Heart-Rate Profile during Exercise as a Predictor of Sudden Death
Xavier Jouven, M.D., Ph.D., Jean-Philippe Empana, M.D., Peter J. Schwartz, M.D., Michel Desnos, M.D., Dominique Courbon, M.S.C., and Pierre Ducimetière, Ph.D.
Background Changes in heart rate during exercise and recoveryfrom exercise are mediated by the balance between sympatheticand vagal activity. Since alterations in the neural controlof cardiac function contribute to the risk of sudden death,we tested the hypothesis that among apparently healthy persons,sudden death is more likely to occur in the presence of abnormalheart-rate profiles during exercise and recovery.
Methods A total of 5713 asymptomatic working men (between theages of 42 and 53 years), none of whom had clinically detectablecardiovascular disease, underwent standardized graded exercisetesting between 1967 and 1972. We examined data on the subjects'resting heart rates, the increase in rate from the resting levelto the peak exercise level, and the decrease in rate from thepeak exercise level to the level one minute after the terminationof exercise.
Results During a 23-year follow-up period, 81 subjects diedsuddenly. The risk of sudden death from myocardial infarctionwas increased in subjects with a resting heart rate that wasmore than 75 beats per minute (relative risk, 3.92; 95 percentconfidence interval, 1.91 to 8.00); in subjects with an increasein heart rate during exercise that was less than 89 beats perminute (relative risk, 6.18; 95 percent confidence interval,2.37 to 16.11); and in subjects with a decrease in heart rateof less than 25 beats per minute after the termination of exercise(relative risk, 2.20; 95 percent confidence interval, 1.02 to4.74). After adjustment for potential confounding variables,these three factors remained strongly associated with an increasedrisk of sudden death, with a moderate but significantly increasedrisk of death from any cause but not of nonsudden death frommyocardial infarction.
Conclusions The heart-rate profile during exercise and recoveryis a predictor of sudden death.
Sudden and unexpected death from cardiac causes is an importanthealth burden in the Western world. Its effect is accentuatedby the fact that sudden death is often the first manifestationof cardiovascular disease.1,2 Thus, identification of apparentlynormal persons who actually are at higher-than-average riskfor sudden death is a major challenge.
The past two decades have witnessed growing evidence (both experimentaland clinical) of a tight relationship between abnormalitiesin the autonomic nervous system and death from myocardial infarction,both sudden and not sudden.3,4,5,6 Autonomic imbalance, a termused to indicate a relative or absolute decrease in vagal activityor an increase in sympathetic activity, has been associatedwith an increased risk of death from cardiac causes7 and fromarrhythmic causes.8 One common feature has been that whenevermarkers of tonic or reflex vagal activity are reduced, the riskof death is increased.6 This is true for baroreflex sensitivity,4,5,6for heart-rate variability,9 for heart-rate turbulence (immediatelyfollowing a premature ventricular beat),10 and for heart-raterecovery after an exercise stress test.11 The last is independentof the angiographic severity of coronary artery disease,12 suggestingthat alternative mechanisms are involved. Indeed, survival duringa first ischemic episode is predicted by autonomic responses,4suggesting a genetic predisposition.13
However, all these previous findings were obtained in studiesof patients with known cardiac disease. We explored the possibilitythat abnormalities in the control of heart rate in apparentlyhealthy men may indeed precede clinical symptoms and may allowearly identification of persons at increased risk for death,particularly for sudden death from myocardial infarction.
Since exercise stress testing is an easily performed and inexpensivetool that provides a wealth of information on the state of theautonomic nervous system and on its responsiveness, we assessedthe heart-rate profile during exercise as a potential predictorof sudden death in a long-term cohort study of asymptomaticmiddle-aged men.
Methods
Details of the Paris Prospective Study I concerning the recruitment,design, and procedures have been described elsewhere.14,15,16Briefly, the consecutive examination of 7746 native Frenchmenemployed by the Paris Civil Service (age range, 42 to 53 years)was carried out from 1967 to 1972. Oral informed consent wasobtained from each participant, and the research protocol wasapproved by the appropriate institutional board (CommissionNationale Informatique et Liberté). This sample represented93.4 percent of the total number of employees in early 1967who were born between 1917 and 1928. Subjects underwent electrocardiographicand physical examinations conducted by a physician, providedblood samples for laboratory tests, and answered questionnairesadministered by trained interviewers. Resting heart rate wasdetermined by measurement of the radial pulse during a one-minuterecording, after a five-minute rest in the supine position.Diabetes was defined as past or present reported diabetes, whetheror not the condition was being treated.
