Mechanisms of Altered Ca 2+ Handling in Heart Failure A Challenges,

of myocardial that can lead congestive heart failure myocardial infarction (MI) the most common in the developed world. 1 The hallmark features of heart failure include reduced contractile function manifested as blunted, slowed, dysynchronous contraction and impaired relaxation. The physiological positive force–frequency relationship and increased myocardial contractile response to increased preload are compromised in heart failure. 2 The failing heart attempts to compensate for injury by various mechanisms, such as myocardial hypertrophy, increasing filling pressure, and enhanced neurohumoral signals, which together drive a feed-forward pathophysiological spiral leading to adverse ventricular remodeling and electric instability. 3 Each of these maladaptive events is associated with loss of myocardial Ca 2+ homeostasis. Abstract: Ca 2+ 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 Ca 2+ homeostasis is a central cause of contractile dysfunction and arrhythmias in failing myocardium. Defective Ca 2+ homeostasis in heart failure can result from pathological alteration in the expression and activity of an increasingly understood collection of Ca 2+ homeostatic and structural proteins, ion channels, and enzymes. This review focuses on the molecular mechanisms of defective Ca 2+ cycling in heart failure and considers how fundamental understanding of these pathways may translate into novel and innovative therapies. ( Circ Res . 2013;113:690-708.) Matrix Heart Failure Recognition Emerging Cardiomyopathies Therapies Electromechanical Dyssynchrony Resynchronization of the Failing Heart Molecular Changes After Left Ventricular Assist Device Support for Heart Failure Heart Failure Gene Therapy: The Path to Clinical Practice Cell Therapy for Heart Failure: Comprehensive Overview of Experimental and Clinical Studies, Current and channels (mostly Na V 1.5) that further depolarize the cell membrane, allowing opening of voltage-gated Ca 2+ channels (mostly Ca V 1.2). Inward Ca 2+ current triggers opening of ryanodine receptor 2 (RyR2) channels by a Ca 2+ -induced Ca 2+ release process, resulting in coordinated release of sarcoplasmic reticulum (SR) Ca 2+ that contributes the major portion of the myofilament-activating increase in [Ca] 2+i . The Ca 2+ released from the SR binds to troponin C of the troponin–tropomyosin complex on the actin filaments in sarcomeres, facilitating formation of cross-bridges between actin and myosin and myocardial contraction. Voltage-gated K + channels open to allow an outward current that favors AP repolarization, establishing conditions required for relaxation. Relaxation occurs when Ca 2+ is taken back up into the SR through the action of the SR Ca 2+ adenosine triphosphatase SERCA2a and is extruded from the cell by the sarcolemmal Na + and Ca 2+ exchanger (NCX). SERCA2a is constrained by phospholamban (PLN) under resting conditions. , of these proteins by CaMKII increases Ca 2+ influx and storage by the sarcoplasmic reticulum (SR), which leads to increased systolic [Ca] 2+i and increased rate and magnitude of force (pressure) generation and improved lusitropy. PKA is activated by β -AR agonists and catalyzes phosphorylation of the same Ca 2+ regulatory proteins modified by CaMKII, but at different amino acids. Classical PKC isoforms are activated downstream to a variety of G-protein-coupled receptors and are activated by increased [Ca] 2+i , leading to decreased activity of SERCA2 by phosphorylating inhibitor 1 (I-1), resulting in PLN dephosphorylation, reducing SR Ca 2+ load and Ca 2+ release, causing reduced contractility. S100A1 interacts with the SERCA2a/PLN complex in a Ca 2+ dependent manner to augment SR Ca 2+ uptake and increase SR Ca 2+ content. S100A1 also directly regulates RyR2 function, stimulates ATP synthase activity, and promotes the adenosine nucleotide translocator (ANT) function to increase ATP synthesis and mitochondrial ATP efflux in cardiomyocytes. the RyR2-mediated diastolic Ca 2+ leak by inhibiting 12.6 depletion any fatal sudden arrhythmias in DMD mice, suggesting that leaky RyR2 triggers ventricular arrhythmia in DMD. 172 Recent studies show that CaMKII inhibition or in-terbreeding into a genetic background with a knock-in RyR2 S2814A mutation that is resistant to CaMKII prevents arrhythmogenic Ca 2+ waves and ventricular tachycardia in MDX mice, 173 suggesting that CaMKII phosphorylation at S2814A of RyR2 contributes to the arrhythmia in MDX mice and pos-sibly in DMD patients. Combined, these studies suggest that myofilament and cytoskeletal proteins are intimately involved in Ca 2+ homeostasis and contribute to pathogenesis of heart failure and arrhythmias.