By David N. Leff
Gardeners along the Gulf Coast of the U.S. take pride in the massed purple flowers of their Showy Crotalaria shrubs (Crotalaria spectabilis). The plant's alkaloid toxin makes it poisonous to livestock and poultry.
Laboratory rats obliged to accept injections of monocrotaline - extracted from the seeds, leaves and stems of C. spectabilis - develop the signs and symptoms of a lethal human lung disorder, pulmonary hypertension (PH). This fairly uncommon disease results from obstruction of the arteries feeding the lungs. In its spontaneous form, PH affects 80 people per million and leads to progressive heart failure and - unless treated - death within two or three years.
PH strikes five times as many women as men, most of them in their 30s. Although the malady's root cause is unknown, this age and gender risk factor hints at a major self-inflicted etiology - appetite suppressants, notably fen-phen. Clinical psychologist Armond Aserinsky is president of Pulmonary Hypertension Central Inc. in Philadelphia, which he founded after his wife contracted PH from fen-phen. Its fenfluramine component was pulled from the market in North America and Europe three years ago.
Sudden, extreme and progressive fatigue, fainting spells and shortness of breath upon exertion are the warning signs of PH, but most patients, Aserinsky pointed out, don't seek medical diagnosis and therapy until the disease is far advanced. One unusual sign that worsens a patient's survival outlook is Raynaud's phenomenon - spasms of arteries in the fingers or toes.
"There are other causes of the disease that make it much more common than its status as a 'rare' disease," Aserinsky pointed out. "What's really rare is what has been called primary or spontaneously occurring pulmonary hypertension," he went on. "But PH as a secondary consequence of cardiac anomalies is not so uncommon, and the numbers have risen as more and more people with terrible heart problems are being rescued from death. There are small kids, for example, who if they were born 50 years ago with an atrial septal defect, or something like that, would simply die. These were the 'blue babies.'"
Pediatric Pulmonary Hypertension On Rise
"Now what the pediatric cardiovascular surgeons are doing," he continued, "is repairing those holes in the septum, but afterward it seems as if the strange circulation of the blood has triggered the mechanism that set off pulmonary hypertension. So now there are a lot of kids with PH, due to these cardiac anomalies. There are little children running around with fusion pumps on. So the disease is becoming more common than less common. Because of improvements in medical technology, operations that couldn't be performed a couple of generations ago are now commonplace."
About one in 10 cases of primary PH is congenital, with an autosomal dominant inheritance pattern. In these families, females outnumber males 2 to 1. And AIDS infection is another risk factor.
"But in terms of numbers of people affected," Aserinsky pointed out, "the most common cause of PH is schistosomiasis - a widespread Third World tropical infection. Its pathology often includes obliteration of lung arterioles, and resulting pulmonary hypertension. Schistosomiasis," he noted, "is one of the obstructive diseases of the lungs, where its actual bellows function is affected.
"Then there are the chronic, obstructive pulmonary diseases like emphysema, asthma, fibrosis, scleroderma and so forth," Aserinsky continued. "Those not uncommonly result in pulmonary hypertension You won't see PH as a stand-alone consequence of smoking. You may see it when one of the obstructive diseases has occurred."
The only definitive cure for PH is lung transplantation, which entails a lifetime of immunosuppression. Short of that drastic intervention, a PH patient must spend his or her life wearing a surgically implanted, 24-hour-a-day intravenous infusion pump, which delivers prostacyclin - a potent vasodilator and inhibitor of clot-forming platelets - directly to the heart. (See BioWorld Today, Nov. 10, 1999, p. 1.)
But rescue may be in the offing, thanks to those PH rat models and a team of Canadian pediatric cardiovascular scientists. Nature Medicine for June 2000 carries their paper, titled: "Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor." Its senior author, Marlene Rabinovitch, at the Hospital for Sick Children in Toronto, is a pioneer PH investigator.
Elastase is an enzyme that gets increasingly active as PH progresses. That enzymatic activity consists of unleashing a protein called tenascin-C, which promotes the growth of smooth-muscle cells. These cells line the blood vessels and keep them supple, but firm. When elastase makes them put on extra muscle, that narrows the pulmonary arteries and arterioles, constricting blood flow to the lungs. Ergo, PH.
Rabinovitch and her co-authors reasoned that stopping serine elastase in its tracks could cut PH off at the pass. So they treated rat models of the disease by injecting them with monocrotaline. This induced severe PH by 21 days. Then they dosed the sick animals with one of two synthetic oral elastase inhibitors. A one-week treatment left 92 percent of the rats alive, as compared with only 39 percent survival in control animals. After two weeks, arterial pressure and structure were back to normal, and survival was 86 percent vs. zero controls still alive.
Strategy Seen Applicable Beyond PH
"In human patients," the paper observed, "after correction of congenital heart disease, reversal of right ventricular hypertrophy lags behind a reduction in right ventricular pressure, and future long-term studies will be necessary to confirm that this also occurs in our model."
In a press statement, Rabinovitch made two added points: "This research may lead to new avenues in the treatment of many cardiovascular conditions, including the serious problems of pulmonary hypertension. While this study deals with obstructed pulmonary arteries, a similar mechanism may be applicable in reversing coronary disease as well.
"Initially," she went on, "we would like to try the use of an elastase inhibitor with patients who have pulmonary hypertension. The drug that we have tested on animals needs to be developed for clinical trials in people."