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(Circulation. 2003;107:1456.)
© 2003 American Heart Association, Inc.

Editorial

A Guide for the Perplexed

Towards an Understanding of the Molecular Basis of Heart Failure

Andrew R. Marks, MD

From the Center for Molecular Cardiology, Department of Physiology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.

Correspondence to Andrew R. Marks, Center for Molecular Cardiology, Box 65, Columbia University College of Physicians & Surgeons, Rm 9-401, 630 West 168th St, New York, NY 10032. E-mail arm42@columbia.edu

Key Words: Editorial • calcium • heart failure • sarcoplasmic reticulum

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

Heart failure is a complex disorder involving maladaptive responses that result in defective regulation and function of multiple biological systems. Central to our understanding of heart failure and to the ability to design and test novel therapeutic approaches that will prolong survival and improve quality of life for the millions of individuals worldwide is the need to gain a better understanding of the molecular pathogenesis of the disorder.

In the search for molecular physiological defects in failing hearts, it is logical to examine the mechanism of excitation-contraction (EC) coupling in which cardiomyocyte membrane depolarization, because of the cardiac action potential, is translated into mechanical contraction in the heart. This system requires the normal function of 3 key elements: (1) calcium (Ca²⁺) entry via the voltage-gated Ca²⁺ channel (VGCC) on the plasma membrane (transverse tubule); (2) Ca²⁺ release via the ryanodine receptor/Ca²⁺ release channel (RyR2); and (3) Ca²⁺ uptake via the Ca²⁺-ATPase on the sarcoplasmic reticulum (SR) (Figure 1).

View larger version (128K): [in this window] [in a new window]   Figure 1. Regulation of key molecules in cardiac EC coupling by stress activated pathways. The normal fight or flight stress response activates 3 key molecules involved in cardiac EC coupling via PKA phosphorylation: (1) the trigger for cardiac EC coupling, the voltage-gated Ca2+ channel (VGCC); (2) the SR Ca2+ release channel RyR2; and (3) the Ca2+ uptake pathway (via PKA phosphorylation of phospholamban which reduces inhibition of the Ca2+-ATPase SERCA2a). These regulatory events conspire to increase systolic SR Ca2+ release and thereby increase contractility, providing increased cardiac . . . [Full Text of this Article]

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