CHAPTER 79: MECHANISMS OF CARDIAC ARRHYTHMIAS AND CONDUCTION DISTURBANCES

Recent years have witnessed important advances in our understanding of the molecular and electrophysiologic mechanisms underlying the development of a variety of cardiac arrhythmias (Table 79–1) and conduction disturbances. Progress in our understanding of these phenomena has been fueled by innovative advances in our understanding of the genetic basis and predisposition for electrical dysfunction of the heart. These advances notwithstanding, our appreciation of the basis for many rhythm disturbances is incomplete. This chapter examines our present understanding of cellular, ionic, and molecular mechanisms responsible for cardiac arrhythmias, placing them in historical perspective whenever possible.

Cardiac activation and repolarization are controlled by movement of ions across channels in the cell membrane of cardiomyocytes, which in turn are strongly influenced by the activity of the autonomic nervous system. Abnormal activity of these ionic movements is important in cardiac arrhythmogenesis.^1,2,3 Arrhythmic activity can be categorized as passive (eg, atrioventricular [AV] block) or active. The mechanisms responsible for active cardiac arrhythmias are generally divided into two major categories: (1) enhanced or abnormal impulse formation, and (2) reentry (Fig. 79–1). Reentry occurs when a propagating impulse fails to die out after normal activation of the heart and persists to reexcite the heart after expiration of the refractory period. Evidence implicating reentry as a mechanism of cardiac arrhythmias stems back to the turn of century.^4,5,6 Multichannel mapping studies subsequently documented that reentrant wavefronts may underlie the mechanisms of atrial and ventricular tachyarrhythmias.^7,8,9 Phase 2 reentry,¹⁰ spiral waves of excitation,¹¹ mother rotors, and fibrillatory conduction¹² are interesting concepts advanced to explain the development of atrial as well as ventricular fibrillation. Mechanisms responsible for abnormal impulse formation include enhanced automaticity and triggered activity. Automaticity can be further subdivided into normal and abnormal. Triggered activity consists of (1) early afterdepolarizations (EADs), (2) late phase 3 EAD, and (3) delayed afterdepolarizations (DADs).^13,14,15 Although traditionally automaticity and triggered activity were thought to be two distinct mechanisms of arrhythmogenesis, more recent studies suggest that they might share similar mechanisms.

Normal Automaticity

Automaticity is the property of cardiac cells to generate spontaneous action potentials. Spontaneous activity is the result of diastolic depolarization caused by a net inward current during phase 4 of the action potential, which progressively brings the membrane potential to threshold. The sinoatrial (SA) node normally displays the highest intrinsic rate. All other pacemakers are referred to as subsidiary or latent pacemakers because they take over the function of initiating excitation of the heart only when the SA node is unable to generate impulses or when these impulses fail to propagate. There is a hierarchy of intrinsic rates of subsidiary pacemakers that have normal automaticity: atrial pacemakers have faster intrinsic rates than AV junctional pacemakers, and AV junctional pacemakers have faster rates than ventricular pacemakers.

Wit and Cranefield¹⁶ defined automatic activity as activity that arose in the absence of an external cause (ie, activity that did not have to be triggered by a stimulated action potential). The prototypical example of automaticity is the spontaneous beating of the SA node. On the other hand, triggered activity was the activity in which nondriven action potentials were initiated by one or more driven action potentials. The authors used the term “triggered” to explain the mechanisms by which quiescent fibers remained quiescent until driven at fast rate. However, more recent studies have shown that automaticity and triggered activity may share a common mechanism (ie, activation of the sodium-calcium exchange current [I_NCX]).¹⁷

The Voltage Clock and Automaticity

Lakatta and colleagues¹⁷ used the terms membrane clocks and calcium (Ca) clocks to describe the mechanisms of SA node automaticity. These two clocks were mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. The membrane clock is formed by voltage-sensitive membrane currents, such as the hyperpolarization-activated pacemaker current (I_f).^18,19 This current is also referred to as a “funny” current because, unlike the majority of voltage-sensitive currents, it is activated by hyperpolarization (from –40/–50 mV to –100/–110 mV) rather than depolarization. At the end of the action potential, the I_f is activated and is responsible for early diastolic depolarization that gradually depolarizes the sarcolemmal membrane.^20,21 The I_f is a mixed Na-K inward current modulated by the autonomic nervous system through cyclic adenosine monophosphate.²² Sympathetic stimulation (isoproterenol) increases the I_f, whereas parasympathetic stimulation (acetylcholine) reduces I_f . These findings suggest that I_f is responsible for heart rate control by the autonomic nervous system. The depolarization activates L-type Ca current (I_Ca,L), which provides Ca to activate the type 2 (cardiac) ryanodine receptor (RyR2). The activation of RyR2 initiates sarcoplasmic reticulum Ca release (Ca-induced Ca release), leading to contraction of the heart, a process known as excitation-contraction coupling. The intracellular Ca (Ca_i) is then pumped back into sarcoplasmic reticulum by the sarcoplasmic reticulum Ca-ATPase (SERCA2a), which completes the Ca cycle. In addition to I_f, multiple time- and voltage-dependent ionic currents have been identified in cardiac pacemaker cells, which contribute to diastolic depolarization. These currents include (but are not limited to) the I_Ca,L, T-type Ca current, and various types of delayed rectifier K currents.²³ Many of these membrane currents are known to respond to β-adrenergic stimulation. All these membrane ionic currents contribute to the regulation of SA node automaticity by changing the membrane potential. In addition to the contribution of voltage-gated ionic currents, the small conductance Ca-activated K (SK) current also plays an important role in modulating automaticity both in the SA node and in the AV node.²⁴ Overexpression of subtype 2 of SK (SK2) channels in mice results in the shortening of the spontaneous action potentials of the AV node cells and an increase in the firing frequency. However, ablation of the SK2 channel results in the opposite effects. Because the SK current is activated by the Ca_i, this current may play an important role in the interaction between the membrane clock and the Ca clock.

The Calcium Clock and Automaticity

The I_f is not the only depolarizing current active in late phase 3 or phase 4 of the action potential. Another important ionic current that can depolarize the cell is the Na-Ca exchanger current (I_NCX). In its forward mode, the I_NCX exchanges three extracellular Na⁺ with one intracellular Ca²⁺, resulting in a net intracellular charge gain. This electrogenic current is active during late phase 3 and phase 4 because the Ca_i decline outlasts the SA node action potential duration (APD). Multiple studies have shown that I_NCX may participate in normal pacemaker activity.^{25,26,27,28,29,30} The sequence of events includes spontaneous rhythmic sarcoplasmic reticulum Ca release, Ca_i elevation, the activation of I_NCX, and membrane depolarization.¹⁷ This process is highly regulated by cyclic adenosine monophosphate and the autonomic nervous system.³¹ According to findings, sympathetic stimulation accelerates heart rate by phosphorylation of proteins that regulate Ca_i balance and spontaneous sarcoplasmic reticulum Ca cycling. These proteins include phospholamban (a sarcoplasmic reticulum membrane protein regulator of SERCA2a), L-type Ca channels, and RyR2. Phosphorylation of these proteins controls the phase and size of subsarcolemmal sarcoplasmic reticulum Ca releases. The resultant I_NCX is crucial for both basal and reserve cardiac pacemaker function.

Many of the elegant studies on automaticity were performed in isolated SA node cells. However, the SA node is a complex structure, and many factors interact with each other to ensure the initiation of the heart beats. Activation maps in intact canine right atria have shown that the SA node impulse origin is multicentric,^32,33 and sympathetic stimulation predictably results in a cranial (superior) shift of the pacemaking site in humans and dogs.^32,34 Based on evidence from isolated SA node myocytes, late diastolic Ca_i elevation prior to the membrane action potential upstroke is a key signature of pacemaking by the Ca clock. Simultaneous mapping of the membrane potential and Ca_i transient in a Langendorff-perfused canine right atrium preparation³⁵ showed changes consistent with the Ca clock mechanism of impulse generation (Fig. 79–2). In that study, sympathetic stimulation (isoproterenol) induced spontaneous sarcoplasmic reticulum Ca release during phase 4 depolarization of intact canine SA node. The spontaneous Ca release then induced upward (cranial) shift of the leading pacemaker site and heart rate acceleration. Studies performed in human electrophysiologic laboratories have confirmed the presence of multiple early sites in the right atrium during sinus rhythm, consistent with multicentric origin of SA nodal rhythm.³⁶ Heart failure is associated with sinus node dysfunction and a reduction of the number of early sites. Another more recent study confirmed the multicentric origin of SA node rhythm.³⁷ The authors also confirmed that sympathetic stimulation resulted in cranial shift of pacemaking site in patients without SA nodal diseases. In contrast, unresponsiveness of superior SA node to sympathetic stimulation is a characteristic finding in patients with atrial fibrillation (AF) and symptomatic bradycardia (Fig. 79–3).

Subsidiary Pacemakers

In addition to SA node, AV nodes and the Purkinje system are also capable of generating automatic activity. The contribution of the I_f and potassium channel (I_K) differs in SA node/AV nodes and Purkinje fiber because of the different potential ranges of these two pacemaker types (ie, –70 to –35 mV and –90 to –65 mV, respectively). The contribution of other voltage-dependent currents can also differ among the different cardiac cell types. Similar to the SA node, the Ca clock also contributed significantly to the automaticity of the AV node.³⁸ Cells in the SA node possess the fastest intrinsic rates. Thus, the SA node is the primary pacemaker in the normal heart. When impulse generation or conduction within or out of the SA node is impaired, latent or subsidiary pacemakers within the atria or ventricle are capable of taking control of pacing the heart. The intrinsically slower rates of these latent pacemakers result in bradycardia. Subsidiary atrial pacemakers with more negative diastolic potentials (–75 to –70 mV) than SA nodal cells are located at the junction of the inferior right atrium and the inferior vena cava, near or on the Eustachian ridge.^39,40 Other atrial pacemakers have been identified in the crista terminalis⁴¹ as well as at the orifice of the coronary sinus¹⁴ and in the atrial muscle that extends into the tricuspid and mitral valves.^40,41 The cardiac muscle sleeves that extend into the cardiac veins (venae cavae and pulmonary veins) can also have the property of normal automaticity.⁴² Latent pacemaking cells in the AV junction are responsible for AV junctional rhythms.⁴³ Both atrial and AV junctional subsidiary pacemakers are under autonomic control, with the sympathetic system increasing and parasympathetic system slowing the pacing rate.

