Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease and is oftena result of abnormal impulse formation. Such triggered activity are associated with abnormal Ca2+ release from the sarcoplasmic reticulum (SR) and are a hallmark of catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT-associated mutations in the ryanodine receptors (RyR2) or calsequestrin (Casq2), the major intra-SR Ca2+ binding protein render the RyR2 leaky and predispose these patients to arrhythmias. Atrial fibrillation is an another common finding in CPVT, indicating that Ca2+ mishandling in CPVT is not isolated to the ventricles. Despite high response of CPVT to Ca2+ channel- and/or beta-blockers, refractory cases often require Na+ channel inhibitor based therapy. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains poorly understood. The applicant has developed an experimental system using various murine models of CPVT that integrates information of Ca2+ handling at the cellular level with the electrophysiologic phenotype in tissue. The applicant plans to investigate the hypothesis that subpopulation of Na+ channels (neuronal Na+ channels; nNav) contribute to arrhythmogenic aberrant Ca2+ release through the microdomain Na+/Ca2+ signaling. Specifically the proposal will address the following aims during the mentored phase (K99): 1) Elucidate the molecular and subcellular consequences of subdomain-specific Na+/Ca2+ signaling on aberrant Ca2+ release in the genesis of Ca2+ -dependent atrial and ventricular arrhythmias. Here we will test the hypothesis that subdomain-specific Na+/Ca2+ signaling contributes to arrhythmogenic aberrant Ca2+ release while attempting to identify the molecular determinants of local Na+/Ca2+ subdomain signaling. 2) Define the role of Na+/Ca2+ signaling in tissue wide aberrant Ca2+ release synchronization. These translational studies will test the hypothesis that subdomain-specific Na+/Ca2+ signaling facilitates myocardial synchronization of aberrant Ca2+ release and promotes subsequent ectopic activity in intact ventricular tissue. 3) Validate the applicability of Na+/Ca2+ signaling to in vivo settings. During the independent phase (R00) the proposal will: 1) Investigate the role of subdomain-specific Na+/Ca2+ signaling on aberrant Ca2+ release in the genesis of atrial arrhythmias. 2) Examine the regional heterogeneities of the subdomain-specific Na+/Ca2+ signaling in atrial aberrant Ca2+ release synchronization. 3) Validate the therapeutic potential of perturbation of Na+/Ca2+ signaling in settings of atrial arrhythmias and translate the applicability to animal models of acquired Ca2+-mediated arrhythmias. The mechanistic and pharmacological insights gained on the cellular as well as on tissue levels will offer a mechanism-based therapeutic approach that will be tested in vivo. Furthermore, these studies will determine whether such arrhythmogenic mechanism(s) is/are applicable to a clinically-relevant model of Ca2+-mediated arrhythmias. A long term goal of this study is to better understand the cellular and molecular mechanisms of Ca2+-mediated arrhythmogenesis.
Aberrant diastolic Ca2+ release is involved in the pathophysiology of catecholaminergic polymorphic ventricular tachycardia (CPVT); however, the mechanism(s) underlying aberrant Ca2+ release genesis in cell and its synchronization in tissue is elusive. We preliminarily identify a distinct microdomain, where a specific subpopulation of Na+ channels are localized near Ca2+ cycling proteins, and serve as the functional unit underlying arrhythmogenic aberrant Ca2+ release. Our preliminary findings suggest that the unique interplay between Na+ and Ca2+ handling is key to the process and disrupting it via selective inhibition of neuronal Na+ channels effectively suppressed arrhythmias in myocytes, tissue as well as in CPVT mice. Thus our study may reveal a novel arrhythmogenic mechanism, its structural underpinnings and identifie a novel mechanism-based antiarrhythmic therapy.
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