Philadelphia, Pa. — The diet drug combination fenfluramine-phentermine, better known as fen-phen, was removed from the marketplace in 1997 because it was associated with acquired heart valve abnormalities.
Now a research team led by a Children’s Hospital of Philadelphia physician has uncovered some of the cellular events, apparently triggered by the neurotransmitter serotonin, that may help explain the disease mechanisms that are involved.
Fen-phen use was associated with an abnormal thickening of heart valve leaflets in a number of patients. This drug combination strengthens serotonin effects, and therefore the association of fen-phen usage with heart valve disorders suggested to the researchers that serotonin itself may play a role in progressive heart valve disease. Serotonin is a naturally occurring chemical that plays important roles in the nervous system.
"A better understanding of the effects of serotonin on heart valve cells may have broader implications beyond the adverse effects of fen-phen," said Robert J. Levy, M.D., director of the Pediatric Cardiology Research Laboratory at The Children’s Hospital of Philadelphia and senior author of the study.
The researchers explored a chain of chemical reactions, beginning with serotonin and ending with cellular events hypothesized to be associated with valve disease. Cells on heart valves have been shown to have receptors for serotonin. Serotonin takes part in biochemical interactions that lead to increased production of a key signaling molecule called TBF-beta-1. This molecule, in turn, stimulates cells in the aortic valve to produce abnormal structural features comparable to those associated with fen-phen heart valve disease, according to Dr. Levy.
The cell culture study was presented today by Bo Jian, M.D., a cardiology research fellow at Children’s Hospital, during the national scientific sessions of the American Heart Association in New Orleans.
Another aspect of valve disease research is the fact that a naturally occurring amino acid, tryptophan, is a precursor to serotonin. While tryptophan plays an essential roles in health and nutrition, excess amounts of it could possibly contribute to valve disease.
"Since serotonin may also affect the progression of valve disease, the effects of tryptophan in one’s diet may turn out to be important," said Dr. Levy. One next step, he added, is to design clinical studies to further explore possible links between serotonin levels, tryptophan levels and valve disease.
Co-authors with Drs. Levy and Jian are Bruce Liang, M.D., of the University of Pennsylvania Medical Center and colleagues from that institution and from Children’s Hospital.
Founded in 1855 as the nation’s first pediatric hospital, The Children’s Hospital of Philadelphia is recognized today as one of the leading treatment and research facilities in the world.
Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered discoveries that have benefited children worldwide.
Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique outreach and public service programs have brought the 381-bed hospital recognition as a leading advocate for children from before birth through age 19.