The slowest subsidiary pacemakers are found in the His-Purkinje system in the ventricles of the heart.⁴⁴ In the His-Purkinje system, parasympathetic effects are less apparent than those of the sympathetic system. Although acetylcholine produces little in the way of a direct effect, it can significantly reduce Purkinje automaticity by means of inhibition of the sympathetic influence, a phenomenon termed accentuated antagonism.^45,46,47 Simultaneous recording of cardiac sympathetic and parasympathetic activity in ambulatory dogs confirmed that sympathetic activation followed by vagal activation may be associated with profound bradycardia.^48,49 Accentuated antagonism is also important in abnormal automaticity in the His-Purkinje system.⁵⁰ Adenosine has no effects on His-Purkinje System activation rate at baseline, but reduces its activation rate during isoproterenol infusion. These findings suggest that adenosine’s effects on the human His-Purkinje system are primarily antiadrenergic and are thus consistent with the concept of accentuated antagonism. These effects of adenosine may serve as a counterregulatory metabolic response that improves the oxygen supply-demand ratio perturbed by enhanced sympathetic tone. Some catecholamine-mediated ventricular arrhythmias that occur during ischemia or enhanced adrenergic stress may be a result of an imbalance in this negative feedback system.

Biological Pacemakers

Changes of ionic component of cardiac cells by gene transfer can convert ordinary myocytes into cardiac pacemakers. One approach is to suppress inward rectifier current (I_K1) and enhance automaticity of ventricular myocytes.⁵¹ A second approach is to insert a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel into cells using viral gene transfer, cell fusion, or stem cell technologies.^52,53,54,55 Successful HCN expression in the myocytes leads to the activation of I_f, enabling nonpacemaking cells to generate automaticity. These studies further confirm the importance of I_f in the mechanisms of automaticity. A more recent approach is to alter the gene expression during embryonic stem cell development to upregulate the pacemaker gene program and enhance automaticity.^56,57 Although these preliminary studies are exciting, more will need to be done before this approach can be useful in humans.

Automaticity as a Mechanism of Cardiac Arrhythmias

Abnormal automaticity includes both reduced automaticity, which causes bradycardia, and increased automaticity, which causes tachycardia. Arrhythmias caused by abnormal automaticity can result from diverse mechanisms (see Table 79–1). Alterations in sinus rate can be accompanied by shifts of the origin of the dominant pacemaker within the sinus node or to subsidiary pacemaker sites elsewhere in the atria. Impulse conduction out of the SA mode can be impaired or blocked as a result of disease or increased vagal activity leading to development of bradycardia. AV junctional rhythms occur when AV junctional pacemakers located either in the AV node or in the His bundle accelerate to exceed the rate of SA node or when the SA nodal activation rate is too slow to suppress the AV junctional pacemaker.

Hereditary Bradycardia

Bradycardia can occur in structurally normal hearts as a result of genetic mutations that result in abnormalities of either the membrane clock or Ca clock mechanism of automaticity. One example is the mutation of subtype 4 of HCN channel (HCN4), which is part of the channels that carry I_f . Mutations of HCN4 cause changes in HCN4 channel expression and kinetics,⁵⁸ leading to familial bradycardia.^59,60,61 However, the bradycardia caused by HCN4 mutations may be entirely asymptomatic. Although HCN4 mutations cause baseline bradycardia, the heart rate responses to exercise may be either suboptimal, with a maximum rate of 100 bpm,⁶⁰ or entirely normal, with maximum rates of > 150 bpm.⁶¹ The presence of normal heart rate response in patients with HCN4 mutation can be explained by the intact Ca clock, which can accelerate the sinus rate during sympathetic activation.^17,35

Secondary Sinoatrial Node Dysfunction

Common diseases, such as heart failure and AF, may be associated with significant SA node dysfunction.^36,62 Malfunction of membrane voltage clocks and Ca clocks might both be present in these common diseases. Zicha et al⁶³ reported that downregulation of HCN4 expression contributes to heart failure–induced sinus node dysfunction and that upregulation of atrial HCN4 may help to promote atrial arrhythmia formation. Heart failure is also known to be associated with significant abnormalities of Ca_i regulation.⁶⁴ It is likely that abnormalities of both the membrane voltage clock and Ca clock are responsible for the SA node dysfunction in heart failure. Similarly, AF is also associated with malfunction of both membrane and Ca clocks.^35,65 The SA node malfunction is reversible after successful radiofrequency catheter ablation of AF.⁶⁶

Enhanced Automaticity

Atrial and ventricular myocardial cells do not display spontaneous diastolic depolarization or automaticity under normal conditions but can develop these characteristics when depolarized, resulting in the development of repetitive impulse initiation, a phenomenon termed depolarization-induced automaticity.⁶⁷ The membrane potential at which abnormal automaticity develops ranges between –70 and –30 mV. The rate of abnormal automaticity is substantially higher than that of normal automaticity and is a sensitive function of resting membrane potential (ie, the more depolarized the resting potential, the faster the rate). Similar to normal automaticity, abnormal automaticity is enhanced by β-adrenergic agonists and by reduction of external potassium. Depolarization of membrane potential associated with disease states is most commonly a result of: (1) an increase in extracellular potassium, which reduces the reversal potential for I_K1, the outward current that largely determines the resting membrane or maximum diastolic potential; (2) a reduced number of I_K1 channels; (3) a reduced ability of the I_K1 channel to conduct potassium ions; or (4) electrotonic influence of neighboring depolarized zone. Because the conductance of I_K1 channels is sensitive to extracellular potassium concentration, hypokalemia can lead to major reduction in I_K1, leading to depolarization and the development of enhanced or abnormal automaticity, particularly in Purkinje pacemakers. A reduction in I_K1 can also occur secondary to a mutation in KCNJ2, the gene that encodes for this channel, leading to increased automaticity and extrasystolic activity presumably arising from the Purkinje system.^68,69 Interestingly, because β-adrenergic stimulation is effective in augmenting I_K1,⁷⁰ sympathetic stimulation can produce a paradoxical slowing of automaticity and ectopy in this setting. Because of the importance of I_K1 in maintaining membrane depolarization and preventing automaticity, suppression of Kir2 and reduce I_K1 can enhance automaticity of ventricular myocytes. The latter approach has been used as an approach to develop biological pacemakers.⁵¹

Autonomic Mechanisms in Sinoatrial Nodal Tachycardia and Atrial Tachycardia

Normal or subsidiary pacemaker activity also can be enhanced, leading to sinus tachycardia or a shift to ectopic sites within the atria, giving rise to atrial tachycardia. One cause can be enhanced autonomic nerve activity. Direct recording from the stellate ganglion and vagal nerves show that stellate ganglion nerve activity (SGNA) and vagal nerve activity are both important in controlling sinus rate and in triggering atrial tachycardia in ambulatory dogs. Figure 79–4 shows an example of heart rate acceleration induced by SGNA. The SGNA consists of two types of activity. The vast majority of activity was in the form of low-amplitude burst discharge activity. A second form of activity is the high-amplitude spike discharge activity, which occurs less than 10 times daily in normal dogs, and the incidence may more than double in dogs with heart failure or myocardial infarction.^48,49,71 In this and in all dogs studied, there was no latency between the onset of nerve activity and the shortening of the next P-P interval. Vagal nerve activation, on the other hand, induces sinus bradycardia.⁴⁸ Figure 79–5 shows an example of bradycardia associated with increased vagal nerve activity. The same figure shows that simultaneous sympathovagal discharges are common triggers of atrial tachyarrhythmia.

Overdrive Suppression of Automaticity

The automaticity of all pacemakers within the heart is inhibited when they are overdrive paced.⁷² This inhibition is called overdrive suppression. Under normal conditions, all subsidiary pacemakers are overdrive-suppressed by SA nodal activity. The mechanisms of overdrive suppression are thought to be related to pacing-induced intracellular accumulation of Ca and Na.^73,74 The Na accumulation leads to enhanced activity of the sodium pump (sodium-potassium adenosine triphosphatase [Na⁺-K⁺ ATPase]), which generates a hyperpolarizing electrogenic current that opposes phase 4 depolarization.⁷⁴ The faster the overdrive rate or the longer the duration of overdrive, the greater is the enhancement of sodium pump activity, so that the period of quiescence after cessation of overdrive is directly related to the rate and duration of overdrive.

Parasystole and Modulated Parasystole

Latent pacemakers throughout the heart are generally reset by the propagating wavefront initiated by the dominant pacemaker and are therefore unable to activate the heart. An exception to this rule occurs when the pacemaking tissue is protected from the impulse of sinus origin. A region of entrance block arises when cells exhibiting automaticity are surrounded by ischemic, infarcted, or otherwise compromised cardiac tissues that prevent the propagating wave from invading the focus, but which permit the spontaneous beat generated within the automatic focus to exit and activate the rest of the myocardium. A pacemaker region exhibiting entrance block and exit conduction defines a parasystolic focus. The ectopic activity generated by a parasystolic focus is characterized by premature ventricular complexes with variable coupling intervals, fusion beats, and interectopic intervals that are multiples of a common denominator.

Afterdepolarization and Triggered Activity

Oscillatory depolarizations that attend or follow the cardiac action potential and depend on preceding transmembrane activity for their manifestation are referred to as afterdepolarizations. Two subclasses are traditionally recognized: (1) early and (2) delayed. EADs interrupt or retard repolarization during phase 2 and/or phase 3 of the cardiac action potential, whereas DADs occur after full repolarization. When EAD or DAD amplitude suffices to bring the membrane to its threshold potential, a spontaneous action potential, referred to as a triggered response, is the result. These triggered events can be responsible for extrasystoles and tachyarrhythmias that develop under conditions predisposing to the development of afterdepolarizations.

