# Improving Mitral Compensation In Ischemic Regurgitation

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $1,383,663

## Abstract

Ischemic mitral regurgitation (IMR) is a common condition that increases heart failure and doubles mortality
after myocardial infarction (MI). It is caused by left ventricular (LV) remodeling that tethers the mitral valve (MV)
leaflets and restricts their closure. Effective repair has been elusive with standard therapies that do not address
intrinsic valve changes; we aim to reduce this substantial therapeutic gap. We showed that tethering without MI
adaptively increases leaflet area with associated endothelial-to-mesenchymal transition (EMT). However, in
our model of inferior MI (IMI), the most common cause of IMR, as the LV progressively dilates over six months,
MV surface area increases but then plateaus and becomes deficient relative to the LV, so MR increases.
Adaptive leaflet growth is opposed by progressive fibrotic changes: MV thickness and collagen increase along
with transforming growth factor (TGF)-β, a pro-fibrotic EMT activator. Vascular cell adhesion molecule-1
suggests the influence of post-MI inflammatory cytokines. Endothelial cells undergoing EMT unexpectedly
express the protein tyrosine phosphatase CD45, which modulates cell migration. Both CD45 activation and
TGF-β turn on pro-fibrotic endothelial cell gene expression. Losartan, an indirect TGF-β inhibitor, reduces
CD45+ EMT and fibrotic leaflet thickening in our MI models; it inhibits EMT in vitro by blocking TGF-β-mediated
pERK activation. Blocking phosphodiesterase 5 (PDE5) with Tadalafil also reduces CD45+ EMT, fibrotic cells
and MR post-MI. Our central hypothesis is that MV changes post-MI can be improved by preventing or later
interrupting the progressive cycle of cellular changes, leaflet fibrosis and MR. Aim 1 will test the hypothesis that
mechanistically different early and late therapeutic windows exist for improving leaflet adaptation to decrease
IMR. We will compare 3 clinically relevant agents: Losartan and Enalapril, based on their differential reduction
of TGF-β signaling; and PDE5 inhibition, a new pathway in this context for which our preliminary studies also
show adaptive leaflet growth potential. At 6 months post-MI, we will compare sheep treated for all 6 months,
only the first 2 months, or only from 2 to 6 months. Aim 2 will explore early inciting events to test the hypothesis
that circulating substances released from infarcted myocardium stimulate MV fibrotic processes within days of
MI. In addition to histology, whole blood and coronary sinus plasma and conditioned medium from infarcted
myocardium will be tested for induction of MV endothelial transformation to CD45+ fibrocytes producing 
intrinsic TGF-β, cytokines and collagen in a self-reinforcing cycle of progressive fibrosis. Aim 3 will identify 
downstream targets of CD45 protein tyrosine phosphatase, potentially Src kinases (HCK) and their substrates, 
aiming to find valve-specific targets to prevent MV endothelial transition to collagen-producing contractile cells that
likely stiffen the MV and ca...

## Key facts

- **NIH application ID:** 9898446
- **Project number:** 5R01HL141917-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Elena Aikawa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,383,663
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898446

## Citation

> US National Institutes of Health, RePORTER application 9898446, Improving Mitral Compensation In Ischemic Regurgitation (5R01HL141917-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898446. Licensed CC0.

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