The clinical effects of hypokalemia including action potential prolongation and arrhythmogenicity suppressible by lidocaine were reproduced in hypokalemic (3.0 mM K + ) Langendorff-perfused murine hearts before and after exposure to lidocaine (10 μM). Novel limiting criteria for local and transmural, epicardial, and endocardial re-excitation involving action potential duration (at 90% repolarization, APD 90 ), ventricular effective refractory period (VERP), and transmural conduction time (Δlatency), where appropriate, were applied to normokalemic (5.2 mM K + ) and hypokalemic hearts. Hypokalemia increased epicardial APD 90 from 46.6± 1.2 to 53.1 ± 0.7 ms yet decreased epicardial VERP from 41±4 to 29± 1 ms, left endocardial APD 90 unchanged (58.2±3.7 to 56.9±4.0 ms) yet decreased endocardial VERP from 48±4 to 29±2 ms, and left Δlatency unchanged (1.6±1.4 to 1.1±1.1 ms; eight normokalemic and five hypokalemic hearts). These findings precisely matched computational predictions based on previous reports of altered ion channel gating and membrane hyperpolarization. Hypokalemia thus shifted all re-excitation criteria in the positive direction. In contrast, hypokalemia spared epicardial APD 90 (54.8±2.7 to 60.6±2.7 ms), epicardial VERP (84±5 to 81±7 ms), endocardial APD 90 (56.6± 4.2 to 63.7±6.4 ms), endocardial VERP (80±2 to 84± 4 ms), and Δlatency (12.5±6.2 to 7.6±3.4 ms; five hearts in each case) in lidocaine-treated hearts. Exposure to lidocaine thus consistently shifted all re-excitation criteria in the negative direction, again precisely agreeing with the arrhythmogenic findings. In contrast, established analyses invoking transmural dispersion of repolarization failed to account for any of these findings. We thus establish novel, more general, criteria predictive of arrhythmogenicity that may be particularly useful where APD 90 might diverge sharply from VERP.

Alternans and arrhythmogenicity were studied in hypokalaemic (3.0 mM K + ) Langendorff-perfused murine hearts paced at high rates. Epicardial and endocardial monophasic action potentials were recorded and durations quantified at 90% repolarization. Alternans and arrhythmia occurred in hypokalaemic, but not normokalaemic (5.2 mM K + ) hearts (P<0.01): this was prevented by treatment with lidocaine (10 μM, P<0.01). Fourier analysis then confirmed transition from monomorphic to polymorphic waveforms for the first time in the murine heart. Alternans and arrhythmia were associated with increases in the slopes of restitution curves, obtained for the first time in the murine heart, while the anti-arrhythmic effect of lidocaine was associated with decreased slopes. Thus, hypokalaemia significantly increased (P<0.05) maximal gradients (from 0.55±0.14 to 2.35±0.67 in the epicardium and from 0.67±0.13 to 1.87±0.28 in the endocardium) and critical diastolic intervals (DIs) at which gradients equalled unity (from −2.14±0.52 ms to 50.93±14.45 ms in the epicardium and from 8.14±1.49 ms to 44.64±5 ms in the endocardium). While treatment of normokalaemic hearts with lidocaine had no significant effect (P>0.05) on either maximal gradients (0.78±0.27 in the epicardium and 0.83± 0.45 in the endocardium) or critical DIs (6.06±2.10 ms and 7.04±3.82 ms in the endocardium), treatment of hypokalaemic hearts with lidocaine reduced (P<0.05) both these parameters (1.05±0.30 in the epicardium and 0.89±0.36 in the endocardium and 30.38±8.88 ms in the epicardium and 31.65±4.78 ms in the endocardium, respectively). We thus demonstrate that alternans contributes a dynamic component to arrhythmic substrate during hypokalaemia, that restitution may furnish an underlying mechanism and that these phenomena are abolished by lidocaine, both recapitulating and clarifying clinical findings.

Ventricular arrhythmias are the key underlying cause of sudden cardiac death, a common cause of mortality and a significant public health burden. Insights into the electrophysiological basis of such phenomena have been obtained using a wide range of recording techniques and a diversity of experimental models. As in other fields of biology, the murine system presents both a wealth of opportunities and important challenges when employed to model the human case. This article begins by reviewing the extent to which the murine heart is representative of that of the human. It then presents a novel physiological classification of mechanisms of arrhythmogenesis, critically assessing the extent to which the study of murine hearts has offered worthwhile insights.