Early Afterdepolarizations and Triggered Activity

EADs are observed in isolated cardiac tissues exposed to injury, altered electrolytes, hypoxia, acidosis, catecholamines, and pharmacologic agents, including antiarrhythmic drugs. Ventricular hypertrophy and heart failure also predispose to the development of EADs.⁷⁵ However, because of source-sink mismatch in well-coupled cardiac tissues, it is unlikely that the EAD of a single cardiomyocyte will be able to generate propagated wavefronts. Rather, a critical mass of literally thousands of myocytes to develop an EAD synchronously on the same beat is needed for an overt EAD to trigger a premature ventricular contraction. Weiss et al⁷⁶ proposed that the chaotic EAD behavior combined with the smoothing effect of electrotonic gap junction coupling permits normally irregular EADs to synchronize regionally, producing macroscopic “EAD islands” next to areas without EADs. This synchronization mechanism produces shifting focal activations, mixed with reentry, which arise suddenly from normal or bradycardic heart rates and produce characteristic features of polymorphic and torsades de pointes ventricular tachycardia (VT).

EAD characteristics vary as a function of animal species, tissue or cell type, and the method by which the EAD is elicited. Although specific mechanisms of EAD induction can differ, a critical prolongation of repolarization accompanies most, but not all, EADs. Drugs that block potassium currents may reduce repolarization reserve and predispose the cells to EADs.⁷⁷ Figure 79–6 illustrates the two types of EADs generally encountered in Purkinje fiber. Oscillatory events appearing at potentials positive to –30 mV are generally referred to as phase 2 EADs. Those occurring at more negative potentials are termed phase 3 EADs. Phase 2 and phase 3 EADs sometimes appear in the same preparation.

EAD-induced triggered activity is sensitive to stimulation rate. Antiarrhythmic drugs with class III action generally induce EAD activity at slow stimulation rates and totally suppress EADs at rapid rates.^78,79 In contrast, β-adrenergic agonist–induced EADs are fast rate dependent.^80,81 In the presence of rapidly activating delayed rectifier current (rapid outward potassium current [I_Kr]) blockade, β-adrenergic agonists and/or acceleration from an initially slow rate transiently facilitate the induction of EAD activity in ventricular M cells, but not in epicardium or endocardium and rarely in Purkinje fibers.⁸² This biphasic effect is thought to be caused by an initial priming of I_NCX, which provides an electrogenic inward current that facilitates EAD development and prolongs APD. This early phase is followed by recruitment of slowly activating delayed rectifier current (slow outward potassium current [I_Ks]), which abbreviates APD and suppresses EAD activity.

Cellular Origin of Early Afterdepolarizations

EADs develop more in midmyocardial M cells and Purkinje fibers than in epicardial or endocardial cells when exposed to APD-prolonging agents. This is in part a result of the presence of a weaker I_Ks in M cells.⁸³ In addition, a recent study showed that apamin-sensitive SK current (I_KAS) is deficient in the M-cell layer in failing human ventricles.⁸⁴ Because I_KAS current is low, the M-cell myocytes are not able to shorten the APD in conditions associated with increased Ca_i. The reduced SK current can therefore contribute to the development of EADs in the M cells. Chromanol 293B, which blocks both the I_Ks⁸⁵ and the I_KAS,⁸⁶ permits the induction of EADs in canine epicardial and endocardial tissues in response to I_Kr blockers such as E-4031 or sotalol.⁸⁷ The predisposition of cardiac cells to the development of EADs depends principally on the reduced availability of I_Kr, I_Ks, and I_KAS as occurs in many forms of cardiomyopathy and heart failure. Under these conditions, EADs can appear in any part of the ventricular myocardium.

Ionic Mechanisms Responsible for Early Afterdepolarizations

An EAD occurs when the balance of current active during phase 2 or 3 of the action potential shifts in the inward direction. If the change in current-voltage relation results in a region of net inward current during the plateau range of membrane potentials, it leads to a depolarization or EAD. Most pharmacologic interventions or pathophysiologic conditions associated with EADs can be categorized as acting predominantly through one of four different mechanisms: (1) a reduction of repolarizing potassium currents (I_Kr, class IA and III antiarrhythmic agents; I_Ks, chromanol 293B or I_K1); (2) an increase in the availability of calcium current (Bay K8644, catecholamines); (3) an increase in the sodium-calcium exchange current (I_NCX) caused by augmentation of Ca_i activity or upregulation of the I_NCX; and (4) an increase in late Na current (I_NaL) (aconitine, anthoplexurin-A, and ATX-II). Combinations of these interventions (eg, calcium loading and I_Kr reduction) or pathophysiologic states can act synergistically to facilitate the development of EADs.

A sustained component of sodium channel current (I_Na) active during the action potential plateau, originating from channels that fail to inactivate and a nonequilibrium component arising from channels recovering from inactivation during phases 2 and 3, has been shown to contribute prominently to the APD and induction of EADs.^88,89 Reactivation of I_Ca,L may contribute to the development of EADs when there was persistent late I_Na and reduced repolarization reserve.⁸⁸ Calcium-calmodulin kinase II has been linked to the development of EAD in mouse models of cardiac hypertrophy.⁹⁰ Ranolazine, which suppresses late I_Na, is a promising antiarrhythmic agent, especially in the atria.^91,92

Delayed Afterdepolarization–Induced Triggered Activity

DADs occur because of the spontaneous sarcoplasmic reticulum Ca release, which activates the I_NCX and results in oscillations of transmembrane potentials that occur after full repolarization of the action potential.^93,94 When there is spontaneous sarcoplasmic reticulum Ca release, it activates the I_NCX and depolarizes the cell membrane. DADs may reach the threshold and give rise to spontaneous action potentials generally referred to as triggered activity. However, whether or not spontaneous sarcoplasmic reticulum Ca releases can cause a DAD depends in part on the cell type. Maruyama et al⁹⁵ used the term diastolic Ca_i-voltage coupling gain to describe membrane potential (V_m) responses to elevated Ca_i during diastole. This concept is based on the finding that the same magnitude of sarcoplasmic reticulum Ca release may induce DADs in the Purkinje fibers but not in the epicardial cells. The reduced I_K1 in the Purkinje cells⁹⁶ was thought to underlie the higher diastolic Ca_i-voltage coupling gain compared with other myocardial cells. As discussed earlier, recent studies suggest that rhythmic spontaneous sarcoplasmic reticulum Ca release (Ca clock) is also a mechanism of SA nodal automaticity. Specifically, the rhythmic sarcoplasmic reticulum Ca releases in the SA node cause DADs and triggered activity, which underlies the mechanism of sinus rhythm.⁹⁷ Therefore, although spontaneous sarcoplasmic reticulum Ca release is an arrhythmogenic mechanism, it also contributes significantly to the normal automaticity.

Role of Delayed Afterdepolarization–Induced Triggered Activity in the Development of Cardiac Arrhythmias

An excellent example of DAD-induced arrhythmia is catecholaminergic polymorphic ventricular tachycardia (CPVT), which may be caused by the mutation of RyR2, calsequestrin (CSQ2), CALM1, and CALM2.^{98,99,100,101} The fundamental mechanism of these arrhythmias is the “leaky” ryanodine receptor, which is aggravated during catecholamine stimulation to induce DADs.^102,103 A typical clinical phenotype of CPVT is bidirectional VT, which is also seen in digitalis toxicity^104,105 and long QT syndrome type 7 (KCNJ2 mutation).¹⁰⁶ Alternans of Ca_i may play a role in the development of bidirectional VT.¹⁰⁷ Because the genetic defects of CPVT have been well described, it is possible to generate transgenic mice that duplicate the human genotype. One of the transgenic mice (RyR2/RyR2[R4496C]) was subjected to optical mapping studies.¹⁰³ The isolated cells were studied for DADs. The results showed that these mice exhibited both polymorphic VT and bidirectional VT and hence reproduced the most important phenotypes of CPVT. The in vitro studies documented that DADs underlie both polymorphic and bidirectional VT of these mice. In another study, mice carrying a human D307H missense mutation of calsequestrin (CASQ307/307)¹⁰⁸ also demonstrated frequent and prolonged sarcoplasmic reticulum Ca release events. If DADs and triggered activity underlie arrhythmias in CPVT syndrome, it follows that inhibition of spontaneous sarcoplasmic reticulum Ca release from the RyR2 might lead to successful mechanism-based therapy of cardiac arrhythmia. Wehrens et al¹⁰⁹ demonstrated that heterozygous mutation of FKBP12.6 leads to leaky RyR2 and exercise-induced VT and ventricular fibrillation (VF), simulating the human CPVT phenotype. RyR2 stabilization with a derivative of 1,4-benzothiazepine (JTV519) increased the affinity of calstabin2 for RyR2, which stabilized the closed state of RyR2 and prevented the Ca leak that triggers arrhythmias. The authors postulated that enhancing the binding of calstabin2 to RyR2 may be a therapeutic strategy for common ventricular arrhythmias. RyR2 stabilization may also be useful in managing patients with heart failure, a disease condition associated with abnormal Ca_i handling.¹¹⁰ Although RyR2 stabilizers are not yet approved for human use, Knollmann’s laboratory¹¹¹ discovered that flecainide, a commonly used antiarrhythmic drug, prevented adrenergic stress–induced arrhythmias in a mouse model of CPVT and in humans with CASQ2 or RYR2 mutations. The latter study provided the first human data that support the efficacy of RyR2-based therapy in human patients. Subsequent clinical studies that showed flecainide effectively suppresses exercise-induced arrhythmias in patients with CPVT.¹¹²

Taken together, these human and transgenic model studies suggest that spontaneous sarcoplasmic reticulum Ca release, DAD, and triggered arrhythmias underlie the mechanisms of CPVT. However, in order for DAD to induce triggered activity, there is a need for Na channel activation. Therefore, the effects of flecainide in suppressing CPVT could also be explained by its action on Na channels.¹¹³ Other studies indicate that the epicardial origin of these ectopic beats increases transmural dispersion of repolarization, thus providing the substrate for the development of reentrant tachyarrhythmias, which underlie the rapid polymorphic VT/VF.¹¹⁴ In addition to CPVT, DADs may also contribute significantly to arrhythmogenesis in common arrhythmias, such as premature ventricular contractions from the peri-infarct zone in rabbit hearts with subacute myocardial infarction.¹¹⁵ Heart failure is associated with structural and electrophysiologic remodeling, leading to tissue heterogeneity that enhances arrhythmogenesis and the propensity of sudden cardiac death. The mechanisms of arrhythmogenesis in heart failure may be attributed to the upregulation of I_NCX activity, abnormal intracellular calcium (Ca_i) handling, and non-reentrant ventricular arrhythmias as a result of triggered activity.¹¹⁶ DADs occur in heart failure as a result of sarcoplasmic reticulum Ca overload and spontaneous sarcoplasmic reticulum Ca release that activates electrogenic I_NCX during phase 4 of the action potential.¹¹⁷ Genetic suppression reduces both EADs and DADs.¹¹⁸ Because DADs are often induced by rapid activation and Ca_i accumulation, the best time to observe DADs is at the cessation of rapid pacing or tachycardia such as immediately after ventricular defibrillation.^95,119 Figure 79–7 shows an example of spontaneous VF in a Langendorff-perfused failing heart. Panel A shows baseline recording. The arrow in Panel B shows spontaneous Ca_i elevation, associated with a DAD on the epicardium.

