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Ionic mechanisms of cardiac arrhythmias
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Vol. 1, No. 1 2004
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Tamas Bartfai – Harold L. Dorris Neurological Research Center and The Scripps Research Institute, USA
DISEASE Cardiovascular diseases MECHANISMS
Ionic mechanisms of cardiac arrhythmias Fadi G. Akar*, Gordon F. Tomaselli Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Ross 844, Baltimore, MD 21205, USA
The heart pumps >2000 gallons of blood every day through the body’s intricate vascular network. Each heartbeat is initiated and carefully regulated by specialized electrical impulses known as action potentials. These impulses are driven by electrical currents, which are composed of charged particles (ions) that flow in and out of individual cardiac myocytes. Ion currents mediate the contraction of individual cardiac myocytes and synchronize the electrical and contractile behavior of the heart; thereby, allowing its pumping function to remain efficient and highly coordinated. Disruption of normal impulse propagation throughout the heart interrupts the coordinated contraction of the cardiac chambers,
Section Editor: Pascal J. Goldschmidt-Clermont—Duke University Medical Center, Durham, NC, USA Cardiovascular conditions represent the major cause of death in most countries, and death due to malignant arrhythmia represents a dominant mechanism for cardiovascular death. With this review, Tomaselli and Akar explore the fundamental ionic mechanisms of normal and abnormal heart rhythms, with a strong emphasis on opportunities for therapeutic strategies. Their approach is based on the detailed molecular analysis of the individual current components of the global electrical activity of cardiomyocytes. They rely in part on the molecular delineation of specific arrhythmia syndromes, to create an overarching organization to rhythm control, and to identify patients with genetic risk factors for arrhythmias. The challenge has been that so far, drug therapies for arrhythmia control have been limited in efficacy and safety. Tomaselli and his team are world renown in the field, and likely to succeed in their quest for better arrhythmia control, no matter the obstacles.
and produces malignant, lethal rhythm disturbances (arrhythmias), which underlie the majority of sudden cardiac death cases in patients with heart disease. Here, we review our current understanding of normal and abnormal cardiac electrical behavior with emphasis on the ionic mechanisms of cardiac arrhythmias.
Cellular and molecular basis of cardiac electrophysiology The resting membrane potential ( 80 mV) of cardiac myocytes (phase-4, Fig. 1) is set by the flow of K+ ions through specialized, inwardly-rectifying channels (Kir2.x family of genes). In nodal cells, increased inward depolarizing current through hyperpolarization activated channels (i.e. funny cur*Corresponding author: (F.G. Akar) [email protected] 1740-6765/$ ß 2004 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2004.08.005
rent, If; see glossary) and reduced outward K+ current through inwardly rectifying channels (IK1) leads to spontaneous phase4 depolarization and the rhythmic firing of action potentials (APs), underlying the pacemaking activity of the heart. The cardiac AP represents a stereotypic, regenerative phenomenon that is elicited when the membrane potential of the cardiac cell exceeds a crucial voltage threshold ( 60 mV). The profile of the cardiac AP is sculpted by the orchestrated activity of multiple depolarizing and repolarizing ionic currents, each having unique time- and voltage-dependencies (Fig. 1). These currents result from ion flux through complex transmembrane proteins that either passively conduct ions down their electrochemical gradients through selective pores (ion channels), actively transport ions against their electrochemical gradients (pumps, transporters) or electrogenically exchange ionic species (exchangers) [1]. www.drugdiscoverytoday.com
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Glossary Bradycardia: slow heart rhythm. Bundle branch reentrant tachycardia: reentrant circuit that depends on the right or left bundle branches of the conduction system for its initiation and maintenance. Hypokalemia: low extracellular potassium levels. Hypomagnesemia: low extracellular magnesium levels. If (the ‘‘funny’’ current): hyperpolarization-activated inward current. QT intervals: ECG interval corresponding to cardiac systole. Tachycardia: fast heart rhythm.
In general, cardiac myocytes possess much longer APs (200–400 ms) than neuronal or skeletal muscle cells (1– 5 ms). A prototypical AP of a ventricular myocyte is shown in Fig. 1. A sharp depolarizing upstroke (phase-0) is interrupted by an early but brief repolarizing interval (phase-1) representing the notched appearance of the AP, followed by a sustained, slowly decaying plateau (phase-2) that leads to final repolarization (phase-3). Also shown in Fig. 1 are the depolarizing (above) and repolarizing (below) ionic currents that underlie the AP; the corresponding genes that encode these currents are presented on the right. In the heart, a rich heterogeneity of AP waveforms and durations exists, not only between different cardiac chambers, but also within each individual chamber [2,3]. Although regional electrical heterogeneity is crucial for normal cardiac function, allowing nodal cells to act as pacemakers and myocardial cells to achieve strong contractions (Fig. 2), it can under certain conditions promote the formation of malignant arrhythmias and predispose to sudden cardiac death [4].
Excitability and propagation Membrane excitability in cardiac myocytes is primarily determined by the availability of the Na+-current (INa), which is activated upon membrane depolarization above a crucial
Figure 1. Representative ventricular action potential and the underlying depolarizing and repolarizing ion currents. Listed on the right are the probable clones of the channel subunits that form each current. Numbers along the central trace indicate individual phases of the cardiac action potential. Reproduced, with permission, from Ref. [56].
voltage threshold, causing the sharp upstroke of the AP (phase-0). By contrast, excitability in nodal tissues, such as the sinoatrial (SA) and atrioventricular (AV) nodes is mediated by the activity of Ca2+-currents, which are activated at a higher voltage threshold than INa. Interestingly, Na+mediated APs are associated with a faster (>100 V/s) initial AP upstroke (phase-0) and a more rapidly conducted wavefront compared to Ca2+-mediated APs (1–10 V/s). Cardiac impulse propagation depends on both the passive network (cell-to-cell coupling via gap junctions and interstitial resistivity) and active membrane properties (ionic currents) [5]. Under conditions of normal cellular coupling, fluctuations in local myocardial conduction velocity are small: intra- and inter-cellular propagation delays are
Figure 2. Schematic of action potentials in different regions of the heart. The permeability of the cell membrane determines membrane voltage. At rest, cells in all regions of the heart are more permeable to K+ than other cations. The characteristic shapes of the action potentials are determined by the ionic currents that are active in each cell type during the cardiac cycle.
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approximately equal. However, with increasing levels of cellular uncoupling, the interaction between inter-cellular conduction and active membrane properties assumes greater complexity. Excessive activation delays between neighboring cells causes INa, which has a strong time-dependency, to inactivate [6]. Hence, other depolarizing currents (particularly the L-type Ca2+-current, ICa-L) become essential for driving excitatory waves across gap junctions [7]. The level of cellular uncoupling is a crucial determinant of the ‘‘safety factor’’ of AP propagation, which represents the ratio of the amount of current available to activate downstream tissue compared to that required to generate a local AP [6]. Moderate cell-to-cell uncoupling causes slower but safer conduction (safety factor > 1), because ‘‘wasted’’ electrotonic, nondepolarizing current is minimized. However, with more extreme cellular uncoupling, the transmitted current from one cell to its neighbors ultimately becomes small enough such that insufficient INa is recruited to initiate a full-blown AP, and therefore the safety factor for propagation decreases dramatically [8].
