Cardiac heterogeneity and drug‐provoked arrhythmias

Functioning of the heart as a mechanical pump depends on electrical impulse formation in the sinus node, conduction of the excitatory wave along its preformed pathways and orderly repolarization. The resulting action potentials exhibit heterogeneity at various levels, that is from apex to base, across the ventricular wall between endo- and epicardium, between right ventricle and left ventricle.1 This heterogeneity is essential for coordination of cardiac contraction as a prerequisite for optimal pumping function of the heart.2 Any perturbation of impulse formation, conduction or electrical recovery can lead to arrhythmia, among which sustained ventricular tachycardia and ventricular fibrillation are life-threatening events, accounting for two-thirds of sudden cardiac deaths.3 Despite detailed understanding of arrhythmia mechanisms, currently available antiarrhythmic drugs – perhaps with exception of amiodarone – are not sufficiently effective in disrupting or preventing life-threatening events. To the contrary, evidence from groundbreaking clinical trials suggests that antiarrhythmic drugs themselves may even worsen rather than improve survival4, 5 due to proarrhythmic effects. Thus, safe treatment or prevention options in ventricular arrhythmias are catheter ablation techniques6 or implantable cardioverter-defibrillator devices7 rather than antiarrhythmic drugs. Proarrhythmic effects are not limited to cardiac medications but also occur in many other drug groups used for treating non-cardiac diseases, and many clinical conditions exacerbate risk, such as bradycardia, hypokalaemia, female sex, long QT syndrome (LQTS), and pharmacodynamics and pharmacokinetic interactions with co-medication.8 Thus, there has been a long-standing interest in reliable risk predictors for proarrhythmic propensity both under pre-clinical and clinical conditions. This is exactly the problem that Olag E. Osadchii has addressed at theoretical and experimental levels in his thesis ‘Role of abnormal repolarization in the mechanism of cardiac arrhythmia’.9 The thesis provides an excellent overview of basic electrophysiological characteristics in single cardiomyocytes and the whole heart. Abnormal automaticity, early afterdepolarizations, delayed afterdepolarizations and re-entry phenomena are explained as basal mechanisms for ventricular tachyarrhythmias. As outlined above, temporal and spatial depolarization and repolarization gradients are essential for physiological mechanical activation of the heart, but perturbation of the physiological balance in either direction (increase or decrease in heterogeneity) can exacerbate into tachyarrhythmia (index of cardio-electrophysiological balance, iCEB.10 Important known concepts for risk assessment are the electromechanical window11 and the TRIaD concept [triangulation, reverse rate-dependence, instability and dispersion].12 In this context, electrical restitution and transmural and right-left chamber heterogeneity are investigated to estimate their potential as markers for proarrhythmic risk stratification. The drugs selected for the purpose of validating the markers of proarrhythmic risk belong to class I (Na+ channel blockers; Ia: quinidine, procainamide; Ic: flecainide) and class III (action potential-prolonging drugs; dofetilide) of the Vaughan Williams classification.13 Class I antiarrhythmics suppress excitability by reducing the availability of Na+ channels required for propagated action potentials. Rapidly dissociating agents will only suppress ectopic stimuli, whereas drugs that dissociate slowly from their binding sites will also impair normal impulses and hence prolong refractoriness, and reduce conduction velocity. Class III drugs prolong action potential duration (APD) mainly by blocking K+ channels. They also increase effective refractory period (ERP) and possess well-described proarrhythmic potential (for recent review see14). While class I drugs that preferentially block open or inactivated Na+ channels are more effective at high pacing rates (frequency-dependent action), the reverse is true for class III drugs: they produce more prominent ADP prolongation at low stimulation rates (reverse frequency dependence),15 and some drugs, such as quinidine, exhibit both properties at the same time.16 The experimental model was the standard Langendorff-perfused guinea pig heart. Monophasic action potentials and effective refractory period were recorded at different locations, and volume-conducted ECG was monitored after electrical pacing either from the endocardial or epicardial side or from the left or right ventricle. Regular beating was perturbed by transient or constant changes of pacing cycle length, and functional adaptation to this perturbation was measured (‘restitution curve’). The generated information about spatial and temporal heterogeneity of activation time, repolarization and refractoriness was used to estimate the risk of the proarrhythmic potential for two clinically relevant conditions, that is hypokalaemia and exposure to antiarrhythmic drugs. From the wealth of data, we wish to highlight three findings: (i) Using sustained changes in beating rate rather than a single cycle length change (‘dynamic’ vs. standard pacing protocol), APD shows exponential shortening with decreasing preceding diastolic interval until the stimulus fails to be captured at the ERP. The steeper the maximum slope of the exponential curve fitted to the restitution curve, that is with slopes >1, the larger the propensity of the preparation to exhibit repolarization alternans or ventricular tachycardic runs. Indeed, the author can show that antiarrhythmic agents that increase the maximum slope of the restitution curves, be it for APD or ERP, are more prone to proarrhythmic effects than those that do not. (ii) In accordance with a vast body of literature,17 the duration of spontaneous APs was found to be larger in endo- than epicardium. The physiological heterogeneity was enhanced when pacing from the endocardial and reduced when pacing from the epicardial side of the left vetricular wall. With epicardial pacing, the transmural repolarization gradient is actually reversed because of shorter activation time.18 From this, the author concludes that arrhythmic susceptibility in guinea pig heart is greater during endocardial than epicardial pacing because of greater transmural dispersion of APD. Although this mechanism could also explain pacemaker-evoked tachyarrhythmias observed in the clinics,19 epicardial stimulation cannot be recommended because reversing the mechanical activation sequence reduces cardiac output.20 (iii) The last study in the thesis11 also includes measurements of mechanical performance of the heart by means of a balloon-tipped catheter, together with ECG recordings. These parameters are particularly interesting for a clinical setting where invasive studies of monophasic action potentials are not routinely possible. Under physiological conditions, there is a distinct difference between the end of the ventricular contraction and end of the QT interval (electromechanical window). Because of APD prolongation, class III drugs may convert the electromechanical window to negative values and this has been suggested as a proarrhythmic risk marker. Interestingly, hypokalaemia which clearly induces ventricular tachyarrhythmias did not reverse the electromechanical window; that is, the mechanical systole still ended before the electrical systole, and therefore, the arrhythmogenic effects of hypokalemia are more likely to be due to abnormal changes in ventricular refractoriness and spatial repolarization gradients. Based on the classical Langendorff heart, relevant experimental findings on spatial and temporal heterogeneities within the heart are provided that help our understanding of proarrhythmic mechanisms. Nevertheless, the concept of maximum slope of electrical restitution will have to be tested in a clinical setting to prove eventually its value for risk prediction of drug therapy. In this context, it is worthwhile mentioning that novel techniques are being developed for clinical assessment of functional heterogeneity within the heart and to study the feedback mechanisms between electrical and mechanical activity in health and cardiac disease.21, 22 The authors declare that they do not have any conflict of interests.