Triggering of Sudden Death from Cardiac Causes by Vigorous Exertion
Christine M. Albert, M.D., M.P.H., Murray A. Mittleman, M.D., Dr.P.H., Claudia U. Chae, M.D., M.P.H., I.-Min Lee, M.B., B.S., Sc.D., Charles H. Hennekens, M.D., Dr.P.H., and JoAnn E. Manson, M.D., Dr.P.H.
Background Retrospective and cross-sectional data suggest thatvigorous exertion can trigger cardiac arrest or sudden deathand that habitual exercise may diminish this risk. However,the role of physical activity in precipitating or preventingsudden death from cardiac causes has not been assessed prospectivelyin a large number of subjects.
Methods We used a prospective, nested case–crossover designwithin the Physicians' Health Study to compare the risk of suddendeath during and up to 30 minutes after an episode of vigorousexertion with that during periods of lighter exertion or none.We then evaluated whether habitual vigorous exercise modifiedthe risk of sudden death that was associated with vigorous exertion.In addition, the relation of vigorous exercise to the overallrisk of sudden death and nonsudden death from coronary heartdisease was assessed.
Results During 12 years of follow-up, 122 sudden deaths wereconfirmed among the 21,481 male physicians who were initiallyfree of self-reported cardiovascular disease and who providedinformation on their habitual level of exercise at base line.The relative risk of sudden death during and up to 30 minutesafter vigorous exertion was 16.9 (95 percent confidence interval,10.5 to 27.0; P<0.001). However, the absolute risk of suddendeath during any particular episode of vigorous exertion wasextremely low (1 sudden death per 1.51 million episodes of exertion).Habitual vigorous exercise attenuated the relative risk of suddendeath that was associated with an episode of vigorous exertion(P value for trend= 0.006). The base-line level of exercisewas not associated with the overall risk of subsequent suddendeath.
Conclusions These prospective data from a study of U.S. malephysicians suggest that habitual vigorous exercise diminishesthe risk of sudden death during vigorous exertion.
Physical activity clearly benefits cardiovascular health.1,2,3In prospective epidemiologic studies, both vigorous physicalactivity and moderate activity are consistently associated witha reduced risk of coronary heart disease.4,5,6,7 However, itis also recognized that sudden death from cardiac causes seemsto occur with an unusually high frequency during or shortlyafter vigorous exertion.7 Approximately 6 to 17 percent of allsudden deaths occur in association with exertion,8,9,10,11 andthere is evidence to suggest that vigorous exertion simultaneouslytriggers and protects against sudden death.11 However, the roleof vigorous exertion in precipitating or preventing sudden deathhas not been assessed prospectively in a large number of subjects.The prospective data compiled in the Physicians' Health Studypresented a unique opportunity to determine whether vigorousexertion triggers sudden death and whether habitual vigorousexercise diminishes the risk.
Methods
Study Population
The methods of the Physicians' Health Study have been describedin detail elsewhere.12 Briefly, 22,071 male physicians who werefrom 40 to 84 years of age in 1982 and had no history of myocardialinfarction, stroke, transient ischemic attacks, or cancer wereassigned to receive aspirin, beta carotene, or both, accordingto a randomized, placebo-controlled, two-by-two factorial design.At base line, the physicians completed questionnaires on theircardiovascular risk factors, intake of selected foods, and frequencyof vigorous exercise. In this investigation, we excluded 590men who reported having angina or having undergone coronaryrevascularization, or for whom data on physical activity weremissing, at base line, leaving 21,481 participants as the basepopulation for the analysis.
Study Design
We used a nested case–crossover design to quantify therelative risk of sudden death from cardiac causes during orup to 30 minutes after an episode of vigorous exertion as comparedwith the risk during periods of lighter exertion or none (Figure 1).The case–crossover study design permits the assessmentof change in the risk of an event during a brief "hazard period"during and after exposure to a transient risk factor.13 Foreach subject who had an event (i.e., who died), the prospectivelydetermined habitual frequency of exertion for that subject servedas the control information, and each such subject thereforeserved as his own control in this "self-matched" analysis.
