Cedars-Sinai investigators identify a potential way to avert heart failure for survivors of heart attacks.


Summary:

Researchers at Cedars-Sinai have developed a drug, PR-364, that prevents heart failure in laboratory mice following heart attacks by improving mitochondrial function and heart repair mechanisms. The study, published in the European Heart Journal, demonstrates the drug’s ability to preserve heart function when administered two hours after a heart attack, offering a promising pathway for developing human treatments. Further research will focus on optimizing the drug, exploring gender differences, and deepening understanding of its mechanisms.

Key Takeaways:

  1. Preventing Heart Failure: PR-364 prevented heart failure in mice by enhancing mitochondrial function, including increased mitophagy, production of new mitochondria, and improved mitochondrial performance.
  2. Post-Heart Attack Timing: Unlike many preventive drugs, PR-364 showed effectiveness when administered two hours after a heart attack, increasing its potential applicability for human patients.
  3. Future Research Directions: Researchers aim to improve the drug’s efficacy, study gender-based differences, and further investigate its mechanisms to advance development for human use.

A specially designed drug prevented laboratory mice from developing heart failure after heart attacks, according to new research from Cedars-Sinai. 

Researchers say 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.

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. 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.

PR-364 Enhances Mitochondrial Function

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.

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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

Path Toward Heart Failure Prevention

“Taken together, these effects suggest how PR-364 helped prevent the development of heart failure after heart attacks in laboratory mice,” says 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, in a release. “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 says 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, says 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 says in a release. “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.”

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