Subjects with known or suspected cardiovascular disease of anygrade or cause were excluded from the study and did not undergothe exercise stress test. Also excluded from the study werepatients with a resting systolic blood pressure of more than180 mm Hg or an abnormality on a resting 12-lead standard electrocardiogram(Minnesota code). Ventricular function was not assessed. A totalof 6565 men completed exercise testing, but complete data wereavailable for only 6456 (98.3 percent). Only those subjectswho performed the exercise test were considered for the presentanalysis; therefore, numbers vary from those in previous reportsthat considered all subjects at enrollment.16
Exercise Test Protocol
The standardized protocol of the bicycle exercise test consistedof three successive workloads: 2 minutes at 82 W, 6 minutesat 164 W, and the last 2 minutes at 191 W, for a maximum 10-minutetest duration without a cool-down period.15 The subjects' cardiacrhythm was continuously monitored, and a bipolar lead (V5 andV5R) was recorded at rest and for 30 seconds every 2 minutesduring exercise at maximum effort and every minute during the10-minute recovery time or whenever the monitoring physicianobserved an arrhythmia. Heart rate was measured at rest, beforeexercise, every two minutes during exercise, at peak exercise,and every minute during recovery. The heart-rate increase wasdefined as the difference between the peak exercise rate andthe resting rate, and heart-rate recovery was defined as thereduction in rate from the peak exercise level to the rate oneminute after the cessation of exercise. Testing was terminatedbecause of fatigue, dyspnea, leg discomfort, chest pain, a systolicblood pressure of more than 250 mm Hg, a heart rate of morethan 180 beats per minute, ventricular tachycardia, or ischemicelectrocardiographic changes. An ischemic response was definedas a J-point depression of 1 mm or more, with a flat or downslopingST-segment depression during exercise or recovery. The 271 subjectswho had an ischemic response to exercise and the 117 subjectswho had an impaired chronotropic response (i.e., those who didnot achieve 80 percent of the predicted maximum heart rate,defined as 220 beats per minute minus age) were excluded fromthe analysis.
Follow-up
Until the retirement of the study subjects, the administrativedepartment in charge of the study population provided an annuallist of all the subjects who had died. All available data relevantto the causes of death were collected by means of specific inquiries(i.e., medical records from hospital departments or generalpractitioners). An independent medical committee then reviewedthe data. After the subjects' retirement, causes of death wereobtained from death certificates. The ninth revision of theInternational Classification of Diseases17 was used for coding.Sudden death from myocardial infarction was defined as a naturaldeath that occurred within one hour after the onset of acutesymptoms. Nonsudden death from myocardial infarction was codedonly if the death was found to be strictly related to myocardialinfarction and had occurred more than one hour after the onsetof symptoms.
The end of the follow-up period was January 1, 1994. The vitalstatus could not be determined for 355 subjects (4.6 percentof the original 7746 subjects). Their characteristics at baselineand during exercise were not significantly different from thoseof the remaining 5713 men studied in the present analysis.
Statistical Analysis
Because of the skewed distribution of triglycerides, log-transformedvalues were used in the analysis. The Mantel–Haenszelchi-square test for trend was used for comparisons among quintilesof heart rate. Two-sided P values are reported. The relativerisk of death was estimated with a Cox proportional-hazardsmodel and was assessed for each quintile of heart rate. In analysesof both sudden and nonsudden death from cardiac causes, datafor subjects who died from other causes were censored at theirdate of death. Data were analyzed with the use of SAS software(SAS Institute).
Results
Among the 5713 men, and during the mean follow-up of 23 years,there were 1516 deaths (26.5 percent) from all causes, including400 deaths from cardiac causes (7.0 percent), of which 81 weresudden deaths and 129 were nonsudden deaths from myocardialinfarction. The mean (±SD) interval between the initialclinical examination and death was 11.7±5.1 years forsudden death from cardiac causes and 16.8±5.9 years fornonsudden death from cardiac causes, and the mean duration offollow-up was 21.8±4.9 years for all other participants.Baseline characteristics of the subjects are given in Table 1according to the cause of death.
