THE NEW ASSAULT ON HEART ATTACKS The across-the-board approach to prevention through diet and exercise is giving way to medical advances that will pinpoint those truly at risk and treat them more effectively. That's good news for everyone, including genetic engineering companies.
By Gene Bylinsky RESEARCH ASSOCIATE Alicia Hills Moore

(FORTUNE Magazine) – BY NOW MANY health-conscious Americans can readily reel off the four main risk factors commonly associated with heart disease: a high cholesterol level, a diet heavy in saturated fats, high blood pressure, and cigarette smoking. Possibly because more and more people are trying to cut down those risks, the U.S. death rate from heart disease fell 39% from 1964 through 1984. Now even better news is breaking. Medical researchers are perfecting tests that will single out people with an unusually high risk of heart disease, helping that group take precautionary measures and allowing everyone else to relax a little about low-cholesterol, low-fat, low-salt diets. In the next two to five years, new tests and therapies will also make the diagnosis and treatment of people who develop heart disease cheaper and more effective. Among the expected advances that will help tame America's No. 1 killer: A test that can spot fatty deposits in the arteries, the primary cause of heart attacks, much earlier than they can be detected now. Specially selected proteins that help doctors identify destroyed heart tissue and treat the problem more precisely. A new kind of computerized tomography (CT) scanner that can take pictures of a beating heart, helping doctors learn more quickly what has gone wrong. Genetically engineered natural enzymes that dissolve blood clots, which are major contributors to heart attacks, faster, more safely, and more reliably than existing drugs. Other relatively new approaches are already in use. Studies demonstrating the connection between stress and heart disease are encouraging employers to hire consultants who help workers manage stress on and off the job. In the new assault on heart disease, experts in stress management and a gaggle of genetic engineering companies are looking for fast growth and big markets. Cardiovascular diseases -- mainly heart attacks and strokes -- remain almost epidemic, despite the steep decline in the rate at which they are killing people. The American Heart Association estimates that 63 million people in the U.S. have some form of cardiovascular disease. About two million Americans will have heart attacks or strokes this year, more than one-third fatal. In the workplace, cardiovascular diseases account for more deaths and disabilities than any other cause. Total costs will be about $79 billion this year. The latest sorties against heart disease are taking place on terrain that remains ill-mapped. No one knows exactly why the percentage of people who die from cardiovascular causes has dropped so sharply in the past two decades. The death rate from all causes, except lung cancer and other pulmonary diseases such as emphysema, has been declining steeply, so obviously more is involved than risk factors that affect the heart. Thomas Thom, a statistician at the National Heart, Lung, and Blood Institute in Bethesda, Maryland, suspects that a general improvement in health care plays a large part: the decline in death rates from nearly all diseases began after Medicare and Medicaid were introduced in the early 1960s. Moreover, heart disease mortality is declining with puzzling uniformity across different age, race, and sex groups; in other words, people who may have been paying less attention than others to risk reduction nonetheless have similar death rates. As a result, more and more specialists are beginning to question whether blanket prescriptions about diet for the population at large are really the best way to cut the risks of heart disease and strokes still further. Cardiovascular illnesses have complex causes and their origins remain largely unknown. Beyond the much publicized risk factors lurk less obvious, less explored, but probably equally important hazards. For instance, some people are more likely than others to form blood clots that can lead to heart attacks. Many scientists are therefore urging a major shift in emphasis toward more individualized treatment of people found to be at high risk. Genetic factors, among others, are increasingly implicated in heart disease. In January, scientists who had studied 13,852 people in a dozen U.S. cities reported that about 9% of the subjects appeared to be protected against heart disease by an above-average ability to clear cholesterol from the blood. An additional 13% had difficulty metabolizing cholesterol, making them more susceptible to heart attacks and strokes than the general population. In the workplace, many scientists think, other big risk factors are at play, some created by corporate clumsiness in dealing with people, others by workers' problems handling