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September 15, 2003

Experimental Cancer Drugs May Halt Events That Lead To Cardiac Hypertrophy and Heart Failure

(Philadelphia, PA) - The events that lead to cardiac hypertrophy, the enlargement of heart muscle cells, may be stopped by histone deacetylase (HDAC) inhibitors, a class of therapeutic agents currently under development as cancer drugs, according to researchers at the University of Pennsylvania School of Medicine. Cardiac hypertrophy is one of the leading causes of congestive heart failure, the most common diagnosis given for discharged hospital patients in the United States.

In the September issue of Journal of Clinical Investigation, the Penn researchers suggest novel genetic causes for - and new therapeutic agents against - cardiac hypertrophy and heart failure. Furthermore, the researchers demonstrate that anti-HDAC drugs can block the development of hypertrophy in animal models.

"In our studies, we determined that valproic acid, an HDAC inhibitor used to treat seizure disorders, is effective in preventing heart muscle cells from enlarging," said Jonathan A. Epstein, MD, Associate Professor in the division of Cardiovascular Medicine within Penn's Department of Medicine. "In recent years, drug companies have also begun developing more advanced HDAC inhibitors to treat cancer. These HDAC inhibitors may be among the first known medications to prevent cardiac hypertrophy."

Cardiac hypertrophy can be a healthy physiological response to events, such as aerobic exercise, where heart cells grow larger like any other well-conditioned muscle. Pathological hypertrophy, however, may result from genetic mutation or, most commonly, from the consequences of an unhealthy cardiovascular system.

"The exertion of pushing blood against high resistance in the setting of high blood pressure or overcompensation for heart muscle lost during a heart attack can cause heart muscle cells to enlarge," said Epstein. "While it might be helpful at first, hypertrophy can increase the stress placed on the heart and begin a downward spiral of events that ultimately leads to heart failure. Despite the fact that this is a common every-day problem for clinicians and patients, we have very few, if any, medications that are directed at halting the cellular events responsible for this deterioration. That's why our present studies are so encouraging."

Unlike most cells, cardiac muscle cells largely stop dividing after birth and only then grow larger through hypertrophy. The disease form of hypertrophy is associated with the re-activation of a genetic program that normally stops soon after birth. "Mature heart cells are naturally programmed to be anti-hypertophic, but mutation or the cumulative effects of cellular stress seems to restart a program of events that we've only seen in developing fetuses, " said Epstein.

Epstein and his colleagues previously linked fetal cardiac development to a protein called Hop, which is thought to control heart cell growth. Hop is abundant in fetuses and newborns, but less so in adults, where it seems that the over-production of Hop overrides the cell's normal genetic programming. Hop does so by recruiting HDAC, which blocks a set of genes that normally protect the heart from hypertrophy. In effect, HDAC unlocks genes that have been kept hidden since birth.

"This genetic control of cell growth is why HDAC inhibitors also make for promising anti-cancer drugs," said Epstein. "Although we do not know for certain what this genetic program entails, it clearly results in severe cardiac hypertrophy and premature death in animal models."

The elucidation of these chemical pathways and genetic programs will offer more new targets for the treatment of congestive heart failure, Epstein believes. The Penn researchers hope to continue to study HDAC inhibitors and their possible therapeutic roles in clinical trials to prevent hypertrophy in at-risk patients.

Contributing Penn researchers include Hyun Kook, John Lepore, Aaron D. Gitler, Min Min Lu, and Victor Ferrari from the Division of Cardiovascular Medicine and Rong Zhou from the Department of Radiology. Other contributing researchers include Wendy Wing-Man Yung and Joel Mackay from the University of Sydney and Peter Gruber from The Children's Hospital of Philadelphia.

Funding for this research was provided through grants from the National Institutes of Health.

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PENN Medicine is a $2.2 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation's first integrated academic health system). Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report's most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

Penn Health System consists of four hospitals (including its flagship Hospital of the University of Pennsylvania, consistently rated one of the nation's "Honor Roll" hospitals by U.S. News & World Report), a faculty practice plan, a primary-care provider network, three multispecialty satellite facilities, and home health care and hospice.




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