Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure

Introduction: Type-2 ryanodine receptor (RyR2) located on the sarcoplasmic reticulum initiate systolic Ca2+ transients within cardiomyocytes. Proper functioning of RyR2 is therefore crucial to the timing and force generated by cardiomyocytes within a healthy heart. Improper intracellular Ca2+ handing secondary to RyR2 dysfunction is associated with a variety of cardiac pathologies including catecholaminergic polymorphic ventricular tachycardia (CPVT), atrial fibrillation (AF), and heart failure (HF). Thus, RyR2 and its associated accessory proteins provide promising drug targets to scientists developing therapeutics for a variety of cardiac pathologies. Areas covered: In this article, we review the role of RyR2 in a variety of cardiac pathologies. We performed a literature search utilizing PubMed and MEDLINE as well as reviewed registries of trials from clinicaltrials.gov from 2010 to 2019 for novel therapeutic approaches that address the cellular mechanisms underlying CPVT, AF, and HF by specifically targeting defective RyR2 channels. Expert opinion: The negative impact of cardiac dysfunction on human health and medical economics are major motivating factors for establishing new and effective therapeutic approaches. Focusing on directly impacting the molecular mechanisms underlying defective Ca2+ handling by RyR2 in HF and arrhythmia has great potential to be translated into novel and innovative therapies.