Repolarization and refractoriness Membrane refractoriness is normally dictated by the duration of the cardiac AP, which limits the number of impulses that can be conducted through the heart in a given amount of time. Refractoriness is essential to cardiac mechanical function because it ensures proper muscle relaxation before subsequent activation. Refractoriness is classified as either absolute or relative: the absolute refractory period begins immediately after phase-0 of the AP and persists during the plateau (phase-2); representing a time when no stimulus, regardless of strength, can re-excite the cell. By contrast, during the relative refractory period (phase-3), the cell is excitable but the stimulus strength required for excitation is relatively high (Fig. 3). In ischemic myocardium, an important divergence between AP repolarization and membrane refractoriness occurs, the former is decreased whereas the latter is increased, a phenomenon known as post-repolarization refractoriness [9,10]. By contrast, under certain conditions, specialized tissues such as Purkinje fibers, exhibit supranormal excitability during the terminal phase of repolarization when the threshold for reactivation of INa is even lower than at rest [11]. Supranormal excitability is thought to contribute to the ‘‘vulnerable period’’ of the cardiac cycle, a time of enhanced susceptibility to reentrant excitation with a single premature stimulus (i.e. R-on-T arrhythmias).
Ionic mechanisms contributing to cardiac arrhythmias Cardiac arrhythmias arise from abnormalities of impulse generation, conduction, or both. In what follows, we consider the cellular and ionic changes that lead to the devel-
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Figure 3. Absolute and relative refractory periods of a ventricular myocyte. The horizontal bars delineate the periods of absolute refractoriness, when no stimulus regardless of strength can elicit another action potential, and relative refractoriness when subsequent action potentials can only be initiated with high stimulus strengths. Under appropriate circumstances during the period of relative refractoriness, the cell might exhibit supranormal excitability.
opment of clinically significant rhythm disturbances. A summary of these changes, and their putative mechanisms are shown in Table 1.
Alterations in impulse initiation: automaticity Spontaneous phase-4 diastolic depolarization underlies the property of ‘‘automaticity’’, characteristic of cells in the SA and AV nodes, His-Purkinje system, atrial tissue adjacent to the coronary sinus and the pulmonary veins. Phase-4 depolarization results from the concerted action of several ionic currents, but the relative importance of these currents remains controversial [12]. As mentioned, IK1 maintains the resting membrane potential and resists depolarization. Therefore, down-regulation of this current might contribute to spontaneous, gradual phase-4 depolarization and therefore enhanced automaticity. Indeed, genetic suppression of Kir2.1 channels, which mediate IK1, can convert ventricular myocytes with fast upstroke APs to ‘‘biological pacemakers’’ with spontaneously-depolarizing phase-4 [13]. Enhanced depolarizing currents during phase-4 might also allow cells to spontaneously reach firing threshold. For example, If might play a particularly prominent role in the automaticity of Purkinje fibers [14]. Moreover, recently Plotnikov et al. [15] have used a gene therapy approach for the induction of biological pacemaker activity in the left bundle branch of dogs by adenoviral mediated delivery of HCN2, the gene encoding cardiac If. Such an approach might form the basis for the treatment of conduction system disorders. Furthermore, human mesenchymal stems cells have also been used as carriers of HCN2 for www.drugdiscoverytoday.com
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Table 1. Arrhythmia mechanismsa Molecular components
EP manifestation
Prototypic arrhythmia
Disease
Potential therapy
Automaticity If, ICa-L, ICa-T IK, IK1
Suppression Acceleration
Bradycardia Tachycardia
SSS, TBS TBS
Gene therapy Calcium blockers, If blockers
Experimental In clinical use, experimental
Triggered activity ITI
DADs
TdP PMVT PMVT PMVT
NCX block Calcium channel blockers
Experimental In clinical use
Beta blockers
In clinical use
PMVT VF
HF Digitalis toxicity CPVT Ischemiareperfusion injury HF HF
ICD ICD
In clinical use
EADs
TdP PMVT
LQTS, HF Hypertrophy/HF
ICD*, calcium channel blockers ICD*, calcium channel blockers
In clinical use In clinical use
AP prolongation, disperison, EADs, altered calcium homeostasis AP shortening, inexcitability, dispersion Uncoupling, dispersion of repolarization Uncoupling
TdP, PMVT
LQTS, HF
K supplements, Mg supplements
In clinical use
VF
Ischemia
In clinical use
PMVT
HF, ischemia
Beta blockers, nitrates, revascularization Alter gap junction conductance
MVT
HF, MI
ICa-L, IK, INa
Reentry ICa-L, IK, INa INa, ICa-L, IKATP Connexins Fibrosis
ACE inhibitors, spirolachtone, anti-oxidants
Experimental In clinical use
a Abbreviations: AP, action potential; DADs, delayed afterdepolarizations; EADs, early afterdepolarizations; HF: heart failure; ICD: internal cardioverter defibrillator; MI: myocardial infarction; MVT: monomorphic ventricular tachycardia, PMVT: polymorphic ventricular tachycardia; SSS: sick sinus syndrome; TBS: tachycardia-bradycardia syndrome. * ICD is the most proven choice of therapy for all ventricular arrhythmias in the setting of structural heart disease.