Late Phase 3 Early Afterdepolarizations and Their Role in the Initiation of Cardiac Fibrillation

Panels B and C of Figure 79–7 show V_m and Ca_i at termination and at the onset of spontaneous VF, respectively. Note the presence of short APD in the immediate postshock period (panel B) and that the first ectopic beat that initiated VF occurred from late phase 3 of the preceding action potential (panel C). The mechanism of VF is best explained by the late phase 3 EAD and triggered activity.^15,120,121 This arrhythmogenic mechanism combines properties of both EAD and DAD but has its own unique character (see Fig. 79–7C). Late phase 3 EAD-induced triggered extrasystoles occur because abbreviated repolarization permits normal sarcoplasmic reticulum Ca release to induce an EAD-mediated closely coupled triggered response, particularly under conditions permitting intracellular Ca loading (such as AF and VF). These EADs are distinguished by the fact that they interrupt the final phase of repolarization of the action potential (late phase 3). In contrast to previously described DAD or intracellular calcium (Ca_i)–dependent EAD, it is normal, not spontaneous, sarcoplasmic reticulum Ca release that is responsible for the generation of the EAD. Late phase 3 EADs are observed when APD is markedly abbreviated as with acetylcholine (see Figs. 79–6C and 79–7B). Based on the time course of contraction, levels of Ca_i would be expected to peak during the plateau of the action potential (membrane potential of approximately –5 mV) under control conditions but during the late phase of repolarization (membrane potential of approximately –70 mV) when there is an abbreviated APD. As a consequence, the two principal Ca-mediated currents, I_NCX and I_Cl(Ca), would be expected to be weakly inward or even outward (I_Cl(Ca)) when APD is normal (control), but strongly inward when APD is very short (such as during acetylcholine infusion).¹⁵ Thus, abbreviation of the atrial APD allows for a much stronger recruitment of both I_NCX and calcium-activated chloride conductance (I_Cl(Ca)) in the generation of late phase 3 EADs.

In the isolated canine atria, late phase 3 EAD-induced extrasystoles have been shown to initiate AF, immediately following the termination of the arrhythmia.¹⁵ The same mechanisms may play an important role in the development of triggered activity within the pulmonary veins, where the APD is short even at baseline.^120,121 Simultaneous sympathovagal activation is also known to be the primary trigger of paroxysmal atrial tachycardia and AF episodes in dogs with intermittent rapid pacing.⁴⁹ In addition to the atrial arrhythmias, late phase 3 EAD may also be responsible for the development recurrent VF in failing hearts.¹¹⁹ As shown in Figure 79–7, Langendorff-perfused failing hearts develop acute and transient APD shortening immediately after successful defibrillation. Because of Ca_i accumulation during fibrillation, a combination of short APD and large Ca_i allows late phase 3 EAD to occur. Subsequently, studies showed that I_KAS is upregulated during heart failure^84,122 and may play an important role in modulating cardiac memory.¹²³ VF results in the Ca_i elevation, which activates I_KAS and shortens the postshock APD. A combination of high Ca_i and short APD results in spontaneous VF as shown in Figure 79–7. Apamin, a specific blocker of I_KAS, prevents the spontaneous recurrences of VF.¹²² Therefore, in addition to recurrent atrial arrhythmias, late phase 3 EADs may also be the mechanism responsible for ventricular arrhythmias associated with heart failure.

Reentry is a fundamentally different mechanism of arrhythmogenesis than automaticity or triggered activity. The circus movement reentry occurs when an activation wavefront propagates around an anatomical or functional core and reexcites the site of origin. In this type of reentry, all cells take turns recovering from excitation and get ready to be excited again when the next wavefront arrives. In comparison, reflection and phase 2 reentry occur when there are large differences of recovery from one site to another. The site with delayed recovery serves as a virtual electrode that excites its already recovered neighbor, resulting in reentry. A circus movement is not observed. In addition, reentry can also be classified as anatomical and functional, although there is a gray zone in which both functional and anatomical factors are important in determining the characteristics of reentrant excitation.

Circus Movement Reentry Around an Anatomical Obstacle

The ring model is the prototypical example of reentry around an anatomical obstacle. It first emerged as a concept shortly after the turn of the last century when Mayer reported the results of experiments involving the subumbrella tissue of a jellyfish (Sychomedusa cassiopeia).⁴ The muscular disk did not contract until ringlike cuts were made and pressure and a stimulus applied. This caused the disk to “spring into rapid rhythmical pulsation so regular and sustained as to recall the movement of clockwork.”⁴ Mayer demonstrated similar circus movement excitation in rings cut from the ventricles of turtle hearts, but he did not consider this to be a plausible mechanism for the development of cardiac arrhythmias. His experiments proved valuable in identifying two fundamental conditions necessary for the initiation and maintenance of circus movement excitation: (1) unidirectional block—the impulse initiating the circulating wave must travel in one direction only; and (2) for the circus movement to continue, the circuit must be long enough to allow each site in the circuit to recover before the return of the circulating wave. G. R. Mines⁶ was the first to develop the concept of circus movement reentry as a mechanism responsible for cardiac arrhythmias. He confirmed Mayer’s observations and suggested that the recirculating wave could be responsible for clinical cases of tachycardia.¹²⁴ The clinical importance of reentry was reinforced with the discovery by Kent of an accessory pathway connecting the atrium and ventricle of a human heart,¹²⁵ and that successful surgical ablation of the accessory pathway results in the cure of the paroxysmal supraventricular tachcardia.¹²⁶ The following three criteria developed by Mines for identification of circus movement reentry remain in use today:

1. An area of unidirectional block must exist.

2. The excitatory wave progresses along a distinct pathway, returning to its point of origin and then following the same path again.

3. Interruption of the reentrant circuit at any point along its path should terminate the circus movement.

It was recognized that successful reentry could occur only when the impulse was sufficiently delayed in an alternate pathway to allow for expiration of the refractory period in the tissue proximal to the site of unidirectional block. Both conduction velocity and refractoriness determine the success or failure of reentry, and the general rule is that the length of the circuit (path length) must exceed or equal that of the wavelength, the wavelength being defined as the product of the conduction velocity and the refractory period or that part of the path length occupied by the impulse and refractory to reexcitation. The theoretical minimum path length required for development of reentry was therefore dependent on both the conduction velocity and the refractory period. Reduction of conduction velocity¹²⁷ or APD¹²⁸ can both significantly reduce the theoretical limit of the path length required for the development of reentry.

Circus Movement Reentry Without an Anatomical Obstacle

That reentry could be initiated without the involvement of anatomical obstacles and that “natural rings are not essential for the maintenance of circus contractions” was first suggested by Garrey in 1914.¹²⁹ Years later, Allessie and coworkers¹³⁰ provided direct evidence in support of this hypothesis in experiments in which they induced a tachycardia in isolated preparations of rabbit left atria by applying properly timed premature extra-stimuli. Using multiple intracellular electrodes, they showed that although the basic beats elicited by stimuli applied near the center of the tissue spread normally throughout the preparation, premature impulses propagate only in the direction of shorter refractory periods. An arc of block thus develops around which the impulse is able to circulate and reexcite its site of origin. Recordings near the center of the circus movement showed only subthreshold responses. The authors proposed the term leading circle to explain their observation.⁷ They argued that the functionally refractory region that develops at the vortex of the circulating wavefront prevents the centripetal waves from short circuiting the circus movement and thus serves to maintain the reentry. The authors also proposed that the refractory core was maintained by centripetal wavelets that collide with each other. Because the head of the circulating wavefront usually travels on relatively refractory tissue, a fully excitable gap of tissue may not be present; unlike other forms of reentry, the leading circle model may not be readily influenced by extraneous impulses initiated in areas outside the reentrant circuit and thus may not be easily entrained. Although leading circle reentry was for a time widely accepted as a mechanism of functional reentry, there is significant conceptual limitation to this model of reentry. For example, the centripetal wavelet was difficult to demonstrate either by experimental studies with high-resolution mapping or with computer simulation studies.