Table 1. Baseline Characteristics and Their Association with Selective Outcomes during Follow-up.
The mean maximum heart rate (expressed as the percentage ofthe predicted maximum heart rate) during exercise was 96±0.8in subjects who died suddenly from cardiac causes, 97±0.6in subjects who died from cardiac causes but not suddenly, and98±0.1 in subjects who either died from other causesor survived (controls). The duration of exercise was 6.0±2.3minutes in the sudden-death group, 6.7±2.6 minutes inthe nonsudden-death group, and 7.3±2.5 minutes in thecontrol group. The exercise stress test was stopped during the164-W stage in 64 of 81 subjects who died suddenly from cardiaccauses (79.0 percent), in 88 of 129 of subjects who died fromcardiac causes but not suddenly (68.2 percent), and in 3247of 5503 controls (59.0 percent). The rest of the men reachedthe last, 191-W stage.
After adjustments were made for age, use or nonuse of tobacco,level of physical activity, presence or absence of diabetes,body-mass index, basal systolic blood pressure, cholesterollevel, presence or absence of a parental history of sudden deathor myocardial infarction, and exercise duration, the risk ofsudden death increased progressively with the resting heartrate; as compared with the risk in the lowest quintile, therisk in the highest quintile was 3.5 times as high (P for trend<0.001); the relationship was weaker, although significant,between resting heart rate and the risk of nonsudden death anddeath from any cause (1.5 times that in the lowest quintile[P=0.02] and 1.9 times that in the lowest quintile [P<0.001],respectively) (Figure 1).
Figure 1. Relative Risks of Death from Any Cause and of Nonsudden and Sudden Death from Myocardial Infarction, According to the Quintile of Resting Heart Rate.
The reference group was subjects with a resting heart rate of less than 60 beats per minute (lowest quintile). The numbers over the bars indicate the numbers of subjects. Comparisons were performed with the Mantel–Haenszel chi-square test for trend. The test for trend showed a significant difference among quintiles with respect to the risk of death from any cause (P<0.001), nonsudden death from cardiac causes (P=0.02), and sudden death from cardiac causes (P<0.001). Adjustments were made for age, use or nonuse of tobacco, level of physical activity, presence or absence of diabetes, body-mass index, basal systolic blood pressure, cholesterol level, presence or absence of a parental history of sudden death or myocardial infarction, and exercise duration. Data are missing for five subjects who died of any cause, including one who died suddenly from myocardial infarction.
A statistically significant association was observed betweenan increase in heart rate and mortality. With a heart-rate increaseof more than 113 beats per minute (highest quintile) used asthe reference category, subjects with a heart-rate increaseof less than 89 beats per minute (lowest quintile) had 4.0 timesthe risk of sudden death, 1.2 times the risk of nonsudden death,and 1.5 times the risk of death from any cause (Figure 2).
Figure 2. Adjusted Relative Risks of Death from Any Cause and from Nonsudden and Sudden Death from Myocardial Infarction, According to the Difference between the Resting and Maximum Heart Rate.
The reference group was subjects with a difference of more than 113 beats per minute between the resting and maximum heart rates (highest quintile). The numbers over the bars indicate the numbers of subjects. Comparisons were performed with the Mantel–Haenszel chi-square test for trend. The test for trend showed a significant difference among quintiles with respect to the risk of death from any cause (P<0.001), nonsudden death from cardiac causes (P=0.01), and sudden death from cardiac causes (P<0.001). Adjustments were made for age, use or nonuse of tobacco, level of physical activity, presence or absence of diabetes, body-mass index, basal systolic blood pressure, cholesterol level, presence or absence of a parental history of sudden death or myocardial infarction, and exercise duration. Data are missing for five subjects who died of any cause, including one who died suddenly from myocardial infarction.
During recovery, the patients' mean heart rate decreased progressively.Heart rates at one, two, three, and four minutes after the cessationof exercise were all associated with death from any cause andparticularly with sudden death, but not with nonsudden deathfrom myocardial infarction. With subjects who had a heart-raterecovery (the decrease from the maximum heart rate) at one minuteof more than 40 beats per minute (the highest quintile) usedas the reference group, subjects with a heart-rate recoveryof less than 25 beats per minute (the lowest quintile) had 2.1times the risk of sudden death, 0.9 times the risk of nonsuddendeath, and 1.3 times the risk of death from any cause (Figure 3).