the induction of biological pacemaker activity in vitro and in vivo, further providing credence for the use of gene based therapies for the treatment of conduction abnormalities [16]. Deactivation of the delayed rectifier K+ currents (IKr and IKs) might also permit other depolarizing currents to move the membrane potential towards the threshold for activation of excitatory Ca2+ currents in nodal cells. Finally, several timeindependent currents such as those through the electrogenic Na+–K+ ATPase and Na+–Ca2+ exchangers might influence the rate of phase-4 diastolic depolarization. Several factors, including autonomic nervous system tone, regulate the rate of phase-4 diastolic depolarization in nodal tissue [17]. For example, activation of the parasympathetic nervous system has a strong negative chronotropic effect due to release of acetylcholine which activates a repolarizing current (IKACh) in nodal and atrial cells [18]. Agonist activation of muscarinic receptors also antagonizes sympathetic nervous system activation through inhibition of adenylyl cyclase, reducing cAMP and inhibiting protein kinase A (PKA). Conversely, augmentation of sympathetic nervous system tone increases myocardial catecholamine concentrations, which activate both a and b adrenoceptors. In pacemaker cells, adrenoceptor-stimulation enhances ICa-L and shifts the voltage-dependence of If to more positive potentials [19,20]. This increases the slope of phase-4 and rate of AP 26
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firing in nodal tissue. Moreover, ICa-L density is increased by PKA-mediated phosphorylation of Ca2+ channels [21] resulting in a net increase in the slope of phase-4 and AP upstroke velocity. Normal automaticity is modulated by several factors associated with heart disease. Hypokalemia (see Glossary) and ischemia reduce the activity of the Na+–K+ ATPase, a background repolarizing current that contributes to phase-4 diastolic depolarization and rate of pacemaker firing [22]. Moreover, subtle increases in extracellular K+ concentration can depolarize the resting membrane potential and increase the firing rate of pacemaker cells. By sharp contrast, a more significant increase in extracellular K+ renders the heart inexcitable by inactivating INa [23]. Sympathetic stimulation underlies the normal response of the SA node to stresses such as exercise, fever, and thyroid hormone excess [24]. Automaticity of subsidiary latent pacemakers produces escape rhythms when other dominant pacemakers are suppressed. Suppression of pacemakers by a faster rhythm leads to increased intracellular Na+ load, extrusion of Na+ by the Na+–K+ ATPase, and increased background repolarizing currents, which slow the rate of phase-4 diastolic depolarisation [25]. Atrial and ventricular myocytes exhibit spontaneous activity under pathological conditions associated with membrane
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depolarization to levels > 60 mV [26]. The mechanism of spontaneous depolarization in contractile cells is uncertain but most probably involves the activity of several depolarizing and repolarizing currents. Although ventricular myocytes express If, the threshold for its activation is well below the resting membrane potential and, hence, its functional significance remains uncertain [27]. Currents mediating the AP upstroke of abnormally automatic cells depend on the resting membrane potential. At normal resting membrane potentials abnormal automaticity can be suppressed by Na+-channel blockers, whereas at more positive potentials (> 50 mV) Ca2+-channel blockers are more effective [28]. Abnormal automaticity might underlie various forms of atrial tachycardia (see Glossary), accelerated idioventricular rhythms and ventricular tachycardia (VT). Moreover, injury currents at the borders of an ischemic zone might also depolarize adjacent non-ischemic tissue predisposing to automatic VT [28].
Afterdepolarizations and triggered activity Triggered activity refers to the formation of premature impulses (Fig. 4, dotted lines) arising from early (EAD) or delayed (DAD) afterdepolarizations, which represent membrane voltage oscillations during or following an AP, respectively [29]. In the early 1970s, DADs were experimentally observed in Purkinje fibers exposed to toxic concentrations of
Figure 4. Early and delayed afterdepolarizations which represent membrane voltage oscillations occurring during and following repolarization, respectively. Most early afterdepolarizations (EAD), especially in phase-2 and early phase-3, are believed to result from reactivation of the L-type Ca2+ current and perhaps Na+–Ca2+ exchanger current. Later phase-3 EADs might also involve reactivation of Na+ currents. Afterdepolarizations that occur after the completion of repolarization are referred to as delayed afterdepolarizations (DAD). The mechanism of DAD involves intracellular Ca2+ overload and oscillatory release of Ca2+ from the sarcoplasmic reticulum activating several Ca2+-dependent currents. Dashed lines indicate the ability of EADs and DADs to reach threshold and initiate a new full-blown action potential.
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digitalis glycosides [30]. Subsequently, the dependence of DADs on increased Ca2+ load in the cytosol and sarcoplasmic reticulum (SR) has been demonstrated [31]. For example, inhibition of the Na+–K+-ATPase by digitalis glycosides increases Ca2+ load by raising intracellular Na+, which gets exchanged for Ca2+ by the Na+–Ca2+ exchanger. Increased intracellular Ca2+, in turn, activates a depolarizing transient inward current, ITI [32] which underlies DAD formation [33]. Moreover, catecholamine stimulation can sufficiently enhance Ca2+ load to produce DADs via an increase in transmembrane Ca2+ flux through ICa-L and/or the Na+– Ca2+ exchanger [34]. Also, accumulation of lysophosphoglycerides in ischemic myocardium with consequent Na+ and Ca2+ overload has been suggested as a mechanism for DADs and triggered automaticity [35]. Cells in areas of healed myocardial infarction often display spontaneous release of Ca2+ from the SR, which can generate ‘‘waves’’ of intracellular Ca2+ elevation and arrhythmias [36]. The AP duration is an important determinant of DAD formation. Longer APs are associated with greater trans-sarcolemmal Ca2+ influx and a higher likelihood of DAD formation [37]. However, fast rates associated with relatively short APs appreciably increase the size of DADs and facilitate triggered activity [30], presumably because of frequency-dependent loading of the SR with Ca2+. Mutations in the ryanodine receptor (see review by Wehrens and Marks, in this issue), which forms the cardiac SR Ca2+ release channel have been identified in kindreds exhibiting catecholamine-induced polymorphic ventricular tachycardia (CPVT) and fibrillation with short QT-intervals (see Glossary) [38]. It seems probable that perturbed intracellular Ca2+ concentration and DAD-mediated triggered activity underlie arrhythmias in this syndrome. It is also probable that VT arising from digitalis intoxication is initiated by triggered activity [39], and that DADs underlie some forms of idiopathic VT such as those arising from the right ventricular outflow tract (Table 1) [40]. However, at present, there are no clinical arrhythmias in humans that have been definitively attributed to DADs. Unlike DADs, EADs occur during the cardiac AP and are classified as phase-2 or -3 depending on their timing within the AP (Fig. 4). Traditionally, EADs were believed to depend exclusively on reactivation of depolarizing currents following AP prolongation [31]. However, more recent experimental evidence suggests a previously unappreciated interrelationship between intracellular Ca2+ loading and EAD formation. For example, bulk cytosolic Ca2+ levels rise when APs are prolonged, and might enhance ICa-L (possibly via Ca2+-calmodulin kinase activation) [31]. This further prolongs the AP and promotes EADs [41]. Alternatively, increased intracellular Ca2+ might also hasten ICa-L inactivation directly and act to shorten the AP. Nonetheless, the interrelationship between intracellular Ca2+ and EADs might explain the enhanced susceptibility of Ca2+-loaded hearts (e.g. in ischewww.drugdiscoverytoday.com
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mia or congestive heart failure) to the development of arrhythmias, particularly on exposure to AP prolonging drugs. Ionic mechanisms underlying phase-2 and -3 EADs differ. Because APs caused by phase-2 EADs occur at relatively depolarized membrane voltages when INa is inactivated, their upstrokes are mediated by ICa-L [31]. By contrast, Na+–Ca2+ exchanger current and possibly INa might cause the inscription of phase-3 EADs [42]. As a result, phase-2 EADs are associated with a slower phase-0 rate of rise and a lower safety factor of propagation compared to their phase-3 counterparts. Because AP prolongation increases the likelihood of EAD formation, hypokalemia, hypomagnesemia (see Glossary), bradycardia (see Glossary) and drug therapy often predispose to EADs [43]. Of particular note are anti-arrhythmics and some non-cardiac drugs (e.g. phenothiazines, non-sedating anti-histamines and antibiotics), which delay cardiac repolarization heterogeneously and promote EAD-mediated polymorphic VT. EAD-mediated triggered activity is also thought to underlie the initiation of Torsades de Pointes (TdP), a characteristic polymorphic VT prevalent in patients with congenital or acquired long QT syndrome (LQTS). The acquired form is mainly caused by drug therapy, electrolyte imbalances, or structural heart diseases, such as cardiac hypertrophy and failure, which delay ventricular repolarization (so-called electrical remodeling) and predispose to arrhythmias [44]. In fact, repolarization abnormalities in hypertrophy and failure are often magnified by concomitant drug therapy or electrolyte imbalances.
