Background Previous studies have suggested that higher levelsof regular physical activity and cardiorespiratory fitness areassociated with a reduced risk of coronary heart disease. Weinvestigated the independent associations of physical activityduring leisure time and maximal oxygen uptake (a measure ofcardiorespiratory fitness) with the risk of acute myocardialinfarction.
Methods During the period 1984 to 1989, we performed base-lineexaminations in 1453 men 42 to 60 years old who did not reporthaving cardiovascular disease or cancer. Physical activity wasassessed quantitatively with a detailed questionnaire, and maximaloxygen uptake was measured directly by exercise testing. Duringan average follow-up of 4.9 years, 42 of the 1166 men with normalelectrocardiograms at base line had a first acute myocardialinfarction.
Results After adjustment for age and the year of examination,the relative hazard (risk) of myocardial infarction in the thirdof subjects with the highest level of physical activity (>2.2hours per week) was 0.31 (95 percent confidence interval, 0.12to 0.85; P = 0.02), as compared with the third with the lowestlevel (P = 0.04 for linear trend over all three groups). Therelative hazard in the third with the highest maximal oxygenuptake (>2.7 liters per minute) was 0.26 (95 percent confidenceinterval, 0.10 to 0.68; P = 0.006) (P = 0.006 for linear trend),after adjustment for age, the year and season when the examinationwas performed, weight, height, and the type of respiratory-gasanalyzer used. After up to 17 confounding variables were controlledfor, the relative hazards for the third of subjects with thehighest level of physical activity (0.34; 95 percent confidenceinterval, 0.12 to 0.94; P = 0.04) and maximal oxygen uptake(0.35; 95 percent confidence interval, 0.13 to 0.92; P = 0.03),as compared with the values in the lowest third, were significantly(P<0.05) less than 1.0.
Conclusions Higher levels of both leisure-time physical activityand cardiorespiratory fitness had a strong, graded, inverseassociation with the risk of acute myocardial infarction, supportingthe idea that lower levels of physical activity and cardiorespiratoryfitness are independent risk factors for coronary heart diseasein men.
Higher levels of physical activity1,2,3,4,5,6,7,8,9,10,11 andcardiorespiratory fitness11,12,13,14,15,16,17 have been foundto be associated with a decreased incidence of and mortalityfrom coronary heart disease. However, only a few previous studies7,9,11,12,14,16have simultaneously investigated the associations of physicalactivity and cardiorespiratory fitness with the risk of coronarydisease.
Data on the type, duration, and intensity of physical activityneeded to protect against coronary heart disease are limitedand inconsistent. Some studies5 suggest that regular and vigorousexercise is necessary, whereas others7,9,10 indicate that exerciseof moderate duration and intensity is sufficient to reduce therisk. Furthermore, little is known about the level of cardiorespiratoryfitness required to protect against coronary heart disease.
Most studies of the association of physical activity with therisk of coronary heart disease have not used truly quantitativeassessments of physical activity1. Furthermore, there is littleor no information on the relation of direct measurements ofmaximal oxygen uptake, the most accurate method for assessingcardiorespiratory fitness,18 to risk. Few studies have adequatelycontrolled for confounding variables1.
We investigated the associations of the type, duration, andintensity of leisure-time physical activity, assessed quantitativelyby means of a detailed questionnaire, and directly measuredmaximal oxygen uptake with the risk of acute myocardial infarctionin men from eastern Finland, after controlling for a numberof potentially relevant confounders. We also attempted to estimatethe "dose-response" relations of leisure-time physical activityand maximal oxygen uptake to the risk of coronary heart disease.
Methods
Subjects
The Kuopio Ischemic Heart Disease Risk Factor Study is a population-basedstudy undertaken to investigate previously unestablished riskfactors for acute myocardial infarction and extracoronary atherosclerosis19among men in eastern Finland, a group with one of the highestrecorded risks of coronary heart disease20. The study populationis a random sample of men living in the town of Kuopio or neighboringrural communities, stratified and balanced according to age,who were 42, 48, 54, or 60 years old at the base-line examination.The base-line study was carried out between March 1984 and December1989. Of 3235 eligible men, 2682 (83 percent) participated.