First introduced by Wiener and Rosenblueth in 1946,¹³¹ the concept of spiral waves (rotors) has attracted a great deal of interest. Originally used to describe reentry around an anatomic obstacle, the term spiral wave reentry was later adopted to describe circulating waves in the absence of an anatomic obstacle.^{11,78,132,133} Because the concept of spiral waves of excitation is a well-described phenomenon in many excitable media,¹³² the application of the spiral waves of excitation to cardiac tissues is met with great enthusiasm. Spiral wave theory has advanced our understanding of the mechanisms responsible for the functional form of reentry. Although leading circle and spiral wave reentry are considered by some to be similar, a number of distinctions have been suggested. The curvature of the spiral wave is the key to the formation of the core.¹³⁴ The curvature of the wave forms a region of high impedance mismatch (source-sink mismatch), where the current provided by the reentering wavefront (source) is insufficient to charge the capacity and thus excite a larger volume of tissue ahead (sink). The ability of impulse propagation to succeed depends critically on the ability of source current generated by already activated cells to excite the cells ahead that have not yet been activated, generally referred to as the sink. When the source current generated by a few cells is required to activate a large number of cells in the sink, the dilution of the current may lead to conduction failure or block. A prominent curvature of the spiral wave is generally encountered following a wave break, where the wavefront meets the wavetail and a large curvature (and short action potential) is present. As a result of a very small source in part related to a short action potential (wavefront and wavetail meets), the broken end of the wave moves most slowly. Figure 79–8 shows the formation of the spiral wave by wavefront interaction with the refractory tail of a previous activation.¹³⁵ This three-dimensional computer simulation study reproduced the wavebreak observed in the optical mapping studies of VF in swine ventricle.¹³⁶ The wavebreak occurs when the wavefront encountered the refractory tail of a previous activation, inducing two spiral waves (panel A). A three-dimensional view of the scroll wave is shown in panel B. Panel C is a close-up of the wavebreak. Note that the newly formed wavebreak has a very high curvature. As curvature decreases along the more distal parts of the spiral, propagation speed increases. The high curvature prevents the wave from propagating in the direction of wavebreak. The wavefront (red) then circles around the wavebreak site to form circus movement. In three dimensions, there are two new scroll waves formed by these interactions. Another difference between the leading circle and spiral wave is the state of the core; in the former, the core is refractory because of repetitive centripetal wavelet that invades the core. In the latter, the core remains unexcited because the source-sink mismatch prevents the propagation of the wavefront into the core.¹³⁷

The term spiral wave is usually used to describe reentrant activity in two dimensions. The center of the spiral wave is called the core, and the distribution of the core in three dimensions is referred to as the filament. The three-dimensional form of the spiral wave forms a scroll wave (see Fig. 79–8B). In its simplest form, the scroll wave has a straight filament spanning the ventricular wall (ie, from epicardium to endocardium). Theoretical studies have described three major scroll wave configurations with curved filaments (L-, U-, and O-shaped), although numerous variations of these three-dimensional filaments in space and time are assumed to exist during cardiac arrhythmias.

Spiral wave activity has been used to explain the electrocardiographic patterns observed during monomorphic and polymorphic cardiac arrhythmias as well as during fibrillation. Monomorphic VT results when the spiral wave is anchored and not able to drift within the ventricular myocardium. In contrast, a meandering or drifting spiral wave causes polymorphic VT/VF-like activity.^138,139 VF seems to be the most complex representation of rotating spiral waves in the heart. VF is often preceded by VT. One of the theories suggests that VF develops when a single spiral wave responsible for VT breaks up, leading to the development of multiple spirals that are continuously extinguished and re-created.¹⁴⁰

Stability of Circus Movement Reentry

The stability of reentry is critical to the understanding of the electrocardiographic manifestations of arrhythmias. If only a single stable reentrant wavefront is present, the electrocardiogram is likely to show consistent beat-to-beat QRS morphology (such as during monomorphic VT) or consistent beat-to-beat P-wave morphology (such as during cavotricuspid isthmus–dependent atrial flutter). However, if the reentrant circuit either meanders or breaks down into multiple reentrant circuits, then the electrocardiographic manifestation becomes polymorphic or fibrillatory. Many different factors independently determine the stability of the circus movement reentry.^138,139,140

Size of the Anatomical Obstacle

Although circus movement reentry can be conveniently classified as anatomical and functional, there is a gray zone in which the features of these two mechanisms are both present. Ikeda et al¹⁴¹ performed a study in isolated superfused canine atria. The authors punched holes with 2- to 10-mm diameters in the center of the tissue. Figure 79–9 shows the effects of a central hole (anatomical obstacle) on reentrant wavefronts (spiral waves). In the absence of a lesion (see Fig. 79–9A), the induced single (functional) reentrant wavefront, in the form of a spiral wave, meandered irregularly from one site to another before terminating at the tissue border. Holes with 2- to 4-mm diameters (see Fig. 79–9B) had no effect on meandering. However, when the hole diameters were increased to 6 to 10 mm (see Fig. 79–9C), the tip of the spiral wave attached to the holes, and reentry became stationary. This model shows that a critically sized anatomic obstacle converts a nonstationary meandering reentrant wavefront to a stationary one. This electrical activation changed from irregular “fibrillation-like” activity into regular monomorphic activity. However, there was no abrupt transition from functional reentry to anatomical reentry. Rather, with a small anatomical obstacle, the reentrant wavefront exhibits the characteristics of both functional and anatomical reentry. Many previous studies showed that functional reentrant wavefronts tend to have a very short life span and are frequently unstable in whole hearts. For example, electrically induced reentry in the ventricles usually has a life span averaging a few seconds in the whole heart.^9,142 Under normal conditions, it is unlikely for the initial reentrant wavefronts to persist and continue to serve as the source of rapid excitation to induce sustained ventricular arrhythmia. To induce sustained arrhythmia in the whole heart, these initial spiral waves will need to break down and induce multiple spiral waves to induce VF or to anchor to a large anatomical barrier to induce VT.

Figure-Eight Reentry

Figure-eight reentry was first described by El-Sherif and coworkers in the surviving epicardial layer overlying infarction produced by occlusion of the left anterior descending artery in canine hearts in the late 1980s.^143,144 The same patterns of activation can also be induced by creating artificial anatomical obstacles in the ventricles¹⁴⁵ or during functional reentry induced by a single premature ventricular stimulation.⁹ In the figure-eight model, the reentrant beat produces a wavefront that circulates in both directions around a long line of conduction block (Fig. 79–10) rejoining on the distal side of the block. The wavefront then breaks through the arc of block to reexcite the tissue proximal to the block. The reentrant activation continues as two circulating wavefronts that travel in clockwise and counterclockwise directions around the two arcs in a pretzel-like configuration. The diameter of the reentrant circuit in the ventricle can be as small as a few millimeters or as large as a several centimeters. When the line of block is short and functional, the reentrant circuits are unstable and the figure-eight pattern may soon terminate.¹⁴² However, more sustained figure-eight reentry can be induced when large anatomical obstacles are present in the preparation.¹⁴⁵

Critical Mass

A second factor that determines the stability of circus movement reentry is the tissue size. As first documented by Garrey,¹²⁹ a critical mass must be present for VF to be sustained. If the tissue mass reduces to below that critical mass, VF invariably terminates. Kim et al¹⁴⁶ induced VF in isolated and perfused swine right ventricular free wall. The tissue mass was then progressively reduced by sequential cutting. The critical mass to sustain VF in this preparation was around 20 g. As tissue mass was decreased, the number of wavefronts decreased, the life span of reentrant wavefronts increased, and the cycle length, diastolic interval, and duration of action potential lengthened. When the mass is small enough, the remaining wavefront might anchor to the papillary muscle and convert VF to VT.¹⁴⁷ Figure 79–11 shows typical examples of activation patterns after progressive tissue mass reduction. In addition, the APD progressively lengthened and the average activation rate progressively reduced with the tissue size reduction. There was a parallel decrease in the dynamical complexity of VF as measured by Kolmogorov entropy and Poincaré plots. A period of quasiperiodicity became more evident before the conversion from VF (chaos) to a more regular arrhythmia (periodicity). Therefore, reducing tissue size is antifibrillatory. It causes a decrease in the number of wavefronts in VF by tissue mass reduction, which causes a transition from chaotic to periodic dynamics via the quasiperiodic route.¹⁴⁷ This observation might explain the ameliorative effects of the Maze procedure in the setting of AF.^148,149

Action Potential Duration Restitution and Effective Refractory Period

A third important factor in determining the stability of circus movement reentry is the APD restitution properties of the cardiac tissue. The APD restitution describes the relationship between APD and the preceding diastolic interval. The slope of APD restitution in theory determines the stability of cardiac activation.^150,151 When the slope is less than 1.0, repeated pacing of the system will induce APD alternans and dynamic instability, leading to fibrillation. However, flattening the restitution might be an antifibrillatory strategy.¹⁵² Figure 79–12 illustrates this concept with the help of computer simulation and a rabbit heart experiment. Panel A shows APD shortening and APD alternans as pacing cycle length decreases. Panel B shows two different APD restitution curves; one with slope > 1 (solid line) and one with slope < 1 (dashed line, obtained with 50% block of the calcium current). Panels C and D are results of computer simulation studies, whereas panels E and F are actual experimental data from a Langendorff-perfused rabbit heart. Flattening of the restitution curves in both simulation studies and in rabbit hearts resulted in the conversion of VF to VT.

In normal hearts, atrial effective refractory period (ERP) approximates APD at 70% repolarization in atria and at 90% repolarization in the ventricle (APD70-90).^153,154 Abbreviation of ERP is associated with increased susceptibility for development of reentry. In experimental models of AF, without cardiovascular disease, abbreviation of atrial ERP, secondary to pharmacologic interventions or sustained rapid atrial activation, is associated with a significant increase in AF vulnerability.^{15,130,155,156} In structurally remodeled atria or following exposure to sodium channel blockers, ERP can outlast APD70-90 secondary to reduced excitability, leading to development of postrepolarization refractoriness. Prolongation of ERP, whether by prolongation of APD or development of postrepolarization refractoriness, can terminate and/or prevent the development of reentry and is an effective treatment for paroxysmal AF.¹⁵⁷

In addition to APD restitution, the conduction velocity restitution is also an important factor that determines the stability of the reentrant wavefronts.^158,159 Figure 79–13 shows the primary findings of those studies. At baseline, the activation rate was fast, and the dominant frequency of VF was around 16 Hz. D600 flattened the APD restitution curve and converted baseline fast (type I) VF to VT. Further increasing the D600 concentration to 2.5 or 5.0 mg/L converted VT to slow (type II) VF with an average dominant frequency around 11 Hz. Because high concentrations of D600 block Na channels as well as Ca channels, the authors hypothesized that reduced excitability might underlie type II VF, which was not driven by steep APD restitution, but was a result of broad conduction velocity restitution. Whereas steep APD restitution drives wave instability by making the waveback sensitive to small changes in diastolic interval, conduction velocity can drive wave instability by making the wavefront sensitive to small changes in diastolic interval, especially if structural and electrophysiologic heterogeneities are present.