Abnormal impulse conduction: reentry Reentry, the most common arrhythmia mechanism in man, refers to the circuitous propagation of an electrical impulse around inexcitable obstacles. For this to happen, two conditions must be met: (1) the impulse must undergo unidirectional conduction block, and (2) the circuit must be long enough or the wavefront slow enough to allow each site within the circuit to recover before the return of the circulating impulse. During reentry, the obstacle around which the wavefront circulates could be determined either anatomically (i.e. scar tissue, myocardial infarction) or functionally (structurally normal myocardium) [45]. Although in anatomically determined reentry, the core region around which the wavefront circulates is inexcitable due to intrinsic damage or absence of viable myocardium, it is usually excitable but not excited in functionally determined reentry [46]. Moreover, anatomically determined reentry is associated with monomorphic rhythms because the wavefront anchors around the fixed obstacle and traverses the same path. By contrast, functional reentry tends to be associated with polymorphic rhythms 28
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because the inexcitable region is not fixed and the circulating wavefront(s) meanders across the heart. Anatomically-determined reentry underlies several clinically-relevant tachycardias including atrioventricular reentry, atrial flutter and bundle branch reentrant tachycardia (see Glossary). By contrast, there is compelling evidence suggesting that atrial and ventricular fibrillation are associated with more complex reentrant activation patterns associated with functional reentry [47,48]. Because functional reentry is not associated with a fixed anatomic circuit, it is difficult to disrupt the reentrant rhythm with pacing (either by pace-termination or entrainment) or terminate the rhythm by radiofrequency or surgical (maze) ablation of parts of the circuit. Furthermore, the circuit in functionally determined reentry tends to be less stable than that in anatomically determined reentry, and exhibits shorter but wider fluctuations in cycle length. A key feature of reentrant arrhythmias is their excitable gap, which represents the spatial difference between the pathlength of a given reentrant circuit and its wavelength [49]. The cardiac wavelength is defined as the product of the effective refractory period (or action potential duration, APD) and conduction velocity. Hence, interventions that prolong APD (class III anti-arrhythmic agents) are beneficial in either preventing or terminating reentrant VT by increasing the wavelength of the reentrant circuit and eliminating the excitable gap. This can cause wavefront head-tail collision and extinction. Unfortunately, many such agents have the property of reverse use dependence (they work best at relatively slow heart rates) and therefore they are not very effective in terminating VT. Moreover, conduction slowing in disease (heart failure, ischemia) is thought to shorten the cardiac wavelength and render the heart more vulnerable to reentrant arrhythmias. Currently, there is considerable debate as to the origin of atrial (AF) and ventricular (VF) fibrillation [50,51]. One school of thought advocates multiple wavelet reentry as the culprit mechanism [52]. This involves the development of several reentrant circuits across the heart. These ‘‘independent’’ circuits occasionally collide and extinguish or break down into more circuits. Alternatively, the existence of a single ‘‘mother rotor’’ as a driver of AF or VF has also been proposed [53]. In fact, recent work using high-resolution optical mapping has demonstrated the presence of these high-frequency rotors in the left ventricle (in the case of VF) and the left atrium (in the case of AF) [48,54]. Interestingly, it has been suggested that interventricular differences in IK1 underlie the localization of the driver of VF in the left ventricle, due to its greater IK1 density, and therefore shorter APD (and wavelength) compared to the right ventricle [55]. In recent studies, pharmacological blockade of IK1 with BaCl2 and reduction of IK1 by increasing extracellular K+ have been shown to reduce the dominant frequency of the mother rotor or terminate it altogether [47,55].
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Conclusions The science of cardiac electrophysiology has its roots in clinical medicine: it began and continues to evolve with descriptions of specific arrhythmia syndromes. Understanding fundamental ionic mechanisms of normal and abnormal heart rhythms is key to the development of modern therapies. Elucidating the role of individual current components, and their underlying molecular bases, in normal and abnormal electrogenesis presents an opportunity for the development of novel therapeutics. Indeed, the molecular delineation of specific syndromes has poised us to further revolutionize arrhythmia therapy by identifying patients with genetic risk factors for arrhythmias and might open the way to effective therapies in these groups. Currently, anti-arrhythmic drug therapy has provided insufficient control of cardiac arrhythmias and many non-cardiac therapies have the potentially dangerous side effect of promoting serious heart rhythm disturbances. Further understanding of the cellular and ionic mechanisms underlying the initiation and maintenance of complex and common arrhythmia syndromes such as AF or VF will ultimately lead to the development of novel drug therapies.
