Intramyocardial hemorrhage drives fatty degeneration of infarcted myocardium

Ivan Cokic, Shing Fai Chan, Xingmin Guan, Anand R. Nair, Hsin-Jung Yang, Ting Liu, Yinyin Chen, Diego Hernando, Jane Sykes, Richard Tang, John Butler, Alice Dohnalkova, Libor Kovarik, Robert Finney, Avinash Kali, Behzad Sharif, Louis S. Bouchard, Rajesh Gupta, Mayil Singaram Krishnam, Keyur Vora, Balaji Tamarappoo, Andrew G. Howarth, Andreas Kumar, Joseph Francis, Scott B. Reeder, John C. Wood, Frank S. Prato and Rohan Dharmakumar ()
Additional contact information
Ivan Cokic: Cedars-Sinai Medical Center
Shing Fai Chan: Indiana University School of Medicine/IU Health Cardiovascular Institute
Xingmin Guan: Indiana University School of Medicine/IU Health Cardiovascular Institute
Anand R. Nair: Cedars-Sinai Medical Center
Hsin-Jung Yang: Cedars-Sinai Medical Center
Ting Liu: Cedars-Sinai Medical Center
Yinyin Chen: Cedars-Sinai Medical Center
Diego Hernando: University of Wisconsin
Jane Sykes: University of Western Ontario
Richard Tang: Indiana University School of Medicine/IU Health Cardiovascular Institute
John Butler: University of Western Ontario
Alice Dohnalkova: Pacific Northwest National Laboratory
Libor Kovarik: Pacific Northwest National Laboratory
Robert Finney: Cardio-Theranostics
Avinash Kali: Cedars-Sinai Medical Center
Behzad Sharif: Indiana University School of Medicine/IU Health Cardiovascular Institute
Louis S. Bouchard: University of California
Rajesh Gupta: University of Toledo
Mayil Singaram Krishnam: Stanford University
Keyur Vora: Indiana University School of Medicine/IU Health Cardiovascular Institute
Balaji Tamarappoo: Indiana University School of Medicine/IU Health Cardiovascular Institute
Andrew G. Howarth: University of Calgary
Andreas Kumar: Northern Ontario School of Medicine
Joseph Francis: Louisiana State University
Scott B. Reeder: University of Wisconsin
John C. Wood: University of Southern California
Frank S. Prato: University of Western Ontario
Rohan Dharmakumar: Indiana University School of Medicine/IU Health Cardiovascular Institute

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Sudden blockage of arteries supplying the heart muscle contributes to millions of heart attacks (myocardial infarction, MI) around the world. Although re-opening these arteries (reperfusion) saves MI patients from immediate death, approximately 50% of these patients go on to develop chronic heart failure (CHF) and die within a 5-year period; however, why some patients accelerate towards CHF while others do not remains unclear. Here we show, using large animal models of reperfused MI, that intramyocardial hemorrhage - the most damaging form of reperfusion injury (evident in nearly 40% of reperfused ST-elevation MI patients) - drives delayed infarct healing and is centrally responsible for continuous fatty degeneration of the infarcted myocardium contributing to adverse remodeling of the heart. Specifically, we show that the fatty degeneration of the hemorrhagic MI zone stems from iron-induced macrophage activation, lipid peroxidation, foam cell formation, ceroid production, foam cell apoptosis and iron recycling. We also demonstrate that timely reduction of iron within the hemorrhagic MI zone reduces fatty infiltration and directs the heart towards favorable remodeling. Collectively, our findings elucidate why some, but not all, MIs are destined to CHF and help define a potential therapeutic strategy to mitigate post-MI CHF independent of MI size.

Date: 2022
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DOI: 10.1038/s41467-022-33776-x

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