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Biomedicine

Penetrating the Riddle of Heart Attack

Many people who are vulnerable to heart attack don’t know it. Researchers are now pinning down new risk factors–and some suggest preventive measures.

The death toll from heart ailments remains the nation’s largest disease problem. The human suffering has been compared in scope to several fully loaded jumbo jets crashing each day. And the economic cost for medical care and lost productivity will total about $167 billion this year, according to the American Heart Association. Moreover, contrary to popular opinion, heart disease is not an easy way to go. Just ask anyone who has suffered the searing pain of angina, survived a heart attack, or undergone heart surgery. Nor is heart disease the exclusive province of older people. Children have never been exempt. An estimated 32,000 babies are born each year with congenital heart defects, and early signs of heart disease can be found in teenagers and young adults who consume high-fat, high-cholesterol diets. People in these age groups are putting themselves at risk by gaining more weight, exercising less, and smoking more, too. And heart disease among people in their forties and fifties may soon become a great deal more common. Indeed, as baby boomers enter middle age after living a life of affluence, we may face a twenty-first century epidemic.

Heart pain and suspected heart attack lead Americans to call the 911 emergency system or visit a doctor or a hospital about 6 million times a year. About 10 percent of the time the problem is a bonafide heart attack; the other 90 percent of the time it’s gallbladder pain, indigestion, a panic attack, or something else entirely. But about 2 to 3 percent of those sent home with a diagnosis of no heart attack incur an attack in the next day or so, according to Thomas J. Ryan, chief cardiologist at Boston University. “Patients don’t appear at the ER with acute myocardial infarction [heart attack] tattooed on their foreheads,” he notes. “Sometimes you just can’t diagnose this disease.”

An even bigger mystery is exactly who is at risk. The truth is that the medical profession often does not know. In fact, of the 50 percent or so of heart-attack deaths classified as “sudden,” meaning that death comes within an hour, about one-fifth to one-third occur in people with no previously identified risk factors. Yet we are learning more and more about heart disease. Researchers are closing in on a range of suspect risk factors. And the answers they find could suggest innovative prevention strategies as well.

Microbes and Genes

One somewhat surprising potential risk factor is the presence of bacteria and viruses in the blood. While these microbes may not directly cause heart disease, the infection they do cause appears to affect the endothelium, a thin, protective layer of cells that lines blood vessels. The result may be atherosclerosis, in which deposits of smooth muscle cells, calcium, and cholesterol build up, reducing blood flow through the coronary arteries that provide blood to the heart. Such deposits, called plaques, also provide sites where clots may form, further blocking blood flow and setting the stage for heart attack.

Researchers at Cornell University have done pioneering work implicating an avian herpesvirus as the cause of an atherosclerosis-like disease in chickens. Biochemist David P. Hajjar of Cornell Medical School has expanded that work to humans. He has demonstrated that the common herpes simplex virus can stimulate the production of “blood factor X,” a binding protein that helps anchor other proteins to the blood vessel wall, where they form atherosclerotic plaques. The lab team has also shown that herpesvirus prompts the production of thrombin, a blood-clotting enzyme, which makes impaired blood flow even more likely.

The U.S.-based study Atherosclerosis Risk in Communities, begun in 1987 and conducted on 16,000 men and women ranging in age from 45 to 64, is providing still more evidence that viruses may help bring on atherosclerosis in people. The project manager, epidemiologist A. Richey Sharrett of the National Heart, Lung, and Blood Institute in Bethesda, Md., says the subjects’ blood samples, which have been checked for antibodies that the body manufactures in response to specific viruses, have also been tested for clot-promoting factors, as well as for lipoproteins, the fatty proteins that envelop cholesterol and carry it through the bloodstream. One type is high-density lipoproteins (HDLs), which appear to protect against atherosclerosis; another major kind, low-density lipoproteins (LDLs), tend to promote the development of cholesterol-laden plaques within arteries.

