Genetic Defects Make Hearts Grow Too Big

A strong heart may be healthy, but too much heart muscle can be fatal: A leading cause of sudden death in young people--particularly in world-class athletes--is a condition called hypertrophic cardiomyopathy, or enlarged heart. Now biophysicists have worked out the mechanism by which a genetic defect produces this dangerous disorder, and the finding may suggest new approaches to treatment.

Scientists have known for a few years that a mutation in a gene coding for the protein troponin T is associated with the disease. They assumed that the defective gene simply failed to produce the protein, which is a normal component of heart muscle. But when physiologist H. Lee Sweeney of the University of Pennsylvania School of Medicine in Philadelphia and his colleagues put this faulty gene into embryonic quail muscle cells growing in lab dishes, the cells made a shortened version of the protein and incorporated it into their contractile machinery. As a result, the cell "contracts, but it produces less than normal force," Sweeney says. The researchers report their results in the current issue of the Journal of Clinical Investigation.

As the heart tries to compensate for this weak contraction, it prompts the growth of more heart muscle. Then, when the heart gets too big to be nourished properly, areas that fail to receive enough oxygen can start beating out of sync with the rest of the heart, causing heart failure. "[The study] is the first functional assessment [of this genetic problem]," comments Michael Sanguinetti, a cardiac electrophysiologist at the University of Utah, Salt Lake City. "It appears that the primary signal [for hypertrophy] is this decrease in contractility."

Other genetic defects associated with hypertrophic cardiomyopathy--six different genes have been linked to the disease--may work similarly by producing abnormal proteins involved in contraction, says Sweeney. He notes that all are thought to produce a weaker contraction of the heart muscle, and therefore "a common treatment may work for all these genetic abnormalities." The findings, Sweeney says, suggest that medications that block the release of excess calcium--which further stimulates contractions and prompts new growth--will lessen the effects of any of these genetic defects.