stress. Scientists increasingly cite lack of social interaction as a risk: single men and women, for instance, have higher death rates from heart disease than their married counterparts. As the mortality figures suggest, the chances of surviving a heart attack or stroke and continuing to lead a productive life are much better today than even five years ago. Early diagnosis and emergency treatment have improved to the point that fewer people who have heart attacks die either en route to the hospital or in the first few hours after they get there. That trend should continue as some remarkable advances come into wide use, among them the genetically engineered natural enzyme TPA (tissue plasminogen activator) for dissolving blood clots. TPA works faster than synthetic drugs, with far fewer side effects. Its principal developer, Genentech Inc. of South San Francisco, expects the market for the enzyme to reach $500 million a year by 1990. Partly in anticipation, investors have valued Genentech's stock at $1.3 billion; the company is also an important player in the promising new field of anticancer drugs based on the body's own defenses (FORTUNE, November 25). Right behind Genentech in blood clot treatment is Collaborative Research Inc. of Lexington, Massachusetts, which is working with Sandoz, a Swiss pharmaceutical giant, on the enzyme KPA (kidney plasminogen activator). So far, however, KPA's development lags about two years behind TPA, and it hasn't bolstered the company's stock. Ideally, a person susceptible to heart disease and strokes should be spotted in early childhood. But aside from such obvious indicators of potential trouble as high blood pressure and cholesterol levels, which can be inherited, no test can yet spot people prone to heart attacks. One is under development, however, at California Biotechnology Inc., in the Silicon Valley town of Mountain View. The test pinpoints people with a congenital propensity to form fatty deposits, called atherosclerotic plaques, in their arteries. Atherosclerosis, or thickening and hardening of the artery walls, is responsible for most heart attacks and many strokes. The plaques apparently begin to form when crystals of cholesterol, a fatlike substance, become embedded in artery walls. Cal Bio's test will single out for special attention those who are most likely to form atherosclerotic plaques. ''You can't take the whole world and make them live perfectly,'' says John D. Baxter, an endocrinologist and a founder and director of Cal Bio. ''The more we can zero in on what a person needs to do, the better opportunity we have to modify his life.'' His test is a DNA probe that analyzes a blood sample for specific defects in the heredity- determining DNA molecules. So far the probe has found a defect in 37.5% of the heart attack victims tested. Anyone with a defect, in effect some scrambled letters in the genetic code in part of a gene, is nearly four times as likely as other people to have a heart attack. The new test, expected in about two years, would make it possible to zero in on people who should follow stringent low-cholesterol diets. Recent studies at Rockefeller University in New York City seem to confirm that only some people accumulate dietary cholesterol. In the Rockefeller trial, only 15 of 75 men who ate three eggs a day for six weeks showed even a small rise in blood cholesterol. Researchers have also discovered that there is good cholesterol and bad cholesterol. So-called high-density lipoproteins (HDLs) containing cholesterol help rid the body of any excess, while low-density lipoproteins (LDLs) ferry cholesterol through the body. The higher the ratio of HDLs to total cholesterol the better: if the ratio is below 1 to 4.5, it may be important to reduce dietary cholesterol. In a study at the University of Oregon at Corvallis, 21 men ate three eggs daily for a month. Eight showed an increase in HDLs, protecting them better against heart disease. In the other 13, LDL levels rose -- more evidence that people handle cholesterol differently. CLAUDE LENFANT, director of the National Heart, Lung, and Blood Institute, confesses, ''In all honesty, I can't look you in the eye and say you're going to have an increased cholesterol level because you eat eggs.'' He thinks two to four eggs a week is reasonable. (The egg industry, determined to cleanse its product's cholesterol-stained reputation, has been making similar claims for several years.) At the other end of the spectrum, another test Cal Bio is developing identifies people who seem to be genetically immune to heart disease despite slightly elevated cholesterol levels. Presumably they could forgo the standard risk-reduction measures entirely. The combination of elevated cholesterol with little or no risk of a heart attack underscores the unreliability of cholesterol level as the sole predictor of heart disease, according to Phillipe Frossard, a molecular biologist who is leading the work on the Cal Bio