HARTFORD, Conn. – Dr. Bruce Liang and his colleagues at the University of Connecticut Health Center originally thought that boosting heart contractions in mice with heart failure might prove fatal to the animals.

Liang, director of the Pat and Jim Calhoun Cardiology Center, also believed that blocking a gene that spurred heart contractions could lead to longer life for people with congestive heart failure.

Instead, the scientists discovered that triggering heart contractions actually helped mice with heart failure survive longer.

“This was unexpected,” Liang said. “There was a school of thought that with heart failure you should not increase cardiac contractility; that making the failing heart work harder promotes deterioration of heart function.”

Such pleasant surprises in the field of congestive heart failure are badly needed, experts say. Heart failure may no longer be an automatic death sentence, but more than half of those diagnosed with the disease die within five years.

“Most people don’t realize that mortality from heart failure is worse than many forms of cancer,” Liang said.

Each year, there are an estimated 400,000 new cases of congestive heart failure, according to the National Heart, Lung, and Blood Institute, part of the National Institutes of Health.

In the past five years, dramatic advances have been made in pacemaker therapies, which can help the 40 percent to 50 percent of people with heart failure who also have irregular heartbeats.

As many as 80 percent of people who undergo cardiac resynchronization surgery can experience dramatic reductions in hospital visits, said Dr. Christopher Clyne, director of interventional electrophysiology at Hartford Hospital.

But the $50,000 average operation isn’t a cure, he acknowledged.

“We’re not going to put the heart-failure guys out of business,” Clyne said.

“There has been a dramatic reduction in mortality, but patients are still dying at a high rate and we need to do better,” said Dr. Michael Bristow, director of the Cardiovascular Institute at the University of Colorado Health Sciences Center in Denver.

Bristow was a leader in developing the use of beta-blockers to treat heart failure. He is very interested in what happens when the heart tries to compensate for its reduced function.

“The brain flogs the heart to get more performance, and the heart responds in many ways,” many of them dangerous to patients, Bristow said.

For instance, the heart begins to express genes that are usually only activated during the development of the fetus, which Bristow says may have adverse health consequences. Understanding why these genes are expressed may lead to new therapies, he says.

Bristow notes that another way the body responds to a failing heart is to decrease production of an intracellular messenger called cyclic-AMP, which is involved in the contraction of the heart.

Some drug development efforts are aimed at modulating this response, he says.

But Liang says previous efforts to boost the heart’s ability to contract sometimes have led to a decline in heart function. So he feared that stepping up the heart’s ability to contract might be damaging.

He found the reverse was true in his experiments.

Liang created a mouse with heart failure that over-expressed the P2X gene, which helps regulate electric signaling in the heart. Mice with the active P2X gene had improved heart contractility but did not die more quickly. They actually lived 21/2 times longer than heart failure mice which lacked the gene.

Liang says it turns out that the P2X gene does not affect cyclic-AMP levels, but he is unsure why the mice showed such improvement.

He suspects that by increasing the performance of a failing heart, the gene blocks the development of cardiac enlargement that precedes heart failure. More work needs to be done to discover the effects of manipulating the genes in humans, he says.

“We hope that we can one day develop a drug that can selectively act on this gene.”



(c) 2004, The Hartford Courant

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AP-NY-07-16-04 0617EDT



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