# Controlled and Uncontrollable Calcium release in heart

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2020 · $30,273

## Abstract

Abstract:
Cardiac arrhythmias remain a leading cause of morbidity and mortality in the US. In multiple forms of cardiac
disease, arrhythmias result from disturbances in intracellular calcium (Ca) cycling, the process that normally
couples electrical excitation to mechanical function. Despite significant progress, the fundamental mechanisms
underlying Ca-dependent arrhythmias remain elusive, owing mainly to the complex, nonlinear nature of cardiac
Ca signaling, which hinders the development of effective antiarrhythmic therapies. Based on our work in the
previous funding period, we have established that Ca signaling refractoriness provides a powerful concept for
understanding cardiac intracellular Ca handling at multiple biological scales (from molecular and subcellular
domains to myocardial tissue and intact heart) in normal and diseased hearts. Ca signaling refractoriness
refers to a state of temporary deactivation of the sarcoplasmic reticulum (SR) Ca release channels (Ryanodine
receptors, RyRs) in the wake of systolic release from the sarcoplasmic reticulum (SR). This Ca signaling
refractoriness is critical in maintaining stable Ca-induced Ca release (CICR) by preventing aberrant diastolic
Ca release (DCR) – a cause of arrhythmias. Using this new framework, our proposed research will establish
the subcellular and molecular bases of aberrant Ca release synchronization, including the refractory properties
of functionally distinct Ca release units and determine how these properties are influenced by genetic and
acquired intrinsic RyR defects as well as by extrinsic local Na/Ca microdomain homeostasis and SR Ca load.
Our quantitative studies of aberrant Ca-excitation coupling will provide a new understanding of characteristic
differences in arrhythmogenic properties of ventricular and atrial tissue including ectopic firing propensity and
self-sustaining Ca/Vm oscillations. Our multiscale studies of inhibition of arrhythmogenic propensity through
the targeting of both intrinsic and extrinsic mechanisms using genetic mouse models of arrhythmia and pre-
clinicalmodels of cardiomyopathy as well as preparations from failing and rejected donor human hearts. Taken
together these will provide a “proof-of-principle” for new therapeutic strategies based on desynchronization of
aberrant SR Ca release.

## Key facts

- **NIH application ID:** 10005532
- **Project number:** 3R01HL063043-20S1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Sandor Gyorke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $30,273
- **Award type:** 3
- **Project period:** 1999-09-20 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10005532

## Citation

> US National Institutes of Health, RePORTER application 10005532, Controlled and Uncontrollable Calcium release in heart (3R01HL063043-20S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10005532. Licensed CC0.

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