Abstract

Dysfunctional sarcoplasmic reticulum Ca2+ handling is commonly observed in heart failure, and thought to contribute to arrhythmogenesis through several mechanisms. Some time ago we developed a cardiomyocyte-specific inducible SERCA2 knockout mouse, which is remarkable in the degree to which major adaptations to sarcolemmal Ca2+ entry and efflux overcome the deficit in SR reuptake to permit relatively normal contractile function. Conventionally, those adaptations would also be expected to dramatically increase arrhythmia susceptibility. However, that susceptibility has never been tested, and it is possible that the very rapid repolarization of the murine action potential (AP) allows for large changes in sarcolemmal Ca2+ transport without substantially disrupting electrophysiologic stability. We investigated this hypothesis through telemetric ECG recording in the SERCA2-KO mouse, and patch-clamp electrophysiology, Ca2+ imaging, and mathematical modeling of isolated SERCA2-KO myocytes. While the SERCA2-KO animals exhibit major (and unique) electrophysiologic adaptations at both the organ and cell levels, they remain resistant to arrhythmia. A marked increase in peak L-type calcium (ICaL) current and slowed ICaL decay elicited pronounced prolongation of initial repolarization, but faster late repolarization normalizes overall AP duration. Early afterdepolarizations were seldom observed in KO animals, and those that were observed exhibited a mechanism intermediate between murine and large mammal dynamical properties. As expected, spontaneous SR Ca2+ sparks and waves were virtually absent. Together these findings suggest that intact SR Ca2+ handling is an absolute requirement for triggered arrhythmia in the mouse, and that in its absence, dramatic changes to the major inward currents can be resisted by the substantial K+ current reserve, even at end-stage disease.

Highlights

  • Dysfunctional sarcoplasmic reticulum (SR) Ca2+ handling is known to destabilize cardiac electrophysiology in a broad range of arrhythmogenic diseases, from rare channelopathies (Priori et al, 2001, 2002) to prevalent acquired diseases such as heart failure (Pogwizd et al, 2001; Pogwizd and Bers, 2002)

  • These changes exist in the absence of significant rate-corrected QT prolongation (p = 0.07, Figure 1A, right), suggesting that terminal repolarization is not delayed in the knockout mouse (KO) mice

  • These outcomes will be discussed in more detail later, but are consistent with a markedly altered action potential (AP) morphology in the KO myocytes

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Summary

Introduction

Dysfunctional sarcoplasmic reticulum (SR) Ca2+ handling is known to destabilize cardiac electrophysiology in a broad range of arrhythmogenic diseases, from rare channelopathies (Priori et al, 2001, 2002) to prevalent acquired diseases such as heart failure (Pogwizd et al, 2001; Pogwizd and Bers, 2002). Approximately 30% of the Ca2+ that fuels cardiac contraction is obtained from L-type Ca2+ current (ICaL)-mediated Ca2+ influx (Shannon et al, 2004; Fearnley et al, 2011), and this can increase to near 50% in chronic diseases such as heart failure (Pogwizd and Bers, 2002). Such large transmembrane Ca2+ fluxes are permitted by a prolonged action potential (AP) plateau, which itself results from a relatively delicate balance of inward and outward currents in large mammals (Weiss et al, 2010). It is for exactly this reason that significant investments have been made to establish and study large animal models of human arrhythmogenic diseases thought to result from repolarization abnormalities (Brunner et al, 2008; Koren, 2009)

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