Men who reported that they had cardiovascular disease (includingcoronary disease21) or cancer (1042 men) were excluded. Completedata on physical activity and maximal oxygen uptake were availablefor 1453 of the remaining 1640 men. Men with hypertension (811subjects) were not excluded from most analyses.
Data on the following factors were missing for some men: plasmafibrinogen level, 117 men; serum level of high-density lipoprotein-subfraction2 (HDL2) cholesterol, 59; serum apolipoprotein B level, 51;serum copper level, 45; serum ferritin and insulin levels, 43;smoking, 33; serum triglyceride level, 33; serum low-densitylipoprotein (LDL) cholesterol level, 30; blood glucose level,15; blood leukocyte count, hemoglobin level, and diastolic bloodpressure, 7; and systolic blood pressure, height, and body-massindex (the weight in kilograms divided by the square of theheight in meters), 6. If a value was missing, the mean valuefor all 1453 men was substituted.
Assessment of Physical Activity
Leisure-time physical activity was assessed from a 12-monthhistory22,23,24 modified from the Minnesota Leisure Time PhysicalActivity Questionnaire25. The checklist included the most commonleisure-time physical activities of middle-aged Finnish men,selected on the basis of a previous population study in Finland26.For each activity performed, the subjects were asked to recordthe frequency (number of sessions per month), average duration(hours and minutes per session), and intensity (scored as 0for recreational activity, 1 for conditioning activity, 2 forbrisk conditioning activity, and 3 for competitive, strenuousexercise). A trained interviewer collected missing data.
The intensity of physical activity was expressed in metabolicunits (MET, or metabolic equivalents of oxygen consumption).The four categories of intensity of activity (range of possiblescores, 0 to 3) were assigned their own metabolic-unit values,revised on the basis of a synthesis of available empirical data26,27,28.The metabolic unit is the ratio of the metabolic rate duringexercise to the metabolic rate at rest. One metabolic unit correspondsto an energy expenditure of approximately 1 kcal per kilogramof body weight per hour, or an oxygen uptake of 3.5 ml per kilogramper minute.
Physical activity was categorized according to type: (1) conditioningphysical activity -- walking (mean intensity, 4.2 MET), jogging(10.1 MET), skiing (9.6 MET), bicycling (5.8 MET), swimming(5.4 MET), rowing (5.4 MET), ball games (6.7 MET), and gymnastics,dancing, or weight lifting (5.0 MET); (2) nonconditioning physicalactivity -- crafts, repairs, or building (2.7 MET), yard work,gardening, farming, or snow shoveling (4.3 MET), hunting, pickingberries, or gathering mushrooms (3.6 MET), fishing (2.4 MET),and forest activities (7.6 MET); and (3) walking (3.5 MET) orbicycling (5.1 MET) to work.
Assessment of Cardiorespiratory Fitness
Cardiorespiratory fitness was assessed with a maximal, symptom-limitedexercise-tolerance test on an electrically braked bicycle ergometer.For 349 men examined before June 1986, the testing protocolcomprised a three-minute warm-up at 50 W followed by a step-by-stepincrease in the workload by 20 W per minute (Tunturi EL 400bicycle ergometer, Turku, Finland). The remaining 1104 men weretested with a linear increase in the workload by 20 W per minute(Medical Fitness Equipment 400 L bicycle ergometer, Mearn, theNetherlands).
Respiratory gas exchange was measured in the 349 men by themixing-chamber method, with use of a Mijnhardt Oxycon 4 analyzer(Mijnhardt, Odijk, the Netherlands), and in the other 1104 menby the breath-by-breath method, with use of an MGC 2001 analyzer(Medical Graphics, St. Paul, Minn.). The Mijnhardt Oxycon 4analyzer expressed the maximal oxygen uptake as the averageof values recorded over a 30-second period, whereas the MGC2001 analyzer expressed it as the average of values recordedover 8 seconds. Maximal oxygen uptake was defined as the highestvalue for or the plateau in oxygen uptake. The mean maximaloxygen uptake was 2.4 liters per minute when measured with theMijnhardt Oxycon 4 analyzer and 2.6 liters per minute when measuredwith the MGC 2001 analyzer. Pearson's coefficient for the correlationbetween simultaneous Mijnhardt Oxycon 4 and MGC 2001 measurementsin 13 men was 0.97, indicating a close correlation.
