Background Despite many studies suggesting that poor physicalfitness is an independent risk factor for death from cardiovascularcauses, the matter has remained controversial. We studied thisquestion in a 16-year follow-up investigation of Norwegian menthat began in 1972.
Methods Our study included 1960 healthy men 40 to 59 years ofage (84 percent of those invited to participate). Conventionalcoronary risk factors and physical fitness were assessed atbase line, with physical fitness measured as the total workperformed on a bicycle ergometer during a symptom-limited exercise-tolerancetest.
Results After an average follow-up time of 16 years, 271 menhad died, 53 percent of them from cardiovascular disease. Therelative risk of death from any cause in fitness quartile 4(highest) as compared with quartile 1 (lowest) was 0.54 (95percent confidence interval, 0.32 to 0.89; P = 0.015) afteradjustment for age, smoking status, serum lipids, blood pressure,resting heart rate, vital capacity, body-mass index, level ofphysical activity, and glucose tolerance. Total mortality wassimilar among the subjects in fitness quartiles 1, 2, and 3when the data were adjusted for these same variables.
The adjusted relative risk of death from cardiovascular causesin fitness quartile 4 as compared with quartile 1 was 0.41 (95percent confidence interval, 0.20 to 0.84; P = 0.013). The correspondingrelative risks for quartiles 3 and 2 (as compared with quartile1) were 0.45 (95 percent confidence interval, 0.22 to 0.92;P = 0.026) and 0.59 (95 percent confidence interval, 0.28 to1.22; P = 0.15), respectively.
Conclusions Physical fitness appears to be a graded, independent,long-term predictor of mortality from cardiovascular causesin healthy, middle-aged men. A high level of fitness was alsoassociated with lower mortality from any cause.
Physical activity beyond a certain level and duration is necessaryto improve physical fitness1 and may be an important factorin the prevention of death from ischemic heart disease2. Sincephysical activity is more difficult to quantify than the levelof physical fitness, however, the latter has gained popularityin the assessment of both cardiovascular function and long-termcardiovascular health. Recent reports3,4,5,6,7,8,9,10,11 concludethat a low level of physical fitness is associated with increasedmortality from cardiovascular causes during the subsequent fiveto eight years, a finding that corroborates our observationsover a seven-year period in 2014 apparently healthy men 40 to59 years of age12.
The aims of the present study were to search for a possiblegraded association between physical fitness and overall mortalityor mortality from cardiovascular causes and to determine whetherour results after 7 years12 would persist after the substantiallylonger observation period of 16 years.
Methods
Subjects
The subjects participating in this study were recruited fromfive companies in Oslo, Norway, from 1972 through 1975. Themale employees of these companies included both white-collarand blue-collar workers considered to be typical of the healthyworking male population of Norway. All 2341 healthy men 40 to59 years of age working for the companies were invited to participatein the study, and 2014 of them (86 percent) accepted. None wereusing cardioactive drugs or drugs that might affect exerciseperformance or heart-rate response.
A subject was considered healthy if none of the following disorderswere present, as determined by a thorough screening of the healthfile or by medical examination: coronary heart disease, otherheart diseases, hypertension treated with drugs, diabetes mellitus,cancer, advanced pulmonary disease, advanced renal disease,liver disease, and miscellaneous diseases, including disordersof the musculoskeletal system preventing the subject from takinga symptom-limited bicycle exercise test. The details of theselection procedures have been presented elsewhere13.
Base-Line Measurements
The study was carried out at the National University Hospitalof Oslo (the Rikshospitalet). The examination included a comprehensivemedical history, physical examination, a panel of blood tests(including a lipid profile and an intravenous glucose-tolerancetest), phonocardiography, chest radiography, a spirographicstudy, resting electrocardiography, and a symptom-limited bicycleexercise-tolerance test12. Physically active men were definedas those who exercised at least twice a week to the level ofsweating and becoming short of breath, participated in sportscompetitions, or both14. With respect to smoking habits, theparticipants were described as having never smoked, as havingformerly smoked, or as currently smoking either 1 to 9 or 10or more cigarettes daily. Resting blood pressure and heart ratewere measured after the patient had been in the supine positionfor five minutes. Cholesterol and triglyceride concentrationswere determined by standardized methods, as reported elsewhere,15as were details of the intravenous glucose-tolerance test16.To measure glucose tolerance, the rate of disappearance of glucose,expressed as the percentage disappearing per minute (the K value),was used16. In the spirographic study, vital capacity and forcedvital capacity in one second were measured with a Bernsteinspirometer, and peak expiratory flow with a Wright peak flowmeter,as described elsewhere17. All the participants were examinedbetween 7:30 a.m. and 10:30 a.m. after abstaining from eatingand smoking for at least 12 hours.