Interestingly, blood samples with antibodies for type one and type two herpesviruses have turned up the kinds of clot-promoting factors and lipoproteins suggestive of heart-attack risk. And researchers have found that the same is true of blood samples with antibodies to cytomegalovirus, another virus of the herpes family. They have also noted a strain of bacteria called chlamydia pneumoniae in people with atherosclerotic plaques. University of Utah scientists reported in June 1996 that they had discovered this strain of bacteria in diseased tissue taken from 66 of 90 patients who underwent surgery to clear a blocked coronary artery. Evidence of the bacteria appeared in only 1 of 24 patients who did not have coronary disease.

Another promising area of study is genetics: researchers, including many cardiologists, are intrigued by the possibility of a family of heart-attack genes. Some especially troublesome members of this family are the recently discovered genes for “long QT syndrome,” a disease affecting children and young adults. It strikes insidiously, much like crib death. The warning signs are spells of fainting during exercise, unconsciousness during sleep, or episodes of sudden fright or other unexplained emotional distress. The peculiar name of the syndrome derives from the way electrocardiograms, which track electrical activity in the heart, are recorded: readings for each heartbeat are divided into a waveform with key reference points called P-Q-R-S-T. With long QT, the interval between Q and T is 500 to 600 milliseconds at a heart rate of 60 beats per minute, in contrast to the normal interval of 400 to 440 milliseconds. Long QT engenders irregular heartbeat and an insufficient supply of blood to the brain. This can cause a brain seizure, leading to death.

Other genes can increase the likelihood of a heart attack by causing structural problems in major blood vessels and in the muscle walls of the heart. For instance, cardiomyopathies, inherited disorders that make the muscle walls either too thick or too thin, result in enlarged hearts with dramatically reduced pumping efficiency. Still other gene defects interfere with the way the body handles salt, thereby bringing on high blood pressure, a notorious heart-attack risk factor: it wears down blood vessels and thus promotes atherosclerosis. An estimated 15 to 20 percent of the U.S. population has a genetically determined sensitivity to salt that is expressed as high blood pressure when they consume too much of it.

Even more leads are pouring in from genetic studies on the enzymes and lipoproteins that determine how effectively the body deals with cholesterol. Geneticists Joseph Goldstein and Michael Brown at the University of Texas Southwestern Medical Center have isolated the “LDL receptor”-the cellular mechanism that keeps harmful LDL cholesterol from accumulating in the body’s tissues and bloodstream. Those who lack the gene that allows them to manufacture such receptors develop a life-threatening condition called familial hypercholesteremia (FH), which can result in astronomical levels of cholesterol and early death from heart attack.

And physician Ronald Krauss and his associates at the University of California, Berkeley, have discovered a particle called “small, dense LDL” that they believe is the form of LDL most likely to cause atherosclerosis, because of its ability to penetrate the blood vessel wall. This particle seems to be influenced by a single dominant gene, Krauss says, and he estimates that up to one-third of people over age 40 have that gene and run triple the heart-attack risk of those without it. Moreover, levels of small, dense LDL are closely related to blood levels of triglycerides, another lipoprotein that has itself been proposed as a major risk factor for coronary artery disease.

Research in other areas is also advancing scientists’ understanding of the genes behind atherosclerosis. Physician Daniel Steinberg of the University of Southern California in San Diego believes that LDL molecules do their damage when they are oxidized-and that this happens when they are captured by oxygen-like molecules called free radicals. The connection with genetics comes from physician Alan M. Fogelman at UCLA’s Atherosclerosis Research Unit, who has shown that when mildly oxidized LDL is injected into mice, troublesome genes similar to those found in humans begin to create harmful proteins; those proteins in turn cause the endothelium to become inflamed. These results suggest that “the inheritance of one or more major genes can determine susceptibility or resistance to the development of the inflammatory component of atherosclerosis,” he notes.

The Role of Psychology

The sophisticated machinery that keeps the heart functioning is strongly influenced by the brain and central nervous system-particularly the sympathetic nervous system, which controls stress responses, and the autonomic nervous system, which makes sure vital organs keep working to maintain life. Thus, an important question driving risk-factor research is how we can use nervous system activity and the psychological forces that so strongly affect it as bases for determining who is most prone to heart attack.

