Determinants of Cardiorespiratory Fitness in Men Aged 42 to 60 Years With and Without Cardiovascular Disease

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1 Determinants of Cardiorespiratory Fitness in Men Aged 42 to 60 Years With and Without Cardiovascular Disease Jari Antero Laukkanen, MD, PhD a,b,f, *, David Laaksonen, MD, PhD d, Timo Antero Lakka, MD, PhD a,c, Kai Savonen, MD, PhD a,e, Rainer Rauramaa, MD, PhD a,e, Timo Mäkikallio, MD, PhD f,g, and Sudhir Kurl, MD b Good cardiorespiratory fitness has been found to protect against cardiovascular diseases and type 2 diabetes. The purpose of this study was to investigate determinants of directly measured cardiorespiratory fitness (maximal oxygen uptake [VO 2max ]), including age, body composition, prevalent diseases, cardiovascular and pulmonary functions, biochemical factors, physical activity, nutrition, smoking, and alcohol consumption, in a populationbased study of 936 men 42 to 60 years of age. Variables that had the strongest direct associations with VO 2max (milliliters per minute) in a linear multivariate step-up regression model were body weight, heart rate at maximal exercise, mean intensity and frequency of conditioning physical activity, intake of carbohydrates, blood hemoglobin, and forced expiratory volume in 1 second. The strongest inverse associations with VO 2max were heart rate at rest, age, fasting serum insulin, waist-to-hip ratio, coronary heart disease, and asthma. This model accounted for 67% of the variation of VO 2max. In conclusion, mean intensity, frequency, and duration of conditioning physical activity were associated directly with VO 2max. However, measurements of the function of pulmonary and cardiovascular systems, carbohydrate intake, and body composition were powerful determinants of cardiorespiratory fitness, especially in older middle-aged men Elsevier Inc. (Am J Cardiol 2009;103: ) Cardiorespiratory fitness has been related to several factors, such as age, 1 5 gender, 4,5 heredity, 6,7 prevalent cardiovascular disease, 4,5 use of medications, 8 quantity and quality of physical activity, 1,5 cigarette smoking, 1,9,10 obesity, 3 and nutrition. 1 Furthermore, maximal oxygen uptake (VO 2max )is an accurate measurement of the functional capacity of the cardiovascular system. 8 Indeed, small stroke volume, low maximal heart rate, and small arteriovenous oxygen difference at exercise have partly explained lower cardiorespiratory fitness. 8,11 However, little information is available on determinants of cardiorespiratory fitness in populationbased samples. 12 We therefore studied determinants of directly measured cardiorespiratory fitness, including age, chronic diseases, use of medications, biochemical factors, body weight, and several health habits such as physical activity, cigarette smoking, alcohol consumption, and nutrition, in a population-based sample of middle-aged men, and whether the relative importance of these factors differs with respect to age and health status. a Kuopio Research Institute of Exercise Medicine, b School of Public Health and Clinical Nutrition and c Institute of Biomedicine and Physiology, University of Kuopio, Departments of d Medicine and e Clinical Physiology and Nuclear Medicine, Kuopio University Hospital, Kuopio, f Lapland Central Hospital, Rovaniemi, and g Division of Cardiology, Department of Internal Medicine, University of Oulu, Oulu, Finland. Manuscript received November 16, 2008; revised manuscript received and accepted January 31, This work was supported by grants from the Finnish Academy, the Ministry of Education of Finland, and the town of Kuopio, Finland. *Corresponding author: Fax address: jariantero.laukkanen@uku.fi (J.A. Laukkanen). Methods Subjects were participants in the Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD), which was designed to investigate risk factors for cardiovascular disease, carotid atherosclerosis, and related outcomes in a random population-based sample of men. Of the 3,433 men 42 to 60 years of age who resided in the town of Kuopio, Finland, or its surrounding rural communities, 198 were excluded because of death, serious disease, or migration away from the area, and of the remainder, 2,682 (82%) agreed to participate in the study. Baseline examinations were conducted from March 1984 to December In the first cohort men were 54 years old and in the