# Effect of Neprilysin Inhibition on Myocardial Interstitial Fibrosis

> **NIH NIH K23** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $195,480

## Abstract

PROJECT SUMMARY / ABSTRACT
Heart failure with preserved ejection fraction (HFpEF) affects 2.5 million Americans and is associated with high
morbidity and mortality. Few effective treatments are available. This proposal will investigate an important cause
of HFpEF: myocardial interstitial fibrosis (MIF). Hypertension, diabetes, and systemic inflammation lead to MIF
by activating fibroblasts, which secrete regulatory proteins that deposit, process, and cross link collagen fibers
in the myocardial extracellular matrix. Treatment of MIF is a potential strategy to prevent or treat HFpEF, but will
require scalable diagnostic tests and proven anti-fibrotic therapies.
Dr. Cunningham, a heart failure cardiologist and early career investigator at Brigham and Women’s Hospital in
Boston, proposes to study MIF using cardiac MRI, large-scale proteomics, and clinical trial methods. Preliminary
data show that inhibition of neprilysin (an enzyme which degrades natriuretic peptides) by the heart failure drug
sacubitril/valsartan reduces plasma levels of several extracellular matrix regulatory proteins. These results
suggest that neprilysin inhibition may attenuate MIF. However, it remains unknown 1) whether plasma levels of
extracellular matrix regulatory proteins are associated with MIF, 2) which extracellular matrix regulatory proteins
are modified by neprilysin inhibition, and 3) whether neprilysin inhibition reduces or slows progression of MIF.
In this proposal, Dr. Cunningham hypothesizes that plasma levels of extracellular matrix regulatory proteins
identify MIF and that neprilysin inhibition reduces MIF through its effect on these proteins. In Aim 1, he will
evaluate whether plasma levels of pre-specified extracellular matrix regulatory proteins are associated with MIF
measured by cardiac MRI in community participants from the UK Biobank. In Aim 2, he will investigate the effect
of neprilysin inhibition on plasma levels of these proteins in a previously conducted HFpEF randomized trial. In
Aim 3, he will conduct a pilot randomized trial directly assessing the effect of neprilysin inhibition on the most
reproducible marker of MIF, extracellular volume measured by contrast cardiac MRI. If successful, these studies
will form the foundation for future R01 applications identifying patients with MIF using proteomics and cardiac
imaging and evaluating the benefit of neprilysin inhibition or other anti-fibrotic therapies in these patients.
These specific aims are part of a comprehensive career development program designed to provide Dr.
Cunningham with the skills to become an independent R01-funded physician-scientist. Dr. Scott Solomon, an
expert in heart failure clinical trials at Brigham and Women’s Hospital, and Dr. Patrick Ellinor, an expert in
cardiovascular epidemiology at the Broad Institute, will mentor Dr. Cunningham. Dr. Cunningham will develop
expertise in the biostatistical analysis of large-scale physiological data, the interpretation of cardiac MRI, ...

## Key facts

- **NIH application ID:** 10801055
- **Project number:** 1K23HL168163-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jonathan Woo Cunningham
- **Activity code:** K23 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $195,480
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10801055

## Citation

> US National Institutes of Health, RePORTER application 10801055, Effect of Neprilysin Inhibition on Myocardial Interstitial Fibrosis (1K23HL168163-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10801055. Licensed CC0.

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