tests. Cal Bio is also developing tests to identify people prone to high blood pressure. Another test will single out people whose blood pressure rises as a result of eating salt. It turns out that perhaps only 15% to 20% of people with high blood pressure are sensitive to salt and should limit their intake. The rest need not worry about salt consumption. The arrival of all these Cal Bio tests on the market could well propel the relatively little-known company, which has been living off research and development revenues and investment income, into the big leagues of genetic engineering. Security analysts foresee U.S. sales of about $300 million a year & for the DNA probe of susceptibility to atherosclerosis. A recombinant DNA version of a hormone produced by the heart that reduces blood pressure could fetch another $150 million a year. That could grow significantly as Cal Bio develops the hormone in pill form and as a nasal spray. One of the most impressive of the emerging diagnostic and treatment tools allows doctors a better look at and even into the heart without cutting open the chest cavity or inserting catheters or other devices. A new type of computerized tomography machine called a Cine-CT Scanner, pioneered at the University of California medical school in San Francisco, recently made its commercial debut. The machine, manufactured by Imatron Inc. of South San Francisco, can show images of a beating heart with blood flowing through it, giving doctors information more quickly about its condition -- such as how normally the heart is beating and whether its blood supply is adequate. Work is also under way on another important diagnostic test that spots early plaque formation in the arteries. Robert and Ann Lees of M.I.T. and Boston's New England Deaconess Hospital take molecules of low-density lipoproteins from a patient, tag them with radioisotopes, and return them to the patient's blood. A gamma-ray camera then can show if the cholesterol-bearing particles collect at plaque sites. After a heart attack, the destroyed part of the heart muscle could be labeled with specially selected radioisotope-tagged proteins called monoclonal antibodies to determine the exact extent of damage and help choose the best therapy. Such a test is being developed by Centocor Corp., a Malvern, Pennsylvania, biopharmaceutical company. With Massachusetts General Hospital, Centocor is also working on a test that would use monoclonal antibodies to detect blood clots. Besides the breakthrough laboratory work on pinpointing those most likely to have a stroke or a heart attack, and treating them more effectively when they do, researchers are exploring behavior modification as a preventive measure. If little more than one-third of heart attack victims have a genetic propensity to atherosclerosis, other factors are clearly at work. Some scientists feel, for instance, that simply living and working in industrialized America, or any other industrialized country except Japan, may be hazardous to your heart. Cardiovascular diseases generally have a close correlation to population crowding and industrialization. In this view, Japan, with one-sixth the U.S. heart disease death rate for middle-aged men, has solved conflicts through cultural conditioning that suppresses individual aggressiveness. Even after all the familiar risk factors are taken into account, studies show that a middle-aged man living and working in Paris, Hawaii, Yugoslavia, or Puerto Rico runs a quarter to half the risk of a heart attack that the average middle-aged American runs. The reasons are unclear. Short of moving to Paris, a manager or worker can try to change his response to challenges on the job. Researchers are pretty sure by now that hard or stressful work by itself does not raise the risk of heart attacks and strokes. What matters is how individual workers respond to pressure and how much control they have over stressful conditions. Cardiologists Meyer ''Mike'' Friedman of Mount Zion Hospital in San Francisco and Ray H. Rosenman, now at SRI International, a Menlo Park, California, consulting company, devised the famous Type A and Type B personality classifications. They described the classic Type A individual as prone to anger and hostility, compulsively competitive, and impatient. Type B, on the other hand, is easygoing, unhurried, content. Studies have confirmed that Type As are twice to three times as prone to heart attacks as Type Bs. To teach Type A managers how to reduce that risk, Friedman began giving courses last year at corporations such as Pacific Gas & Electric and Mervyn's stores. A typical Friedmanism: ''Sweetness is not a weakness.'' Some typical advice: Stop wasting time on little things, because the trivial errors of others don't always require your correction; in a traffic jam, listen to a cassette of classical music. Friedman, a self-reconstructed Type A, has been stopped twice by police in recent years for driving too slowly. While