second cohort men were 42 to 60 years old. Complete data on cardiorespiratory fitness and its determinants were available for 936 men. Data were limited due to assessment of pulmonary function, which was limited to only the second cohort that included men 42 to 60 years old. Those men who underwent exercise testing and assessment of cardiorespiratory fitness and pulmonary function were from the second cohort and that cohort with different age groups was included in the study. Cardiorespiratory fitness was assessed with a maximal, symptom-limited exercise-tolerance test on an electrically braked bicycle ergometer. The testing protocol consisted of a linear increase in workload by 20 W/min (400 L bicycle ergometer, Medical Fitness Equipment, Mearn, The Netherlands). Respiratory gas exchange was measured by the breath-by-breath method, using a MGC 2001 analyzer (Medical Graphics, St. Paul, Minnesota). The MGC 2001 analyzer expressed VO 2max as the average of values recorded over 8 seconds. VO 2max was defined as the highest /09/$ see front matter 2009 Elsevier Inc. doi: /j.amjcard

2 Miscellaneous/Cardiorespiratory Fitness and Determinants 1599 value for or the plateau on oxygen uptake. Electrocardiogram was monitored continuously during and 8 minutes after the test. Heart rates at rest and during exercise were recorded. The most common reasons for stopping the exercise test were leg fatigue (574 men), exhaustion (117 men), breathlessness (64 men), and pain in the leg muscles, joints, or back (56 men). The test was discontinued in 86 men because of cardiorespiratory symptoms or abnormalities such as dyspnea (48 men), chest pain (26 men), ischemic electrocardiographic changes (4 men), arrhythmias (3 men), a marked change in systolic or diastolic blood pressure (2 men), and dizziness (3 men). Leisure-time physical activity was assessed using the KIHD 12-month leisure-time physical activity questionnaire The checklist included the most common leisuretime physical activities of middle-aged Finnish men, selected based on a previous population study in Finland For each activity performed, subjects were asked to record the frequency (number of sessions per month), average duration (hours and minutes per session), and intensity (scored as 0 for recreational activity, 1 for conditioning activity, 2 for brisk conditioning activity, 3 for strenuous exercise). Mean intensity of physical activity was expressed in METs. The 4 categories of intensity of activity (range of possible scores 0 to 3) were assigned their own MET values, revised based on a synthesis of available empiric data. 15 A MET is the ratio of metabolic rate during exercise to metabolic rate at rest. One MET corresponds to an energy expenditure of approximately 1 kcal/kg of body weight per hour, or an oxygen uptake of 3.5 ml/kg/min. Physical activity was categorized according to type: (1) conditioning physical activity walking (mean intensity 4.3 METs, range 3.0 to 7.0), jogging (10.2 METs, 7.0 to 12.5), skiing (9.6 METs, 7.0 to 12.5), bicycling (5.9 METs, 4.0 to 9.0), swimming (5.4 METs, 4.0 to 10.0), rowing (5.4 METs, 3.0 to 10.0), ball games (6.7 METs, 4.9 to 9.0), and gymnastics, dancing, or weight lifting (4.9 METs, 3.0 to 8.0); (2) nonconditioning physical activity crafts, repairs, or building (2.7 METs, 2.0 to 6.0), yard work, gardening, farming, or snow shoveling (4.3 METs, 3.0 to 7.0), hunting, picking berries, or gathering mushrooms (3.6 METs, 3.0 to 7.0), fishing (2.4 METs, 2.0 to 5.0), and forestry (7.6 METs, 3.0 to 10.0); and (3) walking (3.5 METs, 3.0 to 6.0) or bicycling (5.2 METs, 4.0 to 7.0) to work. Lifelong exposure to smoking (cigarette pack-years) was estimated as the product of the number of years spent smoking and the number of tobacco products smoked daily at time of examination. Number of cigarettes, cigars, and pipefuls of tobacco currently smoked daily and duration of regular smoking in years were recorded using a self-administered questionnaire. Consumption of alcohol in the previous 12 months was assessed with the Nordic Alcohol Consumption Inventory. 16 Consumption of foods was assessed when blood was sampled by recording intake over 4 days with a questionnaire, which was checked at the interview. 