A guide for the perplexed: towards an understanding of the molecular basis of heart failure.

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). 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 output to meet metabolic demands of stressful conditions. In failing hearts, this system becomes defective because of the maladaptive chronic hyperadrenergic state of heart failure, resulting in PKA-hyperphosphorylated RyR2 channels that cause a diastolic SR Ca2+ leak1 that conspires with …