Ventricular arrhythmogenesis: Insights from murine models

Abstract

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.

Ventricular arrhythmogenesis following slowed conduction in heptanol-treated, Langendorff-perfused mouse hearts

“…This study therefore investigated whether slowed conduction can induce arrhythmogenic effects in the absence of the remaining repolarization abnormalities previously also implicated in arrhythmogenesis. This was achieved by applying heptanol to Langendorff-perfused mouse hearts, which have previously been used to study the consequences of genetic modification on ion-channel abnormalities [1]. Electrical stimulation took the form of both regular pacing at 8 Hz, which is close to the mouse heart rate observed in vivo [27], and programmed electrical stimulation (PES) [18,19].…”

“…Disruption of this pattern can arise from re-excitation of previously activated tissue, and result in ventricular tachyarrhythmia. Mouse hearts have been used to study arrhythmogenesis, because they enable the use of genetic modification to study the consequences of ionchannel abnormalities [1]. The latter can be used to produce action potential abnormalities in repolarization and conduction.…”

Cardiac electrophysiology in mice: a matter of size

“…In the human ventricle, a fast repolarizing phase (phase 1) is followed by the action potential plateau (phase 2) (Nerbonne, 2004). In the mouse heart, the L-type Ca 2+ current (I CaL ) contributes less to the ventricular AP than in humans (Sabir et al, 2008) and therefore the murine AP shows a gradual repolarization rather than a distinct plateau phase. In the mouse ventricles, α 1C channels are primarily responsible for I CaL .…”

“…In the human ventricle, the rapid and slow delayed outward rectifier K + currents (I Kr and I Ks ) are predominantly responsible for phase 3 repolarization (Li et al, 1996). In contrast, the much faster repolarization in mice ventricles is mediated by transient outward K + currents with a fast and slow recovery from inactivation (I to,f and I to,s ), a slowly inactivating K + current (I K,slow1 and I K,slow2 ) and a non-inactivating, steady state current (I ss ) (Guo et al, 1999; Xu et al, 1999; Zhou et al, 2003; Brouillette et al, 2004; Sabir et al, 2008). In humans, the I to,f current is mainly involved in phase 1 repolarization, with more prominent expression in the epicardium (Nerbonne, 2004).…”

“…In mice, I to,f is expressed throughout the left and right ventricles, whereas I to,s is confined to the septal myocardium (Xu et al, 1999). The equivalents of murine I ss and I Kslow have not been detected in human ventricles (Sabir et al, 2008). Studies in mice did observe the rapid and slow delayed rectifier K + currents (I Kr and I Ks ), but their contribution to repolarization under physiological conditions is probably negligible or minor (Babij et al, 1998; Drici et al, 1998; Balasubramaniam et al, 2003; Nerbonne, 2004; Salama et al, 2009).…”