Figure 3. Adjusted Relative Risks of Death from Any Cause and from Nonsudden and Sudden Death from Myocardial Infarction, According to the Difference between Maximum Heart Rate and Heart Rate at One Minute after Cessation of Exercise.
The reference group was subjects with a difference of more than 40 beats per minute between the maximum heart rate and the heart rate at one minute after cessation of exercise (highest quintile). The numbers over the bars indicate the numbers of subjects. Comparisons were performed with the Mantel–Haenszel chi-square test for trend. The test for trend showed a significant difference among quintiles with respect to the risk of death from any cause (P<0.001) and sudden death from cardiac causes (P=0.03) but was not significant for nonsudden death (P=0.20). Adjustments were made for age, use or nonuse of tobacco, level of physical activity, presence or absence of diabetes, body-mass index, basal systolic blood pressure, cholesterol level, presence or absence of a parental history of sudden death or myocardial infarction, and exercise duration. Data on heart-rate recovery at one minute are missing for 102 subjects who died of any cause, including 5 who died suddenly from myocardial infarction and 5 who died, but not suddenly, from myocardial infarction.
The risks of death associated with these heart-rate markersare shown in Table 2. In the univariate analysis and after adjustmentfor confounding factors — age, use or nonuse of tobacco,level of physical activity, presence or absence of diabetes,body-mass index, basal systolic blood pressure, cholesterollevel, presence or absence of a parental history of sudden deathor myocardial infarction, and exercise duration — theheart-rate profile was strongly associated with sudden deathand less strongly associated with death from any cause, butit was not associated with nonsudden death from myocardial infarction(except for basal heart rate). Among these three heart-ratemarkers, the strongest predictor of sudden death was a lowerincrease in heart rate (i.e., the difference between the rateat peak maximum exercise and the rate at rest), with a relativerisk of 6.18 in the univariate analysis (95 percent confidenceinterval, 2.37 to 16.11) for the lowest as compared with thehighest quintile and 3.98 after adjustment for confounding factors(95 percent confidence interval, 1.49 to 10.61). When thesethree markers were simultaneously introduced in the analysis,sudden death was significantly associated with a lower increasein heart rate but not with the resting heart rate or the heart-raterecovery (because of the markers' high mutual correlations).When the analysis was restricted to subjects who stopped exerciseat the 164-W level, the results were similar (data not shown).
Table 2. Relative Risk of Sudden Death and Nonsudden Death from Myocardial Infarction and Death from Any Cause According to Heart-Rate Variables.
Discussion
Our findings, obtained in a study of a large cohort of apparentlyhealthy persons, indicate that the heart-rate profile duringexercise and recovery is a strong predictor of sudden death.Since heart-rate responses to exercise are under the controlof the autonomic nervous system, these data support the conceptthat abnormalities in autonomic balance may precede manifestationsof cardiovascular disease and may contribute to the early identificationof persons at high risk for sudden death.
In most cases of sudden death in adults, coronary lesions arepresent18 together with traditional risk factors for atherosclerosis.In addition, it has been suggested19 that reflex sympatheticactivation elicited by acute myocardial ischemia20 might playa triggering role. Here, we explored the possibility that autonomicimbalance would be associated with increased risk of arrhythmiaand could be unmasked by observing changes in heart rate duringexercise.
The association between altered heart-rate responses duringexercise and sudden death from cardiac causes and the absenceof such an association with nonsudden death from myocardialinfarction suggest that this risk factor is directly associatedwith a particular susceptibility to cardiac arrhythmia and doesnot reflect the development of atherosclerosis. It is consistentwith the notion that autonomic imbalance predisposes personsto life-threatening arrhythmias.4,8
The mechanism underlying the present findings is not immediatelyobvious. Current knowledge, which is based on multiple associationsbetween an increased risk of sudden death and reduced vagalactivity or increased sympathetic activity,3,4,5,6 could explainour observation that subjects who died suddenly of cardiac causeshad a higher heart rate before exercise16 and a more sluggishdecrease in heart rate during the recovery period. However,one would have expected them to have a greater increase in heartrate during exercise, whereas the opposite was found.