Since researchers have long recognized that a family history of heart attack, heart pain, or other heart problems-particularly in blood relatives before age 60-is important in assessing a patient’s risk, it seems reasonable to suggest that specific conditions passed down through the generations deserve a careful look. One issue that is just starting to receive the kind of attention it warrants is the neurological wiring particular individuals may have inherited. Experimental evidence has shown some men and women who may be subject to heart attack apparently have nervous systems set on high. Stress expert and cardiologist Robert Eliot of Phoenix and his colleagues have done pioneering studies measuring heart and blood pressure responses to stressful situations. They have been able to identify some of their subjects as “hot reactors.”
Cardiologist Rodman D. Starke, senior staff physician at the American Heart Association, agrees that such individuals may be prone to heart attack, and adds that the people who respond badly to stress are those who “find it wherever [they] go-at home, in the car at red lights, in a line at the supermarket.”

Research by a team from Ohio State University led by psychology professor Tilmer Engebretson suggests that anger, in particular, is a dangerous emotion. Engebretson and his colleagues, who tracked anger characteristics and cholesterol levels in 116 middle-aged male airplane pilots, found large differences between those categorized as “flexible” and those who seemed overwhelmed by their anger and acted in extreme ways. Men judged to have the most trouble with anger registered total cholesterol levels about 40 points higher than normal, and levels of artery-clogging LDLs about 30 points higher than normal.

A good case can be made that depression poses another serious threat to the heart. About 70 percent of people who have had a heart attack suffer depression-often severe depression-in the year afterward, and patients with severe depression that goes untreated have about twice as many heart attacks during that first year, according to Robert Carney, a psychiatrist at Washington University in St. Louis. “There are now six published studies that show depression increases risk of mortality for patients with coronary disease by several fold,” Carney says. How do these deaths occur? Nobody knows for sure, but depressed patients do show elevated levels of sympathetic nervous system activity.

Findings from psychologist John C. Barefoot of Duke University confirm that depression can be hard on the heart. In early 1996, Barefoot’s group, reporting on a 27-year study of 513 men and women, noted that individuals who scored high on measures of despair, concentration difficulties, weak motivation, and poor self-esteem in 1964 and 1974 had a 70 percent higher risk of heart attack, as well as a 60 percent higher risk of death, compared with those who had low scores. And S. Leonard Syme, an epidemiologist at the University of California at Berkeley, suspects that social isolation might be a heart-attack risk factor as well. He notes that the theme of “interrupted social ties” seems to play through much of the research on heart disease, including his own studies charting the impact of broken family ties on Japanese men and women who have migrated to Hawaii and then to the San Francisco Bay Area. His subjects experienced a rise in heart attacks and heart attack deaths when they moved into Westernized societies, and he speculates that while some of the increase may be attributable to changes in their diets, psychological factors, including loss of contact with loved ones, may be implicated as well.

Finally, job stress could be a crucial factor in determining heart-attack risk. Workplace studies show that employees who feel the most stress are not top executives, as some people might expect, but rather middle managers intent on climbing the corporate ladder. And at the DuPont Corp. in Wilmington, Del., where primary prevention programs and healthier lifestyles are thought to be largely responsible for a decrease in heart attack deaths, corporate medical researchers have discovered that the drop in mortality was about 38 percent in salaried employees with job security but only 18 percent in hourly employees who were more subject to layoffs. Yet another job-stress risk factor for coronary disease might be characterized as situations of “high demand and low control.” Studies of telephone operators working at computer terminals and given only so many seconds to look up a phone number show that a significant number reported chest pain during the experience.

Research on the central nervous system has also provided clues about what specific circumstances precipitate heart attack in those who have already been identified as high risk according to traditional criteria. Cardiologist James Muller of the University of Kentucky in Lexington believes certain triggers act through the nervous system of a susceptible person. He and other scientists theorize that pulling one of these triggers sets a specific sequence of events in motion. First, blood pressure surges, constricting arteries. Then a vulnerable plaque breaks open. This plaque rupture is followed rapidly by formation of a blood clot, and the total blocking of blood flow through the artery. The result is a heart attack.

