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Review
, 98 (7), 536-43

Sudden Cardiac Death and Inherited Channelopathy: The Basic Electrophysiology of the Myocyte and Myocardium in Ion Channel Disease

Affiliations
Review

Sudden Cardiac Death and Inherited Channelopathy: The Basic Electrophysiology of the Myocyte and Myocardium in Ion Channel Disease

Claire A Martin et al. Heart.

Abstract

Mutations involving cardiac ion channels result in abnormal action potential formation or propagation, leading to cardiac arrhythmias. Despite the large impact on society of sudden cardiac death resulting from such arrhythmias, understanding of the underlying cellular mechanism is poor and clinical risk stratification and treatment consequently limited. Basic research using molecular techniques, as well as animal models, has proved extremely useful in improving our knowledge of inherited arrhythmogenic syndromes. This offers the practitioner tools to accurately diagnose rare disorders and provides novel markers for risk assessment and a basis for new strategies of treatment.

Conflict of interest statement

Competing interests: None.

Figures

Figure 1
Figure 1
Mechanisms contributing to arrhythmogenesis. (A) Triggered activity, the upper trace shows an early after-depolarisation (EAD) occurring during repolarisation. The lower trace shows a delayed after-depolarisation (DAD) occurring following repolarisation. Dotted lines indicate the generation of an extra action potential with a sufficiently sized after-depolarisation. (B) Re-entrant circuit, the upper diagram shows a normal pattern of excitation with impulse propagating equally at each bifurcation and extinguishing in the middle. The lower diagram shows an area of slowed conduction velocity in one of the branches. The normal impulse shown by the solid arrow does not get extinguished as indicated by the delayed dotted arrow, allowing it to excite the myocardium. The delayed impulse is then able to circulate around the junctions resulting in inappropriate excitation of the rest of the myocardium. (C) Spatial heterogeneities in the form of transmural gradients. The epicardial action potential duration is much shorter than the endocardial potentially leading to re-excitation. (D) Temporal heterogeneities in the form of discordant action potential duration alternans. Regions which alternate out of phase generate a line of block called the nodal line between them. This has the potential to act as a focus for re-entrant circuits following the addition of a triggered beat.
Figure 2
Figure 2
Restitution curve with action potential duration (APDn) plotted against the previous diastolic interval (DIn−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.
Figure 3
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, Morita et al, Matthews et al and Martin et al, with permission.
Figure 4
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, Stokoe et al and Fabritz et al, with permission.
Figure 5
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 al and Cerrone et al, with permission.

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