P&S Journal: Winter 1998, Vol.18, No.1
Clinical Advances

Help for Primary Pulmonary Hypertension Primary pulmonary hypertension is a rare, progressive disease in which the blood pressure in the pulmonary artery soars, severely affecting the normal functioning of the heart and lungs. Although only about 500 new cases of PPH are diagnosed in the United States each year, the disease made headlines last year when medical reports connected the diet drugs Redux and fenfluramine to some cases of PPH, subsequently leading to recall of the drugs in September 1997. At P&S, research on PPH has continued at a steady pace for 12 years at the Children's Pulmonary Hypertension Center, under the direction of Dr. Robyn J. Barst, associate professor of pediatrics and of medicine. The center was the first of its kind in the country and has been actively involved in pioneering new treatments that have helped improve survival rates for this deadly disease.
Scientists are not sure what causes PPH. The currently accepted theory holds that people who are predisposed to it develop PPH when exposed to certain triggers, including HIV, fen-phen, and Redux. Researchers believe these triggers somehow indirectly injure the endothelial cells lining the small blood vessels of the lungs so that they no longer interact normally with the smooth muscle cells in the walls of the blood vessels. This change sets off a damaging sequence of events:
First, the abnormal interaction between the endothelial cells and the smooth muscle cells causes the smooth muscle to contract, narrowing the blood vessels and increasing blood pressure. In response to the increased blood pressure, new muscle cells begin to grow in the blood vessel. These cells eventually form scar tissue, which further narrows and also thickens the blood vessel, increasing blood pressure even more. As blood pressure increases, the heart must work harder to pump blood through the lungs. This causes the heart--especially the right ventricle--to grow bigger. Eventually, the right ventricle weakens and fails, resulting in death. Although no cure exists for PPH, a number of treatments can extend and improve the lives of people with this disease. Calcium channel blockers given orally have been shown to slow the progression of the disease and, in rare instances, cause a regression of PPH. And last year, the FDA approved the drug prostacyclin for use in PPH. Prostacyclin is the only FDA-approved drug shown to be efficacious in the disease. It appears to work via three mechanisms: by relaxing the small muscles in the small arteries in the lungs, by preventing the formation of clots, and by reversing scarring in the lungs. In a study published last year in the New England Journal of Medicine, a multi-center trial led by Dr. Barst found that prostacyclin therapy improved exercise capacity, quality of life, clinical and hemodynamic measures, and survival time. One drawback to prostacyclin, however, is that it must be administered continuously through an intravenous catheter using a portable pump, which places the patient at risk for infection. Dr. Barst and colleagues are evaluating a prostacyclin analog delivered via a subcutaneous pump.
The risk of infection, as well as the cost of the drug, also mean that prostacyclin must undergo secondary trials for any off-label use. P&S researchers are part of a 12-week multicenter trial studying the effectiveness of prostacyclin on pulmonary hypertension in patients with the scleroderma spectrum of diseases. Many patients with collagen/vascular disease also have pulmonary hypertension. Other studies are investigating additional abnormal mediators in the lungs. Patients with too little prostacyclin often have too much thromboxane, the opposing mediator. P&S researchers will soon begin a study of a drug that blocks thromboxane's formation and its actions. Ultimately, we may have to use several drugs to treat pulmonary hypertension," says Dr. Barst. "But while we're getting better at treating the disease, we still don't know the cause." To help remedy that situation, Dr. Barst is collaborating with Dr. Jane H. Morse, professor emeritus of clinical medicine, to identify the gene locus for a subset of patients with PPH--those with an inherited form known as familial PPH.	Resources The Center for Women's Health Columbia-Presbyterian/Eastside (212) 326-8540 or 1-800-91-WOMEN Center for Menopause, Hormonal Disorders, and Women's Health Columbia-Presbyterian/Eastside (212) 326-8548 Children's Pulmonary Hypertension Center Dr. Robyn J. Barst, Director (212) 305-8509