SUDDEN DEATH AND EXERCISE
Timothy D Noakes MBChB MD
Physiology, University of Cape Town Medical School, Observatory 7925, South Africa. Email: firstname.lastname@example.org
Sportscience 2(4), sportsci.org/jour/9804/tdn.html, 1998 (6281 words)
Reviewed by George D Swanson, Physical Education and Exercise Science, California State University, Chico, California
How is it possible to reconcile the apparently irreconcilable: that habitual physical activity may protect from heart disease, yet exercise per se may be an important risk factor for sudden death? It is a problem with which medicine has grappled since antiquity.
The Greek physicians Hippocrates and Galen were among the first to express an opinion on the risk of exercise on the heart. Hippocrates attacked athleticism in his treatise on Nutrient, writing that "...the condition of the athlete is not natural." Six centuries later Galen wrote that "athletes live a life quite contrary to the precepts of hygiene, and I regard their mode of living as a regime far more favorable to illness than to health... While athletes are exercising their professions, their body remains in a dangerous condition but, when they give up their professions, they fall into a condition more parlous still; as a fact, some die shortly afterwards; others live for some little time but do not arrive at old age."
The first modern sport to attract a similar concern was rowing. In 1845, the seventh Oxford and Cambridge Boat Race was the first to be rowed on the current course on the Thames between Putney and Mortlake. No sooner had it moved to its longer course through the British capital than an irate letter written by one Frederick C. Skey, past president and fellow of the Royal College of Surgeons, appeared in the Times, charging that "the University Boat Race as at present established is a national folly." Skey claimed that rowing was bringing young men to an early grave.
A scientific study published shortly thereafter by John Morgan, a Birmingham physician, proved that Skey was in error. Morgan showed that the life expectancy of university oarsmen was not reduced. If anything, it was slightly longer than that of the average Englishman of the period.
Almost a century later the issue was revived by a letter that appeared in the Journal of the American Medical Association stating that all members of the 1948 Harvard rowing crew had since died "of various cardiac disease". The assertion was enthusiastically denied by these oarsmen, who reported that they were all alive and well.
Surprisingly, cycling was the next sport to attract similar attention. In the 1890s North Americans suddenly discovered the bicycle, and medicine had another sport about which to express its alarm. Prospective cyclists were warned that prolonged bending over the handlebars could cause "kyphosis bicyclistarum" or in lay terms "cyclist's stoop" or "cyclist's figure" or even "cyclist's spine". Then, as expected, there was "cyclist's heart". The working life of the heart was limited to only a certain number of heart beats, these physicians asserted, and the faster heart rate during cycling would only waste these precious beats and so lead to premature heart failure.
One of the first references to the dangers of running on the heart was made in 1909 by five eminent British physicians who started a correspondence in the Times by stating that "school and cross-country races exceeding one mile in distance were wholly unsuitable for boys under the age of nineteen, as the continued strain involved is apt to cause permanent injury to the heart and other organs." Again, this view was easily refuted. From an analysis of 16,000 schoolboys covering a period of twenty years, Lempriere could find only two cases of sudden death during exercise that were not due to accidents. He concluded that "heart strain through exercise is practically unknown", a conclusion echoed by Sir Adolphe Abraham, who denounced the concept of the strained athletic heart.
Running again became a medical cause célébre in the 1970's as the popularity of the sport mushroomed. One of the first articles to question the safety of such activity reported that half of 59 sudden deaths occurred during or immediately after severe or moderate physical activity, especially jogging. The authors questioned "whether it is worth risking an instantaneous coronary death by indulging in an activity, the possible benefit of which.....has yet to be proved." They also considered "the possible lethal peril of violent exercise to [heart-disease] patients."
On the other hand, in the early 1970âs a review of the American Medical Joggers Association failed to document a single death due to coronary atherosclerosis amongst athletes who had completed marathons. The review suggested that athletes might be protected from coronary artery disease. I formulated the "Bassler hypothesis" which claimed that the absence of fatal coronary atherosclerosis in marathon runners proved that marathon running provided immunity against coronary artery disease and fatal myocardial infarction. This optimism was reinforced by a boom in marathon running in the mid-1970âs and increasing medical and popular literature and media support for the sport.
