Abnormal AP formation

Abnormal AP formation may occur as a result of enhanced automaticity, parasystole or triggered activity. Enhanced automaticity describes the accelerated depolarisation of pacemaker tissue that might occur as a result of increased sympathetic activity, hypokalaemia or drugs such as digitalis. Parasystole refers to the parallel activation of two of more pacemaker regions, which may override their usual suppression through protection by a region of conduction block. Both are rare causes of arrhythmias.6

Triggered activity describes the generation of extra systoles produced in regions other than the primary cardiac pacemaker (figure 1A). These are usually produced by after-depolarisations. These are oscillations of membrane potential that are a function of the preceding AP and which may generate a premature AP, and if of sufficient magnitude locally to cause a propagated wave of depolarisation can produce a triggered beat. Early after-depolarisations (EADs) occur during repolarisation of the AP while delayed after-depolarisations (DADs) do not occur until repolarisation is complete or nearly complete. EADs occur when a prolonged AP duration (APD) allows time for L-type Ca²⁺ channels to recover from inactivation while the membrane is still depolarised. When sufficient recovery has occurred, inward I_Ca-L further depolarises the membrane and initiates the after-depolarisation, thereby exerting a positive feedback effect.7 DADs are caused by enhanced Ca²⁺ release from the sarcoplasmic reticulum (SR) due to either to activation of the Na⁺/Ca²⁺ exchanger or Ca²⁺ activated Cl⁻ current. Thus, DADs tend to occur under conditions of Ca²⁺ overload such as during digitalis toxicity and CPVT.8

Abnormal AP propagation: mechanisms of re-entry

The mammalian ventricular myocardium normally has a highly regulated sequence of AP activation. Abnormal AP propagation can occur when the depolarisation wavefront fails to completely extinguish after normal activation, and can therefore lead to the re-excitation of regions that have recovered excitability. This circulating wave results in the spread of depolarisation, termed re-entry (figure 1B).

There are three principal requirements for the initiation of re-entrant arrhythmias:

• an obstacle around which the AP is able to circulate

• a conduction velocity sufficiently slow such that each region recovers excitability before the wave returns

• an existence of unidirectional conduction block, preventing the wave from self-extinguishing.

Such criteria have been demonstrated in numerous previous experiments, the earliest of which used an anatomical block,9 as may be seen in patients with ventricular scarring, usually from old myocardial infarction, but potentially also from cardiomyopathy and infiltrative disease. Mapping studies have shown the development of a line of functional unilateral block, which prevents the wave from self-extinguishing. The conduction velocity is slowed so that each region recovers excitability before the wave returns.10 Re-entry can also occur in the absence of scar, if there are regional heterogeneities in membrane excitability. Unilateral block can result if there are spatial gradients in the time taken between stimulation and depolarisation (latency) or in the time taken between depolarisation and recovery from the ventricular effective refractory period (VERP).

Spatial electrophysiological heterogeneity

The normal mammalian ventricular myocardium similarly has a highly regulated sequence of repolarisation, proceeding from epicardium to endocardium and from base to apex. The gradients that are observed in the normal heart may serve to protect the normal sequence of electro-mechanical activation and enable the correctly timed mechanical contractile activity that enables coordinated mechanical activation and relaxation of the heart. These spatial differences are determined predominantly by regional differences in repolarising K⁺ channels, including variations in channel density, kinetics and cycling between membrane and cytoplasm. Disturbances in these gradients may allow depolarised regions to re-excite already repolarised areas and serve as substrates for re-entry. Transmural gradients have been suggested to be particularly important as differences in repolarisation are exerted across a relatively short distance, with alterations in transmural gradients correlated with arrhythmogenic tendencies in a number of both pharmacological canine and genetic murine models for LQTS and BrS (figure 1C). As well as transmural gradients, heterogeneities within the ventricle from base to apex have been demonstrated in a number of animal models. Clinical increases in this dispersion have been associated with arrhythmogenesis in cardiomyopathies and have been linked with an increased incidence of T wave alternans and ventricular tachycardia (VT).11 Data from the canine right ventricular (RV) wedge preparation12 and the Scn5a^+/− mouse model13 implicate re-entry as a result of epicardial dispersion of repolarisation as the trigger for ventricular arrhythmia. Last, differences in APDs between the left ventricle and RV may play a role in arrhythmogenesis in BrS, as demonstrated by electrocardiographic ST elevation in the right precordial leads, RV delay and changes specific to RV epicardial AP waveforms in BrS patients.14

