Mechanisms of arrythmogenic cardiac alternans
The Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, 2500 MetroHealth Drive, Hamman 330, Cleveland, OH 44109-1998, USA
* Corresponding author. Tel: +1 216 778 2005; fax: +1 216 778 4924. E-mail address: drosenbaum{at}metrohealth.org
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T-wave alternans, a powerful marker for the risk of sudden cardiac death is directly related to alternans of the cellular action potential. When action potential alternans is first initiated, it occurs with identical phase in all cells of a particular region of the heart. However, above a critical heart rate threshold, action potential alternans switches phase in some cells but not in others, such that some cells undergo a prolongation of action potential duration (APD), whereas neighbouring cells undergo APD shortening on the same beat (i.e. discordant alternans). Discordant alternans is linked to a mechanism of arrhythmogenesis because when ventricular action potentials from neighbouring cells are alternating out of phase, repolarization gradients are amplified, producing conduction block and re-entrant excitation. In this review, we discuss potential mechanisms which may underlie discordant alternans in the heart, including (i) conduction velocity restitution, (ii) spatial heterogeneities of calcium cycling and the sarcolemmal ionic currents which govern repolarization, and (iii) intercellular uncoupling.
Key Words: Action potentials, Repolarization alternans, Ventricular arrhythmia, Discordant alternans, Calcium cycling proteins, Optical mapping
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Cellular basis of T-wave alternans
There is compelling evidence that T-wave alternans (TWA) results from beat-to-beat alternation in the time course of membrane repolarization (action potential alternans) at the cellular level.1
,2–4 This was definitively established through detailed measurements of the time course of membrane voltage throughout the ventricle at a time when TWA was elicited on the surface ECG using high-resolution optical mapping techniques in a guinea pig model of pacing-induced TWA.1–3 These studies demonstrated that TWA on the electrocardiogram actually corresponds to substantially greater alternans of cellular repolarization at the myocyte level1 and may explain why the detection of very subtle (‘microvolt level’) TWA has physiological and prognostic significance in patients. Importantly, in these studies, TWA was a consistent (actually requisite) precursor to ventricular fibrillation (VF).
Although the cellular mechanism for action potential alternans is not completely elucidated, there is convincing data for a primary role of sarcoplasmic reticulum (SR) calcium (Ca) cycling in its mechanism.5 Experiments performed in normal myocytes subjected to pharmacological inhibition of either the ryanodine release channel (RyR) or SR calcium ATPase (SERCA2a) have demonstrated, at least conceptually, that dysfunction of either of these key calcium cycling proteins can cause alternans of intracellular calcium cycling.6–8 These findings support the contention that calcium cycling proteins, in general, and two general properties of SR calcium handling, calcium release and reuptake, are directly implicated in the mechanism of beat-to-beat alternans of the calcium transient. Alternans of intracellular calcium cycling then results in cellular action potential alternans through calcium-sensitive sarcolemmal ionic currents.9–11
However, other mechanisms involving membrane ionic and intracellular processes governing repolarization have also been asserted as potential mechanism to explain action potential alternans.4,12 An alternative hypothesis for the genesis of cellular alternans relates to action potential duration (APD) restitution. Action potential duration restitution is the normal attenuation of APD that occurs in response to faster heart rates and is thought to be an adaptive mechanism for preserving diastole at rapid heart rates. Action potential duration restitution is presumed to cause action potential alternans since, at a constant cycle length, APD prolongation during one beat is necessarily followed by a short diastolic interval, which, according to restitution, will shorten APD on the following beat, which will then lengthen the diastolic interval causing repeated long–short–long APD cycles. The ‘restitution hypothesis’ states that APD alternans will occur when the slope of the APD restitution curve exceeds unity. Although the restitution hypothesis for action potential alternans has been primarily demonstrated in modelling studies and has not been well supported experimentally,4,12 it may nevertheless have significant impact on the spatial organization of alternans, and therefore discordant alternans in the heart, as is discussed below.
