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DURHAM, N.C. -- By screening the genomes of mice with heart
failure, Duke University Medical Center researchers have
discovered multiple stretches of DNA containing genes that
modify the heart's pumping ability and survival with the
disease. The findings could point researchers to genes that
determine the severity of heart failure in patients, according
to the Duke team.

"Our goal is to find novel genes that modify human heart
failure by letting the mouse point us in the right direction,"
said Duke cardiologist Howard Rockman, M.D., noting that 99
percent of mouse genes are shared by humans. "Such genes would
provide us the means to identify those heart failure patients
having subtle genetic differences that make them more
susceptible to poor outcomes."

That information would allow physicians to identify those
patients in need of the most aggressive therapies and provide
new targets for drug development, Rockman said. He and
geneticist Douglas Marchuk, Ph.D., also of Duke, reported their
findings in the Dec. 1, 2003, issue of Human Molecular Genetics. The
work was supported by the National Institutes of Health, the
French Federation of Cardiology and the Burroughs Wellcome
Fund.

Heart failure -- a condition characterized by the inability
of the heart muscles to pump enough blood to the body's tissues
-- affects nearly 5 million patients in the U.S. and is a
growing public health concern, Rockman said. Despite the
development of novel treatments, the one-year mortality rate
for patients with heart failure is as high as 42 percent.

Yet heart failure patients exhibit significant variability
in quality of life and survival with the condition, he said.
"Following a heart attack, some patients are able to return to
their normal lifestyle, while others are horribly debilitated,"
said Rockman.

In their study, the researchers set out to uncover
chromosomal regions containing heart failure modifier genes
responsible for some of that difference.

The researchers mated males of one mouse strain that had
genetic mutations that conferred a very reproducible and severe
form of heart failure, with females of another healthy mouse
strain. Some of the resulting offspring exhibited severe heart
failure, while others inherited genes from their healthy
mothers that protected them from the disorder. By screening the
genomes of the offspring, the team uncovered those genetic
regions that modified the severity of heart failure.

The researchers found two genetic regions -- one on
chromosome 13 and another on chromosome 18 -- linked to heart
function and survival with heart failure. An additional region
on chromosome 2 affected cardiac function with no effect on
survival, while another on chromosome 4 influenced survival
without impacting heart function in mice with heart failure,
the team reported.

"The immediate cause of death for patients with heart
failure can be the consequence of two different mechanisms:
gradual pump failure or sudden death due to irregularities in
heartbeat," Rockman said. "That some genes affect cardiac
function without affecting survival and vice versa suggests
that distinct genes may underlie the gradual decline in heart
function characteristic of heart failure and the risk of sudden
death associated with the disease."

The next step will be to identify the precise genes within
these regions that modify heart failure outcome, using the
sequenced mouse and human genomes to identify likely
candidates, said the researchers.

Additional researchers on the study include first author
Philippe Le Corvoisier, M.D., Hyun-Young Park, M.D., and Kerri
Carlson, all of Duke University Medical Center. The team has
already begun a collaboration with others at Duke to identify
genes that affect outcome in patients with heart failure.