Background Exercise testing is widely used in the diagnosisof coronary artery disease, but the long-term outcome for asymptomaticpersons with exercise-induced premature ventricular depolarizationsremains unclear. We used data from the Paris Prospective StudyI to assess the long-term outcome of such persons.
Methods A total of 6101 asymptomatic French men (42 to 53 yearsof age) who were free of clinically detectable cardiovasculardisease underwent a standardized graded exercise test between1967 and 1972. Subjects were prospectively classified as havingor not having frequent premature ventricular depolarizations(a run of two or more consecutive premature ventricular depolarizationsor premature ventricular depolarizations constituting more than10 percent of all ventricular depolarizations during any ofthe 30-second electrocardiographic recordings).
Results During exercise, 138 subjects had frequent prematureventricular depolarizations. After 23 years of follow-up, thesesubjects had a higher risk of death from cardiovascular causesthan the men without frequent premature ventricular depolarizationsduring exercise (relative risk, 2.67; 95 percent confidenceinterval, 1.76 to 4.07). In a multivariate model, with adjustmentfor standard coronary risk factors and the presence or absenceof premature ventricular depolarizations before exercise andduring recovery from exercise, both exercise-induced ischemiaand the occurrence of frequent premature ventricular depolarizationsduring exercise remained independently associated with an increasedrisk of death from cardiovascular causes, with similar relativerisks (2.63 [95 percent confidence interval, 1.93 to 3.59] and2.53 [95 percent confidence interval, 1.65 to 3.88], respectively).
Conclusions The occurrence of frequent premature ventriculardepolarizations during exercise in asymptomatic middle-agedmen is associated with a long-term increase in the risk of deathfrom cardiovascular causes.
Exercise testing is widely used to detect coronary heart diseaseand to assess the short- and long-term prognosis in patientswith the disease. Numerous studies have shown that an ischemicST-segment response to exercise is a powerful predictor of majorcoronary events, including death, in apparently healthy persons.1,2,3,4,5,6,7
Whether the occurrence of premature ventricular depolarizationsduring exercise is useful in the diagnosis of coronary heartdisease and in the assessment of prognosis remains controversial.Although an association between the occurrence of prematureventricular depolarizations during exercise and coronary heartdisease has been described in patients at high risk for coronaryheart disease, it is uncertain whether there is such an associationin asymptomatic men.8,9,10,11,12,13 The short- and long-termprognosis of persons with exercise-induced premature ventriculardepolarizations is also uncertain.1,14,15,16,17,18,19
The occurrence of premature ventricular depolarizations duringexercise in asymptomatic subjects raises the question of whethersuch depolarizations may be a normal response to exercise.20If so, long-term mortality should not be affected. We used datafrom 23 years of follow-up in the Paris Prospective Study Ito answer this question.
Methods
Subjects
Details of the study have been described elsewhere.21 Briefly,after their oral informed consent was obtained, 7746 Frenchmenwho were employed by the Paris Civil Service and who were between42 and 53 years of age were examined from 1967 through 1972.This sample represented 93.4 percent of all the men employedby the Paris Civil Service in early 1967 who had been born inFrance between 1917 and 1928. The subjects underwent electrocardiographyand physical examinations, provided blood samples for laboratorytests, and supplied information on questionnaires administeredby trained interviewers. The means of three measurements ofdiastolic and systolic blood pressure were used for analysis.The subjects were classified as diabetic if they reported havingever had diabetes, whether or not it was treated.
Subjects could be excluded for technical or medical reasons.Subjects underwent exercise testing unless they had known orsuspected cardiovascular disease of any grade or cause, a systolicblood pressure above 180 mm Hg at rest, or any abnormality on12-lead standard electrocardiography at rest according to theMinnesota code (definite Q waves, atrioventricular block orconduction defects, ST-segment abnormalities, supraventriculartachycardia, or polymorphic premature ventricular depolarizations).No attempt was made to assess ventricular function. Completedata were available for 6456 of 6565 men who completed the exercisetest.
