For years doctors have debated whether the progressively destructive course of genetic heart disease is due principally to the altered genes that set it in motion, or to the body's ceaseless efforts to compensate for and cope with the initial damage. Now results of a Johns Hopkins-led study in mice, published in the March issue of Nature Medicine, show that many of the disease's common features are better explained by the latter theory.
Using a miniaturized catheter developed at Hopkins, researchers compared the heart pumping action of healthy young and old mice to those of same-age mice harboring a defective gene that causes familial hypertrophic cardiomyopathy (FHC) -- a potentially fatal form of inherited heart disease in which the heart wall thickens and obstructs blood flow.
Hypertropic cardiomyopathy is associated with changes in the proteins principally responsible for the capacity of heart muscle to contract and relax as it pumps blood throughout the body. As a result, the wall of the left ventricle -- the heart's main pumping chamber -- thickens, leaving little room inside the chamber for blood to fill. The wall also can stiffen, further impairing the heart's ability to contract.
While the hearts of both younger and older mice with FHC had the identical gene defect, they performed differently. Both contracted faster but relaxed abnormally slowly. However, the hearts of the older FHC mice squeezed much harder only to pump less blood. The higher pressure, reduced volume, and accompanying stiffness were seen only in the older, FHC mice, indicating evolving responses do the damage over time. The same traits are hallmarks of the disease in humans.
"This study provides a major new window to the development of this disease," says David A. Kass, M.D., senior author of the study and professor of medicine and biomedical engineering at Hopkins. "The data support the hypothesis that although genetic mutations can have primary effects, chronic responses to these mutations may be equally important in the progression of disease.
"Continuing studies will need to determine the exact nature of these adaptations and the extent to which inhibiting the responses can modify disease progression. These insights may help us design new therapies."
More than half of hypertrophic cardiomyopathy cases are hereditary. The disease affects about one in 1,000 people, causing shortness of breath, dizziness, fainting and chest pain. It is often treated by medications such as beta-blockers or calcium channel blockers.
The study's other authors were Dmitrios Georgakopoulos of Hopkins; Michael E. Christe, Michael Giewat and J.G. Seidman of Howard Hughes Medical Institute; and Christine M. Seidman of Brigham and Women's Hospital.
Relevant Web sites:
Johns Hopkins Cardiomyopathy and Heart Transplant Service -- http://www.med.jhu.edu/heart/
American Heart Association -- http://www.amhrt.org/
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