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39 Gorgels, A.P. et al. (1987) Triggered activity induced by pacing during digitalis intoxication: observations during programmed electrical stimulation in the conscious dog with chronic complete atrioventricular block. Pacing Clin. Electrophysiol. 10, 1309–1321 40 Lerman, B.B. et al. (1996) Idiopathic right ventricular outflow tract tachycardia: a clinical approach. Pacing Clin. Electrophysiol. 19, 2120– 2137 41 Wu, Y. et al. (1999) Calmodulin kinase inhibition prevents development of the arrhythmogenic transient inward current. Circ. Res. 84, 906–912 42 Szabo, B. et al. (1994) Role of Na+:Ca2+ exchange current in Cs(+)induced early afterdepolarizations in Purkinje fibers. J. Cardiovasc. Electrophysiol. 5, 933–944 43 Roden, D.M. et al. (1996) Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS. Circulation 94, 1996–2012 44 Tomaselli, G.F. et al. (1994) Sudden cardiac death in heart failure. The role of abnormal repolarization. Circulation 90, 2534–2539 45 Allessie, M.A. et al. (1989) Experimental electrophysiology and arrhythmogenicity. Anisotropy and ventricular tachycardia. Eur. Heart J. 10 (Suppl. E), 2–8 46 Ikeda, T. et al. (1996) Mechanism of spontaneous termination of functional reentry in isolated canine right atrium. Evidence for the presence of an excitable but nonexcited core. Circulation 94, 1962–1973
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47 Jalife, J. et al. (2003) Toward an understanding of the molecular mechanisms of ventricular fibrillation. J. Interv. Card. Electrophysiol. 9, 119–129 48 Jalife, J. (2003) Rotors and spiral waves in atrial fibrillation. J. Cardiovasc. Electrophysiol. 14, 776–780 49 Kawase, A. et al. (2003) Widening of the excitable gap and enlargement of the core of reentry during atrial fibrillation with a pure sodium channel blocker in canine atria. Circulation 107, 905–910 50 Valderrabano, M. et al. (2003) Spatial distribution of phase singularities in ventricular fibrillation. Circulation 108, 354–359 51 Janse, M.J. et al. (1995) Ventricular fibrillation is not always due to multiple wavelet reentry. J. Cardiovasc. Electrophysiol. 6, 512–521 52 Chen, J. et al. (2000) Dynamics of wavelets and their role in atrial fibrillation in the isolated sheep heart. Cardiovasc. Res. 48, 220–232 53 Jalife, J. et al. (1998) Mechanisms of atrial fibrillation: mother rotors or multiple daughter wavelets, or both? J. Cardiovasc. Electrophysiol. 9, S2– S12 54 Sarmast, F. et al. (2003) Cholinergic atrial fibrillation: I(K,ACh) gradients determine unequal left/right atrial frequencies and rotor dynamics. Cardiovasc. Res. 59, 863–873 55 Warren, M. et al. (2003) Blockade of the inward rectifying potassium current terminates ventricular fibrillation in the guinea pig heart. J. Cardiovasc. Electrophysiol. 14, 621–631 56 Tomaselli, G.F. and Marban, E. (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc. Res. 42, 270–283
DRUG DISCOVERY
TODAY
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Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Tamas Bartfai – Harold L. Dorris Neurological Research Center and The Scripps Research Institute, USA
DISEASE Cardiovascular diseases MECHANISMS
Ionic mechanisms of cardiac arrhythmias Fadi G. Akar*, Gordon F. Tomaselli Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Ross 844, Baltimore, MD 21205, USA
The heart pumps >2000 gallons of blood every day through the body’s intricate vascular network. Each heartbeat is initiated and carefully regulated by specialized electrical impulses known as action potentials. These impulses are driven by electrical currents, which are composed of charged particles (ions) that flow in and out of individual cardiac myocytes. Ion currents mediate the contraction of individual cardiac myocytes and synchronize the electrical and contractile behavior of the heart; thereby, allowing its pumping function to remain efficient and highly coordinated. Disruption of normal impulse propagation throughout the heart interrupts the coordinated contraction of the cardiac chambers,
Section Editor: Pascal J. Goldschmidt-Clermont—Duke University Medical Center, Durham, NC, USA Cardiovascular conditions represent the major cause of death in most countries, and death due to malignant arrhythmia represents a dominant mechanism for cardiovascular death. With this review, Tomaselli and Akar explore the fundamental ionic mechanisms of normal and abnormal heart rhythms, with a strong emphasis on opportunities for therapeutic strategies. Their approach is based on the detailed molecular analysis of the individual current components of the global electrical activity of cardiomyocytes. They rely in part on the molecular delineation of specific arrhythmia syndromes, to create an overarching organization to rhythm control, and to identify patients with genetic risk factors for arrhythmias. The challenge has been that so far, drug therapies for arrhythmia control have been limited in efficacy and safety. Tomaselli and his team are world renown in the field, and likely to succeed in their quest for better arrhythmia control, no matter the obstacles.
and produces malignant, lethal rhythm disturbances (arrhythmias), which underlie the majority of sudden cardiac death cases in patients with heart disease. Here, we review our current understanding of normal and abnormal cardiac electrical behavior with emphasis on the ionic mechanisms of cardiac arrhythmias.
Cellular and molecular basis of cardiac electrophysiology The resting membrane potential ( 80 mV) of cardiac myocytes (phase-4, Fig. 1) is set by the flow of K+ ions through specialized, inwardly-rectifying channels (Kir2.x family of genes). In nodal cells, increased inward depolarizing current through hyperpolarization activated channels (i.e. funny cur*Corresponding author: (F.G. Akar) [email protected] 1740-6765/$ ß 2004 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2004.08.005
rent, If; see glossary) and reduced outward K+ current through inwardly rectifying channels (IK1) leads to spontaneous phase4 depolarization and the rhythmic firing of action potentials (APs), underlying the pacemaking activity of the heart. The cardiac AP represents a stereotypic, regenerative phenomenon that is elicited when the membrane potential of the cardiac cell exceeds a crucial voltage threshold ( 60 mV). The profile of the cardiac AP is sculpted by the orchestrated activity of multiple depolarizing and repolarizing ionic currents, each having unique time- and voltage-dependencies (Fig. 1). These currents result from ion flux through complex transmembrane proteins that either passively conduct ions down their electrochemical gradients through selective pores (ion channels), actively transport ions against their electrochemical gradients (pumps, transporters) or electrogenically exchange ionic species (exchangers) [1]. www.drugdiscoverytoday.com
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Glossary Bradycardia: slow heart rhythm. Bundle branch reentrant tachycardia: reentrant circuit that depends on the right or left bundle branches of the conduction system for its initiation and maintenance. Hypokalemia: low extracellular potassium levels. Hypomagnesemia: low extracellular magnesium levels. If (the ‘‘funny’’ current): hyperpolarization-activated inward current. QT intervals: ECG interval corresponding to cardiac systole. Tachycardia: fast heart rhythm.
In general, cardiac myocytes possess much longer APs (200–400 ms) than neuronal or skeletal muscle cells (1– 5 ms). A prototypical AP of a ventricular myocyte is shown in Fig. 1. A sharp depolarizing upstroke (phase-0) is interrupted by an early but brief repolarizing interval (phase-1) representing the notched appearance of the AP, followed by a sustained, slowly decaying plateau (phase-2) that leads to final repolarization (phase-3). Also shown in Fig. 1 are the depolarizing (above) and repolarizing (below) ionic currents that underlie the AP; the corresponding genes that encode these currents are presented on the right. In the heart, a rich heterogeneity of AP waveforms and durations exists, not only between different cardiac chambers, but also within each individual chamber [2,3]. Although regional electrical heterogeneity is crucial for normal cardiac function, allowing nodal cells to act as pacemakers and myocardial cells to achieve strong contractions (Fig. 2), it can under certain conditions promote the formation of malignant arrhythmias and predispose to sudden cardiac death [4].