Heavy exertion such as snow shoveling is one trigger, because it stresses the autonomic nervous system and puts an unusual physical workload on the heart. Another potential trigger is any disturbance in bodily rhythms, he says, noting that more heart attacks happen in the morning, particularly after getting out of bed, and that more happen on Monday than on any other day of the week. The third trigger Muller has identified is fear. Its effects surfaced dramatically in Los Angeles during an earthquake on January 17, 1996, he points out. When it hit, “an enormous peak in coronary deaths” occurred, because “the whole population was exposed at the same time.”

Spreading the Word

Some of these potential risk factors, such as those related to bacteria and viruses, simply identify individuals who need to be monitored more carefully-such people might do well to watch their cholesterol, weight, and blood pressure more closely. But other potential risk factors could indicate new ways to stave off heart attacks. For example, beta-blocker drugs are beneficial in treating long QT in some children, because they slow down the heart and make the heart muscles less responsive to adrenaline, and thus decrease the possibility that the heart will become unstable. In children on whom these drugs do not work, surgeons have implanted devices that will deliver an electrical shock if the heart needs to regain stability.

The results of acting on good information can be impressive. Roger R. Williams, a cardiologist and genetics researcher at the University of Utah in Salt Lake City, has proven as much. He and more than 20 other physicians interested in the genetics of cholesterol have set out to locate people with the gene for familial hypercholesterolemia, or FH. Toward this end, they have formed a 10-nation network called MED-PED-FH, which stands for “making early diagnosis to prevent early deaths in medical pedigrees with FH.” Workers process questionnaires from the blood relatives of known FH victims and track down carriers of the gene. In Utah, such efforts have paid off with the identification of 800 carriers of the FH gene from a base of only 50 known victims. All could be candidates for drugs named statins that Bristol-Myers Squibb, Merck, and Sandoz have developed; based partially on Goldstein and Brown’s research, these drugs block a key enzyme involved in cholesterol production.

For people who may be prone to heart attack because they are depressed, drugs such as Prozac and Zoloft and psychologist-led therapy show much promise. Although doctors still lack an economical way to tell whether specific patients are likely to develop high blood pressure if they consume too much salt, discovery of the gene responsible for such sensitivity has spawned a new class of drugs called “angiotensin converting enzyme inhibitors” that help the kidneys handle salt more effectively. And Searle has recently come out with a drug to control blood pressure that is designed to deliver its peak dose in the morning hours, when, as Muller’s research on heart-attack triggers has demonstrated, people are particularly vulnerable.

At least three major studies could help pin down some of the new risk factors that have been proposed. The World Health Organization’s MONICA project (for “multinational monitoring of trends and determinants in cardiovascular disease”) is charting heart attacks and heart-attack deaths at 38 locations in 21 nations, with final results expected by 1998. The Atherosclerosis Risk in Communities study-the one that has already turned up much of the information linking heart attacks to bacterial and viral infection-will also be completed in 1998. And a newer study called Enhancing Recovery from Coronary Heart Disease, sponsored by the National Heart, Lung, and Blood Institute, began in October 1996 to look specifically at loneliness and social isolation as heart-attack risk factors.

But new findings are not enough. In fact, even the new interventions that may grow out of those findings are not enough. The professional organizations that represent doctors in practice-for instance, the American College of Cardiology, the American Heart Association, and the National Heart, Lung, and Blood Institute-must spread the word about the latest research. They need to convince doctors that it is based on sound science and that it will help them deliver better care to their patients.

Such efforts could enable medical workers to save many patients around the world from untimely death or disability. To be sure, more people with established high-risk conditions such as diabetes or high blood pressure need to be identified and convinced to take their medications, follow their diets, keep their appointments, stop smoking, or make other changes in their behavior. And those who have already suffered from heart problems need the kind of rehabilitation and education that could keep their situation from deteriorating. Physician Sidney C. Smith Jr., a recent president of the American Heart Association, reports that only about 30 percent of patients who have had heart attacks or procedures like bypass surgery are being sent on to rehabilitation, and that few are being counseled by their doctors to stop smoking and eat a healthful diet. Still, the importance of ferreting out new heart-attack risk factors cannot be overestimated. Until we know more about the conditions that contribute to heart disease, prevention programs will remain sadly limited.

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