How to Stop Dangerous Scarring After a Heart Attack

Heart failure is the end-stage of many heart diseases, including and most commonly, heart attack (myocardial infarction). Acute myocardial infarction (MI) causes inflammation and scarring (fibrosis) in response to cardiac muscle cell death. While these processes promote healing of the damaged part of the heart muscle, there is a natural overreaction that causes scarring in the undamaged tissue as well. This excessive scarring leads to inefficient heart function and ultimately leads to heart failure. Currently, there are no drug treatments approved for treating cardiac fibrosis in humans.

Galectin-3, which is a human lectin (a carbohydrate binding protein), plays a crucial role in the healing process and the fibrotic overreaction after MI. As a result, elevated levels of galectin-3 in the blood are strongly associated with adverse outcomes post-MI and in heart failure.

In a study publishing August 21, 2023 in Cardiovascular Research, researchers from UCSF and biotech company MandalMed performed a preclinical assessment of a galectin-3 protein inhibitor (called Gal-3C) to limit excessive scarring resulting from MI. The researchers found that treating rats with Gal-3C improved long-term cardiac function post-MI and prevented the infarcted heart from extensive fibrosis that would accelerate the development of heart failure.

The researchers delivered Gal-3C to rats using an implanted continuous release device
over 7 days, starting either at the time of MI or several days later. Heart function, measured in several ways including echocardiography, was much better in rats that received the drug than in those that received a placebo only. Scarring in the heart was also much lower in rats receiving the drug.

Gal-3C showed impressive results in MI models that mimicked heart attacks that received prompt care to open clogged coronary arteries in the ER and models that mimicked more serious cases in which arteries are not quickly opened. It was effective in both young and aged rats, which is important given heart attacks commonly occur in middle-aged and elderly people.

Profound therapeutic benefit

The researchers also compared treatment with Gal-3C to that with drugs that are currently used to treat or limit heart failure, losartan and spironolactone. They found that Gal-3C therapy had better therapeutic efficacy than either of the other two drugs.

“As we did these experiments over several years, we were continuously impressed and surprised at how therapeutic Gal-3C was,” said co-senior author, Matthew L. Springer, PhD, UCSF professor of Medicine. “It’s not all that hard to see an experimental therapy work in young otherwise healthy rats under ideal experimental conditions, but when we tried treating the old rats, or the more extreme MI model, we half-expected to see it not work as well and were frankly astonished at how well it worked. This therapy has real clinical potential.”

To better understand how Gal-3C caused these therapeutic effects, the team studied how cells in culture dishes responded to the drug and studied cellular and molecular changes in serum, a component of blood, and the hearts of the treated rats. Gal-3C changed how the heart responded to the tissue injury of MI. It limited various molecular damage signals that are generated by the injury and, in a notable result, altered the character of macrophages (inflammatory cells that either cause initial inflammation or subsequent healing response) by making them less active in the healing process and preventing them from causing the excessive scarring.

“Our results show that effectively limiting galectin-3-induced post-MI scarring in the heart that has very little regenerative capacity could potentially have profound therapeutic benefit,” said senior author, Constance M. John, RPh, PhD, CEO of MandalMed, Inc. and UCSF professor of Laboratory Medicine. “This is significant because each year about 2 million people in the U.S. and EU alone have a non-fatal MI that is the most common single cause of heart failure.”

Authors: Other UCSF authors include Xiaoyin Wang, MD, Hilda J. Rodriguez, Huiliang Qiu, MD, PhD, Ming Chen, MD, Liqiu Yan, MD, Shilpa Narayan, MS, CGC, Ronak Derakhshandeh, MS, Poonam Rao, MBBS, Daniel D. Han, BA, and Pooneh Nabavizadeh, MD. For other authors, see the study.

Funding: The study was supported by National Institutes of Health Small Business Innovation Research (SBIR) grants (R43 HL120645 and R44 AG054386).

Disclosures: MandalMed is a privately-held company focused on modulation of glycobiology and innate immunity to develop treatments for organ fibrosis. C.M.J., M.L.S. and X.W. are inventors on issued and pending patents for methods and compositions for preventing and treating damage to the heart (issued: US 10369195, US 11179439; pending: EP3496738A1, CN201780062232.1A). C.M.J. is an employee of and has equity in MandalMed, Inc., USA. All other authors declare that they have no competing interests.

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