One of the first reports disproving the Bassler hypothesis was from a group in Cape Town who documented the presence of coronary atherosclerosis in two marathon runners who died suddenly during training. The authors concluded that marathon running could not ensure absolute protection from coronary atherosclerosis. In a subsequent publication, I and several other colleagues described 36 cases of sudden cardiac death in marathon runners, 75% of who had coronary artery disease proven at angiography or autopsy.
More fuel was added to this controversy in the early 1980's by the sudden death while running of James Fixx, the celebrated American runner and author. Fixx had achieved international celebrity status as author of the book that became an international best-seller because it best captured the mood of the running explosion that occurred in the late 1970s. Paradoxically, in a later book Fixx had written an appropriate epitaph both to himself and to the concept that runners could earn immunity from both heart disease and death: "...runners are much like ordinary mortals. They can, sad to say, get sick. They can even die."
The first component of this issue that needs attention is whether these deaths during exercise actually prove that exercise is the real culprit and therefore a dangerous activity; or, stated differently, whether exercise and sudden death are causally related. The overriding conclusion from a large number of studies of sudden death, including sudden deaths that occur during exercise, has shown that virtually all persons who die suddenly during exercise have a serious disease, usually of the heart, that adequately explains the cause of death.
While a large number of cardiac conditions have been associated with sudden death during exercise, the most common cause of death in Westernized communities is coronary artery disease. Coronary artery disease is the major cause of death in persons aged 40 or older.
Sportsmen below the age of 40 who die suddenly during exercise are more likely to have hypertrophic cardiomyopathy. However, some young athletes who die suddenly during exercise are likely to have severe coronary artery disease as a result of familial hypercholesterolemia (inherited high level of blood cholesterol).
Other less common causes of sudden death during exercise include congenital anomalies of the coronary arteries, right ventricular dysplasia, aortic rupture associated with Marfanâs syndrome, coronary artery dissection, myocarditis and ill-defined conduction disturbances presumed to be related to pathological changes found in the conduction pathways at autopsy (Table 1).
But the more important point is that none of these conditions is caused by exercise, however vigorous. Rather, the evidence is clear that regular exercise acts against the development especially of coronary atherosclerosis. There is also no evidence that exercise accelerates the progression of these other potentially-lethal cardiac conditions.
At present the exact mechanism causing exercise-related sudden death in persons with established disease, especially of the coronary arteries is not known. Whereas plaque rupture or thrombosis are present in up to 95% of sudden cardiac deaths in the general population, the incidence seems to be lower in exercise-related deaths. Thus exercise-induced ischemia or coronary spasm may be involved in exercise-related deaths.
In 1996 the Consumer Product Safety Commission described 38 deaths (1973-1995) from baseball blows to the chest. Commotio cordis predominantly affects children and adolescents 5 to 15 years of age without pre-existing heart disease. Recently a swine model has been developed which suggests that ventricular fibrillation may develop, depending on the precise timing of the impact of a hard object, traveling at speed, against the anterior chest wall. Impacts occurring between 15 and 30 milliseconds before the T wave produced ventricular fibrillation.
Because athletes who die suddenly have advanced cardiac disease, they are at high risk of dying suddenly, whether or not they exercise. A number of studies have attempted to determine whether or not exercise increases the risk that persons with advanced heart disease will die suddenly during exercise rather than at rest. Some have found that moderate exercise does not increase the risk of sudden death, whereas other have found that more vigorous forms of exercise such as cross-country skiing or running are associated with a five- to seven-fold greater risk of sudden death.
Possibly the first detailed study of this question was reported by Thompson and his colleagues. They found that, in the state of Rhode Island between 1975 and 1980, 11 of 12 men died while jogging had heart attacks. Five of these men were known to have heart disease before their deaths. They calculated that the incidence of death during jogging was one per 396,000 hours, which is about seven times the estimated heart attack rate during more sedentary activities. In this study the unequivocal evidence was that jogging increased the risk that the jogger with severe heart disease would die while exercising.
