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Possible Trigger For Heart Failure Identified In Lab Animal Studies

Date:
April 16, 1998
Source:
American Heart Association
Summary:
Researchers have demonstrated in laboratory animals that tumor necrosis factor alpha, a protein produced in the heart, can lead to congestive heart failure. The finding may pave the way for a new treatment for the nation's fastest-growing heart disease.

DALLAS, April 14 -- Researchers have demonstrated in laboratory animals that tumor necrosis factor alpha, a protein produced in the heart, can lead to congestive heart failure. The finding may pave the way for a new treatment for the nation's fastest-growing heart disease. The studies, from two different research teams, appear in today's Circulation: Journal of the American Heart Association.

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Released by the body to help heal injured tissue, tumor necrosis factor alpha (TNF), can initiate an "inflammatory cascade," or immune reaction, that may turn against the heart and weaken it, resulting in congestive heart failure, according to scientists at the University of Texas Southwestern Medical Center in Dallas and Baylor College of Medicine in Houston. One study also found that TNF is produced not just by white blood cells, but also by heart muscle cells called myocytes.

The Dallas scientists demonstrated that laboratory mice who were genetically altered so their heart cells produced an excess of TNF pumped less blood and developed an enlarged heart -- the primary features of congestive heart failure in humans.

Afflicting almost 5 million Americans, congestive heart failure is the single most frequent cause of hospitalizations for people age 65 or older, according to the American Heart Association. From 1979 to 1995, deaths from heart failure increased 115.7 percent.

In the study, researchers developed two lines of transgenic mice which expressed TNF in the heart. The two lines, which included 30 mice, died prematurely of heart failure. The progression of heart failure was directly related to the amount of TNF. Mice which did not express TNF in the heart proved to be free of disease, notes Deborah Bryant, B.S., the study's lead author. She is a senior research associate at U.T. Southwestern's department of pediatrics.

"Production of TNF by cardiac myocytes is sufficient to cause myocarditis, myocardial dysfunction, cardiac failure and premature death, and therefore supports a causal role for TNF in the development of diverse cardiac diseases," she says.

Previous research on congestive heart failure has implicated TNF -- so called because it sometimes is associated with weight loss and tissue degradation in cancer patients.

Bryant and her Dallas colleagues say their findings indicate that heart muscle cells are "a primary source of TNF secretion" during infection, burn injury and end-stage congestive heart failure. "We have proved that TNF, which originates in the heart and not just in circulating immune cells, can be harmful," she says. "A small amount of TNF may be adaptive, but too much can be deadly."

In their Circulation paper, the Houston scientists Biykem Bozhurt M.D., the lead author, and Douglas Mann, M.D., professor of medicine, add to the growing array of scientific evidence incriminating TNF in damaging heart tissue. They showed that infusion of TNF at levels that are similar to those observed in patients with heart failure led to dilation of the main pumping chamber of the heart in laboratory rats, as well as depression of the main pumping chamber of the heart, thus mimicking what happens in patients with heart failure. These investigators also showed that the harmful and noxious effects of TNF could be partially reversed using a soluble "antagonist" (a decoy) that binds to TNF and inactivates it.

This is the first experimental study to show that the harmful effects of "heart failure levels" of TNF could be partially reversed using a specific TNF antagonist, says Mann.

At the American Heart Association 70th Scientific Sessions last November, Mann, head of the Houston team, reported that a single infusion of the antagonist improved how patients felt and how they walked. In addition, the Houston team observed that there was a moderate improvement in pumping capacity for the patients who received the antagonist.

In an editorial commentary on the new study by the Dallas team, Michael R. Bristow, M.D., Ph.D., of the University of Colorado, notes that the heart makes "very powerful" compensatory adjustments in response to inflammation that include overstimulation of the immune system to produce a family of cells, including TNF, which are intended as wound-healing.

Bristow, an international scientific expert on heart failure, says that the Dallas team's research "provides additional evidence that cardiac inflammation can evolve" to a severe form of degenerative heart muscle disease called dilated cardiomyopathy, with TNF being "an important mediator of both processes."

The "one remaining step in the proof of the 'TNF hypothesis'" is to demonstrate that treatment with agents that inhibit the production or action of TNF prevent or reverse heart muscle dysfunction and damaging "remodeling" in response to the molecules' errant assault on the failing human heart, Bristow writes.

Co-authors with Bryant in Dallas are Lisa Becker, B.S.; James Richardson, D.V.M., Ph.D.; John Shelton, B.S.; Fatima Franco, M.D.; Ronald Peshock, M.D.; Marita Thompson, M.D.; and Brett Giroir, M.D.

Mann's co-authors are Scott B. Kribbs, B.S. Fred J. Clubb, Jr., Ph.D.; Lloyd H. Michael, Ph.D; Vladimir Didenko, Ph.D.; Peter J. Hornsby, Ph.D.; Yukihiro Seta, M.D.; Hakan Oral, M.D.; and Francis G. Spinale, Ph.D.


Story Source:

The above story is based on materials provided by American Heart Association. Note: Materials may be edited for content and length.


Cite This Page:

American Heart Association. "Possible Trigger For Heart Failure Identified In Lab Animal Studies." ScienceDaily. ScienceDaily, 16 April 1998. <www.sciencedaily.com/releases/1998/04/980416081712.htm>.
American Heart Association. (1998, April 16). Possible Trigger For Heart Failure Identified In Lab Animal Studies. ScienceDaily. Retrieved December 17, 2014 from www.sciencedaily.com/releases/1998/04/980416081712.htm
American Heart Association. "Possible Trigger For Heart Failure Identified In Lab Animal Studies." ScienceDaily. www.sciencedaily.com/releases/1998/04/980416081712.htm (accessed December 17, 2014).

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