Figure 1. Design of Nested Case–Crossover Analysis.
The hatched portion of the time line represents the 60-minute hazard period (30 minutes during and 30 minutes after vigorous exertion). If a sudden death occurred during this period, there was considered to have been exposure to vigorous exertion. If a sudden death occurred during the shaded portion of the time line, there was considered to have been no exposure to vigorous exertion.
Frequency and Timing of Vigorous Exertion
Frequency of Vigorous Exertion at Base Line
At base line, the subjects were asked, "How often do you exercisevigorously enough to work up a sweat?" The possible responseswere rarely or never, one to three times a month, once a week,two to four times a week, five or six times a week, or daily.This measure of physical activity correlates with maximal oxygenuptake,14 time on the treadmill during exercise testing,15 andthe high-density lipoprotein cholesterol level.16 The midpointvalue was assigned to each response category and multipliedby 52 to estimate the usual annual frequency. Subjects werenot asked about the average duration of exertion at base line,but the question was asked of those who reported engaging ina regular program of exercise in a questionnaire administeredat 36 months (59 percent of the total cohort). The median durationreported (30 minutes) was used as an estimate of the usual durationof vigorous exercise at base line. In our primary analysis weassessed the risk of sudden death during and 30 minutes afterexertion (Figure 1). We therefore assumed that each episodeof exertion was associated with 60 minutes of exposure time.To calculate the unexposed person-time, the person-time of exposure(in hours) was subtracted from the number of hours in a year.
Activity at the Time of Death
The specific activity in which the subject was engaged at thetime of sudden death and for one hour before death was ascertainedfrom the medical record or from the next of kin. The degreeof physical exertion was quantified on a scale of 1 to 8 metabolicequivalents (MET).17 The subject was considered to have beenexposed to vigorous exertion if the activity was estimated as6 MET or more. If the activity was unknown or was at a levelof less than 6 MET, there was considered to have been no exposure.
Definitions
An end-points committee of physicians confirmed all events byreview of medical records. Deaths for which there was evidenceof coronary heart disease at or before death and no evidenceof a noncoronary cause were classified as due to cardiac causes.To identify sudden deaths, medical records and reports fromthe next of kin for all subjects who had died from cardiac causeswere reviewed again by two cardiologists, and agreement wasreached on whether the death was sudden.
Sudden death was defined as death within one hour after theonset of symptoms or death after a witnessed cardiac arrestor abrupt collapse that was not preceded by symptoms lastingmore than one hour. Information from the death certificate wasnot used to determine the timing of death. To increase the specificityof our method for identifying death from arrhythmia, we excludedanyone who had evidence of circulatory collapse (hypotension,exacerbation of congestive heart failure, or altered mentalstatus) before the disappearance of the pulse.18
Absolute Risk during Vigorous Exertion
Each physician's reported frequency of vigorous exertion atbase line (episodes per week) was multiplied by the follow-uptime in weeks to generate an estimate of the total number ofepisodes of vigorous exertion in the population, and the absoluterisk of sudden death associated with an episode of vigorousexertion was calculated. This risk was then compared with theincidence of sudden death during lighter physical activity,and the difference in absolute risk was estimated.
Case–Crossover Analysis
The analysis of case–crossover data is similar to thatof a crossover experiment in which the risk to each subjectis assessed during periods of exposure and nonexposure. Theratio of the observed frequency of exposure in the 60-minutehazard period (Figure 1) to the frequency of exposure expectedon the basis of the usual frequency of exercise reported atbase line was used to calculate an odds ratio as a measure ofrelative risk.13,19 The data were then stratified for each subjectand analyzed by methods for cohort studies with sparse datain each stratum.20 Modification of the relative risk by habitualvigorous exertion was assessed by comparison of the relativerisks for three categories of habitual vigorous exertion (lessthan once, one to four times, and five or more times per week),and a test for linear trend21 was performed. The effect of thetime of day on the relative risk of sudden death was assessedby stratification of the analysis according to the time of death,followed by comparison of the relative risks by means of a testfor homogeneity.22 All reported P values are two-sided.
