# Maladaptive Remodeling in Aging Myocardium

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Left ventricular (LV) remodeling is a summation of cellular and extracellular matrix (ECM) events,
which invariably occur following a myocardial infarction (MI) and is an important predictor of clinical
outcomes. Increased inductions of the ECM proteolytic enzymes, the matrix metalloproteinases
(MMPs), occur in the early and late phases of post-MI remodeling. While MMP inhibition remains an
important therapeutic target in the context of post-MI remodeling, systemic delivery of broad spectrum
pharmacologic MMP inhibitors can be associated with adverse events, and these concerns coupled
with difficulties in dosing regimens have hindered clinical progress. During our past performance
period, we have successfully moved the field forward in terms of demonstrating that localized delivery
of a hyaluronic acid based hydrogel (HA-gel) and release of an MMP inhibitory peptide could
effectively attenuate adverse post-MI remodeling. We now propose to further advance the
translational and clinical relevance of these proof of concept studies and “repurpose” MMP inhibitors
that were advanced clinically by overcoming past obstacles regarding systemic delivery and
specificity. Our guiding hypothesis is that using a novel self-assembling HA-gel, which will release a
pharmacological MMP inhibitor selectively into the MI region, will effectively and favorably alter the
course of adverse post-MI remodeling. We will first establish that localized injection of an HA-
gel/MMP inhibitor construct will reduce regional local MMP activity, attenuate post-MI regional
remodeling and fibroblast transdifferentiation, and thereby prevent the progression of LV pump
failure. Next, we will demonstrate that targeted injection of an HA-gel/MMP inhibitor construct will
cause favorable effects on the natural history of post-MI remodeling, whether injected early or late
post-MI. Finally, we will advance the translational relevance of these studies by demonstrating the
beneficial effects of the HA-gel/MMP inhibitor construct using novel delivery methods. These studies
will provide the pivotal pre-clinical information in order to further advance the therapeutic avenue of
localized MMP inhibitory control in order to interrupt the inexorable progression of adverse LV
remodeling post-MI and subsequent heart failure.

## Key facts

- **NIH application ID:** 11059043
- **Project number:** 5I01BX000168-15
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** FRANCIS G SPINALE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11059043

## Citation

> US National Institutes of Health, RePORTER application 11059043, Maladaptive Remodeling in Aging Myocardium (5I01BX000168-15). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11059043. Licensed CC0.

---

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