PHILADELPHIA — Of the more than 700,000 Americans who suffer a heart attack each year, about a quarter go on to develop heart failure. Scientists don’t fully understand how one condition leads to the other, but researchers in the Perelman School of Medicine at the University of Pennsylvania have now discovered a significant clue—which ultimately could lead new therapies for preventing the condition.
Heart failure can develop after a heart attack due to a long-term damage response by the immune system that transforms much of the heart muscle into stiff, fibrous, scar-like tissue. In a study published today in the Journal of Clinical Investigation, researchers report that a set of signaling proteins produced in the epicardium, a layer of special cells that lines the heart muscle, appears to play a key role in keeping this wayward damage-response process in check.
"These findings highlight the importance of the heart’s interaction with the immune system in the post-heart-attack response,” said co-senior author Rajan Jain, MD
, an assistant professor of Cardiovascular Medicine. “They hint at the possibility of developing designer therapies aimed at modulating specific aspects of immune system in the future as part of treating patients who have had a heart attack. ”
Prior work from Epstein and colleagues at Penn has shown that in the epicardium, a cascade of protein-to-protein interactions known as the Hippo signaling pathway occurs early in life and is important for normal heart development. Other research has suggested that two key components of the Hippo pathway, the signaling proteins YAP and TAZ, also promote the regeneration of heart muscle after experimental heart-attack-like damage in newborn mice.
In this study, researchers examined the role of epicardial YAP and TAZ after heart attack in the adult heart, which, compared to the fetal or newborn heart, is much less able to regenerate itself following injury. After an experimentally induced heart attack, normal adult mice, as expected, showed a small amount of fibrous change in the heart, limited to the area where a coronary artery were blocked and heart muscle had been deprived of oxygen. By contrast, in adult mice whose YAP and TAZ genes had been deleted from their epicardial cells just before the heart attack, there were signs of widespread inflammation and fibrosis in the heart muscle.
“The hearts of these mice were essentially encased in fibrotic cells,” Jain said. “We found that this extreme fibrotic response was accompanied by a decline in heart function resembling what is seen in human heart failure, as well as rapid weight loss and a much higher death rate.”
Researchers found evidence that the Hippo-pathway proteins normally trigger the increased production of the immune protein interferon gamma. The latter summons regulatory T cells – “T-regs” – which generally calm immune responses, and have been shown in prior research to reduce heart-muscle inflammation after a heart attack. In the YAP-less, TAZ-less mice, a heart attack failed to induce the usual rise in interferon gamma production and recruitment of T-regs, allowing inflammation and fibrosis to run rampant.
“We are hoping to harness the immune system, just as we are doing at Penn to fight cancer, in order to improve the balance between scar formation and regeneration after a heart attack,” said co-senior author Jonathan A. Epstein, MD
, executive vice dean and chief science officer at Penn Medicine. “The more we look, the more we discover that the immune system is regulating how we heal from injury in every way - acting like the conductor of a complex cellular orchestra.”
In a further experiment, the researchers applied a hydrogel laced with interferon gamma to the hearts of some of these mutant mice just after their heart attacks. As hoped, the artificial restoration of interferon gamma led to higher T-reg levels in the heart and much more moderate inflammation and fibrosis.
The findings show that epicardial YAP and TAZ are important not only for the normal development of young hearts but also for a healthier repair process in damaged adult hearts.
Jain, Epstein and their colleagues now plan further experiments to map out the fibrosis-causing immune response in more detail—a project that could reveal multiple targets for future drug interventions to prevent heart failure in heart attack patients. The team also plans to develop mice in which the YAP and TAZ genes are not deleted but are instead overexpressed. “The hope is that higher levels of these proteins will lead to a scar-free healing of the heart after a heart attack,” Jain said.
Additional Penn authors on this study include co-first authors Vimal Ramjee and Deqiang Li, both of the Epstein Laboratory at the time of the study; Lauren J. Manderfield, Feiyan Liu, Kurt A. Engleka, Haig Aghajanian, Christopher B. Rodell, Wen Lu, Vivienne Ho, Tao Wang, Li Li, Anamika Singh, Dasan M. Cibi, and Jason A. Burdick. Co-senior author Manvendra K. Singh, formerly of Penn Medicine and now at Duke-NUS Medical School, also contributed to this research.
The research was supported by the American Heart Association, the Burroughs Wellcome Fund, the Singapore National Research Foundation, the Cotswold Foundation, the WW Smith Endowed Chair, and the National Institutes of Health (U01 HL100405).
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $7.8 billion enterprise.
The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $425 million awarded in the 2018 fiscal year.
The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Home Care and Hospice Services, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.
Penn Medicine is powered by a talented and dedicated workforce of more than 40,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.
Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2018, Penn Medicine provided more than $525 million to benefit our community.