Molecular determinants of altered contractility in heart failure

Abstract

Heart failure remains a leading cause of mortality in the Western world. An important hallmark of heart failure is reduced myocardial contractility. Alterations in intracellular Ca2+ handling play a major role in the pathophysiology of these contractile abnormalities. Several defects in the excitation-contraction (EC) coupling system have been identified in patients with heart failure. Alterations in the density and function of proteins relevant for EC coupling have been reported. Chronic stimulation of the beta-adrenergic signaling pathway leads to protein kinase A (PKA) hyperphosphorylation of the cardiac ryanodine receptor (RyR2), which dissociates FKBP12.6 from RyR2, thereby altering channel gating and promoting diastolic sarcoplasmic reticulum (SR) Ca2+ release. This may deplete the SR Ca2+ stores, which may reduce myocardial contractility. Clinical studies have demonstrated that beta-adrenergic receptor blockers reduce morbidity and mortality in all grades of congestive heart failure. Our experimental data indicate that beta-blockers reverse RyR2 hyperphosphorylation and normalize channel gating, which is associated with increased contractility in heart failure. In conclusion, chronic hyperactivity of the beta-adrenergic signaling pathway impairs intracellular Ca2+ handling, which leads to reduced contractility in patients with heart failure.