Genetic defect leads to electrical instability and mechanical pump failure

In genetic mapping of a large family with several members affected by a type of heart failure called dilated cardiomyopathy (DCM), the Mayo Clinic team found a defect in a gene on chromosome 3 called SCN5A.

By scanning 156 unrelated patients with DCM, they found four additional mutations in the same gene. SCN5A is the gene that encodes the sodium ion channel in the heart, which helps regulate transport of positively charged sodium ions, and therefore the heart's electrical patterns.

Among the individuals with an SCN5A mutation, 27 percent had early features of DCM, 38 percent had full-blown DCM and 43 percent had atrial fibrillation, a rhythm abnormality in the upper chambers of the heart.

"Ironically, the fact that this gene encoding the sodium channel has been strongly implicated in heart rhythm disturbances may have hindered identification of its role in heart failure," says Timothy Olson, M.D. the Mayo Clinic pediatric cardiologist who led the study. "In previous studies of patients and families searching for mutations in this gene, those with structural heart disease such as DCM were normally excluded from consideration in order to better focus on the rhythm disorders. With this new study, we see that heart failure is another important manifestation of this genetic defect."

A Mayo Clinic study led by co-author Virginia Michels, M.D., and published in New England Journal of Medicine in 1992, established the importance of genetics in DCM. Until now, the mutations shown to cause DCM have mainly been related to the proteins involved in the heart's structure and contraction. The new study is important because it establishes another mechanism for heart failure involving the regulation of sodium ion flow, not structural protein defects.

"Our findings may broaden the indications for genetic screening of SCN5A beyond isolated rhythm disorders," says Dr. Olson. "Since these variations hinder sodium transport, it may be wise to avoid using sodium channel-blocking drugs in heart failure patients with SCN5A mutations, because those drugs may make the problem worse. We need more studies to better define how sodium channel defects cause heart failure, and should begin long-term studies of patients with rhythm disturbances caused by SCN5A, to see whether they also are at risk for DCM."

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