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.
Highlights
Cardiac arrhythmias constitute a major public health concern worldwide [1]
Myofilaments relax, either due to calcium re-uptake into the sarcoplasmic reticulum (SR) by the SR Ca2+-ATPase type-2a (SERCA2a) that pumps Ca2+ back into the SR stores, or Ca2+ is extruded and released into the extracellular space through Na+/Ca2+ exchanger (NCX) that exchanges approximately three Na+ ions entering the cell in exchange for one Ca2+ ion leaving [21]
The activation of the adrenergic nervous system through β-adrenergic receptor (β-AR) stimulation has a great impact on Ca2+ handling. β-AR activates a crucial cascade of events, resulting in the phosphorylation of Ca2+-mediating proteins
Summary
Cardiac contraction and relaxation are mediated by a precise and coordinated linkage of electrical activation (excitation) and intracellular Ca2+ homeostasis, resulting in a so-called excitation-contraction coupling. SR Ca2+ release is mediated by RyR2, which is a massive structure comprising the largest known ion channel-bearing macromolecular complex [18,19]. This process is called Ca2+-induced Ca2+-release (CICR) and is the fundamental link between electrical and mechanical activation in the heart [20]. The depolarization and release of Ca2+ into the cytosol and the rapid re-uptake or extrusion results in a Ca2+ wave, which is known as the Ca2+ transient. Any perturbations in intracellular Ca2+ handling could result in changes of electrical stability and cardiac contractility, which may lead to malignant ventricular arrhythmias
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