# Project 2 (Bers)

> **NIH NIH P01** · STANFORD UNIVERSITY · 2020 · $747,660

## Abstract

Project 2 (Bers): Abstract
Project 2 focuses on understanding Na- and Ca-dependent myocyte mechanisms contributing to cardiac
dysfunction and arrhythmias in heart failure (HF). Hallmarks of Na & Ca dysfunction in HF include elevated
diastolic and late Na current (INaL), increased diastolic SR Ca leak, and Na/Ca exchange. These factors reduce
systolic and diastolic function and promote triggered arrhythmias in HF. Ca-Calmodulin dependent protein
kinase (CaMKII) is also chronically active in HF and directly promotes INaL and diastolic SR Ca leak via the
ryanodine receptor (RyR) and is a lynchpin in a newly appreciated vicious cycle where elevated INaL or SR Ca
leak (that cause arrhythmias) promote CaMKII activation to further promote higher INaL and SR Ca leak that
leads to both contractile dysfunction and arrhythmogenesis in HF. Our central aim is to test this working
hypothesis in adult failing hearts (and computer models of human hearts) and identify how breaking the vicious
cycle at different points can be functionally beneficial. Aim 1 will test in rabbit ventricular myocytes if functional
and arrhythmogenic effects of overload-induced HF can be prevented by inhibiting CaMKII, INaL or RyR. Aim 2
extends these tests to the intact rabbit heart level using optical mapping of [Ca]i and voltage Vm (where whole
heart arrhythmias are complicated by cell-cell coupling, source-sink mismatch and conduction/reentry issues).
Aim 3 will enhance and validate computational rabbit ventricular myocyte & tissue models and extend both to
human (using rabbit data from Aim 1 & 2 and incorporating patient-specific iPSC-derived myocyte and clinical
data (from Projects 1 & 3). These 3 Aims will provide valuable mechanistic insight into the vicious feedback
signaling, and how targeting INa, CaMKII or RyR may have benefits in acquired or inherited (Project 1) HF.

## Key facts

- **NIH application ID:** 10006341
- **Project number:** 5P01HL141084-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Donald M Bers
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $747,660
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006341

## Citation

> US National Institutes of Health, RePORTER application 10006341, Project 2 (Bers) (5P01HL141084-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10006341. Licensed CC0.

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