Multiple Genes Lead To Same Problem In Enlarged-Heart Disease Linked To Sudden Death In Athletes, New Study Shows

December 04, 1996

The hearts of people with genetically different forms of a disease called hypertrophic cardiomyopathy (HCM) resemble each other in one critical aspect, according to University of Pennsylvania Medical Center scientists. While each of the disease-causing genes weakens the muscle of the heart in a unique way at the molecular level, the heart's response in every case is apparently the same -- it grows larger to compensate. And it is this enlargement that can lead to heart failure as the heart outpaces its ability to supply itself with oxygen and other resources.

The findings, reported in the December issue of The Journal of Clinical Investigation, suggest that a single therapeutic approach might prove effective for all victims of HCM, whatever the genetic underpinnings of their disease. Among inherited diseases, HCM is the leading cause of sudden death in young adults.

"This work implies that if there is a common functional problem, irrespective of which gene is defective, then one type of treatment may work for all hypertrophic cardiomyopathy patients," says H. Lee Sweeney, PhD, an associate professor of physiology and senior author on the study. "The solution to treating the disease may lie in blocking or decreasing the signals in the heart that cause it to enlarge."

HCM is an inherited form of heart disease that has gained notoriety in recent years because of the untimely deaths of several well-known athletes, including basketball players Hank Gathers and Reggie Lewis. These athletes, at the peak of physical conditioning, were found to suffer from HCM only after their deaths.

Mutations in a number of genes have been linked to the disease, complicating the search for the exact cause of the disease and for possible treatments. In the current study, the scientists showed that although the mutations that cause this disease affect different proteins, all result in diminished power in the heart muscle. This, in turn, stimulates hypertrophy -- or enlargement -- of the heart, which may progress to heart failure.

The scientists studied one particular type of mutation in a protein called cardiac troponin T (TnT). This mutation was selected because it differed from others that had been studied, suggesting that the mechanism of disease might differ as well. Mutations in TnT occur in approximately 15 percent of cases of familial HCM and are associated with a high incidence of sudden death.

In order to assess the consequences of the mutation, Sweeney and colleagues developed a novel quail muscle cell culture system that allows expression of either normal or mutated human cardiac proteins. This system allows direct measurement of the force of contraction in cultured cells. After the cells were transfected with the genes from normal and mutated TnT, they were examined microscopically and analyzed for the force of contraction they could produce.

Both normal and mutated protein were assembled into normal appearing muscle cells. However, while the cells that incorporated normal protein contracted as expected, the force of contraction was greatly diminished in the cells that incorporated mutant protein. This loss of power was similar to what has been seen with other HCM mutations that have been characterized, indicating a common functional problem in the genetically different forms of HCM.

The lead author on the report is Hugh Watkins, MD, chief of cardiology at the University of Oxford, England; Howard Hughes Medical Institute researchers Christine E. Seldman, MD, and J.G. Seldman, PhD, at Brigham and Women's Hospital, Boston, and Harvard Medical School, Boston, respectively, also contributed to the study. Sweeney's Penn-based colleague H.S. Feng, PhD, collaborated on the project and was key in developing the cell- culture assay system used.

-- Dr. H. Lee Sweeney can be reached at (215) 898-0485.

The University of Pennsylvania Medical Center's sponsored research ranks fifth in the nation, based on grant support from the National Institutes of Health -- $140.5 million in federal fiscal year 1995. In addition, the institution posted the highest growth rate in its research activity -- 11.4 percent -- of the top ten academic medical centers during the same period. Penn news releases are available to reporters by direct e-mail, fax, or U.S. mail, upon request. They are also posted electronically to the NASW (National Association of Science Writers) Online and SciNews-MedNews sections of the Journalism Forum, a component of CompuServe, and to EurekAlert!, an Internet resource sponsored by the American Association for the Advancement of Science. Additionally, they are distributed via the electronic news service Quadnet.

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University of Pennsylvania School of Medicine

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