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Mechanisms of Ca2+-triggered arrhythmias

Abstract

Calcium (Ca2+) - the simplest and most versatile intracellular messenger - couples an action potential with the contraction in cardiac myocytes. Abnormal changes in intracellular Ca2+ homeostasis may cause contractile dysfunction, subcellular Ca2+ alternans and oscillations of the myocyte membrane potential, such as early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs), both of which may evoke a number of triggered arrhythmias that cause sudden cardiac death. EAD occurs during excessive action potential prolongation mainly due to the reactivation of L-type Ca2+ channels. DAD, on the other hand, typically results from the increased diastolic SR Ca2+ release, which is caused by either defective regulation of the sarcoplasmic reticulum (SR) Ca2+ release channel (ryanodine receptor, RyR2), increased SR Ca2+ load or a combination of both. Sufficient cytosolic Ca2+ elevation propagates along myocytes as Ca2+ waves, which may activate an arrhythmogenic depolarizing current largely carried by inward Na+/Ca2+ exchanger. DADs need to reach threshold potential for voltage-gated Na+ channels to evoke premature beats (ectopic activity). Ca2+-dependent triggered arrhythmias occur both in acquired (e.g. heart failure, atrial fibrillation) and in congenital cardiac diseases (e.g. cathecholaminergic polymorphic ventricular tachycardia, CPVT). CPVT is an inherited arrhythmia syndrome associated with mutations in either RyR2 or calsequestrin, SR Ca2+-binding protein. Both mutations destabilize the RyR2 Ca2+ release complex implying increased diastolic SR Ca2+ leak through RyR2 in the presence of beta-adrenergic stimulation (e.g. physical exercise or emotional stress). Several mechanisms underlying the increased diastolic Ca2+ leak in heart failure and CPVT have been proposed, including excessive RyR2 phosphorylation, altered Ca2+ sensitivity of the RyR2 at luminal or cytosolic sites, weaker interdomain interaction and lower threshold for store-overload-induced Ca2+ release. A better understanding of the similarities and differences between the mechanisms underlying triggered arrhythmias in acquired and inherited cardiac diseases, holds the promise to develop new specific diagnostic and therapeutic approaches for effective treatment of defective ion handling in these lethal arrhythmias.
This chapter will review common mechanisms that cause the susceptibility to, and initiation of, Ca2+-dependent arrhythmias with a focus on increased SR Ca2+ release due to congenital or acquired RyR2 dysfunction and increased SR Ca2+ load. Finally, RyR2 stabilizers (e.g. JTV-519, flecainide, dantrolene) and RyR2 phosphorylation inhibitors (e.g. CaMKII inhibitors) as novel therapeutic targets will be discussed.

Keywords

medical physiology

pharmacology

cardiology

Project Leader:

Sedej Simon

Duration:

01.10.2011-30.06.2012

Type of Research

other

Staff

Sedej, Simon, Project Leader

Pieske, Burkert Mathias, Co-worker

MUG Research Units

Division of Cardiology

Funded by

Land Steiermark, Graz, Austria

Project results published

> Mechanisms of Ca2+-triggered arrhythmias... Tachycardia. Rijeka, Croatia: Intech; 2011. (ISBN: 979-953-307-097-0)