Mechanism linking action potential alternans to the genesis of arrhythmias
The mechanism linking action potential alternans (and therefore TWA) to ventricular arrhythmias was recently described and involves the development of spatially discordant alternans (i.e. action potential alternans occurring with opposite phase between neighboring cells, Figure 1A).1 When action potential alternans is initiated, it occurs with identical phase (APD either prolongs or shortens simultaneously in all cells) in cells of a particular region of ventricular myocardium (i.e. concordant alternans, Figure 2B, left). Although concordant action potential alternans itself is not necessarily arrhythmogenic, it is a prerequisite for discordant alternans and the transformation from concordant to discordant alternans has significant consequences on the spatial organization of repolarization across the ventricle. As illustrated in Figure 2B (right), after a premature impulse (asterisk) or change in pacing rate above a critical heart rate threshold, action potential alternans switches phase in some cells (site B) but not others (site A), such that some cells undergo a prolongation of APD, whereas other populations of cells undergo APD shortening on the same beat (i.e. discordant alternans).1,2 A proposed mechanism linking discordant alternans to arrhythmogenesis is demonstrated in Figure 2. During discordant alternans (Figure 2B, right), marked spatial dispersion of repolarization emerges (gray bars) and discordant alternans amplifies physiological heterogeneities of repolarization present at baseline into pathophysiological heterogeneities of sufficient magnitude to produce conduction block and re-entrant excitation (Figure 2B).1–3 Discordant alternans also produces a substrate by which conduction block and re-entrant excitation can be easily initiated by a premature stimulus (Figure 2C). When an impulse (asterisk) propagates (from site A) into still-depolarized myocardium (i.e. in the wake of enhanced dispersion of repolarization after the long beat, gray bar in site B), conduction block, initiating re-entrant excitation can occur (Figure 2C, VF). Consequently, discordant alternans is a mechanism linking TWA to cardiac arrhythmogenesis, and in fact, in experimental models of action potential alternans, VF never occurs without discordant alternans. The same paradigm can explain the initiation of a variety of arrhythmias including polymorphic and monomorphic VT, as the resultant arrhythmias were determined by structural discontinuities in the tissue, but in each case discordant alternans was required to initiate re-entry. Therefore, because it amplifies spatial gradients of repolarization to produce conduction block and re-entrant excitation, discordant alternans is the key to the link between cellular alternans and cardiac arrhythmogenesis.1,2 The potential mechanisms by which cellular action potential alternans may produce discordant alternans is the subject of this review.
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Mechanism of discordant alternans between cells |
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Although it is unclear why neighbouring cells under apparently identical conditions would respond differently with respect to their alternans phase, three fundamental, and not necessarily mutually exclusive, mechanisms for discordant alternans have been proposed: (i) conduction velocity restitution,13
–15 (ii) spatial heterogeneities of calcium cycling and the sarcolemmal ionic currents which govern repolarization, and (iii) intercellular uncoupling.2
Conduction velocity restitution as a mechanism of discordant alternans
Computer modelling studies have suggested a mechanism for discordant alternans based on conduction velocity restitution.13 These simulations of homogenous tissue predict that conduction velocity restitution alone, or interacting with spatial heterogeneities of repolarization, can potentially explain discordant alternans.14,16–18 According to these simulations, although discordant alternans can arise if sufficient heterogeneities of APD restitution are present in myocardium, it is also produced even in the absence of spatial heterogeneity of APD restitution, provided that significant restitution of conduction velocity is present.13,14 Under these circumstances, during steady-state pacing, cardiomyocytes distant from the pacing site will experience a longer diastolic intervals than cardiomyocytes close to the pacing sites. Therefore, in spite of short coupling intervals, cells distant from the pacing site, because they are preceded by longer diastolic intervals, may develop paradoxically longer action potentials giving rise to discordant alternans. Conduction velocity restitution may also arise because conduction slows progressively as the coupling interval of a premature stimulus is progressively shortened. In computer simulations, if a tightly coupled premature stimulus causes marked conduction slowing (Figure 2B, premature beat, asterisk), a spatial heterogeneity of diastolic intervals is introduced such that each cell is operating on a different point of its APD restitution curve. Under these circumstances, discordant alternans can arise because the premature stimulus changes the phase of some cells but not others, depending on where on the APD restitution curve the premature impulse arrives. However, it remains unclear how to extrapolate these modelling findings to the intact heart, which, unlike computer models, is not homogeneous and comprises considerable electrophysiological and structural complexities. Moreover, in contrast to these simulations, experimental studies suggest that in normal myocardium, conduction velocity restitution is minimal relative to APD restitution, because premature stimulus-induced conduction slowing leads to block or fails to capture myocardium before substantial conduction velocity slowing occurs.1,19 In experimental studies, the pattern of discordant alternans is also independent of pacing site, further supporting the role of APD gradients rather than conduction restitution in the mechanism of discordant alternans.