16 History of diseases (coronary heart disease [CHD], cardiac insufficiency, cardiomyopathy, stroke, claudication, asthma, chronic bronchitis, pulmonary tuberculosis, and diabetes mellitus), family history of diseases, and use of Table 1 Distributions of maximal oxygen uptake, conditioning physical activity, other determinants, and diseases in men in eastern Finland (n 936) VO 2max (ml/min) 2, (465 5,034) VO 2max (ml/kg/min) ( ) Conditioning physical activity Duration (h/wk) ( ) Frequency (sessions/wk) ( ) Mean intensity (METs)* ( ) Age (yrs) ( ) Height (cm) ( ) Weight (kg) ( ) Waist-to-hip circumference ratio ( ) Cigarette smoking (pack-years) ( ) Heart rate at rest (beats/min) (18 109) Heart rate at maximal exercise (beats/min) (73 210) Systolic blood pressure (mm Hg) (93 203) Hemoglobin (g/dl) ( ) Hematocrit ( ) Blood leukocytes ( /L) ( ) Serum insulin (mu/l) ( ) Intake of carbohydrate (g/day) ( ) FVC (L) ( ) FEV 1 (L) ( ) FEV 1 % (FEV 1 /FVC) ( ) CHD 20.5% Cardiac insufficiency 6.2% Cardiomyopathy 1.5% Left ventricular hypertrophy 1.2% Stroke 1.6% Claudication 3.3% Asthma 3.5% Chronic bronchitis 7.2% Pulmonary tuberculosis 2.6% Diabetes mellitus 4.2% Use of any blocker 14.4% Values are means SDs (ranges) or percentages of patients. * A metabolic unit is the ratio of metabolic rate during physical activity to metabolic rate at rest. One MET corresponds to an energy expenditure of approximately 1 kcal/kg of body weight per hour and an oxygen uptake of 3.5 ml/kg/min. Pack-years denotes lifelong exposure to smoking, which was estimated as the product of years smoked and the number of tobacco products smoked daily at time of examination. Defined as a diagnosis of heart failure based on clinical findings and symptoms. Includes dilated and hypertrophied cardiomyopathies diagnosed based on echocardiographic findings and symptoms. medicines were recorded using a self-administered questionnaire, which was checked by an interviewer. A physician reinterviewed subjects regarding their medical histories. Prevalent CHD was defined as a history of myocardial infarction or angina pectoris, a positive finding for angina pectoris on effort based on the London School of Hygiene cardiovascular questionnaire, or use of nitroglycerin tablets for chest pain 1 time/week. A family history of CHD was defined as positive when the father, mother, sister, or brother of a subject had a myocardial infarction, angina pectoris, or CHD. Diabetes mellitus was defined as a fasting blood glucose level 6.7 mmol/l or a clinical diagnosis of diabetes with dietary, oral, or insulin treatment. Blood pressure at rest was measured by 1 nurse with a random 0 mercury sphygmomanometer (Hawksley, United

3 1600 The American Journal of Cardiology ( Figure 1. (A) Duration, (B) frequency, and (C) mean intensity of conditioning physical activity and (D) VO 2max in a population-based sample of middle-aged men. Kingdom; from 8:00 to 10:00 A.M.). The measuring protocol included, after a supine rest of 5 minutes, 3 measurements in the supine position, 1 measurement in the standing position, and 2 measurements in the sitting position at 5-minute intervals. The mean of 6 systolic and diastolic pressures was used in these analyses. 17 Pulmonary function was measured using a Medikro 101 spirometer. Three measurements were used to assess pulmonary function: (1) forced vital capacity (FVC), (2) forced expiratory volume in 1 second (FEV 1 ), and (3) percentage of FEV 1 from FVC. Body mass index was calculated by diving a subject s weight in kilograms by his height in square meters. Waistto-hip ratio was computed as the ratio of waist circumference to hip circumference. Main lipoprotein fractions were separated from fresh serum samples by ultracentrifugation and precipitation. 18 Cholesterol and triglyceride contents of all lipoprotein fractions were measured enzymatically (Boehringer Mannheim, Mannheim, Germany). Blood glucose was derived from venous blood samples that were taken after a 12-hour fast. Serum insulin was determined with a Novo Biolabin radioimmunoassay kit (Novo Nordisk, Bagsvaerd, Denmark). Plasma fibrinogen was determined from fresh samples with a coagulometer based on clotting of extra fibrin (Amelung KC4, Heinrich Amelung, Lemgo, Germany). Blood hemoglobin was measured photometrically (Gilford Stasar III, Gilford Instrument Laboratories, Oberlin, Ohio) using the cyanmethemoglobin method within a few hours of blood sampling. 19 Blood hematocrit was determined using a hematocrit centrifuge. Blood leukocyte count was measured using a Coulter Counter (Coulter Counter Electronics, Luton, United Kingdom). Several possible determinants of cardiorespiratory fitness (VO 2max ), including history of diseases, family history of diseases, medications, physical activity, cigarette smoking, alcohol consumption, dietary intake of nutrients, biochemical factors, such as serum lipids and lipoproteins, serum insulin, blood glucose, plasma fibrinogen, blood hemoglobin, hematocrit and leukocyte count, blood pressure, body

