Cardiac contractility is regulated by changes in intracellular Ca concentration ([Ca ²⁺ ] _i ). Normal function requires that [Ca ²⁺ ] _i be sufficiently high in systole and low in diastole. Much of the Ca needed for contraction comes from the sarcoplasmic reticulum and is released by the process of calcium-induced calcium release. The factors that regulate and fine-tune the initiation and termination of release are reviewed. The precise control of intracellular Ca cycling depends on the relationships between the various channels and pumps that are involved. We consider 2 aspects: (1) structural coupling: the transporters are organized within the dyad, linking the transverse tubule and sarcoplasmic reticulum and ensuring close proximity of Ca entry to sites of release. (2) Functional coupling: where the fluxes across all membranes must be balanced such that, in the steady state, Ca influx equals Ca efflux on every beat. The remainder of the review considers specific aspects of Ca signaling, including the role of Ca buffers, mitochondria, Ca leak, and regulation of diastolic [Ca ²⁺ ] _i .

Calcium ions (Ca²⁺) play a major role in the cardiac excitation-contraction coupling. Intracellular Ca²⁺ 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 Ca²⁺ 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 Ca²⁺ handling maladies to inherited and acquired arrhythmias. Finally, the paper will discuss the current therapeutic approaches targeting cardiac arrhythmias.

Based on recent findings, an increased late sodium current (I_Na,late) plays an important pathophysiological role in cardiac diseases, including rhythm disorders. The article first describes what is I_Na,late and how it functions under physiological circumstances. Next, it shows the wide range of cellular mechanisms that can contribute to an increased I_Na,late in heart diseases, and also discusses how the upregulated I_Na,late can play a role in the generation of cardiac arrhythmias. The last part of the article is about I_Na,late inhibiting drugs as potential antiarrhythmic agents, based on experimental and preclinical data as well as in the light of clinical trials.