An increased risk of death is associated with an inability toincrease heart rate properly during exercise, a phenomenon calledchronotropic incompetence.21,22 This reasonable explanation,however, does not apply to our data because the subjects whodid not reach 80 percent of the expected maximum heart ratewere excluded from the study. Although subjects in the sudden-deathgroup did not have chronotropic incompetence, they were nonethelessunable to increase their heart rate at peak exercise to levelsthat are normal for most people, a finding that indicates animpairment in the ability to increase sympathetic activity toits maximum extent.
Thus, a greater risk of sudden death was associated with animpaired ability to increase not only vagal but also sympatheticactivity to appropriate levels. Such a condition could be explainedby a reduced baroreflex sensitivity, with blood pressure changingin either direction. Indeed, it has previously been shown thatamong patients who have had myocardial infarction and have similarleft ventricular ejection fractions, the inability to sustainepisodes of ventricular tachycardia without circulatory collapsewas predicted by depressed baroreflex sensitivity.23,24,25 Thus,an impairment in baroreflex sensitivity involving both sympatheticand vagal responses favors circulatory collapse during ventriculartachycardia, a condition that precipitates ventricular fibrillationand sudden death. The clinical counterpart of this defectivephysiological response would be a reduced ability to increaseheart rate during exercise to the maximum extent — whichrepresents the most puzzling of the features that we found tobe associated with an increased risk of sudden death.
For apparently healthy persons with a heart-rate profile thatis associated with a high risk of sudden death, a possible therapeuticapproach might be the correction of the autonomic imbalance.In addition to traditional management of cardiovascular riskfactors, initiation of a regular exercise-training program shouldbe recommended. Indeed, both experimental26,27 and clinical28data indicate that when exercise training shifts the autonomicbalance through an adequate increase in vagal activity, it cansignificantly improve long-term prognosis.
Assessment of the effects of an exercise-training program forhigh-risk persons within the general population would requirean interventional trial. Our population consisted of asymptomatic,healthy men employed by the Paris Civil Service. Socioeconomicstatus, prevalence of smoking, extent of alcohol use, and otherfactors in this group might differ from those in the generalpopulation. The incidence of coronary heart disease has changedwithin recent decades and was higher in this cohort than itwould be today. Moreover, the study involved only men, and thefindings might be different in women.29 Therefore, the extentto which the present findings could be generalized to a moreunselected or recent population cohort is unclear. Since follow-upwas focused on mortality only, the possible development of cardiovasculardisease and treatment during the follow-up period were not assessed.
Because it was designed to achieve the maximum predicted heartrate in asymptomatic subjects as rapidly as possible, the exercise-testpattern was unusual. The rapidity with which workload was increasedmay have influenced the results, and the findings may not bedirectly applicable to subjects undergoing standard treadmilltesting. The heart-rate values might be different with differentprotocols. The subjects who died suddenly had lower maximumheart rates and reached those levels more rapidly than did theother subjects. Since a heart-rate level above 180 beats perminute was a cause of cessation of the exercise test, the durationof the exercise test for these subjects was shorter. However,the same results persisted after adjustment for the durationof exercise. Moreover, when the subjects who reached the levelof 191 W were excluded from the analysis, similar results wereobserved.
The heart-rate profile during exercise and recovery is a powerfulpredictor of the risk of sudden death in asymptomatic men. Impairmentof the ability to increase both sympathetic and vagal activityrapidly is a possible (but hypothetical) mechanism. These findingsmay have clinical implications in terms of the early identificationof high-risk subjects and raise the possibility of primary prevention.
Supported by INSERM, the city of Paris, and the French Ministryof Health.
We are indebted to Julien DuVignac for his help in preparingthis article.
Source Information
From the Service de Cardiologie, Faculté René Descartes, Université Paris-5, Hôpital Européen Georges Pompidou, Paris (X.J., M.D.); INSERM Avenir Unité 258, Epidémiologie Cardiovasculaire et Métabolique, Hôpital Paul Brousse, Villejuif, France (X.J., J.-P.E, D.C., P.D.); and the Department of Cardiology, University of Pavia and Istituto di Ricovera e Cura a Carattere Policlinico San Matteo, Pavia, Italy (P.J.S.).
Address reprint requests to Dr. Jouven at the Service de Cardiologie, Faculté René Descartes, Université Paris-5, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France, or at xavier.jouven{at}egp.aphp.fr.
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