Restitution Analysis of Alternans Using Dynamic Pacing and Its Comparison with S1S2 Restitution in Heptanol-treated, Hypokalaemic Langendorff-perfused Mouse Hearts

Action potential duration (APD) and conduction velocity restitution explain the dependence of these parameters on the previous diastolic interval (DI). It is considered to be an adaptive mechanism for preserving diastole at fast heart rates. Hypokalaemia is known to induce ventricular arrhythmias that could be prevented by heptanol, the gap junction uncoupler, mediated through increases in ventricular refractory period (VERP) without alterations in APDs. The present study investigated alternans and restitution properties during normokalaemia, hypokalaemia alone or hypokalaemia with heptanol (0.1 mM) in Langendorff-perfused mouse hearts using a dynamic pacing protocol. APD alternans were elicited in the epicardium and endocardium during normokalaemia. Hypokalaemia increased the amplitudes of epicardial APD alternans when basic cycle lengths (BCLs) were ≤65 msec, which was associated with increases in maximum APD restitution gradients, critical DIs and APD heterogeneity. Heptanol (0.1 mM) did not exacerbate or reduce the APD alternans or alter these restitution parameters further. By contrast, endocardial APD alternans did not show increases in amplitudes during hypokalaemia at short BCLs studied, and restitution parameters were also unchanged. This was true whether in the presence or absence of 0.1 mM heptanol. The study demonstrates that anti-arrhythmic effects of heptanol exerted during hypokalaemia occurred despite exacerbation of APD alternans. This would suggest that even in the presence of arrhythmogenic APD alternans, arrhythmias could still be prevented by influencing VERP alone. Restitution data obtained here by dynamic pacing were compared to previous data from S1S2 pacing.