Drug Prevents Heart Failure After Heart Attacks in Mice, Study Finds

A specially designed drug prevented laboratory mice from developing heart failure after heart attacks, according to new research from Cedars-Sinai. This discovery could lead to new treatments to prevent heart failure, a serious cardiac condition that develops in up to 30% of heart attack survivors within one year.

Heart failure occurs when the heart cannot pump enough blood and oxygen to support the body’s other organs. This condition can cause fatigue, shortness of breath, swelling, other debilitating symptoms and shorten life. Heart attacks, which damage the heart muscle, are among the most common causes.

The new study, published in European Heart Journal, analyzed the effect of administering a small molecule known as PR-364 to adult male laboratory mice that endured a heart attack, also known as myocardial infarction. Data showed this treatment preserved the heart’s pumping power and mitigated the progression of heart failure in the treated mice versus mice that were not treated.

To uncover why PR-364 had such a profound impact, the investigators performed additional laboratory experiments using mouse tissue and cells along with human cardiomyocytes, the cells that make up the heart muscle. They also analyzed changes in proteins in mice that had received the drug.

The data indicated that PR-364 enhanced the functioning of mitochondria, the small structures in cells that generate energy to power biochemical reactions. Healthy mitochondria are critical drivers of the processes that protect and repair the heart and other muscles. PR-364 altered the mitochondria in several beneficial ways:

• By increasing mitophagy, the process by which the mitochondria that have been damaged by a heart attack are destroyed and cleared from the body, which aids repair of the heart muscle
• By increasing production of new mitochondria
• By improving the overall functioning of the mitochondria

“Taken together, these effects suggest how PR-364 helped prevent the development of heart failure after heart attacks in laboratory mice,” said Jennifer Van Eyk, PhD, professor of Cardiology in the Smidt Heart Institute at Cedars-Sinai and director of the Advanced Clinical Biosystems Institute at Cedars-Sinai. “While our data does not prove that PR-364 would have this impact on patients, it points to a unique, promising path toward developing heart failure strategies for survivors of heart attacks.” Van Eyk was co-corresponding author of the study along with Roberta Gottlieb, MD, formerly of Cedars-Sinai.

Van Eyk said the next steps in this research are threefold: to study whether a second-generation version of PR-364 may be more effective, to determine whether there are differences in responses based on gender and to delve more deeply into how PR-364 works.

Eduardo Marbán, MD, PhD, executive director of the Smidt Heart Institute at Cedars-Sinai, said the new study’s findings are especially important, given that more people than ever are surviving heart attacks.

“Although several drugs have reduced injury in mice after a heart attack, almost all are preventive: They must be given beforehand. Unfortunately, no one has a crystal ball predicting just when a heart attack will occur in real life,” Marbán said. “What is particularly noteworthy here is the fact that improved recovery was seen when PR-364 was administered a full two hours after the heart attack, improving the likelihood of successful translation to patients.”

Other Cedars-Sinai authors include co-first authors Lizhuo Ai and Juliana de Freitas Germano, and Chengqun Huang, Marianne Aniag, Savannah Sawaged, Jon Sin, Reetu Thakur, Deepika Rai, Yang Song, Honit Piplani, Robert M. Mentzer and Aleksandr Stotland. Other authors include Christopher Rainville, David E. Sterner, Suresh Kumar and Tauseef R. Butt.

Disclosure of interest: The authors declare no conflicts of interest. The Parkin activating compound PR-364 was provided by Progenra Inc., which did not interfere with the results and conclusions presented here. Progenra Inc. plans to file patents on PR-364.

Funding: This work was supported by the National Institutes of Health (NIH) grants R01-HL144509 (J.E.V.E. and R.A.G.), R01-HL132075-01A (J.E.V.E. and R.A.G.), 1 R01 HL155346-01 (E.M. and J.E.V.E.), and1R43HL162163-01 (Progenra, Inc.). L.A. is supported by the California Institute for Regenerative Medicine (CIRM) Scholar Training Program (CIRM EDUC4-12751). A.S. is supported by the Cedars-Sinai Research Institute Winnick award AWD00001135-400023. Progenra’s work was supported by Michael J Fox Foundation, New York, USA. As well, the Erika J Glazer Endowed Chair in Women’s Heart Health (J.E.V.E.) and the Smidt Heart Institute and Cedars-Sinai Medical Center funds to J.E.V.E. for proteomic analysis.