Temporal electrophysiological heterogeneity

As well as spatial heterogeneities, there may also be temporal beat-to-beat variations in the AP amplitude or duration, a phenomenon known as alternans (figure 1D). This has been associated with arrhythmogenesis in both clinical15 and experimental16 studies. Several hypotheses exist for the cellular mechanism for the AP alternans itself; although there is a likely role for SR Ca²⁺ cycling, APD restitution is also a key. The latter specifically concerns the attenuation of APD that occurs in response to faster heart rates and is thought to be an adaptive mechanism for preserving diastolic interval. At a given cycle length, APD prolongation during one beat is necessarily followed by a short diastolic interval, which will shorten APD in the following beat, causing repeated short–long cycles related to the availability of depolarising channels.

Alternans phenomena have classically been analysed by the construction of restitution curves relating APD to the preceding diastolic interval as heart rate is varied.17 The ‘restitution hypothesis’ states that transient APD alternans will occur when the slope of the restitution curve does not equal zero, becomes sustained when it is at unity and becomes unstable when the gradient exceeds one (figure 2). Relationships among restitution curve slopes, alternans and arrhythmogencity have been established in canine preparations made to model congenital LQTS type 218 and of genetic mouse models of LQTS type 3 and BrS.19 More recently, a predisposition of the RV for alternans has been found in the Scn5a^+/− mouse model for BrS.20 Although concordant alternans itself may not be necessarily arrhythmogenic, it is a prerequisite for subsequent development of discordant alternans. This can have significant consequences on the spatial organisation of repolarisation across the ventricle, amplifying the heterogeneities of repolarisation present at baseline into pathophysiological heterogeneities of sufficient magnitude to produce conduction block and re-entrant excitation.

• Download figure
• Open in new tab
• Download powerpoint

Figure 2

Restitution curve with action potential duration (APD_n) plotted against the previous diastolic interval (DI_n−1). Both would be in the order of milliseconds. The thick curve shows the typical monoexponential relationship this provides. Corresponding action potentials (APs) are shown for each numbered point. As the sum of the APD and DI gives the Basic Cycle Length, BCL, this gives the equation APD=−DI+BCL which is in the form of the linear relationship y=mx+c, with m the slope and c the vertical intercept of the function. Hence BCL represents the y-axis and x-axis intercept connected by a line with gradient of −1 (grey lines). Moving from a given BCL to another results in an iterative process which takes the APD to a new steady-state value. This is represented by the dashed lines. Each time a dashed line crosses the restitution function an AP is fired. At (1) the change in BCL results in a rapid iteration to a new steady-state value. As the gradient becomes steeper, the system takes longer to reach the steady-state value, with (2) showing a transient set of alternans. When the gradient of the restitution function reaches unity (3), the system enters a stable positive feedback, never reaching a steady-state value and producing sustained alternans. The DI at this point is known as the critical diastolic interval, DIcrit, and represents the break-point between stability and instability. Finally, surpassing the DIcrit (4) results in an unstable positive feedback, with AP durations spiralling away from each other. This is likely to result in the occurrence of discordant alternans and wavebreak, leading to arrhythmia.

Brugada syndrome

BrS is characterised electrocardiographically by right precordial ST elevation, negative T-waves and RV delay, and clinically by episodes of polymorphic VT and ventricular fibrillation (VF). While many genetic mutations have been associated with BrS, all result in a general imbalance of currents in favour of repolarisation over depolarisation. The most common and best studied of these is the loss-of-function mutation of the SCN5A gene, encoding the α-subunit of the voltage gated Na⁺ channel.

