# Mechanistic Insights to A Translatable Therapy for Acute Reperfused Hemorrhagic Myocardial Infarctions

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $785,920

## Abstract

PROJECT SUMMARY
Chronic heart failure culminating in major adverse cardiovascular events (MACE) has become epidemic in
patients with prior myocardial infarction (MI). According to the Centers for Disease Control, >300,000 deaths
per year are attributable to chronic heart failure in the US. A long-established predictor of chronic heart failure
is infarct size. However, late microvascular obstruction, a condition where microvascular blood flow in the MI
territory is lost despite reperfusion of the epicardial coronary artery, has emerged as another independent
predictor of chronic heart failure. Notably, late microvascular obstruction is often associated with
intramyocardial hemorrhage and that hemorrhagic MIs (hMI) are the most prone to MACE. Accordingly,
therapeutic intervention for hMI patients will substantially curb MACE: establishing the causes, mechanisms
and timing of events linking hMI to MACE risk is key. Several important observations relevant to hMIs in the
acute and chronic phases of MI have been reported, but an overarching mechanism of how hemorrhage drives
adverse outcomes throughout post-infarction period is not known. Key studies have shown that in reperfused
acute MIs (a) large MIs often have hemorrhage; (b) reperfusion itself can cause marked oxidative stress within
the MI zone; and (c) that iron is a critical catalyst contributing to the oxidative stress that drives cardiomyocyte
death. However, it is not known whether hemorrhage, which is rich in iron, exacerbates reperfusion injury and
causes infarct expansion. In the chronic phase of MI, studies have shown that timely resolution of
proinflammatory cytokines is critical, which can otherwise impair scar formation and accelerate adverse
remodeling. But why some MIs have prolonged proinflammatory burden and continue to adversely remodel is
not known. Importantly, current therapies are not beneficial for hMI patients and previously studied therapies
have not targeted iron from hemorrhage. We hypothesize that the evolving changes of hemorrhage within the
infarct zone precipitates (a) a heme-iron mediated death (ferroptosis) of surviving cardiomyocytes in the acute
phase of MI; (b) the formation of ferric-iron crystals within macrophages that attempt to remove them polarize
them to a proinflammatory state in chronic phase of MI; and (c) a therapy that accounts for the temporal
changes in hemorrhage can rescue the hearts from infarct expansion and rapid adverse LV remodeling. To
investigate these hypotheses, Aim 1 will establish the mechanistic framework by which hemorrhage promotes
time-dependent damage to the heart in the post MI period; Aim 2 will determine the time-dependent changes
that alter the features of iron within hemorrhage to tune the development of therapeutic strategies; and Aim 3
will determine optimal iron chelation strategies to reduce the adverse effects of hemorrhage following
reperfusion. To address these Aims, this proposal brings together an interdisciplinary t...

## Key facts

- **NIH application ID:** 10359807
- **Project number:** 7R01HL147133-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Rohan Dharmakumar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $785,920
- **Award type:** 7
- **Project period:** 2020-03-05 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359807

## Citation

> US National Institutes of Health, RePORTER application 10359807, Mechanistic Insights to A Translatable Therapy for Acute Reperfused Hemorrhagic Myocardial Infarctions (7R01HL147133-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10359807. Licensed CC0.

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