Excitability and propagation Membrane excitability in cardiac myocytes is primarily determined by the availability of the Na+-current (INa), which is activated upon membrane depolarization above a crucial
Figure 1. Representative ventricular action potential and the underlying depolarizing and repolarizing ion currents. Listed on the right are the probable clones of the channel subunits that form each current. Numbers along the central trace indicate individual phases of the cardiac action potential. Reproduced, with permission, from Ref. [56].
voltage threshold, causing the sharp upstroke of the AP (phase-0). By contrast, excitability in nodal tissues, such as the sinoatrial (SA) and atrioventricular (AV) nodes is mediated by the activity of Ca2+-currents, which are activated at a higher voltage threshold than INa. Interestingly, Na+mediated APs are associated with a faster (>100 V/s) initial AP upstroke (phase-0) and a more rapidly conducted wavefront compared to Ca2+-mediated APs (1–10 V/s). Cardiac impulse propagation depends on both the passive network (cell-to-cell coupling via gap junctions and interstitial resistivity) and active membrane properties (ionic currents) [5]. Under conditions of normal cellular coupling, fluctuations in local myocardial conduction velocity are small: intra- and inter-cellular propagation delays are
Figure 2. Schematic of action potentials in different regions of the heart. The permeability of the cell membrane determines membrane voltage. At rest, cells in all regions of the heart are more permeable to K+ than other cations. The characteristic shapes of the action potentials are determined by the ionic currents that are active in each cell type during the cardiac cycle.
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approximately equal. However, with increasing levels of cellular uncoupling, the interaction between inter-cellular conduction and active membrane properties assumes greater complexity. Excessive activation delays between neighboring cells causes INa, which has a strong time-dependency, to inactivate [6]. Hence, other depolarizing currents (particularly the L-type Ca2+-current, ICa-L) become essential for driving excitatory waves across gap junctions [7]. The level of cellular uncoupling is a crucial determinant of the ‘‘safety factor’’ of AP propagation, which represents the ratio of the amount of current available to activate downstream tissue compared to that required to generate a local AP [6]. Moderate cell-to-cell uncoupling causes slower but safer conduction (safety factor > 1), because ‘‘wasted’’ electrotonic, nondepolarizing current is minimized. However, with more extreme cellular uncoupling, the transmitted current from one cell to its neighbors ultimately becomes small enough such that insufficient INa is recruited to initiate a full-blown AP, and therefore the safety factor for propagation decreases dramatically [8].
Repolarization and refractoriness Membrane refractoriness is normally dictated by the duration of the cardiac AP, which limits the number of impulses that can be conducted through the heart in a given amount of time. Refractoriness is essential to cardiac mechanical function because it ensures proper muscle relaxation before subsequent activation. Refractoriness is classified as either absolute or relative: the absolute refractory period begins immediately after phase-0 of the AP and persists during the plateau (phase-2); representing a time when no stimulus, regardless of strength, can re-excite the cell. By contrast, during the relative refractory period (phase-3), the cell is excitable but the stimulus strength required for excitation is relatively high (Fig. 3). In ischemic myocardium, an important divergence between AP repolarization and membrane refractoriness occurs, the former is decreased whereas the latter is increased, a phenomenon known as post-repolarization refractoriness [9,10]. By contrast, under certain conditions, specialized tissues such as Purkinje fibers, exhibit supranormal excitability during the terminal phase of repolarization when the threshold for reactivation of INa is even lower than at rest [11]. Supranormal excitability is thought to contribute to the ‘‘vulnerable period’’ of the cardiac cycle, a time of enhanced susceptibility to reentrant excitation with a single premature stimulus (i.e. R-on-T arrhythmias).
Ionic mechanisms contributing to cardiac arrhythmias Cardiac arrhythmias arise from abnormalities of impulse generation, conduction, or both. In what follows, we consider the cellular and ionic changes that lead to the devel-
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Figure 3. Absolute and relative refractory periods of a ventricular myocyte. The horizontal bars delineate the periods of absolute refractoriness, when no stimulus regardless of strength can elicit another action potential, and relative refractoriness when subsequent action potentials can only be initiated with high stimulus strengths. Under appropriate circumstances during the period of relative refractoriness, the cell might exhibit supranormal excitability.
opment of clinically significant rhythm disturbances. A summary of these changes, and their putative mechanisms are shown in Table 1.
Alterations in impulse initiation: automaticity Spontaneous phase-4 diastolic depolarization underlies the property of ‘‘automaticity’’, characteristic of cells in the SA and AV nodes, His-Purkinje system, atrial tissue adjacent to the coronary sinus and the pulmonary veins. Phase-4 depolarization results from the concerted action of several ionic currents, but the relative importance of these currents remains controversial [12]. As mentioned, IK1 maintains the resting membrane potential and resists depolarization. Therefore, down-regulation of this current might contribute to spontaneous, gradual phase-4 depolarization and therefore enhanced automaticity. Indeed, genetic suppression of Kir2.1 channels, which mediate IK1, can convert ventricular myocytes with fast upstroke APs to ‘‘biological pacemakers’’ with spontaneously-depolarizing phase-4 [13]. Enhanced depolarizing currents during phase-4 might also allow cells to spontaneously reach firing threshold. For example, If might play a particularly prominent role in the automaticity of Purkinje fibers [14]. Moreover, recently Plotnikov et al. [15] have used a gene therapy approach for the induction of biological pacemaker activity in the left bundle branch of dogs by adenoviral mediated delivery of HCN2, the gene encoding cardiac If. Such an approach might form the basis for the treatment of conduction system disorders. Furthermore, human mesenchymal stems cells have also been used as carriers of HCN2 for www.drugdiscoverytoday.com
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Table 1. Arrhythmia mechanismsa Molecular components
EP manifestation
Prototypic arrhythmia
Disease
Potential therapy
Automaticity If, ICa-L, ICa-T IK, IK1
Suppression Acceleration
Bradycardia Tachycardia
SSS, TBS TBS
Gene therapy Calcium blockers, If blockers
Experimental In clinical use, experimental
Triggered activity ITI
DADs
TdP PMVT PMVT PMVT
NCX block Calcium channel blockers
Experimental In clinical use
Beta blockers
In clinical use
PMVT VF
HF Digitalis toxicity CPVT Ischemiareperfusion injury HF HF
ICD ICD
In clinical use
EADs
TdP PMVT
LQTS, HF Hypertrophy/HF
ICD*, calcium channel blockers ICD*, calcium channel blockers
In clinical use In clinical use
AP prolongation, disperison, EADs, altered calcium homeostasis AP shortening, inexcitability, dispersion Uncoupling, dispersion of repolarization Uncoupling
TdP, PMVT
LQTS, HF
K supplements, Mg supplements
In clinical use
VF
Ischemia
In clinical use
PMVT
HF, ischemia
Beta blockers, nitrates, revascularization Alter gap junction conductance
MVT
HF, MI
ICa-L, IK, INa
Reentry ICa-L, IK, INa INa, ICa-L, IKATP Connexins Fibrosis
ACE inhibitors, spirolachtone, anti-oxidants
Experimental In clinical use
a Abbreviations: AP, action potential; DADs, delayed afterdepolarizations; EADs, early afterdepolarizations; HF: heart failure; ICD: internal cardioverter defibrillator; MI: myocardial infarction; MVT: monomorphic ventricular tachycardia, PMVT: polymorphic ventricular tachycardia; SSS: sick sinus syndrome; TBS: tachycardia-bradycardia syndrome. * ICD is the most proven choice of therapy for all ventricular arrhythmias in the setting of structural heart disease.
