# Myocyte Repolarization and Cardiac Dysfunction with Age

> **NIH NIH R01** · NEW YORK MEDICAL COLLEGE · 2021 · $404,099

## Abstract

7. Project Summary/Abstract
Aging is the major independent risk factor of chronic heart failure and the leading cause of death in the elderly,
which constitutes a significant segment of the US population predicted to increase in the next decades. Thus,
identification of factors involved in the origin and progression of aging myopathy together with the development
of preventive and therapeutic strategies for elderly patients are necessary to counteract the projected growing
incidence of cardiovascular diseases. The central hypothesis of this proposal is that increased late Na+
current (INaL) with age is a major determinant of the electrophysiological and functional defects of
senescent myocytes and ventricles. The increase in intracellular Na+ secondary to the enhancement of the
late Na+ current in aged cardiomyocytes may influence Ca2+ cycling and provide inotropic support to the aged
myocardium. However, imbalance of the process may result into a vicious positive feedback loop
comprising the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and phosphorylation and operation of
Na+ channels and ryanodine receptors. Thus, aberrant Na+ and Ca2+ homeostasis are viewed as major
components of the delayed electromechanical coupling and diastolic dysfunction in the senescent heart. To
test these possibilities, initially we will establish whether INaL is enhanced in myocytes of aged human heart,
employing donor organ declined for transplantation. Subsequently, we will use engineered genetic gain- and
loss-of-function mouse lines to modulate INaL in cardiomyocytes. The effects of INaL increase or failure to
enhance INaL on Ca2+ cycling, electromechanical coupling, and diastolic function in vivo will be established in
mice at different age, to dissect the contribution of enhanced late Na+ currents on the manifestation of the
aging myopathy. Moreover, modulation of CaMKII activity, intracellular Na+ load, and ryanodine receptor
function will be induced experimentally to gain mechanistic information on the cascade of events linking INaL,
incidence of arrhythmias, and diastolic dysfunction. Whether components of the vicious feedback loop are
critically altered with aging will also be established. Collectively, our work will define the contributions of
electrophysiological remodeling of ventricular myocytes on the defective performance of the aged myocardium.
Also proposed studies have the potential to identify therapeutic targets of pharmacological intervention to
prevent or delay the progressive functional deterioration of the aging heart.

## Key facts

- **NIH application ID:** 10180825
- **Project number:** 5R01AG055407-04
- **Recipient organization:** NEW YORK MEDICAL COLLEGE
- **Principal Investigator:** Marcello Rota
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,099
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10180825

## Citation

> US National Institutes of Health, RePORTER application 10180825, Myocyte Repolarization and Cardiac Dysfunction with Age (5R01AG055407-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10180825. Licensed CC0.

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