The link between abnormalities of calcium handling proteins and catecholaminergic polymorphic ventricular tachycardia

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare autosomal dominant or recessive disease, usually results in syncope or sudden cardiac death. Most CPVT patients do not show abnormal cardiac structure and electrocardiogram features and symptoms, usually onset during adrenergically mediated physiological conditions. CPVT tends to occur at a younger age and is not easy to be diagnosed and managed. The main cause of CPVT is associated with mishandling Ca 2+ in cardiomyocytes. Intracellular Ca 2+ is strictly controlled by a protein located in the sarcoplasm reticulum (SR), such as ryanodine receptor, histidine-rich Ca 2+ -binding protein, triadin, and junctin. Mutation in these proteins results in misfolding or malfunction of these proteins, thereby affecting their Ca 2+ -binding affinity, and subsequently disturbs Ca 2+ homeostasis during excitation–contraction coupling (E-C coupling). Furthermore, transient disturbance of Ca 2+ homeostasis increases membrane potential and causes Ca 2+ store overload-induced Ca 2+ release, which in turn leads to delayed after depolarization and arrhythmia. Previous studies have focused on the interaction between ryanodine receptors and protein kinase or phosphatase in the cytosol. However, recent studies showed the regulation signaling for ryanodine receptor not only from the cytosol but also within the SR. The changing of Ca 2+ concentration is critical for protein interaction inside the SR which changes protein conformation to regulate the open probability of ryanodine receptors. Thus, it influences the threshold of Ca 2+ released from the SR, making it easier to release Ca 2+ during E-C coupling. In this review, we briefly discuss how Ca 2+ handling protein variations affect the Ca 2+ handling in CPVT.

Understanding Calmodulin Variants Affecting Calcium-Dependent Inactivation of L-Type Calcium Channels through Whole-Cell Simulation of the Cardiac Ventricular Myocyte

“…In fact, and experimental optical mapping study in heart by Němec and co-workers suggested that the abnormal Ca 2+ dynamics associated with CPVT, can also be associated with the T-wave lability found in LQT [58]. The underly defect in the Ca 2+ dynamics is the Ca 2+ overload in the myocyte for both LQT and CPVT4 [59,60]. For less severe CaM mutations, the deviation from the wild-type action potential would be difficult to detect using available diagnostic methods, and a mutation which only fractionally decreases the CaM-dependent LCC transition to a closed state would avoid detection in the unstimulated heart.…”

Dual loss of regulator of G protein signaling 2 and 5 exacerbates ventricular myocyte arrhythmias and disrupts the fine-tuning of Gi/o signaling

“…In addition, the expression of cardiomyopathy markers, particularly titin and troponin T, is reduced in Rgs2/5 dbKO hearts of both sexes, and individual cardiomyocyte contractions are markedly decreased despite increased mobilization of intracellular Ca 2+ . The augmented Ca 2+ mobilization, however, appears to contribute to arrhythmogenesis as Ca 2+ recycling is impaired, leading to prolonged elevation of cytoplasmic Ca 2+ concentration, which is known to be arrhythmogenic [ 30 , 52 - 54 ]. Taken together with the decrease in the expression of contractile genes, our data suggest that the cardiomyopathy in Rgs2/5 dbKO is accompanied by unraveling of the mechanisms that couple cardiac electrical excitation and contractility, thereby contributing to the marked decrease in baseline ejection fraction and fractional shortening.…”