# Repetitive Stretch-Induced Myocardial Stiffening in Chronic Coronary Artery Disease

> **NIH VA I01** · VA WESTERN NEW YORK HEALTHCARE SYSTEM · 2024 · —

## Abstract

Abstract
 Heart failure with preserved ejection fraction (HFpEF) has emerged as the most common form of heart failure
among Veterans, yet there is currently a paucity of treatment strategies that have been proven to improve
prognosis. A primary reason for the lack of effective therapies for this increasingly prevalent condition is the
limited understanding of mechanisms underlying myocardial stiffening, a key pathophysiologic component of
HFpEF that is directly linked to exertional dyspnea, the cardinal presenting symptom of the disorder. The
overarching goal of this proposal is to address this problem by elucidating the role of repetitive stretch-induced
remodeling of the cardiac extracellular matrix (ECM) as a mechanistic link between chronic coronary artery
disease (CAD) and HFpEF, two conditions that are extremely common in the Veteran population. Based on our
preliminary data from multiple clinically-relevant swine models of heart disease, we hypothesize that
myocardial stiffening develops in the setting of chronic CAD as a result of repetitive stretch-induced
fibrosis caused by intermittent elevations in left ventricular (LV) preload. If so, this may explain why such
a large proportion of the HFpEF population exhibits angiographically-significant epicardial CAD (~60-70% in
multiple cohorts) and might have important clinical implications related to the use of coronary revascularization
in these patients, since the reversibility of repetitive stretch-induced myocardial fibrosis is unclear.
 To test this hypothesis, we will utilize a porcine model of chronic epicardial CAD to better understand how
exposure to episodic preload elevation influences remodeling of ischemic and non-ischemic regions of the left
ventricle in this setting. In Aim 1, implantable telemetry will be used for continuous hemodynamic monitoring to
quantify the frequency of preload elevation in swine with either multi-vessel (MV-CAD) or single-vessel CAD
(SV-CAD) and determine whether repetitive preload elevation is required for the development of interstitial
fibrosis in remote, non-ischemic myocardium. In Aim 2, percutaneous angioplasty will be performed in swine
with MV-CAD and swine with SV-CAD to determine if repetitive stretch-induced stiffening associated with MV-
CAD dictates whether LV fibrosis is reversed by revascularization. Post-mortem analysis of isolated cardiac
fibroblasts and decellularized cardiac ECM from these models will be completed in Aim 3 to assess the mechanistic
role of ECM-dependent fibroblast activation in repetitive stretch-induced LV stiffening and determine whether
increased ECM stiffness per se causes protracted fibroblast activation that promotes persistent fibrosis through a
self-sustaining positive feedback loop.
 These aims will be addressed by a multi-disciplinary investigative team using an integrative research
approach that combines serial investigation of regional and global myocardial mechanics with ex vivo mechanical
and biological a...

## Key facts

- **NIH application ID:** 10830926
- **Project number:** 5I01BX006124-02
- **Recipient organization:** VA WESTERN NEW YORK HEALTHCARE SYSTEM
- **Principal Investigator:** Brian Raymond Weil
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2023-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10830926

## Citation

> US National Institutes of Health, RePORTER application 10830926, Repetitive Stretch-Induced Myocardial Stiffening in Chronic Coronary Artery Disease (5I01BX006124-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10830926. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*