the induction of biological pacemaker activity in vitro and in vivo, further providing credence for the use of gene based therapies for the treatment of conduction abnormalities [16]. Deactivation of the delayed rectifier K+ currents (IKr and IKs) might also permit other depolarizing currents to move the membrane potential towards the threshold for activation of excitatory Ca2+ currents in nodal cells. Finally, several timeindependent currents such as those through the electrogenic Na+–K+ ATPase and Na+–Ca2+ exchangers might influence the rate of phase-4 diastolic depolarization. Several factors, including autonomic nervous system tone, regulate the rate of phase-4 diastolic depolarization in nodal tissue [17]. For example, activation of the parasympathetic nervous system has a strong negative chronotropic effect due to release of acetylcholine which activates a repolarizing current (IKACh) in nodal and atrial cells [18]. Agonist activation of muscarinic receptors also antagonizes sympathetic nervous system activation through inhibition of adenylyl cyclase, reducing cAMP and inhibiting protein kinase A (PKA). Conversely, augmentation of sympathetic nervous system tone increases myocardial catecholamine concentrations, which activate both a and b adrenoceptors. In pacemaker cells, adrenoceptor-stimulation enhances ICa-L and shifts the voltage-dependence of If to more positive potentials [19,20]. This increases the slope of phase-4 and rate of AP 26
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firing in nodal tissue. Moreover, ICa-L density is increased by PKA-mediated phosphorylation of Ca2+ channels [21] resulting in a net increase in the slope of phase-4 and AP upstroke velocity. Normal automaticity is modulated by several factors associated with heart disease. Hypokalemia (see Glossary) and ischemia reduce the activity of the Na+–K+ ATPase, a background repolarizing current that contributes to phase-4 diastolic depolarization and rate of pacemaker firing [22]. Moreover, subtle increases in extracellular K+ concentration can depolarize the resting membrane potential and increase the firing rate of pacemaker cells. By sharp contrast, a more significant increase in extracellular K+ renders the heart inexcitable by inactivating INa [23]. Sympathetic stimulation underlies the normal response of the SA node to stresses such as exercise, fever, and thyroid hormone excess [24]. Automaticity of subsidiary latent pacemakers produces escape rhythms when other dominant pacemakers are suppressed. Suppression of pacemakers by a faster rhythm leads to increased intracellular Na+ load, extrusion of Na+ by the Na+–K+ ATPase, and increased background repolarizing currents, which slow the rate of phase-4 diastolic depolarisation [25]. Atrial and ventricular myocytes exhibit spontaneous activity under pathological conditions associated with membrane
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depolarization to levels > 60 mV [26]. The mechanism of spontaneous depolarization in contractile cells is uncertain but most probably involves the activity of several depolarizing and repolarizing currents. Although ventricular myocytes express If, the threshold for its activation is well below the resting membrane potential and, hence, its functional significance remains uncertain [27]. Currents mediating the AP upstroke of abnormally automatic cells depend on the resting membrane potential. At normal resting membrane potentials abnormal automaticity can be suppressed by Na+-channel blockers, whereas at more positive potentials (> 50 mV) Ca2+-channel blockers are more effective [28]. Abnormal automaticity might underlie various forms of atrial tachycardia (see Glossary), accelerated idioventricular rhythms and ventricular tachycardia (VT). Moreover, injury currents at the borders of an ischemic zone might also depolarize adjacent non-ischemic tissue predisposing to automatic VT [28].
Afterdepolarizations and triggered activity Triggered activity refers to the formation of premature impulses (Fig. 4, dotted lines) arising from early (EAD) or delayed (DAD) afterdepolarizations, which represent membrane voltage oscillations during or following an AP, respectively [29]. In the early 1970s, DADs were experimentally observed in Purkinje fibers exposed to toxic concentrations of
Figure 4. Early and delayed afterdepolarizations which represent membrane voltage oscillations occurring during and following repolarization, respectively. Most early afterdepolarizations (EAD), especially in phase-2 and early phase-3, are believed to result from reactivation of the L-type Ca2+ current and perhaps Na+–Ca2+ exchanger current. Later phase-3 EADs might also involve reactivation of Na+ currents. Afterdepolarizations that occur after the completion of repolarization are referred to as delayed afterdepolarizations (DAD). The mechanism of DAD involves intracellular Ca2+ overload and oscillatory release of Ca2+ from the sarcoplasmic reticulum activating several Ca2+-dependent currents. Dashed lines indicate the ability of EADs and DADs to reach threshold and initiate a new full-blown action potential.
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digitalis glycosides [30]. Subsequently, the dependence of DADs on increased Ca2+ load in the cytosol and sarcoplasmic reticulum (SR) has been demonstrated [31]. For example, inhibition of the Na+–K+-ATPase by digitalis glycosides increases Ca2+ load by raising intracellular Na+, which gets exchanged for Ca2+ by the Na+–Ca2+ exchanger. Increased intracellular Ca2+, in turn, activates a depolarizing transient inward current, ITI [32] which underlies DAD formation [33]. Moreover, catecholamine stimulation can sufficiently enhance Ca2+ load to produce DADs via an increase in transmembrane Ca2+ flux through ICa-L and/or the Na+– Ca2+ exchanger [34]. Also, accumulation of lysophosphoglycerides in ischemic myocardium with consequent Na+ and Ca2+ overload has been suggested as a mechanism for DADs and triggered automaticity [35]. Cells in areas of healed myocardial infarction often display spontaneous release of Ca2+ from the SR, which can generate ‘‘waves’’ of intracellular Ca2+ elevation and arrhythmias [36]. The AP duration is an important determinant of DAD formation. Longer APs are associated with greater trans-sarcolemmal Ca2+ influx and a higher likelihood of DAD formation [37]. However, fast rates associated with relatively short APs appreciably increase the size of DADs and facilitate triggered activity [30], presumably because of frequency-dependent loading of the SR with Ca2+. Mutations in the ryanodine receptor (see review by Wehrens and Marks, in this issue), which forms the cardiac SR Ca2+ release channel have been identified in kindreds exhibiting catecholamine-induced polymorphic ventricular tachycardia (CPVT) and fibrillation with short QT-intervals (see Glossary) [38]. It seems probable that perturbed intracellular Ca2+ concentration and DAD-mediated triggered activity underlie arrhythmias in this syndrome. It is also probable that VT arising from digitalis intoxication is initiated by triggered activity [39], and that DADs underlie some forms of idiopathic VT such as those arising from the right ventricular outflow tract (Table 1) [40]. However, at present, there are no clinical arrhythmias in humans that have been definitively attributed to DADs. Unlike DADs, EADs occur during the cardiac AP and are classified as phase-2 or -3 depending on their timing within the AP (Fig. 4). Traditionally, EADs were believed to depend exclusively on reactivation of depolarizing currents following AP prolongation [31]. However, more recent experimental evidence suggests a previously unappreciated interrelationship between intracellular Ca2+ loading and EAD formation. For example, bulk cytosolic Ca2+ levels rise when APs are prolonged, and might enhance ICa-L (possibly via Ca2+-calmodulin kinase activation) [31]. This further prolongs the AP and promotes EADs [41]. Alternatively, increased intracellular Ca2+ might also hasten ICa-L inactivation directly and act to shorten the AP. Nonetheless, the interrelationship between intracellular Ca2+ and EADs might explain the enhanced susceptibility of Ca2+-loaded hearts (e.g. in ischewww.drugdiscoverytoday.com