The exercise tests were conducted on an electrically brakedElema bicycle that was repeatedly calibrated during the study.When set at a particular workload, the cycle ergometer demandsa constant output of energy from the test subject, regardlessof the rate at which the subject pedals. The initial workloadwas set at 1.405 kcal per minute in all but 2 percent of thesubjects, who started at 0.703 kcal per minute because theirstate of physical fitness appeared to be very poor. Incrementsof 0.703 kcal per minute were added every six minutes. The subjectswere encouraged to continue exercising until they were exhausted.If a subject stated that he felt unable to continue the test,without giving specific reasons, the test was always terminated,regardless of other findings. The exercise protocol specifiedthe following reasons for terminating a test: major cardiacarrhythmias, a drop in the systolic blood pressure of at least10 percent on two successive measurements one minute apart towardthe end of the test, heart block, ST-segment depression greaterthan 3 mm, severe dyspnea, or increasing chest pain.
Work capacity was calculated as the sum of the work performed(in kilocalories) at each workload until the termination ofthe test. Physical fitness was measured as the difference betweenthe observed and expected work capacities according to the subject'sbody weight (as defined below under Statistical Analysis).
Exercise testing was repeated within two weeks in 130 participants.The two measurements of work capacity were within 5 percentof each other for 90 percent of the men and within 10 percentof each other for the entire group.
Identification of Deaths
Information about the times and causes of death was 100 percentcomplete by December 31, 1989. These data were obtained fromthe Norwegian Central Bureau of Statistics, as described elsewhere12.The specific causes of death are given according to the InternationalClassification of Diseases, 9th Revision. On the basis of thisinformation, each death was classified as having either a cardiovascularor a noncardiovascular cause.
Statistical Analysis
A graph of work capacity and body weight suggested linear associationsin the group with a body weight of 75 kg and in the group witha body weight of >75 kg, with a shallower slope in the lattergroup. Linear regression analysis was performed separately inthe two groups, with work capacity used as the dependent variableand body weight as the independent variable. The resulting regressionfunction was calculated for each subject, and this value waslabeled "expected working capacity according to body weight."
The association between the subject's fitness level and mortality(from cardiovascular, noncardiovascular, and all causes) wasfirst assessed by presenting annual mortality according to thefitness quartiles. The relation between the fitness level andthe variables studied was assessed by determining the mean valuesfor the variables in each fitness quartile.
The association between the time to death (from cardiovascularcauses or all causes) and the measurement of fitness, as wellas selected variables, was investigated by means of the proportional-hazardsmodel18. Three models were investigated. The first referredto mortality from cardiovascular causes and included physicalfitness, age, and smoking status. The second model included,in addition, resting systolic blood pressure, resting heartrate, cholesterol and triglyceride levels, body-mass index (theweight in kilograms divided by the square of the height in meters),vital capacity, physical-activity level, and glucose toleranceas assessed by the intravenous glucose-tolerance test (the Kvalue)16. The third model referred to overall mortality andincluded the same variables as the second model.
The results obtained with the models are presented as relativerisks. For a continuous variable, the relative risk of deathfrom cardiovascular causes associated with a given change inthe variable is presented after adjustment for all other variablesin the model. The change studied was 2 SD (in the directionof increased risk) above the mean values for systolic bloodpressure, cholesterol level, triglyceride level, vital capacity,and body-mass index; for age, the change studied was an increaseof 10 years. For the graded variables (e.g., fitness level andsmoking status) and the binary variables (e.g., K value andphysical-activity level), the relative risks of death from cardiovascularcauses between groups are presented. All the P values presentedare two-tailed.