Exercise-Test Protocol
The bicycle exercise test was conducted according to a standardprotocol.22 It consisted of three successive workloads: 2 minutesat 82 W, 6 minutes at 164 W, and the last 2 minutes at 191 W,for a maximal duration of 10 minutes. Cardiac rhythm was continuouslymonitored, and 30-second recordings were made from a bipolarlead (V5 and V5R) while the subject was at rest and every 2minutes during a maximum of 10 minutes of exercise, at maximaleffort, and every 1 minute during the 10-minute recovery time,or whenever the monitoring physician observed an arrhythmia.Testing was terminated if the subject had fatigue, dyspnea,leg discomfort, any chest pain, systolic blood pressure above250 mm Hg, a heart rate of 180 beats per minute or more, ventriculartachycardia, or electrocardiographic changes indicative of ischemia.An ischemic response was defined as a J-point depression ofat least 1 mm, with a flat or downsloping ST segment, duringexercise or recovery. At the time of each electrocardiographicrecording, the frequency of premature ventricular depolarizationswas assessed as the maximal number of premature ventriculardepolarizations divided by the total number of ventricular depolarizationsduring any of the 30-second recordings. Subjects with a runof two or more consecutive premature ventricular depolarizationsor with premature ventricular depolarizations constituting morethan 10 percent of all ventricular depolarizations on any ofthe electrocardiograms recorded with the subject at rest, duringexercise, or during recovery were classified as having had frequentpremature ventricular depolarizations during that period. Subjectsclassified as having infrequent premature ventricular depolarizationswere those with premature ventricular depolarizations constituting10 percent or less of all ventricular depolarizations. Thesecriteria were defined in the study protocol and coded by thephysician who conducted the examination.
Follow-Up
The administrative department in charge of the study populationprovided an annual list of all subjects not yet retired whohad died during the year. All available data relevant to thecause of death were obtained from hospital records or from thesubjects' general practitioners, as identified by their relatives.The data were then reviewed by an independent medical committee.For subjects who died after retirement, the cause of death wasobtained from death certificates. The cause of death was codedaccording to the eighth revision of the International Classificationof Diseases.23 Sudden death was defined as a natural death occurringwithin one hour after the onset of acute symptoms. Death wascoded as due to myocardial infarction only if the death wasfound to be definitely related to myocardial infarction.
The follow-up period ended on January 1, 1994. Vital statuscould not be determined for 355 (5.5 percent) of the 6456 subjectsfor whom complete exercise-test data were available. Their characteristicsat base line and during exercise were not significantly differentfrom those of the remaining 6101 men whom we studied.
Statistical Analysis
Analysis of variance and chi-square analysis were used for comparisonsbetween groups. Because of the skewed distribution of triglyceridevalues, log-transformed values were used in the analysis ofthis factor. Analysis of variance and logistic regression wereused to identify factors associated with an exercise test thatwas positive for ischemia and factors associated with the occurrenceof frequent premature ventricular depolarizations, after mutualadjustment. The relative risks of death were adjusted for confoundingfactors and estimated by the Cox proportional-hazards model.SAS software (SAS Institute, Cary, N.C.) was used for analysis.
Results
There were no serious complications of exercise testing (suchas death, myocardial infarction, or ventricular fibrillation).The test was positive for ischemia in 271 of 6101 subjects (4.4percent). Frequent premature ventricular depolarizations occurredin 48 subjects (0.8 percent) before exercise, in 138 (2.3 percent)during exercise, and in 174 (2.9 percent) during recovery. Themean (±SD) heart rate at the end of exercise was 167±16beats per minute (96±9 percent of the predicted maximalheart rate). During the 23 years of follow-up, 1635 subjects(26.8 percent) died, including 435 from cardiovascular causes(7.1 percent).
Rates of Death among Subjects with Premature Ventricular Depolarizations
Forty-eight of the 6101 subjects (0.8 percent) had frequentpremature ventricular depolarizations before exercise, 121 (2.0percent) had infrequent premature ventricular depolarizations,and 5932 (97.2 percent) had none (Table 1). There were no significantdifferences among these three groups in the rates of death fromall causes, death from noncardiovascular causes, or death fromcardiovascular causes (which included sudden death, fatal myocardialinfarction, and death from other cardiovascular causes).
Table 1. Death Rates According to the Frequency of Premature Ventricular Depolarizations Occurring before, during, or after Exercise.
