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Editorial

Loss of Intracellular and Intercellular Synchrony of Calcium Release in Systolic Heart Failure

Joshua I. Goldhaber, MD and John H.B. Bridge, PhD

From the Division of Cardiology (J.I.G.), Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, Calif; and Nora Eccles Harrison Cardiovascular Research and Training Institute (J.H.B.B.), University of Utah, Salt Lake City, Utah.

Correspondence to Joshua I. Goldhaber, MD, Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, 675 Charles Young Dr S, 3770 MRL, Los Angeles, CA 90095. E-mail jgoldhaber@mednet.ucla.edu

Key Words: heart failure • myocytes • sarcoplasmic reticulum • calcium cycling/excitation-contraction coupling • contractile function

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

	Introduction

 

Normal contraction of cardiac muscle requires a coordinated cellular mechanical response to the electric pacemaker signal that begins in the sinoatrial node and spreads through the conduction system and ultimately across the ventricular myocardium via gap junctions. In ventricular myocytes, depolarization by the action potential causes clusters of L-type calcium channels (LCCs) to open, allowing a small amount of Ca to enter the diadic cleft space between the sarcolemma and the sarcoplasmic reticulum (SR). When the Ca concentration in this space becomes sufficiently high to gate ryanodine receptors (RyRs), they open and release SR Ca into the cytoplasm, so that it can bind to and activate myofilaments, resulting in force development. Each cluster of LCCs on the sarcolemma, its opposing cluster of RyRs across the 10- to 12-nm diameter diadic cleft space, and associated SR regulatory proteins is a couplon.¹ According to the local control theory of cardiac excitation-contraction (EC) coupling, couplons are activated independently. Independent activation of couplons depends on the extent of LCC activation, providing a mechanism for regulation of contractile force by stochastic recruitment of couplons.² In systolic heart failure, numerous cellular defects in EC coupling and Ca regulation have been identified that contribute to contractile dysfunction (and ventricular arrhythmias), although there is a host of other major abnormalities leading to loss of force development, including fibrosis,³ defective energy metabolism,⁴ pH changes,⁵ heterogeneous conductance across connexin hemichannels,⁶ and defects in sarcomeric proteins.⁷ Thus, it is important to keep in mind that no single defect can explain the . . . [Full Text of this Article]

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