But this finding should not be used to overestimate the risk of exercise. For example, in the Rhode Island study, there was one death per 7,620 joggers per year--clearly an infinitesimal risk for each individual jogger. Furthermore, it would be totally impractical to screen all 7,620 joggers in Rhode Island in an attempt to identify the one jogger at risk of sudden death each year. For example, on the basis of these data, it has been calculated that a middle-aged jogger with no known cardiac disease who decides to continue running for one more year is at considerably lower risk of sudden death than is a middle-aged non-runner who continues to ride in his car during that year.
A recent study examining the prevalence of sudden cardiac death during exercise was conducted on two groups of endurance runners competing in the Marine Corps and Twin Cities marathons in the USA held over a cumulative 30-year period. In the total of 215,413 runners who completed the races there were four exercise-related sudden deaths due to unsuspected cardiac disease. Three of the sudden cardiac deaths were due to coronary artery disease and one due to an anomalous origin of the left coronary artery from the right sinus of Valsalva. The overall prevalence of sudden cardiac death during the marathon was thus 0.002%, strikingly lower than for several other variables of risk for premature death calculated for the general US population. The authors concluded that "although highly trained athletes may harbor underlying and potentially lethal cardiovascular disease, the risk of sudden cardiac death associated with physical effort was exceedingly small (1 in 50,000) and as little as 1% of the annual overall risk associated with living either with or without heart disease."
Recently, Thompson reviewed several studies on the incidence of sudden death during exercise. Thompson reported that the absolute incidence of exercise-related sudden cardiac death to be 0.75 and 0.13 per 100,000 young male and female athletes and 6 per 100,000 middle-aged men die during exertion per year. Thus, while the incidence of sudden cardiac death during exercise is very low, the evidence suggests that exercise seems to trigger or cause sudden cardiac death in athletes with underlying heart disease. Therefore, the next important question is: if exercise does indeed increase the risk of sudden death, by how much did exercise actually shorten the life expectancy of the patient who was in any case at high risk of dying suddenly and unexpectedly? Indirect evidence that the exercise probably does not greatly decrease life expectancy under such circumstances comes from a study of the 1978 Rhode Island blizzard.
In February 1978 a severe blizzard struck Rhode Island causing the daily death rate from heart attack to increase from the usual February average of 27 to 48 deaths per day. This rate remained high for three of the first five days after the storm, but subsequently decreased below the normal daily average, so that the total heart attack deaths for February that year was the same as for previous years. Thompson concluded that: "These results suggest that the added physical and emotional stress arising from the storm eliminated those who would have succumbed to ischemic heart disease (heart attack) in the near future." In the same way, jogging deaths may occur in those whose time is up and who were due to die within the next few day or weeks even if they avoided all forms of exercise, including walking.
The data of Siscovick and his colleagues clearly show that persons who have undetected heart disease and who are therefore at risk of sudden death, reduce their overall risk of sudden death if they exercise regularly. During exercise, however, their risk is increased acutely. The researchers collected detailed information on all persons dying suddenly during a one-year period in Seattle, Washington. They then excluded from their analysis all those persons who were ill, who had been off work or who had experienced any symptoms before their sudden deaths. They were left with a total of 145 sudden deaths in a group of persons who were for all intents and purposes healthy right up to the moment that they suddenly died. Analysis of these data showed that those persons who exercised vigorously on a regular basis had an overall risk of sudden death about two-thirds that of the non-exercisers.
Interestingly, though, the risk of sudden deaths in the exercising group while these persons were exercising was increased acutely for the duration of the exercise bout, above the overall risk of the non-exercisers. Thus although the total group of exercisers had a reduced risk of sudden death, that subset of exercisers with advanced heart disease resistant to all preventive measures including exercise, and who would ultimately die suddenly, were more likely to die while they were exercising rather than when they were at rest. This finding explains why the sudden death of athletes usually occurs during exercise and why such events must not be construed to indicate that exercise is dangerous and to be avoided. In fact, if the exercisers were to stop exercising, their risk of sudden death would, according to these data, increase about threefold.