Sensitivity Analyses
Three sensitivity analyses were performed. First, to examinethe sensitivity of the results to the hazard period chosen,we considered only the period during vigorous exertion (thelabeled portion in Figure 1) as the period of exposure and reexaminedthe relative risk of sudden death during this 30-minute hazardperiod. Second, we examined the sensitivity of the results tochanges in our estimate of the usual duration of vigorous exertion.Third, we examined the sensitivity of the results to our definitionof sudden death, which, although specific for death from arrhythmia,excluded most unwitnessed deaths and deaths during sleep. Someof these deaths could have been sudden, and their systematicexclusion could have biased our results toward a positive associationbetween death and vigorous exercise. Therefore, in this analysis,we included unwitnessed deaths with an autopsy result consistentwith an arrhythmic cause and those that occurred during sleepwithout preceding symptoms as sudden deaths.
Overall Risk of Sudden and Nonsudden Death from Cardiac Causes
The base-line information on the usual frequency of vigorousexertion was modeled in four categories (less than once, once,two to four times, and five or more times per week), and therelative risks of sudden death and nonsudden death from coronaryheart disease for the base population of 21,481 men were computedwith use of Cox proportional-hazards models23 with simultaneouscontrol for potential confounders.
Results
During 12 years of follow-up, 122 sudden deaths from cardiaccauses occurred among the 21,481 participants. The age-adjustedrisk factors at base line and the usual frequency of vigorousexertion for those who died suddenly and for the other participantsare shown in Table 1. The majority of participants reportedexercising vigorously two to four times per week, and the distributionof the categories for usual frequency of vigorous exertion didnot differ significantly between those who died and those whodid not. Complete information on physical activity during thehour before death was available for 80 percent of the suddendeaths. Seventeen such deaths (13.9 percent) occurred duringvigorous exertion, and six (4.9 percent) occurred within 30minutes after vigorous exertion. The majority of the participantswere engaged in dynamic exercise, such as jogging or racquetsports (68 percent). The rest were involved in other sports(25 percent) or heavy yardwork or home repairs (7 percent).
Table 1. Characteristics of the Subjects Who Died Suddenly and Those Who Did Not.
Among the 21,481 men, the incidence of sudden death per person-hourwas 1 death per 19 million hours. The risk of sudden death associatedwith an episode of vigorous exertion was 1 per 1.42 millionepisodes or person-hours at risk. Alternatively, the risk ofsudden death during periods of lighter exertion or none was1 death per 23 million person-hours. From these data, the unadjusteddifference in risk associated with exposure to vigorous exertioncan be estimated at 1 excess sudden death per 1.51 million episodesof vigorous exertion. On the basis of the case–crossovermethod, the relative risk of sudden death during the one-hourperiod associated with vigorous exertion (Figure 1), as comparedwith other time points, was significantly elevated at 16.9 (95percent confidence interval, 10.5 to 27.0; P<0.001).
Effect of the Frequency of Vigorous Exercise
The results after stratification according to the usual frequencyof vigorous exercise at base line are presented in Table 2.The relative risk of sudden death associated with an episodeof vigorous exertion was lower among those who exercised morefrequently (P for trend=0.006). Men who rarely engaged in vigorousexercise (less than once a week) had a relative risk of suddendeath of 74.1 in the period during and 30 minutes after exertion.In comparison, men who exercised at least five times per weekhad a much lower risk (relative risk, 10.9); however, this riskwas still significantly higher than that during periods of lighterexertion or none.
Table 2. Effect of Habitual Vigorous Exercise on the Risk of Sudden Death during Vigorous Exertion.
Effect of Time of Death
It is well known that the incidence of sudden death varies accordingto the time of day. If the subjects tended to exercise duringthe circadian peak in the incidence of sudden death (from 6a.m. to noon),24 this fact could account for part of the increasedrisk associated with exertion. To address this issue, we reexaminedthe relative risks according to the time of death (Table 3).The relative risk associated with an acute episode of vigorousexertion was not significantly modified by the time of death.In addition, the relative risk associated with vigorous exertionremained significantly elevated at times other than the circadianpeak in sudden death, except for the period from midnight to6 a.m., when exposure to exertion was low.