During exercise, 138 subjects (2.3 percent) had frequent prematureventricular depolarizations, 520 (8.5 percent) had infrequentpremature ventricular depolarizations, and 5443 (89.2 percent)had none. The rates of death from all causes and death fromcardiovascular causes were significantly (P<0.001) higherin subjects with frequent premature ventricular depolarizationsthan in the other two groups (death from all causes: 41.3 percent,vs. 27.9 percent in the group with infrequent premature ventriculardepolarizations and 26.3 percent in the group with none; deathfrom cardiovascular causes: 16.7 percent, vs. 7.3 percent and6.8 percent). The rate of death from noncardiovascular causesdid not differ significantly among the three groups. There wereno significant differences in the rates of death from all causes,death from noncardiovascular causes, or death from cardiovascularcauses between subjects with infrequent premature ventriculardepolarizations and those without such depolarizations.
During recovery from exercise, 174 subjects (2.9 percent) hadfrequent premature ventricular depolarizations, 448 (7.3 percent)had infrequent premature ventricular depolarizations, and 5479(89.8 percent) had none. The rates of death from all causesand from noncardiovascular causes were significantly higheramong subjects with frequent premature ventricular depolarizationsduring recovery than in the other two groups. The rates of deathfrom cardiovascular causes were similar in the three groups.
Occurrence of Premature Ventricular Depolarizations during Exercise
There were no significant differences in cardiovascular riskfactors between the subjects with infrequent premature ventriculardepolarizations and those without premature ventricular depolarizationsduring exercise. The 271 subjects (4.4 percent) with a positiveexercise test were equally distributed among the three groups.The exercise test was stopped because of chest pain in 8 subjects(0.1 percent), none of whom had premature ventricular depolarizations;the test was stopped because of runs of two or more prematureventricular depolarizations in 16 subjects (0.3 percent).
Premature Ventricular Depolarizations before, during, and after Exercise
Among the 48 subjects with frequent premature ventricular depolarizationsbefore exercise, 3 (6 percent) continued to have frequent prematureventricular depolarizations during exercise and 15 (31 percent)had a recurrence of frequent premature ventricular depolarizationsduring recovery from exercise. Among the 138 subjects who hadfrequent premature ventricular depolarizations during exercise,3 (2.2 percent) also had frequent premature ventricular depolarizationsbefore exercise, 125 (90.6 percent) had no premature ventriculardepolarizations before exercise, 21 (15.2 percent) continuedto have frequent premature ventricular depolarizations duringrecovery, and 96 (69.6 percent) had none during recovery.
Occurrence of Ischemia or Frequent Premature Ventricular Depolarizations during Exercise
Because of their similar characteristics and mortality rates,the groups with infrequent and with no premature ventriculardepolarizations during exercise were combined and compared withthe group with frequent premature ventricular depolarizationsduring exercise. Older age and higher levels of total cholesteroland triglycerides were significantly associated with a positiveexercise test, but not with frequent premature ventricular depolarizationsduring exercise (Table 2). The body-mass index (the weight inkilograms divided by the square of the height in meters) wassignificantly lower and tobacco consumption was significantlyhigher among subjects with frequent premature ventricular depolarizations,but neither was associated with a positive exercise test. Themaximal heart rate and the percentage of the predicted maximalheart rate achieved during exercise were significantly higherin subjects with evidence of ischemia on the exercise test.The duration of the exercise test was significantly shorteramong subjects with a positive exercise test and among thosewith frequent premature ventricular depolarizations. Diabeticstatus, extent of physical activity, heart rate at rest, systolicblood pressure at rest, and maximal systolic blood pressurewere not significantly associated with either the exercise-testresult or with the presence or absence of frequent prematureventricular depolarizations.
Table 2. Characteristics of Subjects According to the Presence or Absence of Ischemia and Frequent Premature Ventricular Depolarizations (PVDs) during Exercise.
Death Rates and Relative Risks of Death from Cardiovascular Causes
Subjects with evidence of ischemia on exercise testing or withfrequent premature ventricular depolarizations during exercisehad significantly higher rates of death from all causes andfrom cardiovascular causes, but not from noncardiovascular causes(Table 3). Those with a positive exercise test had significantlyhigher rates of death from myocardial infarction and of suddendeath, but not of deaths due to other cardiovascular causes.Those with frequent premature ventricular depolarizations duringexercise had significantly higher rates of death due to myocardialinfarction and other causes of cardiovascular death, but notof sudden death. There was no significant interaction betweenthe exercise-test result and the presence or absence of frequentpremature ventricular depolarizations during exercise.
