Jewish World Review Feb. 28, 2003 / 26 Adar I, 5763

Scientists discover rare genetic mutation causing heart failure and death in young

By Steve Mitchell | (UPI) Scientists said Thursday they have discovered a rare genetic mutation that causes heart failure and death in people in their teens and 20s.

The finding could lead to treatments for other forms of heart failure, which affects nearly 5 million Americans and one in five people in North America, David MacLennan, a geneticist at the University of Toronto and an author of the study, told United Press International.

One cause of heart failure is a rare inherited condition called dilated cardiomyopathy, which is often fatal in the first 20 or 30 years of life. It causes the heart to become so enlarged it cannot pump blood efficiently.

MacLennan's team reports in the Feb. 28 issue of Science they discovered in a small percentage of cases dilated cardiomyopathy is caused by a mutation in a gene that encodes for a protein called phospholamban.

Phospholamban regulates calcium flow in heart muscle cells, which in turn controls the beating of the heart. During normal heart function, calcium is pumped into heart cells, triggering contraction. Then calcium is pumped back out to allow relaxation. Phospholamban regulates the cycle of pumping calcium in and out of the cells.

For people with the mutated form of phospholamban, however, the calcium regulation process is disrupted, leading to heart malfunction and, ultimately, death.

The researchers made a chance discovery that members of a family who shared an inherited dilated cardiomyopathy also shared a mutation in their DNA for phospholamban.

MacLennan's team created a strain of mice with the same mutation and found their hearts became severely affected. The animals developed heart failure and died prematurely, similar to what happens in humans with the mutation.

"Any mutant form of phospholamban would probably lead to dilated cardiomyopathy," MacLennan said, noting at least 10 mutations of this gene have been identified in mice.

"We think that there will be other mutations identified in the phospholamban gene that cause dilated cardiomyopathy" in humans, he said.

The study "is an important validation of concepts ... suggesting that regulation of calcium ... is important and abnormality of this system over time can lead to problems of heart failure," Dr. Peter Liu, director of the Heart & Stroke/Richard Lewar Center of Excellence at the University of Toronto, told UPI.

Liu, who also serves as spokesman for the Heart and Stroke Foundation of Ontario, was not involved with the study.

The defect apparently blocks a key enzyme that is necessary for the function of phospholamban. This disrupts the calcium regulation in the heart muscle, preventing it from fully relaxing between contractions and ultimately leading to heart failure.

There is the potential this could lead to drugs that could be used to treat people who develop the more common forms of heart failure that are due to a combination of high blood pressure, previous heart attacks and aging, MacLennan said.

"The idea has been around for more than a dozen years that if you could disassociate phospholamban from the (calcium) pump with a drug you could improve the function of a failing heart," he said. "Several drug companies have in fact looked for (such) drugs ... but without success," he said. "But the prospect is there," he added, noting drugs "might be able to save (people) with this mutation" and have the potential "to prolong life" in people who develop heart failure due to aging.

The findings also suggest "there may be of course ways to identify people in the population who may be at risk for this problem and institute earlier preventive strategies," Liu said

Appreciate this type of reporting? Why not sign-up for the daily JWR update. It's free. Just click here.

Comment by clicking here.


© 2002, United Press International