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(Circulation Research. 2005;96:1031.)
© 2005 American Heart Association, Inc.

Editorials

Can Novel Therapies for Arrhythmias Caused by Spontaneous Sarcoplasmic Reticulum Ca²⁺ Release be Developed Using Mouse Models?

Steven R. Houser

From the Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pa.

Correspondence to Steven R. Houser, Cardiovascular Research Center, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140, Email steven.houser@temple.edu

See related article, pages e77–e82

Key Words: cardiac arrhythmias • sarcoplasmic reticulum • ryanodine receptor • calcium regulation • heart failure

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Ventricular arrhythmias are a significant cause of premature death in Western society and occur both in the absence and presence of heart disease. For example, in heart failure close to 50% of patients die of lethal forms of ventricular arrhythmias. In spite of a large amount of basic and clinical investigations, current pharmacotherapy for ventricular arrhythmias is inadequate, demonstrating the need for novel therapeutic approaches.

Abnormal automaticity is responsible for induction and maintenance of different types of ventricular tachycardias. The form of abnormal automaticity that results from abnormal release of Ca²⁺ from a Ca²⁺ overloaded sarcoplasmic reticulum (SR), referred to as a "triggered arrhythmia", is the topic of this editorial. In vitro studies have shown that increasing the SR Ca²⁺ load beyond a critical level causes spontaneous opening of the SR Ca²⁺ release channel (ryanodine receptor; RYR) and results in spontaneous SR Ca²⁺ release.¹ The subsequent increase in cytosolic [Ca] activates an inward current through the sarcolemmal Na⁺/ Ca²⁺ exchanger which causes membrane depolarization.^1,2 Spontaneous SR Ca²⁺ release during the diastolic interval causes depolarization (delayed after depolarizations; DADs) which has been shown to result in action potentials in single cells and in the intact heart when the aberrant release is adequately synchronized within and among cardiac myocytes.^3,4 Factors that lead to DADs include increased heart rate and catecholamine stress, which both induce triggered arrhythmias by increasing SR Ca²⁺ loading.³

Whereas many molecules are involved in SR Ca²⁺ overload (DAD) related arrhythmias, abnormal opening of the RYR is an essential . . . [Full Text of this Article]

Related Article:

Bidirectional Ventricular Tachycardia and Fibrillation Elicited in a Knock-In Mouse Model Carrier of a Mutation in the Cardiac Ryanodine Receptor

Marina Cerrone, Barbara Colombi, Massimo Santoro, Marina Raffaele di Barletta, Mario Scelsi, Laura Villani, Carlo Napolitano, and Silvia G Priori
Circ. Res. 2005 96: e77-e82. [Abstract] [Full Text] [PDF]

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