Calcium Dynamics

Electrical activation and calcium dynamics are closely coupled. However, the coupling between the two can be variable, which results in an additional complex dynamics that affect the APD restitution and the stability of the reentrant wavefronts.¹⁵¹ Whereas voltage-Ca_i coupling is generally positive (ie, a longer APD produces a larger Ca_i transient), Ca_i-voltage coupling can be either positive or negative. Positive Ca_i-voltage coupling refers to the mode in which a larger Ca_i transient produces a longer APD. This occurs when the large Ca_i transient enhances net inward current during the action potential plateau by potentiating inward I_NCX to a greater extent than it reduces the I_Ca,L (by facilitating Ca-induced inactivation). However, negative Ca-voltage coupling refers to the mode in which a larger Ca_i transient causes a shorter APD. This occurs when the reduction in I_Ca,L predominates over the increased I_NCX. In addition to complex coupling, the cardiac Ca handling has its own dynamics. It is possible to have a large discrepancy between the Ca_i transient duration and the APD in pathologic conditions. The dynamic V_m-Ca_i coupling underlies the development of arrhythmogenic discordant alternans during rapid ventricular activation^160,161 and increases the probability that an ectopic beat will induce reentrant excitations.¹⁵¹ This dynamic coupling could also affect the stability of the spiral waves and contribute to the degeneration of VT into VF.^162,163,164

Reflection

Reentry may also occur without circus movement. One noncircus movement reentry is reflected reentry (or reflection). The concept of reflection was first suggested by studies of the propagation characteristics of slow action potential responses in K⁺-depolarized Purkinje fibers.¹⁶⁵ In strands of Purkinje fiber, Wit and coworkers demonstrated a phenomenon similar to that observed by Schmitt and Erlanger in which slow anterograde conduction of the impulse was at times followed by a retrograde wavefront that produced a “return extrasystole.”^165,166 They proposed that the nonstimulated impulse was caused by circuitous reentry at the level of the syncytial interconnections, made possible by longitudinal dissociation of the bundle, as the most likely explanation for the phenomenon but also suggested the possibility of reflection. Direct evidence in support of reflection as a mechanism of arrhythmogenesis was provided by Antzelevitch and coworkers in the early 1980s.^167,168 A number of models of reflection have been developed. The first of these involves use of ion-free isotonic sucrose solution to create a narrow (1.5-2 mm) central inexcitable zone (gap) in unbranched Purkinje fibers mounted in a three-chamber tissue bath (Fig. 79–14).¹⁶⁹ In the sucrose-gap model, stimulation of the proximal segment elicits an action potential that propagates to the proximal border of the sucrose gap. Active propagation across the sucrose gap is not possible because of the ion-depleted extracellular milieu, but local circuit current continues to flow through the intercellular low resistance pathways (an Ag/AgCl extracellular shunt pathway is provided). This local circuit or electrotonic current, very much reduced on emerging from the gap, gradually discharges the capacity of the distal tissue, thus giving rise to a depolarization that manifests as a either a subthreshold response (last distal response) or a foot potential that brings the distal excitable tissue to its threshold potential (Fig. 79–15).¹⁷⁰ Active impulse propagation stops and then resumes after a delay that can be as long as several hundred milliseconds. When anterograde (proximal to distal) transmission time is sufficiently delayed to permit recovery of refractoriness at the proximal end, electrotonic transmission of the impulse in the retrograde direction is able to reexcite the proximal tissue, thus generating a closely coupled reflected reentry. Reflection therefore results from the to-and-fro electrotonically mediated transmission of the impulse across the same inexcitable segment; neither longitudinal dissociation nor circus movement needs to be invoked to explain the phenomenon.

A second model of reflection involved the creation of an inexcitable zone permitting delayed conduction by superfusion of a central segment of a Purkinje bundle with a solution designed to mimic the extracellular milieu at a site of ischemia.¹⁶⁸ The gap was shown to be largely comprised of an inexcitable cable across which conduction of impulses was electrotonically mediated. Reflected reentry has been demonstrated in isolated atrial and ventricular myocardial tissues as well.^171,172,173 Reflection has also been demonstrated in Purkinje fibers in which a functionally inexcitable zone is created by focal depolarization of the preparation with long duration constant current pulses.¹⁷⁴ Reflection is also observed in isolated canine Purkinje fibers homogeneously depressed with high K⁺ solution as well as in branched preparations of normal Purkinje fibers.¹⁷⁵

Phase 2 Reentry

Another reentrant mechanism that does not depend on circus movement and can appear to be of focal origin is phase 2 reentry. Phase 2 reentry occurs when the dome of the action potential, most commonly epicardial, propagates from sites at which it is maintained to sites at which it is abolished, causing local reexcitation of the epicardium and the generation of a closely coupled extrasystole. Accentuated spatial dispersion of repolarization is needed for phase 2 reentry to occur.

Spatial Dispersion of Repolarization

Studies conducted over the past 25 years have established that ventricular myocardium is not homogeneous but is comprised of at least three electrophysiologically and functionally distinct cell types: epicardial, M, and endocardial cells.^176,177 These three principal ventricular myocardial cell types differ with respect to phase 1 and phase 3 repolarization characteristics (Fig. 79–16). Ventricular epicardial and M, but not endocardial, cells generally display a prominent phase 1, because of a large 4-aminopyridine–sensitive transient outward current (I_to), giving the action potential a spike and dome or notched configuration. These regional differences in I_to, first suggested based on action potential data,¹⁷⁸ have now been directly demonstrated in ventricular myocytes from a wide variety of species including canine,¹⁷⁹ feline,¹⁸⁰ guinea pig,¹⁸¹ swine,¹⁸² rabbit,¹⁸³ and humans.^184,185 Differences in the magnitude of the action potential notch and corresponding differences in I_to have also been described between right and left ventricular epicardium.¹⁸⁶ Similar interventricular differences in I_to have also been described for canine ventricular M cells.¹⁸⁷ This distinction is thought to form the basis for why the Brugada syndrome, a channelopathy-mediated form of sudden death, is a right ventricular disease.

Recent optical mapping studies using normal and failing human ventricles confirmed the presence of M-cell islands in the midmyocardial layer.^84,188,189 These M-cell islands are characterized by long APDs. A large APD gradient is present between the APD within the island and the surrounding myocardium. Apamin, a specific SK current blocker, prolonged APDs in the surrounding myocardium to a greater extent than within the M-cell island.⁸⁴ Because apamin is a highly specific blocker of I_KAS,⁸⁴ these findings suggest a highly heterogeneous transmural distribution of the I_KAS. The I_KAS deficiency may contribute to the long APD of the M cells.

Between the surface epicardial and endocardial layers are transitional and M cells. M cells are distinguished by the ability of their action potential to prolong disproportionately relative to the action potential of other ventricular myocardial cells in response to a slowing of rate and/or in response to APD-prolonging agents.^176,190,191 In the dog, the ionic basis for these features of the M cell include the presence of a smaller slowly activating delayed rectifier current (I_Ks),⁸³ a larger late sodium current (late I_Na),⁸⁹ and a larger Na-Ca exchange current (I_NCX).¹⁹² In the canine heart, the rapidly activating delayed rectifier (I_Kr) and inward rectifier (I_K1) currents are similar in the three transmural cell types. Transmural and apical-basal differences in the density of I_Kr channels have been described in the ferret heart.¹⁹³ Amplification of transmural heterogeneities normally present in the early and late phases of the action potential can lead to the development of a variety of arrhythmias, including Brugada, early repolarization, long QT, and short QT syndromes as well as catecholaminergic VT. The genetic mutations associated with these inherited channelopathies are listed in Table 79–2. Their resulting gain or loss of function underlies the development of the arrhythmogenic substrate and triggers.

J-Wave Syndrome and Phase 2 Reentry

The J-Wave Syndromes and Phase 2 Reentry

The appearance of prominent electrocardiographic J waves has long been associated with hypothermia^194,195,196 and hypercalcemia,^197,198 and more recently with life-threatening ventricular arrhythmias.¹⁹⁹ Under these circumstances, the accentuated J wave is often so broad as to appear as an ST-segment elevation, as in cases of Brugada syndrome (BrS). A normal J wave in humans typically appears as a J-point elevation, with much of the J wave buried inside the QRS. An early repolarization (ER) pattern in the ECG, characterized by a distinct J wave, J-point elevation, and a notch or slur of the terminal part of the QRS with and without an ST-segment elevation, has traditionally been viewed as benign.^200,201 In 2000, this view was challenged²⁰² based on experimental data showing that this ECG manifestation predisposes to the development of polymorphic VT and VF in coronary-perfused wedge preparations.^{1,202,203,204} This hypothesis was validated by seminal studies of Haïssaguerre et al,²⁰⁵ Nam et al,²⁰⁶ and Rosso et al.²⁰⁷ These formative studies, coupled with many additional case-control and population-based studies, have provided clinical evidence for an increased risk for development of life-threatening arrhythmic events and sudden cardiac death (SCD) among patients presenting with an ER pattern, referred to as early repolarization syndrome (ERS).

An expert consensus statement recently published by MacFarlane and coworkers²⁰⁸ has provided recommendations for measurement and reporting of ER and J waves. The taskforce recommends that peak of an end QRS notch and/or the onset of an end QRS slur be designated as J_p and that J_p should exceed 0.1 mV in two or more contiguous inferior and/or lateral leads of a standard 12-lead electrocardiogram for ER to be present.²⁰⁸ It was further recommended that the start of the end QRS notch or J wave be designated as J_o and the termination as J_t.

BrS and ERS are both associated with vulnerability to development of polymorphic VT and VF leading to SCD^{1,205,206,209} in young adults and occasionally to sudden infant death syndrome.^210,211,212 The region generally most affected in ERS is the inferior region of the left ventricle, and in BrS, it is the anterior right ventricular outflow tract.^{205,207,213,214,215,216,217} BrS is characterized by accentuated J waves, appearing as a coved-type ST-segment elevation in the right precordial leads, V₁-V₃, whereas ERS is characterized by J waves, J_o elevation, notch or slur of the terminal part of the QRS, and ST-segment or J_t elevation in the lateral (type I), inferolateral (type II), or inferolateral plus anterior or right ventricular leads (type III).¹⁹⁹ ER pattern is often encountered in healthy individuals, particularly in young black individuals and athletes. ER pattern is also observed in acquired conditions, including hypothermia and ischemia.^1,218,219

Mechanisms Underlying Electrocardiographic and Arrhythmic Manifestations of Brugada Syndrome and Early Repolarization Syndrome

The J-wave syndromes are so named because they involve accentuation of the electrocardiographic J wave.¹⁹⁹ The J wave is thought to be inscribed as a consequence of transmural differences in the manifestation of the action potential notch between epicardium and endocardium secondary to heterogeneous transmural distribution of the transient outward current (I_to).²²⁰

The ionic and cellular mechanisms underlying J-wave syndromes have been the subject of some controversy.^221,222 Two central hypotheses have been advanced to explain BrS: (1) The repolarization hypothesis maintains that an outward shift in the balance of currents in right ventricular epicardium leads to repolarization abnormalities that give rise to phase 2 reentry and the generation of closely coupled premature beats capable of precipitating VT/VF; and (2) the depolarization hypothesis suggests that slow conduction in the right ventricular outflow tract (RVOT) and other regions of the right ventricle, secondary to structural defects including fibrosis and reduced Cx43, leading to discontinuities in conduction, plays a key role in the development of the electrocardiographic (ECG) and arrhythmic manifestations of the syndrome. These theories are not mutually exclusive and may indeed be synergistic.

