# Preventing and Reversing Interstitial Fibrosis in HFpEF

> **NIH VA I01** · VA WESTERN NEW YORK HEALTHCARE SYSTEM · 2021 · —

## Abstract

Heart failure with a preserved ejection fraction (HFpEF) is an increasingly prevalent problem and particularly so
amongst an aging Veterans population. It accounts for over half of all patients with heart failure. While there
have been considerable advances in understanding the mechanisms and treatment of patients with heart
failure when ejection fraction is reduced, there have been few advances in understanding the mechanisms or
treatment of HFpEF. From a clinical standpoint, the prevalence of comorbid conditions such as obesity,
diabetes, COPD and hypertension in these patients has led to the inflammatory hypothesis where HFpEF is
also associated with coronary microvascular dysfunction. Nevertheless, the causal importance of inflammation
and impaired coronary flow regulation in the development of the HFpEF phenotype remain unclear. Advances
in understanding mechanisms of HFpEF have been limited by the lack of suitable animal models of disease.
At present, the only available models involve uncontrolled chronic hypertension with severe left ventricular
hypertrophy (LVH). While these have informed our understanding of hypertensive heart disease and diastolic
dysfunction over the last 50 years, they may not be directly relevant to the majority of HFpEF patients. First,
most patients with HFpEF have controlled or only mild systolic hypertension and LVH is frequently absent.
Second, in contrast to patients with HFpEF, hypertensive heart disease progresses to systolic dysfunction
(HFrEF). Thus, how the development of reduced left ventricular compliance typical of many HFpEF patients
develops in the absence of sustained hypertension remains an enigma. Completed work during the previous
funding period has resulted in the development of a large animal model of the HFpEF cardiac phenotype
produced by repetitive brief LV pressure overload. This simulates the labile systolic hypertension typical of
patients with reduced systemic arterial compliance accompanying aging where HFpEF is particularly prevalent.
Initially, brief pressure overload is characterized by stretch-induced “stunning” with focal myocyte apoptosis
and troponin I release occurring in the absence of myocardial ischemia. Within 2-weeks, reduced LV
compliance, myocyte loss and myocyte cellular hypertrophy develop with a prominent increase in interstitial
fibrosis. This is accompanied by concentric inward LV remodeling yet, like most patients with HFpEF, the
absence of severe left ventricular hypertrophy or uncontrolled hypertension at rest. The central hypothesis of
this proposal is that stretch-induced myocyte injury associated with repetitive labile systolic hypertension and
preload elevation leads to chronic troponin I release and a myocardial inflammatory response that is initiated
by proinflammatory macrophages. This leads to myocyte loss and to the development of interstitial fibrosis.
This progression can be prevented by interventions that attenuate fibrosis and the macrophage response t...

## Key facts

- **NIH application ID:** 10232045
- **Project number:** 5I01BX002659-07
- **Recipient organization:** VA WESTERN NEW YORK HEALTHCARE SYSTEM
- **Principal Investigator:** John M Canty
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-01-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232045

## Citation

> US National Institutes of Health, RePORTER application 10232045, Preventing and Reversing Interstitial Fibrosis in HFpEF (5I01BX002659-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10232045. Licensed CC0.

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