# Pathophysiology of Extracellular Matrix and Desmin Breakdown in Volume Overload Heart

> **NIH VA I01** · BIRMINGHAM VA MEDICAL CENTER · 2020 · —

## Abstract

The importance of the extracellular matrix loss in adverse LV remodeling is well established in the isolated
pure volume overload of mitral regurgitation. Here the Principal Investigator reports a newly described
breakdown of cardiomyocyte cytoskeletal protein desmin that adds an important intracellular structural defect
with a direct impact on cardiomyocyte contractile function. This extracellular and intracellular protein
breakdown mandates a novel medical therapy that enhances fibroblast extracellular matrix production and
prevents desmin breakdown in order to prevent LV dilatation and heart failure. The novel findings of the current
proposal are: 1) the ability of the highly destructive serine protease chymase to enter the cardiomyocyte via an
endocytic mechanism, 2) the high chymase concentration within cardiomyocytes and fibroblasts in the heart, 3)
evidence of chymase digestion of desmin in the heart with a pure volume overload, 4) evidence of chymase-
mediated intracellular autophagic digestion of procollagen and fibronectin digestion in fibroblasts form the
volume overloaded heart. It is well accepted that a pure volume overload is accompanied by excessive
adrenergic drive. To complement the potential actions of chymase inhibitor, we have shown that β1-receptor
blockade (β1-RB) improves calcium homeostasis and breakdown of the focal adhesion complex. We
hypothesize that desmin and extracellular matrix breakdown are important therapeutic targets in volume
overload that are responsive to a combined β1-RB and chymase inhibition that improves LV dilatation and
function. In the series of aims, we will explore the intracellular (cardiomyocyte desmin) and extracellular
(fibroblast autophagy) mechanisms of protein breakdown and resultant effects on LV remodeling and function.
The mechanism of extracellular matrix loss and desmin breakdown in VO is multifactorial and here we propose
novel mechanisms for a combined therapy of β1-RB and chymase inhibition that will target cardiomyocyte
desmin breakdown (Aim 1) and fibroblast digestion of procollagen by autophagy (Aim 2), resulting in
attenuation of LV dilatation and improvement in LV systolic function in the pure VO of ACF (Aim 3).

## Key facts

- **NIH application ID:** 9867519
- **Project number:** 5I01BX003664-04
- **Recipient organization:** BIRMINGHAM VA MEDICAL CENTER
- **Principal Investigator:** Louis J. Dell'Italia
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867519

## Citation

> US National Institutes of Health, RePORTER application 9867519, Pathophysiology of Extracellular Matrix and Desmin Breakdown in Volume Overload Heart (5I01BX003664-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9867519. Licensed CC0.

---

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