Inhibiting Tumor Necrosis Factor: Novel Treatment For Heart Failure

November 11, 1997

ORLANDO, Nov. 11 -- Researchers may have found another cause and a possible new approach to treatment for individuals with severely failing hearts, according to a study presented today at the American Heart Association's 70th Scientific Sessions.

In a Phase I study of 18 individuals with congestive heart failure (CHF), high levels of a proinflammatory cytokine, tumor necrosis factor (TNF) that can damage the heart were found. However, when TNF was inhibited through treatment, the patients' signs and symptoms of cardiac failure improved. When TNF is present in increased amounts in the heart, it may make heart failure worse by causing the heart to pump less forcefully.

"This is not a cure by any means, but this study begins to address a novel mechanism for why the disease progresses that has not been in previous studies and we may have identified a novel target in heart failure," says Douglas Mann, M.D., professor of medicine at Baylor College of Medicine, who presented the study today.

Those treated were able to walk farther, they felt better, and there also was a modest improvement in the ability of the heart to pump blood.

CHF, the one form of heart disease that is increasing in incidence, occurs when the heart is damaged from high blood pressure, a heart attack or defect such as a defective heart valve. The failing heart keeps working, but is inefficient, resulting in fluid retention and shortness of breath. The condition often progresses and becomes irreversible, with heart transplant surgery, in some cases, being the only option for keeping the person alive.

Treatment using an investigational recombinant TNF receptor which inactivates TNF biological activity resulted in a significant increase in the patient's six-minute walk time, a test given to determine a person's ability to exercise without becoming short of breath. Symptoms such as shortness of breath at rest and fatigue also improved. Both of these effects were greatest during the second week of this two-week study following a single intravenous infusion.

Other findings were improvements in the left ventricular ejection fraction -- an indication of the heart's ability to pump blood -- and a decrease in the levels of biologically active TNF.

While healthy individuals may have low levels of TNF circulating in their blood, immune cells, not the heart, usually produce it. In CHF the heart begins to produce this proinflammatory cytokine.

"Levels of TNF are about seven to eight times higher in people with advanced heart failure," says Mann, also chief of cardiology at the Veterans Administration Medical Center, Houston. Mann's research group previously reported that individuals with advanced heart failure express the gene and make the protein, TNF, whereas the normal heart doesn't express the gene and thus does not make this protein.

The researchers used a specific investigational protein, called a recombinant human tumor necrosis factor receptor that binds to TNF and prevents it from interacting with cell surface TNF receptors which are on the cells in the heart and circulatory system.

The study included 18 individuals, average age 58 years, with late stage CHF and increased levels of TNF. Twelve patients, with elevated levels of TNF were given a single intravenous dose of TNF receptor, while six were given placebo. On the first day of the study, individuals receiving TNF receptor had an 85 percent drop in the amount of biologically active TNF. The decreased level lasted in some patients for up to two weeks.

"The single infusion was well tolerated and suppressed circulating levels of biologically active TNF for at least two weeks in some individuals," says Mann. "In 1998, we hope to conduct a Phase II trial with a longer duration of dosing in heart failure patients across the United States.

"The take home message is that this Phase I study supports the point of view that TNF plays a role in the development of heart failure. In addition, this study provides preliminary evidence that inhibiting TNF may improve congestive heart failure," adds Mann.

TNF receptor is also undergoing clinical testing in other conditions such as advanced rheumatoid arthritis and HIV. Results of a Phase III rheumatoid arthritis study were reported at the recent American College of Rheumatology meeting in Washington, D.C.

The study was reported and supervised by Douglas Mann, M.D., Baylor College of Medicine, Houston; researchers included Anita Deswal, M.D. and Yukihiro Seta, M.D. (research fellows), Baylor, Houston; and Consuelo M. Blosch, M.D., Immunex Corporation, Seattle.

American Heart Association

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