4 Miscellaneous/Cardiorespiratory Fitness and Determinants 1601 Table 2 Strongest determinants of maximal oxygen uptake (n 936)* Variable VO 2max (ml/min) Univariate Model Multivariate Model Crude r Value p Value Standardized In Original Units p Value Heart rate at maximal exercise (beats/min) Weight (kg) Heart rate at rest (beats/min) Age (yrs) Intensity of conditioning physical activity (METs) Intake of carbohydrates (g/day) Fasting serum insulin (mu/l) Waist-to-hip circumference ratio CHD (yes vs no) Frequency of conditioning physical activity NS (session/week) Asthma (yes vs no) Hemoglobin (g/dl) NS FEV * Determinants of VO 2max were selected from a step-up multivariate regression model based on their statistical significance (p 0.05). Spearman correlation coefficient. A metabolic unit is the ratio of metabolic rate during physical activity to metabolic rate at rest. One MET corresponds to an energy expenditure of approximately 1 kcal/kg of body weight per hour and an oxygen uptake of 3.5 ml/kg/min. mass index, and waist-to-hip circumference ratio, were entered into a step-up linear multivariate regression model. Separate regression models were done for men 42 to 48 years old (n 502) and 54 to 60 years old (n 434) and for healthy (n 536) and unhealthy men with any disease that could lower VO 2max (n 400). Determinants of VO 2max were selected based on their statistical significance (p 0.05) from these models. Crude correlations of VO 2max with the determinants were estimated with Pearson correlation coefficients (Spearman coefficient for dichotomous variables). Regression of determinants on VO 2max were estimated and tested for statistical significance with linear multivariate regression analysis. To study how much each variable independently accounted for variation of VO 2max, these variables were dropped out 1 by 1 from the multivariate regression model. All statistical analyses were conducted with procedures from SPSS 14.0 for Windows (SPSS, Inc., Chicago, Illinois). Results Means SDs (ranges) or prevalences of VO 2max and its determinants in the present study population are listed in Table 1. Distributions of duration, frequency, and mean intensity of conditioning physical activity and VO 2max in the study population are presented in Figure 1. The strongest determinants of VO 2max without and after adjustment for other determinants are listed in Table 2. VO 2max had direct crude correlations with heart rate at maximal exercise, body weight, mean intensity of conditioning physical activity, intake of carbohydrates, and FEV 1 and inverse crude correlations with heart rate at rest, age, fasting serum insulin, waist-to-hip ratio, prevalent CHD, and prevalent asthma. After adjustment for all factors listed in Table 2, VO 2max was directly associated with body weight, heart rate at maximal exercise, mean intensity of conditioning physical activity, intake of carbohydrates, frequency of conditioning physical activity, blood hemoglobin, and FEV 1 and inversely with heart rate at rest, age, fasting serum insulin, waist-to-hip circumference ratio, prevalent CHD, and asthma. Determinants listed in Table 2 altogether accounted for 67% of the variation of VO 2max. Body weight accounted independently for 12%, heart rate at maximal exercise for 12%, heart rate at rest for 3.0%, mean intensity of conditioning physical activity for 2.5%, age for 2.2%, intake of carbohydrates for 1.7%, fasting serum insulin for 0.8%, FEV 1 for 0.4%, prevalent asthma for 1.9%, prevalent CHD for 0.5%, waist-to-hip ratio for 0.5%, frequency of conditioning physical activity for 0.4%, and blood hemoglobin for 0.2% of the variation of VO 2max. VO 2max decreased by 53 ml/min (0.61 ml/kg/min) per year of age without adjustment and by 19 ml/min (0.22 ml/kg/min) after adjustment for all determinants listed in Table 2. There was a 136 ml/min (1.96 ml/kg/min) decrease in VO 2max per 1-MET decrease of mean intensity of conditioning physical activity without adjustment and a 66 ml/ min (0.86 ml/kg/min) decrease after adjustment for other determinants. Of different types of leisure-time physical activity, duration of jogging (crude r 0.205, standardized multivariate regression coefficient beta 0.133, p 0.001), cross-country skiing (r 0.256, beta 0.138, p 0.001), leisure-time bicycling (r 0.058, beta 0.070, p 0.001), bicycling to work (r 0.013, beta 0.064, p 0.01), ball games (r 0.191, beta 0.060, p 0.01), and rowing (r 0.083, beta 0.056, p 0.01) were associated directly with VO 2max after adjustment for the determinants listed in Table 2 excluding other variables of leisure-time physical activity. VO 2max also had direct crude correlations with mean intensity of total leisure-time physical activity (r 0.347, p 0.001), FVC (r 0.412, p 0.001), FEV 1 (r 0.479, p 0.001), body height (r 0.427, p 0.001), and diastolic blood pres-

5 1602 The American Journal of Cardiology ( Table 3 Strongest determinants of maximal oxygen uptake (milliliters per minute) in age groups Variable yrs yrs Standardized In Original Units p Value Standardized In Original Units p Value Weight (kg) Heart rate at maximal exercise (beats/min) Heart rate at rest (beats/min) Intensity of conditioning physical activity (METs) Intake of carbohydrates (g/day) Fasting serum insulin (mu/l) CHD (yes vs no) Duration of conditioning physical activity (h/wk) * * * Waist-to-hip ratio , FEV 1 * * * Asthma (yes vs no) Blood hemoglobin (g/dl) * * * Cardiomyopathy (yes vs no) * * * * These variables did not enter into the step-up multivariate regression model because of their statistical nonsignificance (p 0.05). A metabolic unit is the ratio of metabolic rate during physical activity to metabolic rate at rest. One MET corresponds to an energy expenditure of approximately 1 kcal/kg of body weight per hour and an oxygen uptake of 3.5 ml/kg/min. Includes dilated and hypertrophied cardiomyopathies diagnosed based on echocardiographic findings and symptoms. sure (r 0.074, p 0.023) and inverse crude correlations with prevalent cardiac insufficiency (r 0.206, p 0.001), left ventricular hypertrophy (r 0.104, p 0.002), stroke (r 0.067, p 0.005), claudication (r 0.203, p 0.001), chronic bronchitis (r 0.074, p 0.023), and diabetes mellitus (r 0.092, p 0.005), use of any blockers (r 0.326, p 0.001), cigarette smoking (r 0.163, p 0.001), blood leukocyte count (r 0.180, p 0.001), and fasting blood glucose (r 0.180, p 0.001). However, none of these variables was associated with VO 2max after adjustment for other determinants. Prevalent pulmonary tuberculosis, use of medications other than blockers, systolic blood pressure, body height, alcohol consumption, duration of conditioning physical activity, mean intensity, frequency, and duration of nonconditioning physical activity, and alcohol consumption were not associated with VO 2max. Table 3 lists determinants of VO 2max separately in men 42 to 48 years old and in men 54 to 60 years old after adjustment for other determinants. The association of mean intensity of conditioning physical activity with VO 2max was stronger in the younger than in the older men and duration of conditioning physical activity was related to VO 2max only in the younger men. Durations of jogging, cross-country skiing, and bicycling to work were associated with VO 2max in the 2 age groups, duration of leisure-time bicycling and ball games only in the older men, and duration of rowing only in the younger men. Waist-to-hip ratio had a stronger inverse association with VO 2max in the older men. Blood hemoglobin and FEV 1 were related directly and prevalent cardiomyopathy inversely to VO 2max only in the older men. The association of mean intensity of conditioning physical activity with VO 2max was stronger in healthy men (beta 0.218, p 0.001) than in unhealthy men with any disease that could lower VO 2max (CHD, cardiac insufficiency, cardiomyopathy, left ventricular hypertrophy, stroke, claudication, asthma, chronic bronchitis, pulmonary tuberculosis, diabetes, and cancer, beta 0.095, p 0.001) after adjustment for determinants listed in Table 2. Duration of conditioning physical activity (beta 0.129, p 0.001) waist-to-hip ratio (beta 0.139, p 0.001), and blood hemoglobin (beta 0.069, p 0.016) were