The cause of ST elevation in BrS and its strong linkage to VT/VF remains unresolved. Pathophysiological mechanisms responsible for ST segment changes must operate during the cardiac repolarisation phase, and these mechanisms must be based on I_Na reduction. The proposed mechanism which originally appeared to receive the widest support, both from experimental studies using a canine pharmacological ventricular preparation31 and some small clinical studies,32 ascribes BrS to a primary repolarisation disorder. The deep phase 1 notch in the epicardial AP, particularly prominent in the RV, renders it susceptible to the effects of a reduction in the Na⁺ current. The reduction in Na⁺ current establishes a steep voltage gradient across the RV wall due to short-circuiting of the epicardial AP resulting in extreme shortening. The imbalance of currents allows for reactivation of the RV epicardium by neighbouring regions of myocardium, with longer APs producing functional re-entry, referred to as phase 2 re-entry.

An alternative explanation for the ECG signature in BrS is based on conduction delay in the right ventricular outflow tract (RVOT).33 There is clinical evidence implicating conduction alterations, although this mainly employs non-invasive techniques such as echocardiography, signal-averaged ECG and body surface mapping.34 35 A single ex vivo study of the heart from a BrS patient has demonstrated local conduction delays in the RVOT, but in an absence of transmural differences in repolarisation.36 More recently, fractionated late potentials were found exclusively in the anterior aspect of the RVOT epicardium in BrS patients, and catheter ablation over this abnormal area resulted in normalisation of the ECG pattern and prevented VT/VF.37 So far, there is only one available clinical study that has showed both conduction and repolarisation disturbances.38

Recent studies using a heterozygotic Scn5a^+/− mouse model have shed further light on possible pathological mechanisms of arrhythmogenesis. Affected mice demonstrate both depolarisation abnormalities, in the form of delayed conduction latencies29 and slowed activation patterns,39 and repolarisation abnormalities in the form of APD heterogeneities and steep restitution curves13 with an associated propensity to discordant alternans,20 which may act together to initiate arrhythmias (figure 3). Fibrosis and reduced connexin expression associated with ageing41 have also been demonstrated, which may contribute to the slowed conduction and furthermore may itself promote and maintain differences in repolarisation timing between the myocardial layers creating optimal conditions for re-entry. Thus, both structural changes and differences in ion channel kinetics together create optimal proarrhythmic conditions, and the disease can be regarded as a combination of a structural cardiomyopathy in conjunction with a functional channel anomaly.

• Download figure
• Open in new tab
• Download powerpoint

Figure 3

Mechanisms of arrhythmogenesis in Brugada syndrome from animal models. The scales demonstrate that its associated genetic mutations result in a loss of depolarising currents or a gain of repolarising currents. This in turn results in delayed conduction velocity, transmural action potential gradients, a greater propensity to alternans and potentially to phase 2 re-entry. The lowest trace shows an ECG with the initiation of a polymorphic ventricular tachycardia recapitulating the clinical phenotype. All traces shown are from mice except phase 2 re-entry which is from the canine wedge preparation. Adapted in part from Martin et al,29 Morita et al,40 Matthews et al20 and Martin et al,39 with permission.

Long QT syndrome

LQTS forms a genetically heterogeneous group of conditions, characterised by prolonged ventricular repolarisation and increased risk of ventricular arrhythmias, particularly torsade de pointes. In contrast to BrS, the mutations in LQTS result in a favouring of depolarising currents over repolarising ones. Evidence from several mouse models (for references see27) have implicated prolonged APD in two major problems generating an arrhythmic substrate (figure 4). First, increased refractory periods from channels that remain depolarised for greater periods create pockets of functional block, which may act as the focus for re-entry. Second, differences in dispersion of repolarisation across the myocardium may result in a functional re-entry acting as a trigger for torsade de pointes. EADs are also more common due to the extended time of depolarisation, which may in turn trigger polymorphic VT.

