Mechanisms of Altered Ca ²⁺ Handling in Heart Failure

Abstract

Ca2+ plays a crucial role in connecting membrane excitability with contraction in myocardium. The hallmark features of heart failure are mechanical dysfunction and arrhythmias; defective intracellular Ca2+ homeostasis is a central cause of contractile dysfunction and arrhythmias in failing myocardium. Defective Ca2+ homeostasis in heart failure can result from pathological alteration in the expression and activity of an increasingly understood collection of Ca2+ homeostatic binding proteins, ion channels and enzymes. This review focuses on the molecular mechanisms of defective Ca2+ cycling in heart failure and consider how fundamental understanding of these pathways may translate into novel and innovative therapies.

Sarcoendoplasmic Reticulum Ca2+ ATPase. A Critical Target in Chlorine Inhalation–Induced Cardiotoxicity

“…Altered cardiomyocyte Ca 21 homeostasis is a central pathophysiological mechanism of various cardiac diseases, including cardiac hypertrophy and heart failure (6). Sarcoendoplasmic reticulum Ca 21 ATPase (SERCA) critically regulates Ca 21 homeostasis.…”

Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts

“…CaMKII regulates multiple events involved in contractile function and ventricular remodeling, including SR Ca 2ϩ leakage (8,25,47), hypertrophic gene expression and signaling (7,23), apoptosis (7,47), arrhythmias (7,8,46), and high-energy phosphate metabolism (22). Therefore, it is not surprising that CaMKII activity is elevated in most models of heart failure (50).…”

Low-Level Vagus Nerve Stimulation Reverses Cardiac Dysfunction and Subcellular Calcium Handling in Rats With Post-Myocardial Infarction Heart Failure

“…In the failing heart, the β-adrenergic signaling pathway is desensitized and defective Ca 2+ homeostasis can result from the phosphorylation and dephosphorylation of key proteins involved in ECC by kinases and phosphatases. 11) Previous studies have showed that Ca 2+ / calmodulin-dependent protein kinase II (CaMKII)-mediated hyperphosphorylation is a downstream pathway of sympathetic overdrive and increased reactive oxygen species (ROS), whereas the role of protein kinase A (PKA) is controversial. [36][37][38][39][40] Furthermore, CaMKII could phosphorylate an array of Ca 2+ -handling related proteins including SERCA, PLB, and RyR at varied sites.…”

“…It is now well accepted that altered calcium cycling is of significant relevance for the pathophysiology of heart failure and natural autonomic function is essential for maintaining cellular Ca 2+ homeostasis. [11][12][13] Furthermore, electrophysiological studies have shown that VNS has an anti-arrhythmic action against ventricular arrhythmias, partially due to the improvement of calcium handling in ventricular myocytes.…”