Sodium Channel Gene Defects Tied To Cardiomyopathy, Atrial Fibrillation

NEW YORK (Reuters Health) - Individuals with defects in the cardiac sodium channel gene SCN5A, which are often inherited, may be susceptible to early-onset dilated cardiomyopathy (DCM) as well as atrial fibrillation, research suggests.

SCN5A "may be a candidate for comprehensive genetic testing in the future, targeting patients with a syndrome of DCM and rhythm or conduction disturbances," Dr. Timothy M. Olson from the Mayo Clinic in Rochester, Minnesota, and colleagues suggest in the January 26th issue of the Journal of the American Medical Association.

It may also be prudent to avoid sodium channel-blocking drugs in patients with DCM and SCN5A defects, they suggest.

Heritable forms of arrhythmia and heart failure, such as DCM, have been traditionally linked to mutations in genes encoding structural proteins of the contractile apparatus and cytoskeleton. Recently, however, genetic defects in calcium and potassium regulation have been observed in patients with DCM. (see Reuters Health report February 27, 2003).

Dr. Olson's group conducted "refined mapping" studies of a previously identified DCM locus located on chromosome 3p in a multigenerational family and "mutation scanning" studies in 156 unrelated probands with DCM.

Their goals were to detect a novel gene for DCM at this locus, define the scope of mutations in this gene within a DCM cohort, and establish the frequency of DCM among relatives inheriting a mutation in this gene.

Their observations suggest that SCN5A is a candidate gene for DCM.

According to the team, a missense mutation in SCN5A (D1275N) "cosegregated with an age-dependent, variably expressed phenotype of DCM, atrial fibrillation, impaired automaticity, and conduction delay." In the DCM cohort, additional missense and truncation mutations in SCN5A, "segregating with cardiac disease or arising de novo," were observed in unrelated probands.

Among individuals with an SCN5A defect, 27% had early features of DCM diagnosed at a mean age of 20.3 years, 38% had DCM diagnosed at a mean age of 47.9 years, and 43% developed atrial fibrillation diagnosed at a mean age of 27.8 years.

"Our findings," Dr. Olson told Reuters Health, "demonstrate that electrical and mechanical heart disease may share a common genetic basis. Specifically, impaired ion homeostasis can lead to both electrical instability and mechanical pump failure."

"Most interestingly," two New York City-based editorialists write, "patients with SCN5A defects often had disorders of both rhythm and contraction. This is contrary to the traditional paradigm in cardiovascular disease, in which patients are known to have a primary disorder of either rhythm or contraction," Drs. Eric Adler and Valentin Fuster from Mount Sinai Medical Center point out.

The study findings, the physicians add, support the use of beta-blockers for these patients because they may improve contractile function and prevent arrhythmias.

Source: JAMA 2005;293:447-454,491-493. [ Google search on this article ]

MeSH Headings: Ion Channels : Membrane Glycoproteins : Membrane Proteins : Sodium Channels

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