Regional ionic and calcium cycling heterogeneity as a mechanism of discordant alternans
Spatial heterogeneities of calcium handling have recently been investigated as a potential mechanism underlying the spatial organization of action potential alternans and discordant alternans.4,9,10 It is now well established that spatial heterogeneities of cellular calcium handling exist in ventricle, and these contribute to spatial heterogeneities of susceptibility to action potential alternans.20 Just as intrinsic heterogeneities of cellular calcium cycling and/or repolarization properties in myocytes can potentially explain spatial differences in susceptibility to action potential alternans, these same heterogeneities could also explain development of discordant alternans.1 Action potential alternans susceptible myocytes have the slowest time constant for diastolic Ca reuptake, and greatest propensity for rate-dependent cytosolic Ca accumulation, strongly suggesting that Ca cycling dictates susceptibility to action potential alternans (Figure 3).4 Alternans susceptible myocytes express significantly less SERCA2a and RyR compared to alternans resistant myocytes, suggesting a molecular basis for cellular alternans7 and specifically implicating Ca cycling proteins in this mechanism (Figure 4). In addition, it is quite likely that spatial heterogeneities of repolarization and calcium cycling are inter-related.21 As calcium alternans is the source of cellular action potential alternans, it is possible that spatial heterogeneities of Ca cycling explains not only the susceptibility to action potential alternans, but discordant alternans as well.1 Although, experimental evidence for this remains somewhat limited,22 the observations that (i) patterns of discordant alternans are not random and orient themselves along gradients of APD and restitution1 and (ii) patterns of discordant alternans are independent of pacing site in intact hearts strongly suggest a mechanism for discordant alternans intrinsic to the myocyte, rather than related secondary to conduction through tissue.1
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Modelling studies have recently suggested that heterogeneity in the coupling of calcium and action potential alternans can also result in discordant alternans.9
,10 Typically, calcium and action potential alternans are in phase (i.e. large calcium transient is associated with longer APD); however, at least theoretically, since both Ca and Vm can be bi-directionally coupled, spatially discordant alternans could result when Ca and APD alternans are in phase in some cells, but not in others. This mechanism has yet to be demonstrated experimentally.
In addition, discordant subcellular alternans, in which Ca alternans is out of phase within regions in a single myocyte, has been observed in intact myocardium.23 How this relates to the organization of Ca alternans on the level of the intact heart or on patterns of action potential alternans (which is under greater electrotonic influences than Ca) remains unclear.9,10 However, it is further evident that heterogeneities in calcium cycling properties in tissue (or individual myocytes) might influence patterns of Ca (and therefore action potential) alternans in the heart.
As discussed above, the fact that a properly timed premature stimulus applied during cellular alternans changes the magnitude or phase of APD alternans, implicates restitution alone as a possible mechanism in discordant alternans. The ‘restitution hypothesis’ states that cellular alternans occurs when the slope of the APD restitution curve is >1, which has been taken as evidence that sarcolemmal ion channels, rather than SR calcium cycling, determine the action potential alternans.13,14,24–26 As kinetics of APD restitution is heterogeneous between myocytes located in different regions of ventricle, one would postulate that a properly timed premature stimulus may change the phase of APD alternans in some regions but not in others, which is by definition a requirement for discordant alternans.27,28 Recently, a mechanism of discordant based on conduction/repolarization dynamics was proposed.10 As demonstrated in Figure 2A, at slower heart rates where no alternans is present, a premature beat (asterisk) will propagate between ventricular sites (site A to site B) with normal conduction velocity, when dispersion of repolarization (gray bar) is normal and the premature beat propagates into fully repolarized myocardium. However, as shown in Figure 2B, during concordant alternans, a properly timed premature beat (or abrupt increase in heart rate) will propagate more slowly into partially repolarized myocardium (i.e. in the wake of enhanced dispersion of repolarization, gray bar). The conduction slowing prolongs the diastolic interval between the next beats in the downstream myocardium (at site B). Because of APD restitution, downstream myocytes will undergo prolongation instead of shortening of APD, causing a switch in phase of APD relative to the upstream (site A) myocytes. This also might explain a change in the phase of APD alternans of some but not other myocytes, again a pre-requisite for the development of spatially discordant alternans.