• Download figure
• Open in new tab
• Download powerpoint

Figure 4

Mechanisms of arrhythmogenesis in long QT syndrome from animal models. The scales demonstrate that associated genetic mutations result in a gain of depolarising currents or a loss of repolarising currents. This in turn results in triggered activity in the form of early after-depolarisations, the formation of refractory pockets and the generation of abnormal transmural gradients. The lowest trace shows an ECG with the initiation of torsade de pointes recapitulating the clinical phenotype. All traces shown are from mice. Adapted in part from Thomas et al,42 Stokoe et al28 and Fabritz et al,43 with permission.

Catecholaminergic polymorphic ventricular tachycardia

CPVT presents as syncope or SCD due to the action of increased catecholamines during exercise or stress resulting in a bidirectional VT. The underlying mechanism of CPVT revolves around abnormal Ca²⁺ release from the SR, which is often due either to gain-of-function mutations in the gene encoding RyR2, a critical regulator of Ca²⁺ release from the SR for excitation–contraction coupling,44 or loss of function mutations in calsequestrin, a SR calcium buffering protein.45

Such abnormal Ca²⁺ release may cause DADs, similar to digitalis toxicity where baseline Ca²⁺ is also elevated, resulting in an arrhythmic trigger46 (figure 5). Data from in vitro studies show that CPVT-associated RyR2 and CASQ2 mutations8 49 cause cytosolic Ca²⁺ overload which generates a net inward current. Several transgenic mouse models of CPVT have been developed, harbouring mutations in either RyR230 or in CASQ2,50 which demonstrate abnormal Ca²⁺ transients and bidirectional VT. These studies have provided evidence that the transient inward current may underlie the DADs that trigger abnormal beats in this condition.

• Download figure
• Open in new tab
• Download powerpoint

Figure 5

Mechanisms of arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia from animal models. The genetic mutations result in an increase in cytosolic Ca²⁺ which in turn causes the scales to tip in favour of depolarising currents due to the electrogenic nature of the Na⁺/Ca²⁺ exchanger. If sufficient, this may lead to triggered activity in the form of delayed after-depolarisations. The lowest trace shows an ECG with the initiation of a bidirectional ventricular tachycardia recapitulating the clinical phenotype. All traces shown are from mice. Adapted in part from Cerrone et al47 and Cerrone et al,48 with permission.

Other syndromes

While the majority of cases of SCD in the absence of structural heart abnormalities are caused by the three syndromes mentioned above, there are a number of other related syndromes that have come to light. Short QT syndrome, phenotypically characterised by short APDs and hence QT intervals, can be caused by gain-of-function mutations in K⁺ channels51 or loss of function mutations in Ca²⁺ channels.52 Studies in a canine pharmacological wedge preparation have implicated increased transmural repolarisation gradients in the arrhythmogenic mechanism.53

Early repolarisation (ER) disease is characterised by ventricular arrhythmias and sudden death in the presence of an ER pattern on the ECG as characterised by J-point elevation and prominent T waves.54 While preliminary evidence from canine studies suggests that increased transmural differences in early phases of the AP may be responsible,55 the exact mechanism for ER is still unknown. In rare cases, mutations in genes causing either a decrease in inward Ca²⁺ currents56 or an increase in outward K⁺ currents57 have been identified; however, mutations have not been identified in the majority of cases. Given the high frequency of the genetic background underlying the ER pattern in the population, the disease is probably polygenic and influenced by environmental factors.

Progressive cardiac conduction disease (PCCD) encompasses another group of conditions that, while most commonly manifesting as bradycardia, may also cause SCD. The first gene to be associated with PCCD was SCN5A, and indeed some SCN5A mutations may be associated with more complex phenotypes combining characteristics of BrS, PCCD and LQT3, the so-called ‘overlap syndromes’.58 More recently, PCCD has been associated with altered expression of genes encoding other proteins involved in impulse propagation, including those responsible for calcium-activated ion channels and cytoskeletal components. Mouse studies have indicated that the resulting phenotype appears to develop from a combination of these genetic factors, environmental modifiers and other physiologic determinants, including ageing.41