Table 3. Rates and Relative Risks of Death from Cardiovascular Causes Associated with the Presence or Absence of Ischemia or Frequent Premature Ventricular Depolarizations (PVDs) during Exercise.
As Figure 1 shows, the proportion that did not die from cardiovascularcauses did not differ markedly between subjects with an exercisetest that was positive for ischemia and those with frequentpremature ventricular depolarizations during exercise.
Figure 1. Percentage without Death from Cardiovascular Causes among Subjects with an Exercise Test That Was Positive for Ischemia, Subjects with Frequent Premature Ventricular Depolarizations during Exercise, and Subjects with Neither a Positive Exercise Test nor Frequent Premature Ventricular Depolarizations.
The data were analyzed by Cox proportional-hazards methods. Cox estimates were adjusted for age, tobacco use, diabetic status, body-mass index, level of physical activity, systolic blood pressure, the heart rate at rest, total cholesterol level, the presence or absence of premature ventricular depolarizations before exercise, and the presence or absence of premature ventricular depolarizations during recovery from exercise. Data were censored if subjects died of other causes.
A multivariate analysis was performed with adjustment for age,body-mass index, heart rate at rest, systolic blood pressure,tobacco use, level of physical activity, diabetic status, totalcholesterol level, the occurrence of premature ventricular depolarizationsbefore exercise, and the occurrence of premature ventriculardepolarizations during recovery. The results showed that a positiveexercise test and the occurrence of frequent premature ventriculardepolarizations during exercise were independently associatedwith a higher mortality rate from cardiovascular causes, withsimilar relative risks (Table 3). The relative risks were 2.63(95 percent confidence interval, 1.93 to 3.59) for ischemiaand 2.53 (95 percent confidence interval, 1.65 to 3.88) forfrequent premature ventricular depolarizations.
Runs of Premature Ventricular Depolarizations
Runs of two or more consecutive premature ventricular depolarizationswere induced in 16 subjects during exercise and in 6 other subjectsduring recovery, and they all resolved spontaneously. The characteristicsof these subjects did not differ significantly from those ofsubjects who had frequent pre-mature ventricular depolarizationswithout complex runs. When data from the subjects with complexruns were excluded from the preceding analysis, the resultsdid not change significantly: the occurrence of frequent prematureventricular depolarizations during exercise remained independentlyassociated with higher mortality from cardiovascular causes,with a relative risk of 2.17 and a 95 percent confidence intervalof 1.34 to 3.50.
Discussion
The occurrence of premature ventricular depolarizations duringexercise may be related to exercise-induced myocardial ischemia.15,16,17,18,19However, subjects with an exercise test that was positive forischemia and subjects with frequent premature ventricular depolarizationsduring exercise do not share the same pattern of risk factors.It is striking that among the 271 subjects with a positive exercisetest, only 3 percent had frequent premature ventricular depolarizationsduring exercise. Conversely, among the 138 subjects with frequentpremature ventricular depolarizations during exercise, only6 percent had an exercise test that was positive for ischemia.
The occurrence of premature ventricular depolarizations duringexercise may be mediated by the increase in plasma catecholaminesrelated to exercise,24 and both epinephrine and norepinephrinelevels have been shown to continue to increase during the firstthree minutes after exercise.25 Only 21 of 138 subjects (15.2percent) had frequent premature ventricular depolarizationsboth during and after exercise. The outcome for this group wasnot different from that of subjects who had frequent prematureventricular depolarizations only during exercise, but the numberswere too small for any firm conclusions to be drawn.
The higher rate of death from noncardiovascular causes amongsubjects who had frequent premature ventricular depolarizationsduring the period of recovery from exercise than in those withoutsuch depolarizations remains difficult to explain. It is likelythat different mechanisms cause premature ventricular depolarizationsbefore, during, and after exercise. It appears that the occurrenceof frequent premature ventricular depolarizations during exerciseidentifies only subjects at higher risk of death from cardiovascularcauses.