Apparently compelling evidence in support of the depolarization hypothesis was advanced by Nademanee et al²²³ showing that radiofrequency ablation of epicardial sites displaying fractionated bipolar electrograms and late potentials in the RVOT of patients with BrS reduces the ECG and arrhythmic manifestations of the syndrome. Similar results have been reported by Brugada et al²²⁴ and in a case report published by Sacher and coworkers.²²⁵ Sacher et al²²⁵ also observed that accentuation of the Brugada ECG by ajmaline was associated with increasing area of low-voltage and fragmented electrogram activity and a more prominent ST-segment elevation.²²⁴ These authors concluded that the late potential and fractionated electrogram activity are caused by conduction delays within the RVOT and that ablation of the sites of slow conduction is the basis for the ameliorative effect of ablation therapy.^223,224,225

A direct test of this hypothesis by Szél and coworkers²²⁶ provided evidence for an alternative explanation. Using an experimental model of BrS, they showed that low-voltage fractionated electrogram activity nearly identical to that observed by Nademanee et al²²³ in the RVOT of BrS patients develops as a result of desynchronization in the appearance of the second action potential upstroke, secondary to accentuation of the epicardial action potential notch and not to slow or delayed conduction (Fig. 79–17). They also showed that high-frequency late potentials develop in the right ventricular epicardium as a result of concealed phase 2 reentry and not as a result of delayed conduction as generally presumed.²²⁶

In another series of studies, Patocskai et al²²⁷ targeted these regions of fractionated low-voltage electrogram activity and late potentials as a result of abnormal repolarization for ablation. Ablation of the right ventricular epicardium reduced the manifestation of J waves and ST-segment elevation and abolished all arrhythmic activity, a result identical to that obtained by Nademanee and coworkers (Fig. 79–18). They concluded that ablation ameliorates the BrS phenotype not by eliminating regions of delayed conduction but rather by eliminating the epicardial cells responsible for the repolarization abnormalities that give rise to phase 2 reentry and VT/VF.^1,227

In an attempt to create an in vivo model of BrS, Park et al²²⁸ genetically engineered Yucatan minipigs to heterozygously express a nonsense mutation in SCN5A (E558X), which was originally identified in a child with BrS. Atrial myocytes isolated from the SCN5A^E558X/+ pigs showed a loss of function of I_Na, and the minipigs displayed conduction abnormalities consisting of prolongation of the P wave, QRS complex, and PR interval. A BrS phenotype was never observed, not even after the administration of flecainide. These observations are expected as a result of the lack of I_to in the pig, which is a prerequisite for the development of the repolarization abnormalities associated with BrS. These observations were argued to provide strong evidence against the depolarization hypothesis and for the repolarization hypothesis.²²⁷

Additional evidence in support of the repolarization hypothesis derives from the observation that monophasic action potentials recorded from the epicardial and endocardial surfaces of the RVOT of a patient with BrS are nearly identical to transmembrane action potentials recorded from the epicardial and endocardial surfaces of the wedge model of BrS.^229,230 In both cases, the action potential displays a prominent accentuation of the notch in epicardium, but not endocardium, without any major transmural conduction delays.

Zhang et al²³¹ recently conducted noninvasive ECG imaging of 25 patients with BrS and 6 patients with right bundle branch block. The authors reported both slow discontinuous conduction and steep dispersion of repolarization in the RVOT of patients with BrS. ECG imaging was able to differentiate between BrS and right bundle branch block. Interestingly, in studying the response to an increase in rate, they found increased fractionation of the electrogram but reduced ST-segment elevation, again suggesting that conduction impairment was not the principal cause of the BrS ECG.

Using an experimental model of ERS, Koncz et al²¹⁵ recently provided evidence that the ECG and arrhythmic manifestations of ERS are similar to those of BrS. They reported that accentuation of transmural gradients in the left ventricular wall are responsible for the repolarization abnormalities underlying ERS, giving rise to J-point elevation, distinct J waves, or slurring of the terminal part of the QRS. The repolarization defect was accentuated by cholinergic agonists and reduced by quinidine, isoproterenol, cilostazol, and milrinone, accounting for the ability of these agents to reverse the repolarization abnormalities responsible for ERS.^215,232 Higher levels of I_to in the inferior left ventricle were shown to underlie the greater vulnerability of the inferior left ventricular wall to VT/VF.²¹⁵

Using ECG imaging, Rudy and coworkers²³³ provided additional evidence in support of the repolarization abnormalities by identifying abnormally short activation-recovery intervals in the inferior and lateral regions of the left ventricle and a marked dispersion of repolarization. Recent ECG image mapping studies performed in an ERS patient during VF demonstrated VF rotors anchored in the inferolateral left ventricular wall.²³⁴

Similarities and Differences Between Brugada Syndrome and Early Repolarization Syndrome

ERS and BrS display several phenotypic similarities, once again suggesting similar pathophysiologic mechanisms.^{203,220,235,236,237} In both syndromes, (1) males strongly predominate^238,239; (2) patients may be totally asymptomatic until presenting with sudden cardiac arrest; (3) the highest incidence of VF or SCD occurs in the third decade of life, perhaps tied to testosterone levels in males²⁴⁰; (4) appearance of accentuated J waves and ST-segment elevation are generally associated with bradycardia or pauses,^241,242 explaining why VF in both syndromes often occurs during sleep or at a low level of physical activity^243,244; (5) phenotype is associated with mutations or rare variants in the same genes (see Table 9–2); (6) electrical storms and associated J-wave manifestations can be suppressed using β-adrenergic agonists^{245,246,247,248}; and (7) chronic oral pharmacologic therapy using quinidine,^249,250 cilostazol,^{245,247,251,252,253,254,255} denopamine,^245,251 and bepridil²⁴⁷ suppresses the development of VT/VF secondary to inhibition of I_to, augmentation of I_Ca or I_Na, or both.^206,252,256

Differences between the two syndromes include: (1) the region of the heart most affected (RVOT vs inferior left ventricle); (2) greater incidence of late potentials in signal-averaged ECGs in BrS (60%) versus ERS (7%)²⁴⁴; (3) greater inducibility of VF during electrophysiologic study in BrS than in ERS; (4) greater elevation of J_O, J_P, or J_t (ST-segment elevation) in response to sodium channel blockers in BrS versus ERS; and (5) higher prevalence of AF in BrS versus ERS.²⁵⁷

How Can We Distinguish Between a Depolarization Versus Repolarization Defect?

When notches appear in the rising phase of the R wave, it is well established and accepted that these are a result of conduction defects within the ventricular myocardium.¹ When the notch occurs at the terminal portion of the QRS, thus resembling a J wave, it may be a result of either a conduction or repolarization defect.^236,258 The response to prematurity or to an increase in rate may be able to differentiate between the two.²⁵⁹ Delayed conduction invariably becomes more exaggerated at faster rates or during premature beats, thus leading to an accentuation of the QRS notch, whereas repolarization defects are usually moderated, resulting in a diminution of the J wave at faster rates. Although typical J waves are usually accentuated with bradycardia or long pauses, the opposite has also been described.^260,261 J waves are often seen in young males with no apparent structural heart diseases, whereas intraventricular conduction delay is often observed in older individuals or in cases of postmyocardial infarction or cardiomyopathy.^258,260 The prognostic value of a fragmented QRS has been demonstrated in BrS,^262,263 although fragmentation of the QRS is not associated with increased risk in the absence of cardiac disease.²⁶⁴ Another factor that may aid in the differential diagnosis of J wave versus intraventricular conduction delay–mediated syndromes is gender, since the appearance of J waves is strongly male predominant.

Thoracic Veins as an Arrhythmogenic Structure

Because of the discovery that pulmonary veins are important sources of AF,²⁶⁵ the arrhythmogenic mechanisms of the pulmonary veins and other thoracic veins deserve separate discussion. Although the original report showed that rapid activations in the pulmonary veins are responsible for triggering AF, rapid activations from other thoracic veins, such as the superior vena cava and the vein of Marshall,^266,267 are also important for AF to occur and sustain. Both reentrant and non-reentrant mechanisms may underlie the rapid activations within these thoracic veins.^268,269 The embryologic development of the pulmonary veins is closely related to the development of the sinus venosus segment of the heart, which are known to be structures that can generate automaticity.^270,271,272 Brunton and Fayer²⁷³ first demonstrated independent pulmonary vein contractions in rabbits and cats. They also noted that, although both atria subsequently ceased to beat, the pulmonary veins in both lungs continued to pulsate. These seminal observations have two important implications. The first is that the pulmonary vein has contractile muscle fibers. The second is that the pulmonary vein is capable of generating electrical activity independent of the atria. Findings by other investigators are compatible with these results. Masani et al²⁷⁴ showed that node-like cells are present in the myocardial layer of the pulmonary vein of rats. Subsequent studies showed multiple different arrhythmogenic cell types are present in the pulmonary veins. These cell types include periodic-acid Schiff–positive cells,^275,276 Purkinje-like cells,²⁷⁷ interstitial Cajal-like cells,^278,279 and melanocyte-like cells.²⁸⁰ All of these cells are potentially electrically active and can contribute to the generation of either automaticity or triggered activity.

