News | Heart Failure | February 07, 2017

University of Pennsylvania Study Finds New Clues to Causes of Heart Failure

Researchers report that two signaling proteins play key role in preventing muscle inflammation following heart attacks that can lead to heart failure

Penn Medicine, heart failure causes, YAP and TAZ proteins, Journal of Clinical Investigation study

February 7, 2017 — 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 recently 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, M.D., an assistant professor of cardiovascular medicine. “They hint at the possibility of developing designer therapies aimed at modulating specific aspects of the immune system in the future as part of treating patients who have had a heart attack. ”

Prior work 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 was 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, M.D., 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).

For more information:


Ramjee, V., Li, D., Manderfield, L.J., Liu, F., et al. "Epicardial YAP/TAZ orchestrate an immunosuppressive response following myocardial infarction," The Journal of Clinical Investigation. Published online Feb. 6, 2017. doi: 10.1172/JCI88759

Related Content

Livongo Launches Applied Health Signals Product Category
News | Cardiac Diagnostics | November 30, 2018
Healthcare technology company Livongo recently announced the launch of its Applied Health Signals product category,...
HHS Releases Second Edition of Physical Activity Guidelines for Americans. #AHA2018 #AHA18
News | Cardiac Diagnostics | November 14, 2018
The U.S. Department of Health and Human Services (HHS) released the second edition of the Physical Activity Guidelines...
ACC and AHA Release Updated Cholesterol Guidelines for 2018. #AHA18 #AHA2018
Feature | Cardiac Diagnostics | November 13, 2018
November 13, 2018 — New cholesterol guidelines from the American Heart Association (AHA) and the American College of
AMI READMITS Score Predicts Heart Attack Patients at High Readmission Risk
News | Cardiac Diagnostics | October 09, 2018
Tracking just seven factors of heart attack patients when they are first admitted to the hospital can help flag those...
Siemens Healthineers Showcases New In Vivo and In Vitro Cardiovascular Solutions at TCT 2018
News | Cardiac Diagnostics | September 21, 2018
At the 2018 Transcatheter Cardiovascular Therapeutics (TCT) conference, Sept. 21-25 in San Diego, Siemens Healthineers...
Weight Loss Drug Does Not Increase Cardiovascular Events
News | Cardiac Diagnostics | August 31, 2018
A weight loss drug does not increase cardiovascular events, according to late breaking results from the CAMELLIA-TIMI...
Acarix Presents CADScor System at ESC 2018
News | Cardiac Diagnostics | August 27, 2018
Acarix AB’s ultra-sensitive acoustic CADScor System for coronary artery disease risk assessment will be on display at...
NIH Ending Funding for Moderate Alcohol and Cardiovascular Health Trial
News | Cardiac Diagnostics | August 24, 2018
The National Institutes of Health announced in June it plans to end funding to the Moderate Alcohol and Cardiovascular...
Study Shows Multiple Benefits of Patient-to-Patient Connectivity in Familial Chylomicronemia Syndrome
News | Cardiac Diagnostics | August 07, 2018
Akcea Therapeutics Inc., an affiliate of Ionis Pharmaceuticals Inc., announced the publication of results from the...
Being Overweight May Change Young Adults' Heart Structure, Function
News | Cardiac Diagnostics | August 03, 2018
Even as a young adult, being overweight may cause higher blood pressure and thicken heart muscle, setting the stage for...
Overlay Init