Recently, a mechanism of discordant alternans based on both temporal and spatial heterogeneities of restitution during alternans has been proposed.29 Just as different regions of the heart exhibit different restitution properties after a premature stimulus at baseline, they also will exhibit different restitution properties during alternans. Experimentally, both spatial heterogeneities of restitution and beat-to-beat differences in restitution are required to induce discordant alternans. Cells that have greater differences in restitution properties between beats were less likely to switch phase after a premature beat, whereas those with small beat-to-beat differences in restitution were more likely to switch phase after a premature beat. When a properly timed premature beat induced a switch in phase of alternans in one region of the heart (region with small beat-to-beat changes in restitution) but not another, discordant alternans occurs.29
Clearly, as discussed above and illustrated in Figure 2, mechanisms of discordant alternans involving conduction velocity restitution and APD heterogeneities are not mutually exclusive. It is possible that heterogeneity of APD restitution between myocytes play a critical role in discordant alternans, but under circumstances when conduction velocity is pathologically slowed (e.g. by myocardial disease, ischaemia, or drugs), conduction velocity restitution may play an additive role. For example, flecainide can evoke local activation sequence alternans30 or ST-segment alternans31 that precedes VF.
Intercellular uncoupling/insulating barriers as a mechanism of discordant alternans
An additional mechanism contributing to susceptibility to discordant alternans has been proposed related to intracellular uncoupling.2,14 Cardiac myocytes are electrically coupled via gap junctions that allow the flow of ionic current between cells. In general, electrotonic coupling between cells acts to homogenize repolarization. In contrast, cell-to-cell uncoupling tends to unmask intrinsic differences in cellular electrophysiological properties.32 Cell-to-cell uncoupling will have an important effect on spatial heterogeneity of repolarization,15,33 and any tendency for neighbouring myocytes to alternate with opposite phase because of differences in calcium cycling properties, APD restitution, etc., will be opposed by electrotonic coupling between these cells. In a guinea pig model of alternans, introduction of a structural barrier to electrotonically uncoupled neighbouring cells greatly facilitated the development of discordant alternans,2 suggesting that during normal conditions, intercellular coupling electrotonically attenuates differences in ionic properties that may lead to spatially discordant alternans (Figure 5).2 For example, the maintenance of marked APD gradients between epicardial and mid-myocardial layers has been attributed to reduced expression of cardiac gap junctions in this region.14,32 Conversely, disease or drug-induced uncoupling between cells may promote discordant alternans. It seems that the development of discordant alternans is favoured by conditions of cellular uncoupling such as ischaemia, where neighbouring cells can more easily manifest their underlying ionic differences because they are no longer under electrotonic influence of one another.2
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Preliminary data in the guinea pig model of pacing-induced alternans suggest that discordant alternans induced by ischaemia can be suppressed by pharmacologically increasing gap junction intercellular conductance.34
Global low-flow ischaemia in this model significantly promoted the development of concordant and discordant alternans, which was then attenuated by pharmacologically recoupling cells. This is in accordance with previous findings showing an increased level of alternans during ischaemia.27,35 and supports the hypothesis that the transition from concordant to discordant alternans is affected by the degree of gap junction intercellular conductance as suggested by experimental2 and modelling studies.13 Therefore, intercellular uncoupling on a macroscopic scale (i.e. barriers or scar) as well as a cellular scale (i.e. at gap junction level) can promote spatially discordant alternans. |
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Recently, significant progress has been made in our understanding of the spatial organization of alternans in the ventricle. Although yet to be fully elucidated, conduction velocity restitution, spatial heterogeneities of myocyte calcium cycling, and repolarization, as well as intracellular uncoupling have all been experimentally implicated in the mechanism of discordant alternans. These general mechanisms are not mutually exclusive, and each may have varying importance in contributing to discordant alternans in different arrhythmogenic conditions, such as heart failure, drug-induced pro-arrhythmia, or myocardial ischaemia. It is likely that a complex interaction between these and yet to be determined mechanism are responsible for arrhythmogenic discordant alternans in the heart.
Conflict of interest: none declared.
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National Institutes of Health (RO1-HL54 807 to D.S.R.); Emergency Medicine Foundation (Career Development Grant to L.D.W.).
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