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mia or congestive heart failure) to the development of arrhythmias, particularly on exposure to AP prolonging drugs. Ionic mechanisms underlying phase-2 and -3 EADs differ. Because APs caused by phase-2 EADs occur at relatively depolarized membrane voltages when INa is inactivated, their upstrokes are mediated by ICa-L [31]. By contrast, Na+–Ca2+ exchanger current and possibly INa might cause the inscription of phase-3 EADs [42]. As a result, phase-2 EADs are associated with a slower phase-0 rate of rise and a lower safety factor of propagation compared to their phase-3 counterparts. Because AP prolongation increases the likelihood of EAD formation, hypokalemia, hypomagnesemia (see Glossary), bradycardia (see Glossary) and drug therapy often predispose to EADs [43]. Of particular note are anti-arrhythmics and some non-cardiac drugs (e.g. phenothiazines, non-sedating anti-histamines and antibiotics), which delay cardiac repolarization heterogeneously and promote EAD-mediated polymorphic VT. EAD-mediated triggered activity is also thought to underlie the initiation of Torsades de Pointes (TdP), a characteristic polymorphic VT prevalent in patients with congenital or acquired long QT syndrome (LQTS). The acquired form is mainly caused by drug therapy, electrolyte imbalances, or structural heart diseases, such as cardiac hypertrophy and failure, which delay ventricular repolarization (so-called electrical remodeling) and predispose to arrhythmias [44]. In fact, repolarization abnormalities in hypertrophy and failure are often magnified by concomitant drug therapy or electrolyte imbalances.
Abnormal impulse conduction: reentry Reentry, the most common arrhythmia mechanism in man, refers to the circuitous propagation of an electrical impulse around inexcitable obstacles. For this to happen, two conditions must be met: (1) the impulse must undergo unidirectional conduction block, and (2) the circuit must be long enough or the wavefront slow enough to allow each site within the circuit to recover before the return of the circulating impulse. During reentry, the obstacle around which the wavefront circulates could be determined either anatomically (i.e. scar tissue, myocardial infarction) or functionally (structurally normal myocardium) [45]. Although in anatomically determined reentry, the core region around which the wavefront circulates is inexcitable due to intrinsic damage or absence of viable myocardium, it is usually excitable but not excited in functionally determined reentry [46]. Moreover, anatomically determined reentry is associated with monomorphic rhythms because the wavefront anchors around the fixed obstacle and traverses the same path. By contrast, functional reentry tends to be associated with polymorphic rhythms 28
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because the inexcitable region is not fixed and the circulating wavefront(s) meanders across the heart. Anatomically-determined reentry underlies several clinically-relevant tachycardias including atrioventricular reentry, atrial flutter and bundle branch reentrant tachycardia (see Glossary). By contrast, there is compelling evidence suggesting that atrial and ventricular fibrillation are associated with more complex reentrant activation patterns associated with functional reentry [47,48]. Because functional reentry is not associated with a fixed anatomic circuit, it is difficult to disrupt the reentrant rhythm with pacing (either by pace-termination or entrainment) or terminate the rhythm by radiofrequency or surgical (maze) ablation of parts of the circuit. Furthermore, the circuit in functionally determined reentry tends to be less stable than that in anatomically determined reentry, and exhibits shorter but wider fluctuations in cycle length. A key feature of reentrant arrhythmias is their excitable gap, which represents the spatial difference between the pathlength of a given reentrant circuit and its wavelength [49]. The cardiac wavelength is defined as the product of the effective refractory period (or action potential duration, APD) and conduction velocity. Hence, interventions that prolong APD (class III anti-arrhythmic agents) are beneficial in either preventing or terminating reentrant VT by increasing the wavelength of the reentrant circuit and eliminating the excitable gap. This can cause wavefront head-tail collision and extinction. Unfortunately, many such agents have the property of reverse use dependence (they work best at relatively slow heart rates) and therefore they are not very effective in terminating VT. Moreover, conduction slowing in disease (heart failure, ischemia) is thought to shorten the cardiac wavelength and render the heart more vulnerable to reentrant arrhythmias. Currently, there is considerable debate as to the origin of atrial (AF) and ventricular (VF) fibrillation [50,51]. One school of thought advocates multiple wavelet reentry as the culprit mechanism [52]. This involves the development of several reentrant circuits across the heart. These ‘‘independent’’ circuits occasionally collide and extinguish or break down into more circuits. Alternatively, the existence of a single ‘‘mother rotor’’ as a driver of AF or VF has also been proposed [53]. In fact, recent work using high-resolution optical mapping has demonstrated the presence of these high-frequency rotors in the left ventricle (in the case of VF) and the left atrium (in the case of AF) [48,54]. Interestingly, it has been suggested that interventricular differences in IK1 underlie the localization of the driver of VF in the left ventricle, due to its greater IK1 density, and therefore shorter APD (and wavelength) compared to the right ventricle [55]. In recent studies, pharmacological blockade of IK1 with BaCl2 and reduction of IK1 by increasing extracellular K+ have been shown to reduce the dominant frequency of the mother rotor or terminate it altogether [47,55].
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Conclusions The science of cardiac electrophysiology has its roots in clinical medicine: it began and continues to evolve with descriptions of specific arrhythmia syndromes. Understanding fundamental ionic mechanisms of normal and abnormal heart rhythms is key to the development of modern therapies. Elucidating the role of individual current components, and their underlying molecular bases, in normal and abnormal electrogenesis presents an opportunity for the development of novel therapeutics. Indeed, the molecular delineation of specific syndromes has poised us to further revolutionize arrhythmia therapy by identifying patients with genetic risk factors for arrhythmias and might open the way to effective therapies in these groups. Currently, anti-arrhythmic drug therapy has provided insufficient control of cardiac arrhythmias and many non-cardiac therapies have the potentially dangerous side effect of promoting serious heart rhythm disturbances. Further understanding of the cellular and ionic mechanisms underlying the initiation and maintenance of complex and common arrhythmia syndromes such as AF or VF will ultimately lead to the development of novel drug therapies.
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