Cheung²⁸¹ demonstrated that ouabain infusion or norepinephrine infusion could trigger the onset of repetitive rapid responses from the distal pulmonary vein. Chen et al^282,283 performed transmembrane potential recording of isolated canine pulmonary vein myocytes using standard glass microelectrodes. They reported several types of electrical activity within the pulmonary veins, including silent electrical activity, fast response action potentials driven by electrical stimulation, and spontaneous fast or slow response action potentials with or without EADs. The incidence of action potentials with an EAD and of spontaneous tachycardias is much greater in dogs with chronic rapid pacing than in normal dogs. The authors concluded that pulmonary veins have arrhythmogenic ability through spontaneous activities or high-frequency irregular rhythms. Because of the short APD, the pulmonary veins are also prone to the development of late phase 3 EADs and triggered arrhythmias.^120,121,284 In addition to increased propensity for automaticity and triggered activity, the complex myocardial fiber orientation in the pulmonary veins and at the pulmonary vein–left atrial junction can cause conduction blocks and facilitate reentrant excitations in that region.²⁷⁵ In addition, increased fibrosis at the pulmonary vein–left atrial junction in heart failure may play an important role in determining the characteristics of the reentrant wavefronts, thereby perpetuate AF.²⁸⁵

Although genetic arrhythmias often occur in structurally normal hearts, most of the common cardiac arrhythmias (such as AF, VF, and SCD) occur primarily in diseased hearts. Therefore, the cardiac remodeling associated with heart diseases plays an important role in cardiac arrhythmogenesis. The remodeling in diseased hearts includes structural remodeling, electrophysiologic remodeling, and neural remodeling.²⁸⁶ The neural remodeling may include both reduced innervation (denervation) and increased innervation through cardiac nerve sprouting.

Myocardial Remodeling

A common structural remodeling in diseased hearts is increased fibrosis, which occurs in both ischemic and nonischemic cardiomyopathy. Histologic studies of human hearts have shown a strong association between myocardial scars and VT.²⁸⁷ Computerized mapping studies of human hearts with dilated cardiomyopathy²⁸⁸ showed that reentrant wavefronts and transmural scroll waves were present during VF. Although the coronary arteries are open, these diseased hearts have increased fibrosis, and these fibrotic tissues provide a site for conduction block, leading to the continuous generation of reentry. Figure 79–19 shows an example of increased fibrosis in a human heart with nonischemic dilated cardiomyopathy. The patient underwent cardiac transplantation, and the heart was Langendorff perfused and mapped.²⁸⁸ Trichrome staining showed significantly increased fibrosis, which was a consistent finding in all hearts at two different levels of sections. However, these fibrotic tissues were distributed unevenly. As shown in Figure 79–19, significant interstitial replacement and perivascular fibrosis are present in panels C and E. These fibrotic tissues corresponded to the area of conduction block shown panel B. In comparison, areas without conduction block showed either normal tissue (panel A) or mild fibrosis (panel D). Complete reentrant wavefronts have also been documented around the sites of fibrosis in that study.

Atrial fibrosis is a major substrate of AF.^289,290 One possible reason is that atrial fibrosis decreases the safety factor of propagation and promotes anisotropic reentry, similar to that shown in Figure 79–19. The increased anisotropic reentrant activity facilitates the development of AF.^285,291 In addition to synthesis and remodeling of extracellular matrix, fibroblasts have much broader functions in the myocardium. Some studies have suggested a “sentinel” role for fibroblasts that is intimately associated with the global myocardial response to mechanical, electrical, and chemical signals.²⁹² Standard microelectrode recordings showed that the atrial cardiac fibroblasts had resting V_m of –37 ± 3 mV, which oscillated during contraction and relaxation.²⁹³ Through the functional coupling between the myocytes and fibroblasts,²⁹⁴ the oscillating V_m of the fibroblasts could potentially modulate conduction²⁹⁵ and promote cardiac automaticity and triggered activity by raising the diastolic V_m toward depolarization. Fibroblast K(⁺)-current remodeling may be a new component of AF-related remodeling that contributes to arrhythmia dynamics.²⁹⁶

In addition to structural remodeling, electrophysiologic remodeling is also important in the development of cardiac arrhythmia. As described earlier in this chapter, reduction of I_K1 significantly increases the incidence of DADs. Both chronic myocardial infarction²⁹⁷ and heart failure²⁹⁸ can result in significant reduction of I_K1. The mechanisms of I_K1 reduction might be related to the elevated Ca_i.²⁹⁹ In addition to I_K1 downregulation, heart failure and myocardial infarction also significantly upregulate I_NCX.^116,298,300 The increased I_NCX contributes to the developments of DAD-mediated arrhythmias in these settings.¹¹⁷ Heart failure is associated with increased I_NaL,³⁰¹ which helps reduce repolarization reserve and is proarrhythmic. It may also contribute to the diastolic dysfunction in the failing hearts.³⁰² Complete AV block in canine models causes QT prolongation by downregulation of delayed rectifier potassium currents.^303,304 This ionic current remodeling helps reduce repolarization reserve and promotes arrhythmias in diseased conditions. However, recent findings indicate that heart failure, myocardial infarction, complete AV block, and hypokalemia can upregulate the I_KAS, which serves as a countermeasure to preserve the repolarization reserve.^{84,122,305,306,307,308,309} Blocking I_KAS with apamin can further reduce repolarization reserve, leading to EADs and ventricular arrhythmias.³¹⁰

In summary, myocardial remodeling in diseased states includes both structural and electrophysiologic remodeling. These changes significantly increase the propensity of arrhythmia through both reentrant and non-reentrant mechanisms.

Neural Remodeling and Cardiac Nerve Sprouting

Static myocardial remodeling by itself does not provide a trigger for arrhythmia to occur. Additional remodeling of the autonomic nervous system in diseased states might also be important in triggering cardiac arrhythmia.³ In the central nervous system, nerve sprouting is an important mechanism of seizure disorder.^311,312 Vracko et al^313,314 demonstrated an increased number and complexity of cardiac nerve fibers in human myocardial scars and in animal models, suggesting that myocardial ischemia and infarction can also induce nerve sprouting. Compatible with this hypothesis, necrotic injury to the rat myocardium results in denervation followed by proliferative regeneration of both Schwann cells and nerve axons.³¹⁵ Cao et al³¹⁶ performed immunocytochemical studies of the native hearts of transplant recipients. In some patients, there was strong evidence of cardiac nerve sprouting and neural regenerative activity. Abundant nerve twigs are also present in tissues resected from the origin of VT (Fig. 79–20). There was a correlation between nerve density and a clinical history of ventricular arrhythmia. Subsequent studies in dogs confirmed that increased cardiac nerve sprouting and sympathetic hyperinnervation may be responsible for the initiation of VT, VF, and SCD.³¹⁷ In addition to histologic evidence, iodine-123–metaiodobenzylguanidine scanning showed that myocardial infarction can lead to both denervation and reinnervation of the heart.^{318,319,320,321,322} A potential benefit of cardiac reinnervation is the improved hemodynamic performance, as has been demonstrated in the recipients of cardiac transplantation.^{323,324,325,326} These latter studies suggest that nerve sprouting occurs and that sympathetic hyperinnervation after myocardial infarction and cardiac transplantation may contribute to the increased hemodynamic performance of the surviving myocardium. Excessive and heterogeneous nerve sprouting, however, may result in abnormal patterns of myocardial innervation, leading to cardiac arrhythmia and SCD.^{316,317,327,328}

The mechanisms of nerve sprouting after myocardial infarction are not completely understood. However, it is known that multiple neurotrophic factors are overexpressed after myocardial infarction.³²⁹ Among them, nerve growth factor (NGF) is known to promote the survival and differentiation of sympathetic nerves and maintains the catecholamine phenotype, as well as participates in axonal collateral sprouting after injury.³³⁰ An increase in the number and size of neurons in the sympathetic ganglia, as well as a marked elevation of the catecholamine level in the heart, were demonstrated in transgenic mice that overexpressed NGF.³³¹ Enlarged ganglion cells have also been observed in the stellate ganglia of human and canine models of myocardial infarction.^332,333 Zhou et al³³⁴ demonstrated increased NGF both in the myocardium and in the left stellate ganglion after myocardial infarction, suggesting that retrograded axonal transport from the myocardium to the left stellate ganglion might be responsible for the increased growth associated protein 43 (GAP43) and nerve sprouting within the left stellate ganglion. Figure 79–21 illustrates the involvement of the stellate ganglia in cardiac nerve sprouting after acute myocardial infarction. The figure shows that the nerve sprouting is a process that involves not only the site of infarction but also the entire heart. Therefore, a small to medium-sized myocardial infarction in the left anterior descending artery distribution can cause nerve sprouting in the atria and increase the atrial vulnerability to arrhythmia.³³⁵ In the latter study, atria were not involved in the ischemic injury. The structural remodeling of the nerve structures, such as the stellate ganglia, are associated with increased sympathetic nerve activities for at least 2 months after myocardial infarction.³³² The increased cardiac sympathetic outflow might contribute to the cardiac arrhythmia and sudden death after myocardial infarction.

Because autonomic nervous system activity is important in the generation and maintenance of cardiac arrhythmias,^3,336 neuromodulation may be helpful in arrhythmia control. Multiple preclinical and clinical studies suggested that the reduction of autonomic innervation or sympathetic outflow can reduce atrial arrhythmias.^{49,337,338,339,340,341,342,343} Preliminary clinical studies showed that ganglionated plexi ablation may improve the AF ablation outcomes,^344,345 although elimination of vagal responses does not guarantee the absence of AF recurrences.³⁴⁶ A recent prospective randomized clinical trial concluded that the ablation of ganglionic plexi had no benefit over simple isolation of pulmonary veins.³⁴⁷ More studies will be needed in this area before translating these findings into patient care.

In summary, the mechanism of cardiac arrhythmia includes automaticity, triggered activity, and reentry. Myocardial infarction, heart failure, and cardiac hypertrophy are associated with significant structural, electrophysiologic, and neural remodeling. The disease-induced cardiac remodeling may facilitate the development of both reentrant and non-reentrant arrhythmias. Understanding these arrhythmogenic mechanisms is important to providing mechanism-based therapy for cardiac arrhythmia.

Supported in part by National Institutes of Health Grants P01 HL78931, R01 HL 71140, and R01 HL47678, a Medtronic-Zipes Endowments, the Indiana University Health–Indiana University School of Medicine Strategic Research Initiative, and grants from the American Heart Association.