The most common reasons for stopping the exercise test wereleg fatigue (813 men), exhaustion (223), breathlessness (146),and pain in the leg muscles, joints, or back (58). The testwas discontinued because of cardiorespiratory symptoms or abnormalitiesin 138 men. These included dyspnea (44 men), arrhythmias (40),a marked change in systolic or diastolic blood pressure (35),dizziness (8), chest pain (7), and ischemic electrocardiographicchanges (4).
One cardiologist coded the electrocardiograms manually, usingthe Minnesota code29. For resting electrocardiograms, coronaryheart disease was indicated by the codes 1-1 to 1-3, 4-1 to4-3, and 5-1 to 5-3, and arrhythmia by the codes 8-1 to 8-6.The criteria for evaluating ischemia on exercise electrocardiogramshave been described elsewhere21. Evidence of coronary heartdisease or arrhythmia on resting electrocardiograms was foundin 72 men (5 percent) and evidence of ischemia on exercise electrocardiogramsin 232 men (16 percent). Either or both of these electrocardiographicabnormalities were found in 287 men.
Assessment of Confounding Factors
Assessment of demographic variables,23 medical history, familyhistory of diseases, smoking, blood pressure,21 and socioeconomicstatus30 was carried out as described previously. A pulmonary-diseaseindex was calculated from scores for dichotomized disease variables(a score of 0 denoted the absence of chronic bronchitis, asthma,or pulmonary tuberculosis, and a score of 1 denoted the presenceof any of them). The collection of blood specimens21 and themeasurement of serum lipids,23,31 insulin,23 ferritin,21 copper,21plasma fibrinogen,24 blood leukocytes,30 hemoglobin,21 and glucose21have been described previously.
Ascertainment of Follow-up Events
The collection of data on myocardial infarction by the MONICA(Monitoring of Trends and Determinants of Cardiovascular Diseases)registry has been described previously32. A suspected fatalor nonfatal acute myocardial infarction occurring between March1984 and December 1991 was recorded in 57 of the 1453 men atrisk. If multiple events occurred during follow-up, the firstevent in each subject was considered the end point for the analysesin this study. There were 38 deaths due to causes other thancoronary heart disease. Follow-up lasted up to 7.8 years andaveraged 4.9 years.
Statistical Analysis
The associations of physical activity and maximal oxygen uptakewith coronary risk factors were estimated with Pearson's correlationcoefficients, with adjustment for age and year of examination(1985, 1986, 1987, 1988, and 1989 vs. other years). The levelof physical activity and maximal oxygen uptake were enteredas two dummy variables for the approximate upper two thirdsof the sample (with the lowest third serving as the referencegroup) into forced Cox proportional-hazards models33,34. Riskfactors were entered uncategorized into Cox models. Three differentsets of fixed covariates were used. Acute myocardial infarctionwas defined as the outcome event, and deaths from other causesas losses to follow-up. Relative hazards adjusted for risk factorswere estimated as antilogarithms of coefficients from multivariatemodels. Their confidence intervals were estimated under theassumption of asymptotic normality of the estimates. All testsfor statistical significance were two-sided. The fit of theproportional-hazards models was examined by plotting the hazardfunctions in different categories of risk factors over time.The results indicated that the application of the models wasappropriate.
Results
The subjects ranged in age from 42.0 to 61.2 years (mean, 52.0).They spent more of their leisure time in nonconditioning physicalactivity than in any other type (Table 1). The mean intensityof conditioning physical activity was higher than that of otherphysical activities.
Table 1. Leisure-Time Physical Activity and Maximal Oxygen Uptake in 1453 Men in Eastern Finland Who Reported Having No Cardiovascular Disease or Cancer.
