Calcium Handling Defects and Cardiac Arrhythmia Syndromes

Abstract

Calcium ions (Ca 2+) play a major role in the cardiac excitation-contraction coupling. Intracellular Ca 2+ concentration increases during systole and falls in diastole thereby determining cardiac contraction and relaxation. Normal cardiac function also requires perfect organization of the ion currents at the cellular level to drive action potentials and to maintain action potential propagation and electrical homogeneity at the tissue level. Any imbalance in Ca 2+ homeostasis of a cardiac myocyte can lead to electrical disturbances. This review aims to discuss cardiac physiology and pathophysiology from the elementary membrane processes that can cause the electrical instability of the ventricular myocytes through intracellular Ca 2+ handling maladies to inherited and acquired arrhythmias. Finally, the paper will discuss the current therapeutic approaches targeting cardiac arrhythmias.

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

“…The mechanisms underlying arrhythmia development are generally divided into three categories: automaticity, triggered activity, and re-entry (Antzelevitch and Burashnikov, 2011). The role of Ca 2+ in the generation of arrhythmias has been previously extensively reviewed (see Antzelevitch and Burashnikov, 2011;Kistamas et al, 2020). Automaticity is the ability of a cell to spontaneously depolarize and generate an AP.…”

“…Changes to Ca 2+ handling can cause cardiac tissue to become vulnerable to re-entry arrhythmias by increasing the dispersion of refractoriness, leading to unidirectional conduction block, and slowing of conduction (Weiss et al, 2011). Subthreshold EADs and DADs cause electrical homogeneity by increasing dispersion of refractoriness and dispersion of excitability, respectively (Landstrom et al, 2017;Kistamas et al, 2020). In addition, cardiac alternans can act as a substrate from the initiation of re-entry and can arise due to Ca 2+ cycling dysfunction.…”

“…In addition, cardiac alternans can act as a substrate from the initiation of re-entry and can arise due to Ca 2+ cycling dysfunction. Cardiac alternans present as beat to beat variations in Ca 2+ transient amplitude (Ca 2+ alternans), AP duration (APD alternans), or contraction amplitude (mechanical alternans) (Kistamas et al, 2020). Changes in the level of SR Ca 2+ content, reduced SERCA activity, and changes in the refractoriness have been proposed as mechanisms for the generation of Ca 2+ -derived alternans.…”

“…Changes in the level of SR Ca 2+ content, reduced SERCA activity, and changes in the refractoriness have been proposed as mechanisms for the generation of Ca 2+ -derived alternans. DADs can also result in Ca 2+ alternans and subsequent APD alternans (Kistamas et al, 2020).…”

Late sodium current and calcium homeostasis in arrhythmogenesis

“…Besides the depolarizing inward currents, a number of outwardly driven K + currents repolarize the membrane. During repolarization, Ca 2+ is removed from the cytoplasm, therefore complete relaxation of the cell occurs while the membrane potential returns to its resting value so that the next AP can be elicited [1][2][3] .…”