The assumptions of the proportional-hazards model were checkedfor all three models and found to be adequately met. The modelswere computed with the use of the proportional-hazards generalprocedure for a linear model in the SAS computer package19.
Results
All 2014 men included in the study completed the exercise testaccording to the protocol, and 97.4 percent started the secondstage of the test. Twenty-two exercise tests were terminatedbecause the subjects had increasing chest pain during the test.None had reported chest pain during their usual activities.Three exercise tests were interrupted because the subject'sblood pressure reached 300 mm Hg; 1 had a decrease in bloodpressure of at least 10 percent; 21 had arrhythmias; none hadheart block; and 9 had ST-segment depressions of more than 3mm. Of the 54 men who had at least one of these complications32, 11, 5, and 6 belonged to fitness quartiles 1, 2, 3, and4, respectively, when all 2014 men were categorized in fitnessquartiles. Because of the possibility that these 54 men hadcardiovascular disease at base line, they were excluded fromfurther analysis. The remaining 1960 men, who stopped exercisingbecause of obvious exhaustion, because they said they were unableto exercise further, or both, make up the present series. Theirmean age was 49.9 years (range, 40.0 to 59.9). The average follow-upperiod was 15.9 years (range, 14 to 17), during which 271 ofthe men died, 143 (52.8 percent) of them from cardiovasculardiseases (89 percent of these men died from myocardial infarctionor had sudden and unexpected deaths). Of the 143 men who diedof cardiovascular causes, 61 were in fitness quartile 1, 45in quartile 2, 26 in quartile 3, and 11 in quartile 4. Therewere 45, 32, 38, and 13 deaths from other causes in the respectivequartiles, for an overall mortality of 106, 77, 64, and 24,respectively.
Table 1 shows the values in each fitness quartile for a numberof selected base-line variables. The higher the level of fitness,the higher the vital capacity and the lower the resting heartrate, blood pressure, cholesterol level, and prevalence of smoking.A high level of fitness was also strongly associated with ahigh level of physical activity in leisure time. All these associationswere statistically significant (P<0.001). Virtually identicalresults were found when the data were corrected for differencesin mean age among the quartiles (data not shown).
Table 1. Base-Line Clinical and Laboratory Values in 1960 Healthy Men 40 to 59.9 Years of Age, According to Fitness Level.
The relation between the fitness measure and annual mortality(from cardiovascular, noncardiovascular, and all causes) isshown in Table 2. Age-adjusted mortality from cardiovascularcauses decreased with increasing fitness among both smokersand nonsmokers, and in all but the highest fitness quartile,smokers had a higher mortality due to cardiovascular causesthan nonsmokers. In the highest fitness quartile, smokers andnonsmokers had similar mortality from cardiovascular causes.
Table 2. Annual Age-Adjusted Mortality from Cardiovascular, Noncardiovascular, and All Causes in 1960 Men during 16 Years of Follow-up, According to Fitness Level and Smoking Status.
The relation between fitness level and age-adjusted cumulativemortality from cardiovascular causes over the 16-year periodis shown in Figure 1. Mortality from cardiovascular causes wasvery low in all the fitness subgroups during the first fouryears of observation, whereas the difference in mortality betweenquartile 1, the lowest fitness quartile, and the other threebegan to appear only after five years. The difference betweenquartile 4, the highest fitness quartile, and quartiles 2 and3 was first observed after seven years and increased consistentlythereafter. Mortality from cardiovascular causes was similarin quartiles 2 and 3 during the first 13 years, whereas a tendencytoward a difference in favor of quartile 3 was seen at 16 years.
Figure 1. Cumulative Age-Adjusted Mortality from Cardiovascular Causes over 16 Years of Follow-up, According to Fitness Quartile.
Relative Risks among Fitness Quartiles
Mortality from Cardiovascular Causes
The relative risk of death from cardiovascular causes in quartile4 as compared with quartile 1 was 0.30 (95 percent confidenceinterval, 0.15 to 0.61; P<0.001) after adjustment for ageand smoking status. This relative risk was 0.41 (95 percentconfidence interval, 0.20 to 0.84; P = 0.013) after furtheradjustment for systolic blood pressure, cholesterol level, triglyceridelevel, vital capacity, K value, resting heart rate, body-massindex, and physical-activity level (Table 3). The relative riskof death from cardiovascular causes in quartile 4 as comparedwith quartile 3 was 0.50 (95 percent confidence interval, 0.23to 1.05; P = 0.068) after adjustment for age and smoking status.