The risk factors for acute myocardial infarction, adjusted forage and the year of examination, are shown in Table 2. Whenall factors except those that correlated strongly with one another(height, weight, diastolic blood pressure, serum LDL cholesterol,and blood glucose) were entered simultaneously into the Coxmodel, the only factors found to be significantly associatedwith the risk of acute myocardial infarction were the numberof pack-years of cigarette smoking (P = 0.001), a family historyof coronary heart disease (P = 0.01), the maximal oxygen uptake(P = 0.02), and the duration of conditioning physical activity(P = 0.03).
Table 2. Risk Factors for a First Acute Myocardial Infarction in the Study Cohort.
Although the duration of conditioning physical activity hadno association with age, maximal oxygen uptake correlated inverselywith age (r = -0.41) and decreased by 46 ml per minute per yearof age. After adjustment for age and the year of examination,the duration of conditioning physical activity correlated directlywith maximal oxygen uptake (r = 0.11) and inversely with thebody-mass index, the serum level of triglycerides (r = -0.07),the LDL cholesterol level, and the apolipoprotein B level, thenumber of pack-years of cigarette smoking, weight (r = -0.06),and the serum ferritin level (r = -0.05). Maximal oxygen uptakecorrelated directly with height (r = 0.30), weight (r = 0.24),body-mass index (r = 0.14), and the serum HDL2 level (r = 0.11)and inversely with the number of pack-years of smoking (r =-0.23), the blood leukocyte count (r = -0.21), the plasma fibrinogenlevel (r = -0.19), socioeconomic status (r = -0.18), the serumlevels of apolipoprotein B (r = -0.14), LDL cholesterol (r =-0.12), copper (r = -0.12), and triglycerides (r = -0.10), theblood glucose level (r = -0.07), and the serum insulin level(r = -0.05).
Of 1166 men without cardiovascular disease or cancer who hadboth normal resting and normal exercise electrocardiograms,42 had initial myocardial infarctions during the follow-up period.The relative hazards of acute myocardial infarction among themen in the upper two thirds of the sample according to the durationof conditioning physical activity are shown in Table 3, withadjustment for age and the year of the examination. After additionaladjustment for possible confounders (family history of coronaryheart disease, the presence of pulmonary disease, diabetes,or disability, socioeconomic status, the number of pack-yearsof cigarette smoking, and blood leukocyte count), the relativehazards in these two groups were 1.19 in the middle third (95percent confidence interval, 0.61 to 2.31) and 0.34 in the highestthird (95 percent confidence interval, 0.12 to 0.94; P = 0.04)(P = 0.07 for linear trend). After further adjustment for othervariables that might mediate the protective effect of physicalactivity (such as serum HDL2, triglyceride, apolipoprotein B,ferritin, and copper levels, plasma fibrinogen level, bloodhemoglobin level, systolic blood pressure, height, and weight),the relative hazards in the two groups were 1.28 in the middlethird (95 percent confidence interval, 0.65 to 2.51) and 0.38in the highest third (95 percent confidence interval, 0.14 to1.05) (P = 0.12 for linear trend).
Table 3. Relative Hazards of a First Acute Myocardial Infarction in the Groups with Values in the Highest Two Thirds for Duration of Conditioning Physical Activity and Maximal Oxygen Uptake, According to Electrocardiographic Findings.
Table 3 also shows the relative hazards of acute myocardialinfarction among the men in the upper two thirds of the sampleaccording to maximal oxygen uptake, after adjustment for age,year and season of examination, height, weight, and the typeof respiratory-gas analyzer. After additional adjustment forpossible confounders, the relative hazards in the upper twothirds were 0.74 (95 percent confidence interval, 0.36 to 1.51)and 0.35 (95 percent confidence interval, 0.13 to 0.92; P =0.03) (P = 0.04 for linear trend). After further adjustmentfor variables that might mediate the protective effect of physicalactivity, the respective relative hazards were 0.96 (95 percentconfidence interval, 0.45 to 2.03) and 0.45 (95 percent confidenceinterval, 0.16 to 1.25) (P = 0.16 for linear trend).
