta-analysis techniques [101].

One can speculate that ACE inhibitor intervention may be effective in reducing sudden death early after myocardial injury by inhibiting angiotensin II-induced interstitial fibrosis leading to fractionated activation characteristic of arrhythmogenic substrates [112, 116]. Aldosterone stimulates proliferation of cardiac fibroblasts resulting in increased interstitial collagen formation which may influence arrhythmogenic substrate development over time. Other effects of angiotensin-aldosterone activation, such as promotion of inflammation with the resulting increase in oxygen free radicals and destabilization of atherosclerotic plaques, may also increase the risk for ventricular electrical instability. In addition to the direct effects on myocardial structure, angiotensin II facilitates adrenergic effects on ventricular electrophysiology by reducing norepinephrine reuptake, increasing the amount of norepinephrine released with each nerve firing, and increasing the firing rate of sympathetic neurons [117–119] (Chap.​ 36).

Control system interactions operant in the heart failure milieu make it clear that the precise mechanisms involved in the development of lethal arrhythmias are complex and multifactorial. This illustrates that effective sudden prevention strategies must account for multiple potential mechanisms requiring the combination of multiple medications and device therapies.

Sympathetic adrenergic activation in heart failure represents a combination of inherent control system characteristics present before heart disease develops coupled with how individual systems respond to ventricular injury [42]. Sympathetic activation is almost always accompanied by parasympathetic withdrawal, which should be considered when examining how autonomic alterations in heart failure lead to lethal arrhythmias.

In addition to functional changes in global sympathetic outflow to the heart, neural remodeling in the neuroeffector junction can be arrhythmogenic. Sympathetic hypersensitivity in areas of myocardial necrosis alters local cardiac electrophysiology increasing regional repolarization dispersion and increases risk for lethal arrhythmias [122, 123]. Myocardial injury can produce regional differences in nerve growth factors, which can stimulate sympathetic nerve “sprouting” and regionally increase relative sympathetic effect. This phenomenon further destabilizes ventricular electrophysiology and leads to increased risk for sudden death [120, 121].

Neural adverse remodeling relates to several factors, but the neural regeneration process after myocardial injury is mainly directed by growth factors, among which nerve growth factor (NGF) appears to be very important. Experimental data in conscious dogs documented that NGF infusion in the left stellate ganglion induces significant nerve sprouting (evaluated by analysis of the tyrosine hydroxylase (TH) and growth-associated protein 43 (GAP43 markers), leading to excessive expression of cardiac sympathetic innervation. This was directly associated with increased risk for sudden cardiac death [124–126].

Further elaboration of the impact of NGF in ischemic myocardium demonstrated that the factor is produced by cardiac myocytes and specific receptors for this neurotrophin (TrkA, tyrosine protein kinase receptor) are present in the myocyte membrane. NGF may have a beneficial role as it favors neoangiogenesis, which may provide some level of protection to ischemic myocardium [124]. These observations suggest that the process of cardiac nerve regeneration following myocardial injury may be an adaptive response designed to sustain failing cardiac contractility through sympathetic augmentation and angiogenesis, but at the maladaptive cost of higher risk of life-threatening arrhythmias.

The impact of adverse neural remodeling on cardiac electrophysiology is mediated through the development of anatomically fixed arrhythmogenic substrates that permanently disrupt orderly myocardial activation and repolarization characteristics of the heart. In addition, “functional” abnormalities, which are temporary and depend on local conditions such as acute sympathetic activation, myocardial ischemia, or inflammation, are directly mediated particularly through sympathetic remodeling. Functional abnormalities may include changes in local repolarization due to regional increases in sympathetic activation, for example, or may include activation fractionation from conduction delay induced by acute alteration in autonomic tone. Factors such as acute myocardial ischemia or infarction, electrolyte imbalances, or medications can also alter ion channel function resulting in high risk for functional electrophysiologic abnormalities that may lead to sudden death. Functional abnormalities tend to be difficult to predict and may occur shortly before the initiation of a sustained ventricular arrhythmia.

The presence of coexisting conditions has a substantial effect on the outcome of heart failure patients, and specifically kidney disease is associated with one of the highest risks of adverse outcomes driven both by heart failure progression and by lethal arrhythmia [126, 127]. This adverse interaction seems to relate to decreased renal perfusion as cardiac output drops in heart failure patients. Normally, the “renal fraction” is 20 % of cardiac output, but this percentage declines with worsening heart failure. This further enhances renal sympathetic efferent nerve activity that results in marked increases in renal norepinephrine spillover and a sympathetically mediated increase in plasma renin activity [128].

The kidney is robustly innervated by the sympathetic system and acts both as an afferent signaling source and as a conduit for increased sympathetic efferent activation [129], providing an important prognostic tool in evaluating and monitoring heart failure patients. Increased renal norepinephrine spillover predicts reduced survival in heart failure patients.

Activation of renal sensory nerves in patients with heart failure contributes to disease progression and triggers proarrhythmic cardiac substrate enhancing arrhythmia susceptibility [129]. This clearly impacts chronic kidney disease patient survival as lethal arrhythmias are a more frequent cause of death among this group even with moderate (stage 3) chronic kidney disease [131].

Worsening renal function in patients with heart failure is associated with more frequent lethal arrhythmias [129, 130]. A post hoc analysis of the MADIT II database suggests that an estimated glomerular filtration rate below 35 ml/min/1.73 m² in ICD (implantable cardioverter defibrillator) patients was associated with a trend toward unfavorable outcome compared to the control group [131]. The reason ICDs were less effective in the low-GFR group seems related to the defibrillation threshold that progressively increases along with renal function decline. These factors lead to increased risk for arrhythmias [131]; at the same time defibrillation threshold makes ICD therapy less effective. Changes in myocardial tissue in the presence of renal dysfunction seem to be directly related to renal dysfunction which adversely impacts the arrhythmic substrate.

Other abnormalities, including electrolyte imbalances that may occur in the context of more intensive diuretic administration, are closely coupled with increased sympathetic activity. Adverse tissue remodeling in the presence of chronic kidney disease was evaluated in one study using cardiac magnetic resonance tomography in 24 hemodialysis patients. This data found abnormal patterns of late gadolinium myocardial tissue enhancement in 79 % of analyzed cases. Late enhancement was present in three distinctive patterns: a diffuse pattern was present in seven cases, an infarct-related pattern in six cases, a non-infarct related in seven cases, while the absence of structural remodeling was seen in only five cases [132]. The data suggest that a significant increase of myocardial interstitial fibrosis burden was induced by chronic renal failure. The study outlined some of the specific changes that take place in myocardial structure in patients with chronic kidney disease, which lead to proarrhythmic increase of defibrillation threshold.

In summary, neural and hormonal responses to heart failure result in permanent and functional alterations in myocardial activation and repolarization. The impact of neural and hormonal activation is rapid and continuous, which increases the risk for electrical “accidents” leading to sudden death. Understanding these mechanisms has led to very effective means to prevent sudden death, as well as the progression of myocardial dysfunction and heart failure.