Table 3. Relative Risk of Death from Cardiovascular Causes in 1960 Healthy Men during 16 Years of Follow-up, Associated with Specific Changes or Comparisons of Base-Line Variables.
A high level of physical activity as defined in the presentstudy had no independent prognostic value, nor did body-massindex, resting heart rate, or fasting triglyceride level. Allthe other variables were significantly and independently associatedwith mortality from cardiovascular causes (Table 3).
Overall Mortality
After adjustment for the same variables that were used in themodel for mortality from cardiovascular causes, the relativerisk of mortality from any cause was as follows when the threeother quartiles were compared with quartile 1: for quartile4, 0.54 (95 percent confidence interval, 0.32 to 0.89; P = 0.015);for quartile 3, 1.00 (95 percent confidence interval, 0.71 to1.41; P = 0.92); and for quartile 2, 0.92 (95 percent confidenceinterval, 0.66 to 1.28; P = 0.58). It is noteworthy that a comparisonbetween quartiles 4 and 3 revealed a relative risk in quartile4 of 0.53 (95 percent confidence interval, 0.32 to 0.87; P =0.010), whereas the comparison of quartile 4 with quartile 2revealed a relative risk of 0.59 (95 percent confidence interval,0.36 to 0.96; P = 0.031). Thus, overall mortality was significantlylower in quartile 4 than in all three other quartiles.
Discussion
Our study has demonstrated a graded, inverse association betweenphysical fitness and mortality from cardiovascular causes overa period of 16 years that is independent of age and conventionalcoronary risk factors. These findings corroborate and amplifyour previous reports after a follow-up of seven years3,12 andare in close accord with the findings of other recent studies4,5,6,7,8,9,10,11.
After adjustment for age and smoking status, overall mortalityand mortality from cardiovascular causes were both observedto be lower among men in the quartile with the highest levelof fitness than among the men in the remaining quartiles. Thus,although physical fitness appears to be more closely associatedwith mortality from cardiovascular causes than with overallmortality, the men in the quartile with the highest level offitness appeared to be protected from death from all causes.In a previous study, Blair et al. reported an inverse relationbetween fitness and death from cancer6. However, their datawere not adjusted for smoking status.
Maximal work capacity, as defined in the present study, hasbeen shown to be highly correlated with maximal oxygen uptake,20indicating that our measure of fitness is closely related tothis most accepted measure of physical fitness1. To our knowledge,no study has suggested reduced survival in the presence of ahigh level of physical fitness. Instead, all major publishedstudies, both North American4,6,7,8,10 and European,3,5,9 suggesta favorable long-term outcome in subjects with high as comparedwith low levels of physical fitness, regardless of how fitnessis measured and defined4,5,6,7,8,9,10. The unadjusted risk ratioof 4.8 for mortality from cardiovascular causes over seven yearsin our study when subjects from the lowest fitness quartilewere compared with those from the highest3 is close to the riskratios reported by others during follow-up periods of sevento nine years4,6,10,11.
We also observed a marked difference in mortality from cardiovascularcauses between the subjects with intermediate levels of physicalfitness (quartiles 2 and 3) and those with high levels (quartile4). This finding would have remained undetected if our cohorthad been followed for only 10 years (Figure 1), as was the casein previous studies4,5,6,7.
These associations between fitness and mortality from cardiovascularcauses can be used to assess the risk of cardiovascular diseaseamong healthy subjects only if the subjects tested in the citedstudies were truly healthy3,4,5,6,7,8,9,10. This prerequisiteseems to have been met despite variation in the methods of selectingsubjects3,4,5,6,7,8,9,10. Our selection procedure ought to havebeen reasonably successful in excluding subjects with preexistingcardiovascular disease, as the very low initial mortality suggests(Figure 1).
