# Pathophysiology of Left Ventricular Stiffening in Heart Failure

> **NIH NIH R56** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2020 · $397,476

## Abstract

Abstract
 Heart failure with preserved ejection fraction (HFpEF) has emerged as the most common form of heart failure,
yet there are currently no treatment strategies that have been proven to improve prognosis. A primary reason
for the lack of effective therapeutic approaches to treat this increasingly prevalent condition is the limited
understanding of HFpEF pathophysiology. The studies proposed in this application are designed to address this
problem by testing the central hypothesis that impairments in left ventricular (LV) compliance and diastolic
reserve that characterize HFpEF arise as a consequence of myocardial adaptations to repetitive
mechanical stretch-induced myocyte injury. This hypothesis is supported by the applicant's published and
preliminary data from a novel swine model demonstrating that exposure to repetitive intermittent episodes of
stretch-induced injury produces a pattern of LV remodeling exhibited by many HFpEF patients, with elevated
chamber stiffness, myocyte cellular hypertrophy, capillary rarefaction, and increased interstitial fibrosis. These
changes occur in the absence of an overt increase in LV mass and appear to serve an adaptive purpose by
preventing mechanical stretch-induced injury that occurs following hemodynamic overload in the normal heart.
The present proposal will investigate the mechanisms underlying the adaptive reduction in LV compliance and
determine whether it has the adverse consequence of impairing diastolic reserve, leading to elevations in LV
filling pressure and pulmonary congestion upon exertion or with plasma volume expansion, the hallmark
hemodynamic characteristics of HFpEF.
 Using an integrated research approach that combines invasive assessment of hemodynamic performance
during exercise and following pharmacologic volume overload, serial investigation of LV remodeling with
pressure-volume analyses and three-dimensional cardiac imaging, and ex vivo mechanical analysis of
myocardial tissue and isolated cardiomyocytes, the proposed studies will address three Specific Aims: Aim 1
will evaluate the pathophysiologic consequences of repetitive pressure overload (RPO)-induced reductions in
myocardial compliance on resting and exercise hemodynamics in chronically instrumented swine; Aim 2 will
identify the cellular mechanisms responsible for the reduction in LV diastolic compliance caused by RPO-induced
intermittent myocardial stretch; and Aim 3 will determine the mechanistic role of calpain-mediated myocyte
apoptosis in the pathophysiology of RPO-induced reductions in myocardial compliance. Collectively, these
experiments in a translational large animal model will establish a novel paradigm centered upon the role of
mechanical stretch-induced myocyte injury as a primary event in the initiation of LV remodeling in HFpEF. The
results are expected to significantly advance our mechanistic understanding of HFpEF pathophysiology and
facilitate the development of novel strategies to reduce the unaccepta...

## Key facts

- **NIH application ID:** 10241768
- **Project number:** 1R56HL141359-01A1
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Brian Raymond Weil
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $397,476
- **Award type:** 1
- **Project period:** 2020-09-17 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241768

## Citation

> US National Institutes of Health, RePORTER application 10241768, Pathophysiology of Left Ventricular Stiffening in Heart Failure (1R56HL141359-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10241768. Licensed CC0.

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