To put these findings in perspective, consider the following. Studies show that in the population of about 10,000 Comrades Marathon runners there are approximately 3 sudden deaths per year, most of which occur as predicted by the data of Siscovick and his colleagues, during or shortly after exercise. If, on the basis of these three deaths per year, it was decided that marathon running was too dangerous and was summarily and effectively banned, the annual risk of sudden death in the group of ultra-marathon runners would approximately triple. Thus each year after the banning of marathon running, there would be nine, not three, sudden deaths; clearly an undesirable result. But by encouraging the cohort of 10,000 marathon runners to continue running, about six lives per year are being saved.
In summary, the studies of Siscovick and his colleagues confirm the finding that the risk of sudden death is reduced in persons who exercise regularly and suggest that this is almost certainly not due to the presence of confounding variables. However, these studies also show that there is an increased likelihood that those persons who have heart disease in spite of their regular exercise, will die during the short period that they spend exercising. Were such persons to avoid all exercise however, their overall risk of sudden death would be increased, not decreased. The higher the level of coronary risk, the greater the degree of benefit from exercise. Persons who are at low risk of dying suddenly from coronary heart disease benefit less from vigorous physical exercise than do those who are at high risk, either because of a family history of heart disease, or because they are smokers who have other risk factors already described. As Siscovick and colleagues stated, "efforts to discourage clinically healthy persons at risk of primary cardiac arrest from continuing to engage in vigorous exercise may be inappropriate."
It is important to stress that severe heart disease may be present even in person who are extremely physically fit. For example, we have reported cases of marathon runners who completed the 90-km Comrades Marathon only weeks before their subsequent deaths from severe advanced coronary artery disease, in some cases with associated hypertrophic cardiomyopathy. One 42 year-old runner completed a 42.2 km standard marathon in 3 h 6 min just three weeks before autopsy showed he had complete occlusion of one major coronary artery and 75% narrowing, with atherosclerosis, of the other two. In addition, there was evidence of hypertrophic cardiomyopathy. The case of the American runner who died within a minute of setting a regional running record in the United States has already been described. More recently, Sergei Grinikov, a 28 year-old double Olympic gold medalist, collapsed and died suddenly whilst training. His autopsy revealed coronary artery disease.
Persons who die suddenly during exercise frequently have warning symptoms of heart disease which they ignored, choosing to continue exercising rather than to seek medical advice. Thus, my 1987 study of heart attacks and sudden deaths in marathon runners found that fully 81% of these cases had warning symptoms. Six athletes completed marathon races, and three the Comrades Marathon, despite symptoms of chest or abdominal pain sufficiently severe to force them to stop running and to walk and run intermittently. Despite severe chest pain, one athlete continued to run a 16-km race and collapsed at the finish. Another runner continued training for three weeks, including a 64-km training run with chest pain severe enough to force him to walk on numerous occasions.
Lessons from James Fixx's Death
Many of these points were rather tragically illustrated by James Fixx's death while running. Fixx was at high risk of heart disease because his father had died from a heart attack at a relatively very young age (43 years). In addition, Fixx was a reformed smoker with a markedly elevated blood cholesterol concentration. Fixx had also experienced warning symptoms which he chose to ignore and had refused the option of undergoing a maximal exercise stress test.
Autopsy showed that Fixx had severe coronary artery disease with near total occlusion by atherosclerosis of one and 80% occlusion of another coronary artery. There was also evidence of a recent heart attack. In addition, the heart was somewhat large suggesting the possibility of concurrent hypertrophic cardiomyopathy.
On the day James Fixx died, 1000 other Americans would also have died of heart attacks. Few if any would have received nationwide coverage. Yet almost all of those deaths would have occurred in persons who were sedentary, or were smokers, or who had uncontrolled high blood pressure and elevated blood cholesterol concentrations. If only those sudden deaths occurring in athletes are reported in the press, it is understandable why the public acquire a distorted impression of the relationship between exercise and heart disease.
