Sympatho-adrenergic mechanisms in heart failure: new insights into pathophysiology

Abstract

Abstract The sympathetic nervous system is activated in the setting of heart failure (HF) to compensate for hemodynamic instability. However, acute sympathetic surge or sustained high neuronal firing rates activates β-adrenergic receptor (βAR) signaling contributing to myocardial remodeling, dysfunction and electrical instability. Thus, sympatho-βAR activation is regarded as a hallmark of HF and forms pathophysiological basis for β-blocking therapy. Building upon earlier research findings, studies conducted in the recent decades have significantly advanced our understanding on the sympatho-adrenergic mechanism in HF, which forms the focus of this article. This review notes recent research progress regarding the roles of cardiac β2AR or α1AR in the failing heart, significance of β1AR-autoantibodies, and βAR signaling through G-protein independent signaling pathways. Sympatho-βAR regulation of immune cells or fibroblasts is specifically discussed. On the neuronal aspects, knowledge is assembled on the remodeling of sympathetic nerves of the failing heart, regulation by presynaptic α2AR of NE release, and findings on device-based neuromodulation of the sympathetic nervous system. The review ends with highlighting areas where significant knowledge gaps exist but hold promise for new breakthroughs.