Gene defect explains why some hearts are too big.

Gene defect explains why some hearts are too big.


DALLAS—A gene variant found in about 20 percent of the population might explain why some people develop a dangerously enlarged heart after intensive exercise or as a side effect of high blood pressure, according to today’s rapid access publication of Circulation: Journal of the American Heart Association.

An enlarged heart, also called left ventricular hypertrophy (LVH), can lead to congestive heart failure, a condition that affects about 4.8 million Americans. LVH may also cause sudden cardiac death. Among young people, 36 percent of young athletes who die suddenly have probable or confirmed LVH, according to the American Heart Association.

David Flavell, Ph.D., a lecturer at the Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, University College London Medical School, led a study funded by the British Heart Foundation to find out why some individuals who weight train or who have high blood pressure are more likely to develop LVH than others.

“We know there are physical causes for LVH. It is normal for the heart to grow in response to exercise, but we wanted to find out the genetic components contributing to the abnormal growth that leads to LVH,” he says.

Research in animals with LVH found that a gene called peroxisome proliferator activated receptor alpha (PPARa) was linked to enlarged hearts in mice. This gene controls the breakdown of fatty acids so they can be used as fuel for the body. Flavell and his colleagues hypothesized that a mutation in the gene might cause less fatty acids to be burned in the heart, causing them to accumulate.

“When fatty acids build up in the heart, they can be toxic. The heart must work harder and is forced to burn more glucose instead of fatty acids. Glucose is not as efficient as a fuel source, so the heart is further challenged to provide the same level of performance. A vicious cycle ensues that leads the heart to enlarge, which may eventually lead to heart failure,” says Flavell.

To test this theory, the researchers examined the PPARa gene in two studies. They did genetic testing and measured left ventricular mass with magnetic resonance imaging in 144 healthy, young male British Army recruits at baseline and at the end of 10 weeks of high intensity upper and lower body strength and endurance training. They compared measurements to those from 1,148 men and women who were participating in a study called the Third MONICA Augsburg Survey.

Participants were genotyped to determine whether they carried the G or C form of the PPARa gene “intron 7” variant. Researchers found that those with two copies of the C form had three times greater increase in left ventricular mass (LVM) than those with two copies of the G form, while those with one copy of the C form had a doubling of growth. LVM increased an average of 8.6 grams. It was 6.7 g for those without the C form; 11.8 for those with one copy and 19.4 for those with two copies.

There were similar results in the second study (MONICA), and when individuals also had high blood pressure, the enlargement doubled.

Flavell says the PPARa C form is not a rare genotype. It is present in about one in five people. One in 25 people, or about 4 percent of the population, have two copies.

Researchers speculate that the intron 7 genetic variant may lead to a decrease in PPARa levels and a decrease in fatty acid oxidation, which leads to enlargement of the heart muscle and in turn, may result in death of cardiac cells.

“These findings may have therapeutic implications for patients with LVH. Drugs such as fibrates that stimulate fatty acid oxidation by PPARa activation may be a useful treatment for a subset of patients with LVH,” he says. Fibrates are cholesterol-lowering drugs that are primarily effective in lowering triglycerides and, to a lesser extent, in increasing HDL-cholesterol levels.

Currently, high blood pressure medications such as angiotensin-converting enzyme (ACE) inhibitors or beta-blockers are used to reduce LVH.

Flavell and his colleagues are planning to study fibrates for both prevention of LVH and treatment of the condition by examining their effect in normal mice and genetically engineered mice that are bred with the PPARa mutation.

Co-authors are Yalda Jamshidi, Ph.D.; Hugh E. Montgomery, B.Sc., M.D., M.R.C.P.; Saul G. Myerson, M.R.C.P.; Steve E. Humphries, Ph.D., F.R.C.Path., M.R.C.P.; Hans-Werner Hense, M.D., Bart Staels, Ph.D.; Michael J. World, B.Sc., M.D., FRCP, U.K.; Angela Doering, M.D., Ph.D.; Jeannette Erdmann, Ph.D.; Christian Hengstenberg, M.D.; and Heribert Schunkert, M.D.

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