DALLAS, June 29 -- A drug that inactivates a protein in the body that worsens congestive heart failure could eventually lead to a new approach to treating this devastating disease. A preliminary clinical study involving the drug, called etanercept, is reported in today's issue of Circulation: Journal of the American Heart Association.
The drug, called etanercept, evaluated in 18 people with severe congestive heart failure (CHF), is designed to inactivate tumor necrosis factor (TNF), a protein produced by the body in response to cell and tissue damage.
TNF production is one of the three known biological avenues that lead to a worsening of heart failure. "Current CHF medications block the other two: adrenaline, which makes the heart pump faster, and angiotensin, which increases blood pressure, putting an additional strain on the heart. However this is the first clinical attempt to inactivate the third biological factor -- TNF," says Douglas Mann, M.D., the study's principal investigator and professor of medicine at Baylor College of Medicine and chief of cardiology at the Houston VA Medical Center.
New drug therapies to treat heart failure are needed because current medications, while alleviating symptoms and prolonging life, can slow, but don't always halt the progression of the disease, says Mann. He adds that heart failure is the only form of heart disease that is dramatically increasing in the population.
Mann says TNF may worsen heart failure because of its toxic effects on the heart and circulatory system. "TNF levels are seven to eight times higher in people with congestive heart failure than in those with normal hearts," he says. "Since in laboratory animals TNF alone can produce many of the symptoms of congestive heart failure, including dilation of the heart, a weakening of the heart's contraction force and a buildup of fluid in the lungs, it seems likely that it would play a major role in heart failure."
TNF is produced by the immune system and healthy individuals generally have low levels of TNF in their blood. In people with heart failure, TNF is produced by the heart itself.
Twelve of the patients in the study received varying amounts of etanercept, given in a one-time intravenous injection, and six received an inert compound called a placebo. The patients were all similar in age, severity of heart failure, and in the types and dosage levels of heart failure medications they were taking.
In those receiving the higher doses of etanercept, circulating blood levels of TNF decreased within a two-week period. Improvements were also seen in physical function, as assessed by a six-minute walk test and in ejection fraction -- the heart's ability to pump blood. Additionally, the patients perceived that their 'quality of life' improved (based on the patient's assessment of his/her feeling of well being). None of the patients in the study experienced any adverse side effects from the drug.
Congestive heart failure occurs when the heart fails to function as efficiently as it should and can't pump enough blood to meet the body's needs. It can be the result of a heart attack, high blood pressure, a congenital defect in the heart, or an infection or defect in a heart valve. Symptoms, which include shortness of breath, fluid retention and fatigue, can severely hamper an individual's quality of life. In advanced cases of heart failure, a heart transplant is often the only option.
In an accompanying editorial, Gary S. Francis, M.D., of the Cleveland Clinic says that while the results of the study are encouraging, additional studies are needed because of the small number of patients and the short duration of the clinical trial. "The results indicate no significant side effects, a decrease in biologically active levels of TNF, and an increase in quality of life scores, six-minute walk distance and ejection fraction. The study offers further proof of principle and suggests a green light to proceed with a large-scale clinical trial to further test (this) hypothesis."
Clinical studies of etanercept involving more people with heart failure are already underway in North America and Europe, according to Mann. "Heart failure patients should take as a positive sign the fact that we expect to have the results of these trials by the end of next year. It's hoped this will eventually lead to improved medications to treat congestive heart failure, which currently affects over 4.5 Americans."
Co-authors were Anita Deswal; Biykem Bozkurt; Yukihiro Seta; Semahat Parilti-Eiswirth; F. Ann Hayes; and Consuelo Blosch