When the 243 men with hypertension were excluded from the analysis,the numbers of men among the remaining 923 in the thirds ofsubjects defined by the duration of conditioning physical activitywho had an acute myocardial infarction were 15 (4.9 percent),13 (4.3 percent), and 2 (0.7 percent). The relative hazardsof acute myocardial infarction in the upper two thirds of thesample according to the duration of conditioning physical activity,after adjustment for possible confounders, were 1.05 in themiddle third (95 percent confidence interval, 0.48 to 2.28)and 0.15 in the highest third (95 percent confidence interval,0.03 to 0.66; P = 0.01) (P = 0.01 for linear trend). After additionaladjustment for variables that might mediate the protective effectof physical activity, the respective relative hazards were 1.22(95 percent confidence interval, 0.54 to 2.78) and 0.14 (95percent confidence interval, 0.03 to 0.70; P = 0.02) (P = 0.02for linear trend).
Among the 923 men in this analysis, the numbers in the thirdsof the sample according to maximal oxygen uptake who had anacute myocardial infarction were 13 (5.6 percent), 12 (3.9 percent),and 5 (1.3 percent). The relative hazards of acute myocardialinfarction in the upper two thirds according to maximal oxygenuptake, after adjustment for possible confounders, were 0.55in the middle third (95 percent confidence interval, 0.24 to1.28) and 0.30 in the highest third (95 percent confidence interval,0.10 to 0.92; P = 0.04) (P = 0.03 for linear trend). After furtheradjustment for variables that might mediate the protective effectof physical activity, the respective relative hazards were 0.69(95 percent confidence interval, 0.28 to 1.73) and 0.37 (95percent confidence interval, 0.11 to 1.24) (P = 0.11 for lineartrend).
Table 3 shows the relative hazards of acute myocardial infarctionin 287 men without cardiovascular disease or cancer who hadabnormal resting or exercise electrocardiograms, with respectto the two upper thirds defined according to the duration ofconditioning physical activity and maximal oxygen uptake.
Neither nonconditioning physical activity nor walking or bicyclingto work was associated with any change in the risk of acutemyocardial infarction.
Discussion
Conditioning leisure-time physical activity and maximal oxygenuptake had an inverse, graded, and independent association withthe risk of acute myocardial infarction among men in easternFinland who did not have cardiovascular disease or cancer. Thesefindings are consistent with those of the U.S. Railroad Study,in which both leisure-time physical activity9 and heart rateduring a submaximal exercise test16 were inversely associatedwith coronary mortality. Other studies have observed that eitherleisure-time physical activity7,11 or cardiorespiratory fitness12,14alone had an inverse and significant relation to the risk ofcoronary heart disease. In the present study, conditioning physicalactivity and maximal oxygen uptake were inversely associatedwith the risk of acute myocardial infarction among both menwith normal and men with abnormal resting or exercise electrocardiograms.Neither nonconditioning physical activity nor walking or bicyclingto work was associated with coronary risk.
It has been recommended that the large muscles perform dynamicexercise three to four times a week for an average of 30 to60 minutes to produce a cardiovascular benefit35. The presentfindings are consistent with those of the U.S. Railroad Study9and the Multiple Risk Factor Intervention Trial,7 in which alow-to-moderate degree of leisure-time physical activity wasassociated with decreased mortality from coronary disease. Wefound that the risk of acute myocardial infarction was decreasedby just two hours of conditioning physical activity a week.
The decrease in risk among the most active and fit men was greaterthan that observed in most previous studies7,8,9,10,11,12. Afteradjustment for a number of coronary risk factors, men who engagedin more than two hours of conditioning physical activity a weekhad a risk 60 percent lower than that of the least active men;men with a maximal oxygen uptake of at least 2.7 liters perminute, or 34 ml per kilogram per minute, had a risk 55 percentlower than that of the least fit men. Our data do not supportearlier findings of a plateau2,7,9 or an increase6,10 in riskabove a certain level of physical activity.
