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.

ArrhythmoGenoPharmacoTherapy

“…The tool used for the detection and diagnosis of cardiac arrhythmias is the ECG, thus, the aim of antiarrhythmic therapy could be considered for acute termination or long-term treatment to prevent recurrence of various types of arrhythmias. However, antiarrhythmic drugs have multiple effects on the generation of AP and the waves of ECG, and their mechanisms are very complex (Alvarez et al, 2019;Paar et al, 2019). In addition, an antiarrhythmic agent could modulate other targets and tissues in the different parts of the myocardium in comparison with its primary site of action.…”

“…At the time of writing, there is no substantial scientific evidence available, opposite to ischemia-induced arrhythmias, about the direct genetic origin of reperfusion-induced arrhythmias, since their origin itself is the "reperfusion event," and such an approach has not been yet intensively investigated based on its genetic-mediated mechanisms (Szendrei et al, 2002;Kovacs et al, 2013;Ravingerova et al, 2013;Bienvenu et al, 2017;Paar et al, 2019). Therefore, it is reasonable to suppose that some gene encoded proteins and channels are already present upon reperfusion in their inactive forms in the myocardium, which may be immediately or quickly activated upon a reperfusion event, leading to the rapid maldistribution of ionic homeostasis, producing other arrhythmogenic components, and the genesis of reperfusion-induced arrhythmias.…”

Classic and Novel Biomarkers as Potential Predictors of Ventricular Arrhythmias and Sudden Cardiac Death

“…Ventricular tachyarrhythmias are caused by different pathophysiological mechanisms including enhanced automaticity, triggered activity and/or reentry [13,14]. The first two are provoked by cellular phenomena.…”

“…These pro-arrhythmic effects are caused by electrophysiological remodeling processes with consequent impaired heterogeneity of cardiac ion channel expression and function within the different regions and layers of the heart. Furthermore, fibrotic processes influence the electrophysiological characteristics of the cardiomyocyte and have a major impact on cardiac conduction [13,14]. All these processes are presented in major cardiac pathologies with increased risk of ventricular arrhythmias, including heart failure (HF) and cardiac ischemia, as well as inherited arrhythmogenic disorders like hypertrophic cardiomyopathy (HCM), arrhythmogenic right ventricular dysplasia (ARVD) or Brugada syndrome.…”