Table 3. Relative Risk of Sudden Death Associated with an Episode of Vigorous Exertion, According to the Time of Death.
Sensitivity Analyses
Seventeen of the 23 sudden deaths that were associated withvigorous exertion occurred during the exertion. Using the case–crossovermethod, we found the estimated relative risk of sudden deathduring exertion (a 30-minute hazard period) to be higher (relativerisk, 44.9; 95 percent confidence interval, 26.7 to 75.4) thanthat during the 60-minute hazard period, but it was still modifiedby habitual vigorous exercise (P for trend=0.003). When theusual duration of vigorous exercise was estimated to be 20 minutes,the relative risk of sudden death in the 60-minute hazard periodwas 20.4 (95 percent confidence interval, 12.7 to 32.7); itwas 14.6 (95 percent confidence interval, 9.10 to 23.4) whenthe duration was estimated to be 40 minutes. Again, modificationby usual vigorous exercise remained significant (P0.005). Finally,if deaths that occurred during sleep or were unwitnessed wereincluded as sudden deaths, the relative risk of sudden deathin the 60-minute hazard period remained elevated (relative risk,13.8; 95 percent confidence interval, 8.9 to 21.2), and thisexcess risk was still modified by the frequency of vigorousexercise (P for trend=0.003) (Table 4).
Table 4. Results of the Inclusion of Unwitnessed Deaths and Deaths during Sleep as Sudden Deaths.
Overall Risk Associated with Vigorous Exercise at Base Line
The base-line level of vigorous exercise was not significantlyassociated with the risk of subsequent sudden death, eitherbefore or after potential confounders had been controlled for.In contrast, the risk of nonsudden death from coronary heartdisease was lower among the men who participated in vigorousexercise than among those who did not. However, no further reductionin risk was observed for a frequency of exercise of more thanonce a week (Table 5).
Table 5. Multivariate Relative Risk of Sudden Death and Nonsudden Death from Coronary Heart Disease According to the Frequency of Vigorous Exercise at Base Line.
Discussion
In this prospective, nested case–crossover study of apparentlyhealthy male physicians, the risk of sudden death was transientlyelevated in association with an episode of vigorous exertionby a factor of 14 to 45, as compared with the risk during periodsof lighter or no exertion. Despite the high relative risk, theabsolute excess risk of sudden death during any particular episodeof vigorous exertion was extremely low (1 death per 1.51 millionepisodes of vigorous exertion), similar to that reported inother populations.7,9,11
As expected, the base-line level of habitual exercise significantlyattenuated the increase in the risk of sudden death that wasassociated with an episode of vigorous exertion in both theprimary analysis and the three sensitivity analyses. Habituallyactive men had a much lower risk of sudden death in associationwith an episode of vigorous exertion than men who exercisedless than once a week; however, the most active men's risk remainedsignificantly elevated during and after vigorous exertion inall analyses. These results are similar to those reported fornonfatal myocardial infarction17,25 and corroborate those previouslyreported in a population-based, retrospective case–controlstudy of victims of cardiac arrest.11
The effect of vigorous exertion on the sympathetic nervous system,plaque vulnerability, or both, could account for the findings.Acute bouts of exercise activate the sympathetic nervous systemand decrease vagal activity, leading to an acute increase insusceptibility to ventricular fibrillation.26 However, habitualvigorous exertion increases basal vagal tone, resulting in increasedcardiac electrical stability and in protection against ventricularfibrillation.27 In addition, sympathetic surges associated withacute exertion may promote plaque rupture,10,28 and habitualvigorous exercise could modify this risk through favorable effectson lipids or by decreasing the hemodynamic stress at a givenworkload.
