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(Circulation. 2005;111:3342-3346.)
© 2005 American Heart Association, Inc.

Editorial

Defective Ryanodine Receptor Interdomain Interactions May Contribute to Intracellular Ca²⁺ Leak

A Novel Therapeutic Target in Heart Failure

Stephan E. Lehnart, MD; Xander H.T. Wehrens, MD, PhD; Andrew R. Marks, MD

From the Clyde and Helen Wu Center for Molecular Cardiology, Department of Physiology and Cellular Biophysics (S.E.L., X.H.T.W., A.R.M.) and the Department of Medicine, College of Physicians and Surgeons (A.R.M.), Columbia University, New York, NY.

Correspondence to Dr Andrew R. Marks, Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, 630 West 168th St, Box 65, Room 9-401, New York, NY 10032. E-mail arm42@columbia.edu

Key Words: Editorials • calcium • death, sudden • heart failure • sarcoplasmic reticulum

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

	Introduction

 
Heart failure (HF) is a leading cause of morbidity and mortality, and despite optimal medical treatment, patients with NYHA class III-IV symptoms have a 2-year mortality rate approaching 50%.^1,2 About half of the deaths from HF occur suddenly,^3,4 and ventricular arrhythmias account for a large percentage of these sudden cardiac deaths (SCDs).¹ There is a strong correlation between chronic increased activity of the sympathetic nervous system (SNS) and poor prognosis in HF.^5–7 Interestingly, ß-adrenergic receptor (ßAR) blockers that block the target receptors for catecholamines released during SNS activation reduce HF progression and arrhythmia vulnerability in patients with HF, leading to improved survival.^8,9 Activation of the ßAR signaling cascade driven by the SNS caused by HF initially results in a compensatory response aimed at enhancing cardiac contractility, but when SNS activation is sustained, maladaptive changes occur.¹⁰ Chronic SNS activation desensitizes cardiac ßAR signaling,⁵ which further contributes to reduced inotropic reserve and worsens remodeling in HF, as part of a maladaptive response that ultimately fails to protect the heart or preserve cardiac function.¹¹

See p 3400

Defective intracellular Ca²⁺ homeostasis has been consistently reported in HF.^12,13 Because intracellular Ca²⁺ concentrations ([Ca²⁺]_i) directly regulate contractility of cardiomyocytes, a reduced [Ca²⁺]_i transient amplitude in HF results in decreased force development. A prolonged decay of the [Ca²⁺]_i transient and increased diastolic [Ca²⁺]_i may contribute to slowed relaxation of the failing heart.^13–15 Several defects in the intracellular [Ca²⁺]_i metabolism have been reported, including depressed Ca²⁺ uptake, storage, and/or release of . . . [Full Text of this Article]

Related Article:

Defective Regulation of Interdomain Interactions Within the Ryanodine Receptor Plays a Key Role in the Pathogenesis of Heart Failure

Tetsuro Oda, Masafumi Yano, Takeshi Yamamoto, Takahiro Tokuhisa, Shinichi Okuda, Masahiro Doi, Tomoko Ohkusa, Yasuhiro Ikeda, Shigeki Kobayashi, Noriaki Ikemoto, and Masunori Matsuzaki
Circulation 2005 111: 3400-3410. [Abstract] [Full Text]

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