Experimental drug may reduce heart failure after a heart attack

Researchers at the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA say they have developed a novel experimental drug that could improve heart repair after a heart attack, with the potential to reduce the incidence of heart failure in patients. The new drug, details of which were published in Cell Reports Medicinecould improve heart function after a heart attack by targeting a protein called ENPP1, which is linked to inflammation and scar tissue formation in the heart.

Cardiovascular disease remains the leading cause of death worldwide, accounting for approximately one-third of annual deaths. After a heart attack, the heart's ability to regenerate is severely limited, so the organ forms scar tissue to maintain structural integrity. However, this rigid scar tissue impairs the heart's ability to pump blood, which can lead to heart failure in many patients. Of those who suffer from heart failure, 50% do not live longer than five years.

“Despite the prevalence of heart attacks, therapeutic options have stagnated over the past few decades,” said senior author Arjun Deb, MD, professor of medicine and molecular, cellular and developmental biology at UCLA. “There are currently no medications specifically designed to improve healing or repair of the heart after a heart attack.”

The newly developed therapy uses a monoclonal antibody developed by Deb and colleagues that is intended to inhibit the activity of ENPP1. This protein has been shown to increase after heart injury, leading to inflammation and scarring. In preclinical mouse models, the researchers found that a single dose of their experimental drug significantly improved heart repair in the mice and prevented extensive heart damage. Four weeks after a simulated heart attack, only 5% of the treated animals developed severe heart failure, compared to 52% in the control group.

This approach differs from existing treatments, which primarily focus on preventing further damage and instead focus on directly promoting healing of the heart tissue. By improving cell communication in the heart, the therapy benefits various cell types, including cardiac muscle cells, endothelial cells and fibroblasts, all of which play important roles in tissue repair.

Early studies suggest that the antibody not only reduces scar tissue, but does so without increasing the risk of heart rupture, a common problem after heart attacks. Deb noted that further research is needed to evaluate the long-term safety of ENPP1 inhibition due to possible negative effects on bone health or bone calcification.

The team now plans to submit an Investigational New Drug (IND) application to the FDA this winter, with the goal of beginning first-in-human trials early next year. The aim of these studies is to administer the therapy shortly after a heart attack to support the heart's self-healing in the first few days after a heart attack.

Researchers in the Deb lab are also studying whether the experimental drug could be used to treat other organs. “The mechanisms of tissue repair are conserved in different organs, so we are investigating how this approach might help with other forms of tissue damage,” noted Deb. “Because of its effect on cardiac repair, this could represent a new class of drugs to improve tissue repair.”

The impact of successful development of this therapy is significant. By improving the heart's natural repair mechanisms, the treatment has the potential to reduce the mortality rate of patients who may develop heart failure after a heart attack. Current therapies focus primarily on stabilizing the heart after an event, but the ability to actively promote healing may transform how health care providers approach cardiac care.