Our finding that there was no relation between the frequencyof vigorous exercise as reported by the men at base line andthe overall risk of sudden death appears to be at odds withthe findings of numerous studies in which regular exercise wasassociated with reductions in the long-term risk of cardiacevents.4,5,6,29,30,31,32 However, few studies have examinedsudden death specifically and rigorously, and the results ofprospective studies have been conflicting. The Framingham Studyfound no relation between physical activity and sudden deathduring 20 years of follow-up.33,34 In contrast, the BritishRegional Heart Study35 and the Multiple Risk Factor InterventionTrial6 found significant reductions in the risk of sudden deathassociated with both moderate and vigorous exercise.
Several factors may explain why we found no association betweenhabitual exercise and the subsequent risk of sudden death. First,we had no information about moderate levels of activity, inwhich the men in our sedentary category could have been participatingregularly. Moderate physical activity is associated with a markedlyreduced risk of coronary events32,36 and cardiac arrest,37 andtherefore it might also protect against sudden death. Second,activity levels may have changed over the course of the study,and misclassification of the exposure could have contributedto the null result. Finally, the effect of vigorous exerciseon the risk of sudden death may actually be different from itseffect on other cardiovascular end points, such as nonsuddendeath (Table 5).
Our study has several limitations. First, the measure of physicalactivity that we used is limited in comparison with more objectivemeasures of physical fitness, which have been shown to correlatewith rates of cardiac events.38 Second, the base-line data onthe frequency of vigorous exertion were not updated during thestudy. Since levels of physical activity tend to vary over time,39there is likely to have been misclassification in our assessmentof each person's level of habitual exercise; if such errorswere random, this factor would tend to bias our results towarda null finding. However, if participation in vigorous exerciseeither increased or decreased over time, then our estimatesof the relative risk during exertion might have been biasedtoward a positive or negative association, respectively. Inaddition, we lacked information on the duration of vigorousexertion. For both of these reasons, the magnitude of the relativerisk associated with an acute episode of vigorous exertion shouldbe viewed as an estimate.
Third, the rarity of exertion-related sudden death limits thestatistical power of the study and tends to produce unstableestimates of risk. However, although the number is still quitesmall, the 23 sudden deaths that were associated with vigorousexertion in this study make up one of the largest series todate. Finally, our study and the earlier retrospective study11included only men, and therefore these data may not apply towomen.
In summary, prospective data on U.S. male physicians suggestthat bouts of vigorous exertion are associated with a transientincrease in the risk of sudden death and that habitual vigorousexercise diminishes this risk. The absolute magnitude of theincrease in risk associated with vigorous exertion is extremelysmall, and the overall risk of sudden death was not increasedin association with increasing frequency of vigorous exercise.Therefore, these data should not discourage participation inan exercise program. The benefits of a physically active lifestylein terms of multiple health outcomes, including the frequencyof all cardiovascular events, clearly outweigh the small risksdescribed above. However, further research directed at the mechanismsunderlying sudden death during vigorous exertion may lead toinnovative strategies to prevent this rare but devastating event.
Supported by grants (CA-40360 and HL-34595) from the NationalInstitutes of Health. Dr. Albert is the recipient of a MentoredClinical Scientist Development Award (1-K08-HL-03783) from theNational Heart, Lung, and Blood Institute.
Source Information
From the Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Boston (C.M.A., C.U.C., I.-M.L., J.E.M.); the Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (C.M.A., C.U.C.); the Cardiology Division, Beth Israel Deaconess Medical Center, Boston (M.A.M.); the Department of Epidemiology, Harvard School of Public Health, Boston (I.-M.L., M.A.M., J.E.M.); and the Department of Medicine, Epidemiology and Public Health, University of Miami School of Medicine, Miami (C.H.H.).
Address reprint requests to Dr. Albert at the Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Ave. E., Boston, MA 02215-1204, or at calbert{at}partners.org.
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0.005). Finally, if deaths that occurred during sleep or were unwitnessed were included as sudden deaths, the relative risk of sudden death in the 60-minute hazard period remained elevated (relative risk, 13.8; 95 percent confidence interval, 8.9 to 21.2), and this excess risk was still modified by the frequency of vigorous exercise (P for trend=0.003) (Table 4). 
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