# Targeting pathologic intracellular calcium release to prevent lethal arrhythmias

> **NIH NIH F30** · VANDERBILT UNIVERSITY · 2024 · $56,351

## Abstract

PROJECT SUMMARY/ABSTRACT
 RyR2 is an intracellular calcium (Ca) release channel expressed in the sarcoplasmic reticulum (SR) of
cardiomyocytes. In the normal heart, RyR2 Ca release from the SR is tightly regulated and only occurs during
systole to facilitate heart contraction. In heart disease, RyR2 Ca release can occur during diastole and is
considered pathologic. Pathologic Ca release can be caused by RyR2 mutations or RyR2 post-translational
modifications. Pathologic Ca release during diastole reduces cardiac contractility due to depletion of SR Ca
stores and is pro-arrhythmogenic due to delayed after-depolarizations resulting from sodium (Na) flux into the
cell via the Na-Ca exchanger. RyR2 mutations cause catecholaminergic polymorphic ventricular tachycardia
(CPVT), a genetic arrhythmia syndrome, while post-translational modifications have been widely documented
in congestive heart failure (CHF) caused by myocardial infarction. Both conditions are associated with a high
risk of sudden cardiac death (SCD). My mentor discovered that an old antiarrhythmic drug – flecainide –
prevents pathologic rather than physiologic Ca release and is strikingly effective in preventing ventricular
arrhythmias in CPVT patients. Importantly, he recently discovered that flecainide’s efficacy depends not on Na
channel block but rather RyR2 block. Unfortunately, due to its Na channel blocking properties, flecainide
increases mortality in patients with CHF and cannot be used in this patient population. To address these
patients’ risk for SCD – currently unmitigated by available drugs – I aim to develop a flecainide analogue that
maintains RyR2 block but not Na channel block. In doing so, I will investigate the mechanism of action of
flecainide and test the hypothesis that its efficacy depends on a change in the membrane potential across the
SR. My research background and the established use of patch clamp electrophysiology and calcium imaging in
my mentor’s lab will enable me to test flecainide analogues generated by our collaborators in synthetic
chemistry. To probe the mechanism of action underlying flecainide’s voltage-dependent RyR2 block, I will
employ a variety of tools including genetically encoded voltage indicators and voltage-sensitive dyes to capture
the theoretical membrane potential change that occurs at the SR. The results from this aim will not only clarify
flecainide’s mechanism of action but also yield a novel therapeutic principle – that voltage-dependent
block of RyR2 channels is a key feature for the development of future RyR2 inhibitors as
antiarrhythmic drugs.

## Key facts

- **NIH application ID:** 10894619
- **Project number:** 5F30HL168829-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Aaron Gochman
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $56,351
- **Award type:** 5
- **Project period:** 2023-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894619

## Citation

> US National Institutes of Health, RePORTER application 10894619, Targeting pathologic intracellular calcium release to prevent lethal arrhythmias (5F30HL168829-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10894619. Licensed CC0.

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