Thus James Fixx's death followed a familiar pattern and helps emphasize the points already made. One interesting possibility not considered by many is that regular exercise actually allowed James Fixx to outlive his father by nine years. This possibility would be supported by the scientific findings, especially of Siscovick and his colleagues.
There are three postulated mechanisms by which vigorous physical activity may precipitate myocardial ischemia in athletes with coronary artery disease. First, the initial surge of blood pressure with initiation of exercise might precipitate the fissuring of a vulnerable atherosclerotic plaque with the subsequent thrombus formation transforming a previously non-occlusive lesion into a total occlusion. Second, it is possible that a non-occlusive atherosclerotic plaque may precipitate transient ischemia by inducing an imbalance between myocardial oxygen demand and supply. As fewer than one-third of resuscitated athletes subsequently develop evidence of acute myocardial infarction, it is thought that this is the most common mechanism of sudden cardiac death during exercise. Third, myocardial ischemia during exercise might result from coronary-artery spasms, which occur most commonly at sites of established atherosclerosis.
Irrespective of which of the above mechanisms is responsible for the occurrence, the event immediately preceding all cases of sudden cardiac death during exercise is a massive reduction of cardiac output (secondary to either myocardial ischemia or arrhythmia), decreased cerebral blood flow, and loss of consciousness. It is believed that a combination of the triggering event and a susceptible myocardium combine to initiate potentially lethal arrhythmias especially ventricular fibrillation. The fall in cardiac output upon rapid cessation of exercise and the presence of arterial vasodilatation are additional factors that might explain the relatively frequent occurrence of sudden cardiac death in the immediate post-exercise period. Postulated pathophysiological factors during physical exertion that may lead to triggering events or a susceptible myocardium are listed in Table 2.
Exercise has been shown to reduce the rate of development of coronary atherosclerosis in monkeys fed a high-fat atherogenic diet and to increase the resistance of the trained heart to ventricular fibrillation, the lethal abnormal heart rhythm that causes most persons with heart disease to die suddenly. Another potentially important mechanism for this effect is simply the reduction of the coronary risk factors. For example, in one survey 81% of men and 75% of women who were smokers stopped smoking when they started running. Similarly, subjects taking up marathon running show beneficial changes in coronary risk factors.
When approached by a patient who wishes either to commence exercise or to establish that it is safe for him or her to continue exercising at their present level, the clinician's first responsibility is to rule out the presence of the acute or chronic diseases associated with sudden death. The clinical problem has several challenges. First, the incidence of such diseases in the exercising population is extremely low with estimated incidences varying from 1 per 10,000 active exercisers to 1 per 200,000 in children and young adults. Secondly, it is extremely difficult to detect some of these latent forms of heart disease. Indeed, some athletes might have a 30-60% non-critical lesion that does not produce ST segment changes or angina during exercise testing. Third is the finding that most acute coronary events occur due to rapid progression of disease at sites at which a critical lesion was not previously present. Furthermore, even when latent disease is detected, it is not always possible to differentiate absolutely those with the disease who will die suddenly during exercise from those with the same condition who are not at risk.
It is clear that there are many people with latent heart disease, especially coronary heart disease, who are able to exercise quite safely without the risk of sudden death. How these are to be distinguished on clinical grounds from those at risk of sudden death during exercise has yet to be established. Accordingly a more pragmatic approach would seem justified. The following guidelines probably represent the current consensus.
All persons over 50 should undergo cardiovascular screening before starting any type of exercise program. Younger persons (less than 50 years of age) who are either already participating or who wish to start exercising should first be interviewed for a family history of conditions associated with sudden death and screened for symptoms and clinical signs of cardiovascular disease, and for risk factors for heart disease. When either the family history is suggestive, or clinical suspicion is raised, or risk factors such as hypertension, hypercholesterolemia or cigarette smoking are present, subjects should undergo maximal exercise testing for measurement of exercise performance and the electrocardiographic response to exercise. When abnormalities are detected, further specialist cardiological investigation including echocardiography and possibly coronary angiography is indicated. Conditions in which echocardiography is useful in the evaluation of athletes are listed in Table 3. Subjects with identified cardiac disease should then exercise under supervision, at least initially.
