Therapeutic Approaches of Ryanodine Receptor-Associated Heart Diseases

Abstract

Cardiac diseases are the leading causes of death, with a growing number of cases worldwide, posing a challenge for both healthcare and research. Therefore, the most relevant aim of cardiac research is to unravel the molecular pathomechanisms and identify new therapeutic targets. Cardiac ryanodine receptor (RyR2), the Ca2+ release channel of the sarcoplasmic reticulum, is believed to be a good therapeutic target in a group of certain heart diseases, collectively called cardiac ryanopathies. Ryanopathies are associated with the impaired function of the RyR, leading to heart diseases such as congestive heart failure (CHF), catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia type 2 (ARVD2), and calcium release deficiency syndrome (CRDS). The aim of the current review is to provide a short insight into the pathological mechanisms of ryanopathies and discuss the pharmacological approaches targeting RyR2.

Dantrolene and ryanodine receptors in COVID‐19: The daunting task and neglected warden

“…DTN reduces pro‐arrhythmic SR Ca 2+ spark frequency and diastolic Ca 2+ leaks 145 . Similarly, ranolazine stabilizes heart RyRs, by which it prevents prolongation of the QT interval, early after‐depolarization and progression of torsades de pointes, 147,148 so it prevents RyR‐dependent arrhythmia. Therefore, DTN inhibits cellular arrhythmogenic activators by attenuating overload of cytosolic Ca 2+.…”

“…145,146 DTN reduces pro-arrhythmic SR Ca 2+ spark frequency and diastolic Ca 2+ leaks. 145 Similarly, ranolazine stabilizes heart RyRs, by which it prevents prolongation of the QT interval, early after-depolarization and progression of torsades de pointes, 147,148 so it prevents RyR-dependent arrhythmia. Therefore, DTN inhibits cellular arrhythmogenic activators by attenuating overload of cytosolic Ca 2+.145 Of interest, DTN is effective against cardiac glycoside poisoning-induced arrhythmia by regulating intracellular Ca 2+.149 Moreover, downregulation of ACE2 by SARS-CoV-2 increases expression of vasoconstrictor AngII.…”

Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

“…They proposed that the extended Ca 2+ release during EADs help unload the SR in this LoF model, although this will be balanced somewhat by the increased Ca 2+ entry through I Ca at depolarized membrane potentials. Alternatively, it was recently proposed that the reduced Ca 2+ transient rate of rise in RyR2-A4860G +/− could cause less Ca 2+ -dependent inactivation and therefore prolong I Ca during the action potential plateau, which would increase action potential duration both directly and indirectly (through increased I NCX ), although this remains to be demonstrated experimentally [ 135 ]. Sun et al found that transgenic mice carrying the LoF RyR2-D4646A +/− mutation also showed increased EADs and SR Ca 2+ load in isolated myocytes and re-entrant arrhythmias following burst pacing in isolated hearts, although this occurred without a change in steady state Ca 2+ transient amplitude or rate of rise, and a markedly increased I Ca density [ 66 ].…”

Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms

“…A common defect in RyR function is its hyperactivity, resulting in cytoplasmic Ca 2+ overload [ 3 , 11 , 13 ]. Although specific inhibition of the RyR channel would have a beneficial therapeutic effect, currently, only few drugs are available to substantially reduce the RyR activity in in vivo and in vitro experiments (e.g., flecainide, Rycal S107, and dantrolene) (reviewed in [ 14 , 15 ]). Of these compounds with a promising therapeutic potential, dantrolene is the only clinically used agent for the effective treatment of RyR-linked channelopathy, malignant hyperthermia (MH) (reviewed in [ 16 ]).…”