Vascular Disease

1352393 - Intramyocardial Hemorrhage Drives Fatty Degeneration of Infarcted Myocardium

Thursday, January 26, 2023

6:00 PM – 6:10 PM

Location: Silver Pearl 2

Presenting Author(s)

SC

Shing Fai Chan, PhD

Research Assistant Professor
Krannert Cardiovascular Research Center, Indiana University, School of Medicine/IU Health Cardiovascular Institute
Indianapolis, Indiana, United States

Primary Author(s)

SC

Shing Fai Chan, PhD

Research Assistant Professor
Krannert Cardiovascular Research Center, Indiana University, School of Medicine/IU Health Cardiovascular Institute
Indianapolis, Indiana, United States

Co-Author(s)

XG

Xingmin Guan, PhD

Postdoctoral Fellow
Indiana University School of Medicine
San Diego, California, United States
KV

Keyur Vora, MD, MSc, FACC

Assistant Professor of Medicine, Division of Cardiology
Krannert Cardiovascular Research Center, Indiana University School of Medicine
Carmel, Indiana, United States
Behzad Sharif, PhD

Associate Professor of Medicine
Indiana University School of Medicine
Indianapolis, Indiana, United States
Rohan Dharmakumar, PhD

Professor of Medicine, Radiology & Imaging Sciences, Anatomy, Cell Biology & Physiology
Krannert Cardiovascular Research Center, Indiana University School of Medicine
Indianapolis, Indiana, United States

Disclosure(s):

Behzad Sharif, PhD: No financial relationships to disclose

Rohan Dharmakumar, PhD: No relevant disclosure to display

Background: Sudden blockage of coronary artery contributes to approximately one million people in the US experiencing myocardial infarction (MI) each year. Although re-opening the arteries (revascularization therapies) have been instrumental in saving MI patients from immediate death, nearly half of the patients with revascularized MI develop heart failure and die within a 5-year period. Although acute MI size has been hypothesized as the primary driver of heart failure months to years later, why some patients accelerate toward fatal heart failure while others do not remains an open question. We hypothesized that when revascularization leads to intramyocardial hemorrhage (evident in nearly half of the revascularized MI patients), a set of time-dependent cascading events initiated by the red-blood-cell-derived iron, drives fat deposition (lipomatous metaplasia) in the MI territory, which leads to adverse remodeling of the heart defined by loss of cardiac function.

Methods: Using clinically relevant large animal models, non-invasive imaging, histological studies, and Western blot analyses, we investigated the spatial distribution and temporal accumulation of fat deposition in hemorrhagic and non-hemorrhagic MIs over a 6-month period post MI. In addition, we examined the casual relationship between iron and fat within MI zone by serially studying two groups of animals (with similar MI size and iron content in the acute phase of MI) with one group receiving intracellular ferric iron chelator starting 3 days post MI, and the other not.

Results: Herein we demonstrate that fat deposition of MI is a process central to hemorrhagic infarcts, which is driven by continuous iron-induced macrophage activation, lipid peroxidation, ceroid production, and foam cell formation. We found that hemorrhagic MI carries an increased risk of lipomatous metaplasia and accelerated adverse ventricular remodeling towards heart failure, which can be mitigated through timely reduction of iron from the hemorrhagic infarction zone independent of MI size.

Conclusion: Fatty remodeling of infarcted myocardium is causally linked to reperfused MIs with hemorrhage and that persistent iron within the hemorrhagic MI is at the core of developing post MI chronic heart failure. Reducing the pathological concentration of iron within MI zones can reduce the deposition of fat and favor the hearts sustaining hemorrhagic MIs from descending into chronic heart failure. Our findings provide insight into the pathophysiological processes affecting hemorrhagic MIs and define a potential therapeutic strategy to deter the hearts sustaining hemorrhagic MIs from deteriorating into chronic heart failure well after the infarction.