According to our clinical findings, hypertensive cardiomyopathyis unlikely to be the cause of premature ventricular depolarizations,although other types of subclinical nonischemic cardiomyopathycould be involved. Hypertrophic cardiomyopathy is usually afamilial disorder with a variable clinical course26 that frequentlyincludes premature ventricular depolarizations.27,28 Left ventricularhypertrophy may be absent or mild, and the disease may be asymptomaticand clinically undetectable at an early stage. Arrhythmogenicright ventricular dysplasia is characterized by the replacementof right ventricular myocardium by fibrous tissue and fat,29a change that is usually responsible for frequent prematureventricular depolarizations associated with left bundle-branchblock.30 Early diagnosis can be quite difficult, since theremay be only minor signs of disease on the electrocardiogram.Premature ventricular depolarizations may also be due to dilatedcardiomyopathy,31 which may not be detectable at early stages,or to mitral-valve prolapse. The latter condition is associatedwith an increased frequency of premature ventricular depolarizations32and usually has few adverse effects.33
The occurrence of frequent premature ventricular depolarizationsduring exercise is associated with an increase in the rate ofdeath from cardiovascular causes, which is related to an increasein various cardiovascular causes of death. A greater increasein the rate of sudden death was expected in this group, butthe number of patients was too small to allow precise conclusions.
The higher mortality rate from cardiovascular causes that isassociated with frequent premature ventricular depolarizationsduring exercise in asymptomatic men has consequences for clinicalpractice. Such subjects should certainly be evaluated and treatedfor cardiovascular risk factors, and it should be strongly recommendedthat they quit smoking. Regular clinical follow-up is advisable.
The presence or absence of premature ventricular depolarizationsbefore exercise was determined from the analysis of one conventionalelectrocardiogram recorded at entry into the study and one 30-secondelectrocardiogram recorded before the beginning of exercise.The occurrence of premature ventricular depolarizations in anindividual patient is highly variable.34 Therefore, two electrocardiogramstaken at rest are clearly insufficient for us to conclude thata subject has no premature ventricular depolarizations. It islikely that some subjects were wrongly classified as havinginfrequent premature ventricular depolarizations or none, butsuch misclassification would have had only a small effect onour results.
Evidence of ischemia on the exercise electrocardiogram and arun of consecutive premature ventricular depolarizations wereboth reasons for termination of the test. We cannot excludethe possibility that frequent premature ventricular depolarizationsmight have occurred in some subjects who had ischemia if thetest had been prolonged and, conversely, that the exercise testmight have been positive for ischemia in subjects who had prematureventricular depolarizations during exercise.
The study population consisted of healthy men without symptomsof cardiovascular disease who were employed by the Paris CivilService; these men may have differed from the general populationin socioeconomic status, use of alcohol and tobacco, or othercharacteristics. Therefore, caution must be used in extendingthe results to the general population. The study included onlymen, but there is no reason to expect that different conclusionswould have been reached if the study had included women.
In order to achieve the maximal predicted heart rate in asymptomaticsubjects as rapidly as possible, an unusual protocol of exercisetests was used. The rapidity with which the workload was advancedmay have influenced the results, and it is possible that theconclusions may not be applicable to subjects who undergo testingaccording to the standard Bruce protocol, which is now routinelyused.
The occurrence of frequent premature ventricular depolarizationsduring exercise in asymptomatic middle-aged men is associatedwith increased long-term mortality from cardiovascular causes.The relative risk is similar to that associated with an exercisetest that is positive for ischemia, even after adjustment forconfounding variables. For this population, additional examinationsand regular medical follow-up should be encouraged, and patientsshould be urged to modify risk factors and particularly to quitsmoking. Further studies are required to identify the causesand mechanisms of the association between frequent prematureventricular depolarizations during exercise and death from cardiovascularcauses.
We are indebted to Beverley Balkau and Professor Claude Guérotfor their support.
Source Information
From the Service de Cardiologie, Université Paris V, Faculté Necker–Enfants Malades, Hôpital Européen Georges Pompidou, Paris (X.J., M.D.); and INSERM Unité 258 (Epidémiologie Cardiovasculaire et Métabolique), Hôpital Paul Brousse, Villejuif, France (X.J., M.Z., D.C., P.D.).
Address reprint requests to Dr. Jouven at the Service de Cardiologie, Hôpital Européen Georges Pompidou, 20 rue Le Blanc, 75015 Paris, France, or at xavier.jouven{at}bcc.ap-hop-paris.fr.
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