Only vigorous physical activity was associated with a decreasedrisk of coronary heart disease in the British Civil ServantStudy,5 whereas activity of low-to-moderate intensity was associatedwith reduced mortality from coronary disease in the MultipleRisk Factor Intervention Trial7. Both low-to-moderate and vigorousphysical activity were inversely associated with mortality fromcoronary disease in the U.S. Railroad Study9. Our data indicatethat physical activity with a mean intensity of 6 MET (or sixtimes higher than resting metabolic requirements) may be requiredto decrease the risk. The inconsistency among previous studiesin the level of physical activity necessary to reduce risk maybe partly due to differences in the classification of physicalactivity.
In the Seven Countries Study, Keys20 found no association betweenhabitual physical activity and coronary risk among Finnish men.Karvonen,36 however, observed an inverse relation that disappearedwhen he evaluated only men who had no coronary heart diseaseat entry. These findings have been used to argue that physicalinactivity is not an important coronary risk factor. Our datasupport the majority of previous studies, which have shown aninverse association between the level of physical activity andcoronary risk1,2,3,4,5,6,7,8,9,10,11.
It is difficult to distinguish an increased risk of coronarydisease related to physical inactivity or poor cardiorespiratoryfitness from an increased risk due to a prevalent asymptomaticor preexisting cardiovascular disease in sedentary or unfitpersons19. Therefore, it is possible that self-selection biasexaggerated the strength of the associations observed in ourstudy. On the other hand, we assessed asymptomatic coronaryheart disease with a maximal exercise test and used very sensitivediagnostic criteria to reduce the probability of this bias.
Conditioning physical activity and maximal oxygen uptake wereassociated with several variables that might mediate the cardioprotectiveeffects of physical activity. These included increased serumHDL2 cholesterol levels and decreased serum levels of triglycerides,LDL cholesterol, apolipoprotein B, copper, and ferritin, bloodhemoglobin levels, plasma fibrinogen levels, and body-mass index.We have reported some of these findings previously23,24,37.The present data and our earlier studies21,31,38 also indicatethat these variables are risk factors for acute myocardial infarctionin men in eastern Finland. However, these factors account foronly some of the observed relations between physical activityand fitness and coronary risk.
The quantitative methods enabled us to investigate the dose-responserelations of leisure-time physical activity and cardiorespiratoryfitness to the risk of acute myocardial infarction. The 12-monthhistory gives a more accurate estimate of the past level ofphysical activity than shorter-term measurements22. The reproducibilityand validity of the Minnesota Leisure Time Physical ActivityQuestionnaire and our 12-month history have been previouslyconfirmed in the United States,25,39 Belgium,40 and Finland22,23,24.Cardiorespiratory fitness as determined by exercise testingwas one of the criteria used for validation in these studies.
In conclusion, our findings are consistent with the notion thatlower levels of both conditioning leisure-time physical activityand cardiorespiratory fitness are important, independent coronaryrisk factors. Both men with more than two hours of conditioningphysical activity a week and men with a maximal oxygen uptakeof at least 2.7 liters per minute, or 34 ml per kilogram perminute, had less than half the risk of acute myocardial infarctionof the least active or the least fit men. On the basis of thepresent study, physical activity of predominantly moderate-to-highintensity may be needed to decrease coronary risk.
Supported by grants from the Finnish Academy and the Ministryof Education of Finland and by the town of Kuopio. Dr. Lakkareceived grants from the Finnish Academy and the Yrjo JahnssonFoundation.
We are indebted to Dr. Esko Taskinen, Dr. Hannu Litmanen, andDr. Arno Heikela for their participation in the supervisionof exercise tests, to Kari Seppanen, M.Sc., and Kristiina Nyyssonen,M.Sc., for supervising laboratory measurements, to Dr. JaakkoEranen for coding the resting and exercise electrocardiography,and to Kimmo Ronkainen, M.Sc., for carrying out the data analyses.
Source Information
From the Research Institute of Public Health, University of Kuopio (T.A.L., R.S., J.T.S.), and the Kuopio Research Institute of Exercise Medicine (J.M.V., R.R., R.S.), Kuopio, Finland; and the Department of Epidemiology and Health Promotion, National Public Health Institute, Helsinki, Finland (J.T.).
Address reprint requests to Professor J.T. Salonen at the University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland.
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