corporate executives have praised the programs, some scientists, including Friedman's former collaborator, are skeptical. ''I don't believe that you can change personality types,'' says Rosenman. Moreover, a Type A personality may not be wholly hazardous to your health. In a recent follow-up survey of 3,154 California men who were 39 to 59 years old and healthy at the start of the study, Rosenman and his collaborators found that Type As survived a heart attack better than Type Bs, apparently because Type As refused to accept the fact that they were ill. Says Rosenman: ''Maybe Type A is the person who gets things done. Maybe there would be no corporations without these individuals.'' He is now developing behavior-modifying drugs to keep Type As from having heart attacks. Another way to reduce the risk of heart disease in the workplace could be called the change-the-corporate-ways approach. If an employee is hemmed in and has little autonomy, argues S. Leonard Syme, a noted epidemiologist at the University of California's Berkeley campus, Type A or Type B behavior becomes less important. For example, in a North Carolina study last year, telephone operators required to answer information calls within 60 seconds or face pay cuts developed angina, the chest pains typical of heart disease. Blood pressure shoots up and stays there in bus drivers forced to perform on an unrealistic schedule. For the past two years, Syme has been riding buses in San Francisco, interviewing 1,500 city bus drivers. Dr. June Fisher, director of the San Francisco Occupational Health Clinic, has done physical exams of the drivers as part of the study. The drivers turn out to have twice the normal incidence of elevated blood pressure, apparently because they vainly try to maintain schedules by skipping lunch and rest periods, and because they work in a generally stressful setting. For instance, the drivers get rest breaks at the end of a line, in isolated spots. The solitude might seem relaxing, but the drivers prefer to unwind with their co-workers, in part to exchange gripes. The usual approach to the bus drivers' problems would be to give them blood pressure-lowering drugs and teach them how to cope better with job stress. But Syme argues, ''It would be simpler and more efficient to adjust the conditions of work. Put rest stops in the middle of the city. Have workers develop the schedule together. Let them have some input into conditions of work.'' Bus companies around the world, Syme says, are plagued with absenteeism, high turnover, early retirements, and high blood pressure among their drivers. By changing work conditions, Syme suggests, the companies would save more money than they would lose by shifting schedules. BUS DRIVERS are not exactly at the top of the managerial ladder, and that is part of their problem, according to Syme and other epidemiologists. At one time researchers believed that men at the top were the most vulnerable to cardiovascular disease, because they had the greatest responsibility. That view was scotched a few years ago when M. G. Marmot, a former student of Syme's, and Marmot's British colleague, Geoffrey Rose, compared the heart ! disease rates and job rankings of 17,530 male civil servants in London, age 40 to 64. Marmot and Rose found an amazing link: the higher the rank, the lower the chance of a heart attack or a stroke. In fact, employment status was a stronger predictor of the risk of dying of heart disease than any of the familiar risk factors. Nearly four times as many men in the lowest employment grades died from cardiovascular disease as those in the top administrative rank. Other recent studies in Sweden and the U.S. confirm that people who face heavy job demands with little say about how the tasks are done have a high incidence of heart disease. So the healthiest place to be is not the corporate gym but the executive suite. ''The chief executive of a large corporation is protected against stress,'' says Friedman. ''He has a chauffeur. He can live away from the crowds.'' That executive often has access to a corporate gym too, but whether exercise helps prevent heart attacks has not been proved conclusively. Most scientists feel that moderate exercise is beneficial, but many frown on excessive jogging because it may put the heart under too much stress. While confusion remains about why some people have heart attacks and others do not, ''I think we're at the beginning of an era of unprecedented advances in the knowledge of heart disease,'' says Baxter of Cal Bio. ''Across the board, sophisticated technology offers us an awesome potential to get at the fundamental mechanisms of the disease.'' Most of the progress so far has been confined to diagnosis and treatment. Pinpointing the still-mysterious causes of cardiovascular disease would finally enable doctors to go beyond detecting and alleviating symptoms to conquering the disease itself.

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