Pathophysiology of Calcium Mediated Ventricular Arrhythmias and Novel Therapeutic Options with Focus on Gene Therapy

Abstract

Cardiac arrhythmias constitute a major health problem with a huge impact on mortality rates and health care costs. Despite ongoing research efforts, the understanding of the molecular mechanisms and processes responsible for arrhythmogenesis remains incomplete. Given the crucial role of Ca²⁺-handling in action potential generation and cardiac contraction, Ca²⁺ channels and Ca²⁺ handling proteins represent promising targets for suppression of ventricular arrhythmias. Accordingly, we report the different roles of Ca²⁺-handling in the development of congenital as well as acquired ventricular arrhythmia syndromes. We highlight the therapeutic potential of gene therapy as a novel and innovative approach for future arrhythmia therapy. Furthermore, we discuss various promising cellular and mitochondrial targets for therapeutic gene transfer currently under investigation.

Keywords: L-type calcium channel; calcium; gene therapy; genetic mutations; heart failure; ion channels; mitochondria; ryanodine receptor; sarcoplasmic Ca2+-ATPase; ventricular arrhythmias.

Figure 1

Calcium handling in cardiomyocytes illustrating the most important calcium-related organelles and channels. Disturbed ion channel functions or calcium mishandling results in an increased cytosolic calcium concentration. This further promotes the generation of early and delayed afterdepolarizations, leading to Ca²⁺-induced ventricular tachycardia. Ca²⁺: calcium; I_Ca: calcium current; MCU: mitochondrial calcium uniporter; MF: myofilament; NCLX: mitochondrial potassium-calcium exchanger; NCX: sodium-calcium exchanger; RyR2: ryanodine receptor type 2; VES: ventricular extrasystoles; VT: ventricular tachycardia.