Ryanodine Receptors, Calcium-dependent Arrhythmias & HCM

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Linked publications, trials & patents

Abstract

? DESCRIPTION (provided by applicant): Mutations in the cardiac ryanodine receptor gene (RYR2) are associated with Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), an arrhythmogenic syndrome characterized by the development of adrenergically-mediated ventricular tachycardia in individuals with an apparently normal heart. Very recently, point mutations in RYR2 have also been associated with Hypertrophic Cardiomyopathy (HCM), a major cause of sudden death where excessive cardiac mass leads to abnormalities in contraction, relaxation, conduction and rhythm. Hence, RyR2 mutations may lead to dysfunctional Ca2+ relsease, quite possibly the pivotal event for the initiation of tachyarrhythmias (CPVT) and/or pathological structural remodeling (HCM). However, while there has been some progress in the elucidation of the events that lead to CPVT, the molecular and cellular mechanisms that link a RyR2 mutation with the development of HCM are completely unknown. Hypothesis: we propose that RyR2- originated CPVT and HCM phenotypes arise from distinct mechanisms of channel dysfunction, the severity of which is commensurate with the hierarchy of the affected domain in the control of Ca2+ release. CPVT mutations cluster in domains that rev up RyR2 activity under ß-sympathetic stimulation, are normally silent, and throw RyR2 channels into catastrophic Ca2+ release under conditions of stress, leading to tachyarrhythmias; HCM mutations, on the other hand, fall in domains that control basal RyR2 activity, elicit chronic and insidious Ca2+ release due to constitutive activation of RyR2 channels, and lead to pathological cardiac remodeling. Our general aim is to determine the molecular and cellular mechanisms underlying HCM due to RyR2 dysfunction. We have generated a transgenic mouse that harbors a RyR2 mutation (RyR2-P1124L) associated with HCM in humans. Mice heterozygous for the mutation (RyR2-P1124L+/-) recapitulate the cardinal signs of HCM, including chamber remodeling, cellular hypertrophy, and increased propensity for arrhythmias. We will use a combination of molecular, cellular and whole heart studies to elucidate the fundamental mechanisms by which RyR2 dysfunction triggers HCM. Aim 1 will determine the molecular mechanisms by which the RyR2-P1124L mutation gives rise to HCM. Aim 2 will determine the cellular mechanisms by which the RyR2-P1124L mutation gives rise to HCM. Aim 3 will determine the signaling pathways that induce cardiac hypertrophy and arrhythmogenesis in RyR2-P1124L+/- mice. The proposed experimental design is therefore highly innovative and will be carried out with an unprecedented level of integrative physiology.