DALLAS, Jan. 29 – Scientists have unraveled how a defective gene can cause dilated cardiomyopathy, a condition that leads to heart failure, according to a report in today’s Circulation: Journal of the American Heart Association.
The new findings suggest how existing medications could benefit patients with this disease. “We predict that drugs that lower blood pressure and the overall workload on the heart will lessen heart-muscle damage in these patients,” says Timothy M. Olson, M.D., one of the study’s two lead authors and an assistant professor of medicine and pediatrics at the Mayo Clinic in Rochester, Minn.
The findings emerged from an international collaboration by U.S. and German researchers. Genes carry the code, or blueprint, for proteins. A defective gene results in a defective protein. In this case, the mutant gene caused a weakening in one of the proteins that help bind heart-muscle cells to one another.
Olson led the team that identified the three defects in the gene while he was on the faculty at the University of Utah. Cell biologist Susanne Illenberger, Ph.D., of the Technical University of Braunschweig, Germany, led the group that determined the ill effects caused by the defective protein. In cardiomyopathy, the heart enlarges and loses much of its pumping power. As a result, blood pools in the heart and backs up into the lungs, which causes congestive heart failure.
Coronary artery blockage causes most heart disease. But in some patients, physicians cannot identify a cause for heart-muscle disease. Such cases are sometimes called dilated (or idiopathic) cardiomyopathy. Heart failure of unknown cause is present in 36.5 people per 100,000, and accounts for 10,000 deaths each year, says Olson.
A Mayo Clinic study in the early 1990s showed that at least 20 percent to 30 percent of dilated cardiomyopathy cases stem from an inherited abnormal gene. “That was really a surprise because it wasn’t thought at the time that genetics played such a significant role in the disease,” says Olson. “That study set in motion efforts to identify specific genes that are important in the development of this type of heart disease.”
In the current study, researchers focused on the gene for a protein called metavinculin, which is present only in heart-muscle cells and the smooth-muscle cells that line blood vessels and other parts of the body, such as the intestines.
It is the ninth gene discovered in which mutations cause dilated cardiomyopathy. “Our study is unique among genetic studies of this disease in humans because we demonstrated a specific effect that the gene mutations have on the proteins that are made,” Olson says.
He and his colleagues obtained genetic samples from 350 unrelated dilated cardiomyopathy patients. They identified three previously unknown genetic mutations in the gene for metavinculin, one in each of three patients.
They also examined genetic material from 500 people without a diagnosis of dilated cardiomyopathy. Only one had any of the three mutations identified in the cardiomyopathy group, and she had an abnormal electrocardiogram, possibly indicating a more subtle heart problem.
Genes consist of DNA, a molecule made of four compounds called bases. Two of the gene alterations identified by Olson’s team were so-called single-point mutations, in which one base is erroneously substituted for another in the DNA. In the third mutation, the gene was missing three bases it should have had.
Illenberger and her colleagues then produced copies of the abnormal proteins that resulted from each of the three mutations and studied their interaction with another key protein in the heart.
The structures that bind heart-muscle cells to one another are called intercalated discs. “These intercalated discs anchor proteins important in heart muscle contraction and facilitate both electrical and mechanical communication between cells so that they act together and all contract at once,” he explains.
But Olson’s and Illenberger’s teams found that at least two of the mutations in the metavinculin gene disrupt the stability of protein complexes that form the intercalated discs inside each heart-muscle cell. The role of the third mutation was not clear, and the researchers suggest that it might increase a person’s risk of dilated cardiomyopathy rather than actually cause it.
“Our study supports the hypothesis that the weakening of critical proteins can damage cells in the heart,” says Olson. “Although defects in many different genes can lead to dilated cardiomyopathy, it is possible that these defects have a similar adverse effect on cells within heart muscle.”
The only truly effective treatment for severe dilated cardiomyopathy is a heart transplant, but some drugs can prolong patients’ lives. “Our finding suggests why reducing mechanical stress on the heart may be beneficial in patients with dilated cardiomyopathy,” says Olson. “One would predict that drugs that lower blood pressure and lessen the workload of the heart, such as beta-blockers and ACE inhibitors, would reduce mechanical injury to the cells and be beneficial to these patients.”
Co-authors are Nina Y. Kishimoto, M.S.; Stefan Huttelmaier, Ph.D.; Mark T. Keating, M.D.; and Brigitte M. Jockusch, Ph.D.
This research was supported in part by a grant from the American Heart Association.
CONTACT: For journal copies only,
please call: (214) 706-1396
For other information, call:
Carole Bullock: (214) 706-1279
Maggie Francis: (214) 706-1397