But even when these guidelines are followed, less than 20% of subjects at risk of developing a cardiac event during exercise will be identified. Thus Siscovick and his colleagues have argued that routine exercise testing is of limited value for assessing the risk of exercise in middle-aged men. Similarly, Thompson and colleagues have suggested the "physicians can recommend exercise to asymptomatic adults without great concern for possible cardiovascular complications... The risk of exercise is small and suggests that the routine exercise testing of healthy subjects before exercise training is not justified."
The recommendations that I have made specifically for persons who are already active in sport are based on studies of sudden death in marathon runners. These include:
In brief, this experience is in agreement with the conclusion of Thompson and colleagues to the effect that only athletes who are symptomatic should be exhaustively tested and discouraged from exercise when a life-threatening cardiac abnormality is discovered. Because in my experience the majority at least of adults who die suddenly during exercise, like James Fixx, have warning symptoms, this simple procedure could possibly reduce the incidence of sudden death during exercise by as much as 80%. Unfortunately, the condition will never be completely prevented because in about 20% of persons, sudden death remains the first symptom of heart disease that they experience. Some may even have undergone maximal exercise testing without incidence within a reasonably short time before their subsequent deaths.
While most emphasis is placed on the detection of latent coronary heart disease, detection of other conditions is also important. Thus persons with hypertrophic cardiomyopathy are at increased risk of sudden death during exercise. Current practice is that persons with this condition are encouraged to avoid all forms of physical activity, however gentle. Whether this is appropriate, and whether all forms of hypertrophic cardiomyopathy carry an equivalent risk of sudden death is not yet known. Even so, current practice is probably that the physical activity of persons with this condition should be restricted.
With regard to rheumatic heart disease, it seems that severe aortic stenosis is the form of valvular disease most frequently associated with sudden death. Furthermore, deaths in persons with rheumatic heart disease almost always occur in those in whom the diagnosis of serious heart disease is well established and whose exercise tolerance had already been severely restricted by their disease. Thus only those patients with rheumatic heart disease whose exercise tolerance is already restricted should further reduce physical activity. There is no firm evidence that the physical activity of asymptomatic persons with clinical evidence of (mild) valvular dysfunction as a result of rheumatic heart disease needs to be restricted, nor that physical activity detrimentally influences the course of their disease. It must be remembered that the heart of a person with rheumatic heart disease must beat 24 hours a day despite unfavorable hemodynamic loading. It is unlikely that the additional hemodynamic stresses of even one hour of exercise a day would materially influence the adaptations already made to compensate for the hemodynamic abnormalities caused by the valvular disease.
With regard to myocarditis, there is the question that it is a cause of sudden death in persons recovering from a viral infection. Accordingly, persons who suffer from a viral infection or who have had systemic manifestations of the infection (fever, myalgia and arthralgia) should be encouraged not to exercise vigorously for at least 14 days after their body temperature returns to normal and their myalgia and arthralgia subside. A persistent increase in the resting heart rate would also indicate continuing myocardial involvement and would be an absolute contraindication to vigorous exercise.
The screening of young athletes for potentially fatal cardiovascular disease has received special attenion by the American Heart Association, who have set the following recommendations. These can be applied also to the older exercising population:
With respect to the long QT syndrome, recently three genes have been identified that indicate which persons with the long QT syndrome are likely to suffer fainting episodes and to die during physical exertion. A blood-screening test is in development and should be available by mid 1999.
Finally, detection of many of the other conditions listed in Table 1 may be difficult. When identified, the clinician must still decide whether the risk of sudden death posed by the condition exceeds the benefits the patient might expect from continuing to participate in regular exercise.
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