Although the genetic component of physical fitness, as definedby a subject's maximal oxygen uptake, has been suggested tobe approximately 40 percent,21 this leaves about 60 percentof the variation between people attributable to other causes.Among these, physical activity, the key determinant,1,2 is knownto influence favorably a number of risk factors for coronaryheart disease, such as the levels of cholesterol and triglycerides,and blood pressure3,22,23,24,25. Moreover, physical activityimproves glucose tolerance and insulin sensitivity,26 increasesfibrinolysis,27,28 increases levels of high-density lipoproteincholesterol,25 improves oxygen uptake in the heart as well asin peripheral tissues,1 and increases the dimensions of coronaryarteries and the formation of collateral vessels in animals29,30,31.Physical training also reduced the tendency to coronary vasospasmin one animal model29 and increased the threshold for ventricularfibrillation in exercising rats32,33. Regular exercise alsolowers the resting heart rate by increasing vagal tone34. Alow heart rate is associated with a low mortality rate in humans35,36and appears to protect against the development of coronary atherosclerosisin monkeys37. Platelet aggregation has also been shown to decreasein exercising subjects38,39. Furthermore, a high level of physicalactivity appears to protect against death from cardiovasculardisease2.
Although physical activity is not an independent predictor ofmortality from cardiovascular causes, a close, direct correlationbetween reported physical activity and level of physical fitnesswas found in our study, as in previous studies4,40. Our estimatesof physical activity during leisure hours are too crude, however,to allow speculation about its role in the prevention of deathfrom cardiovascular disease14.
The associations in the present report, as in most others, havebeen corrected for differences in well-recognized coronary riskfactors3,4,5,6,7,8,9,10,11,12. Thus, although our findings mayconceivably be explained by important, currently unrecognizedrisk factors, a low level of physical fitness appears to bean important coronary risk factor.
Although studies showing a favorable association between fitnessand mortality might be more likely to be published than negativestudies, the uniformity of the published literature and theobserved graded relation argue against a publication bias ofany consequence. Many previous studies may be criticized forpossible selection biases or inadequate descriptions of selectionprocedures,3,4,5,6,7,8,9,10,11,12 but these shortcomings notwithstanding,the results from all these studies are remarkably similar3,4,5,6,7,8,9,10,11,12.Accordingly, the aggregate data in the literature representa body of evidence that, according to epidemiologic principles,41suggests a causal relation between physical fitness and mortalityfrom cardiovascular causes. The associations observed worldwideare consistent, strong, graded, plausible, coherent, appropriatelysequenced, and reasonably unbiased41. Only experimental evidence,difficult to obtain in humans, is still lacking in the finalchain of proof41.
Whether genetic superiority among fit subjects explains thesefindings is unknown, but the close association between fitnesslevel and mortality from cardiovascular causes tends to argueagainst it as the only explanation. Instead, one may speculatewhether low fitness in the absence of disease often signifiesa lifestyle with inherent unfavorable consequences for cardiovascularhealth.
This apparently simple pattern, also observed by others,3,4,5,6,7,8,9,10is complicated in our study by the finding of strikingly lowoverall mortality in the men from the highest fitness quartileas compared with those in the other three quartiles. The reasonfor this finding remains obscure, although several explanationsmay be conjectured. We have no data to allow further speculations,however, and this finding should be considered an observationthat warrants further study.
We are indebted to Mrs. Solveig Eggen for her assistance inthe preparation of the manuscript.
Source Information
From the Medical Department, Central Hospital of Akershus, Nordbyhagen, Norway (L.S., J.E., G.E.), and the National University Hospital (E.T.), the Ullevaal Hospital (R.M.), and the Department of Work Physiology, University of Oslo (K.R.) -- all in Oslo, Norway.
Address reprint requests to Dr. Jan Erikssen at the Medical Department, Central Hospital of Akershus, N-1474 Nordbyhagen, Norway.
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75 kg and in the group with a body weight of >75 kg, with a shallower slope in the latter group. Linear regression analysis was performed separately in the two groups, with work capacity used as the dependent variable and body weight as the independent variable. The resulting regression function was calculated for each subject, and this value was labeled "expected working capacity according to body weight." 
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