associated independently with VO 2max only in healthy men, whereas prevalent CHD (beta 0.117, p 0.001) and asthma (beta 0.100, p 0.001) were related independently to VO 2max in unhealthy men. Discussion Heart rate at maximal exercise, intensity, frequency, and duration of conditioning physical activity, intake of carbohydrates, body weight, and blood hemoglobin were directly related to cardiorespiratory fitness, whereas age, heart rate at rest, prevalent CHD and asthma, central obesity, and fasting serum insulin were inversely associated. These variables accounted for 67% of the variation of VO 2max. The present study in middle-aged men from eastern Finland is 1 of the few reported studies concerning determinants of cardiorespiratory fitness in unselected population samples. 9,11,20,21 We used directly measured VO 2max as a measurement of cardiorespiratory fitness, which is considered the most accurate method for assessing cardiorespiratory capacity. Few previous studies concerning determinants of cardiorespiratory fitness in population samples have applied this method. 12,21 Quantitive 12-month leisure-time physical activity history, the reproducibility and validity of which have been shown previously, 15 enabled us to investigate associations of different components of leisure-time physical activity with VO 2max. In contrast, biological determinants and diseases can be measured more accurately than most health habits, including physical activity, dietary factors, and alcohol consumption, which may underestimate observed associations of health habits as determinants of cardiorespiratory fitness. In our study, intensity and frequency of conditioning physical activity were associated directly with VO 2max.Intensity of conditioning physical activity had a stronger as-

6 Miscellaneous/Cardiorespiratory Fitness and Determinants 1603 sociation with VO 2max, especially in the younger men. Physical activity can markedly increase VO 2max in sedentary middle-aged subjects. 22 The VO 2max -improving effect of physical activity depends strongly on its frequency, duration, 23 and especially intensity. 1,22,23 Unfit subjects may require lower amounts of physical activity than fit subjects to improve their cardiorespiratory fitness. For example, 2 times/week of physical activity improved VO 2max in subjects with a low initial VO 2max, but 3 times/week was needed in subjects with a high VO 2max. 23 Furthermore, lower-intensity physical activity appears sufficient to improve cardiorespiratory fitness in older unfit subjects compared to younger and fit subjects. 23 In population-based studies, however, the association between physical activity and cardiorespiratory fitness has been relatively weak and physical activity has accounted for only a small part of the variance of VO 2max. 1,12,20 Heredity may in part explain interindividual differences in cardiorespiratory fitness and its sensitivity to endurance training. 6,7 The genetic component of cardiorespiratory fitness has been estimated to be 25% to 40%. 6,7,24 We found that heart rate at maximal exercise had a strong direct relation and that blood hemoglobin, which transports oxygen to tissues, had a weak direct relation to VO 2max. Furthermore, pulmonary expiratory capacity was related directly to VO 2max.VO 2max is an indicator of the oxygen transport capacity of the body, limited primarily by cardiac output, pulmonary gas exchange, peripheral circulation, extraction of oxygen in muscles, and migration of oxygen to mitochondria. 25 These components are determined by age, genetic factors, diseases, medications, and health habits. Exercise training decreases heart rate and blood pressure at rest and submaximal work load, increases cardiac output and maximal aerobic capacity, muscle capillarization, and mitochondrial oxidative enzyme activity. 25 The main reason for the decrease in VO 2max with age is lowering of cardiac output at maximal exercise. 11,26 The observed mean decrease of VO 2max per year of age was 53 ml/min, which is of the same order as shown previously. 3,27 Previous studies have shown an average decrease in VO 2max of 5% to 15% per decade in men 20 to 75 years old, 28 with the smallest decrease in younger groups. However, VO 2max is higher in physically active than inactive subjects, whatever the age. Also, cardiorespiratory fitness seems to decrease at a slower rate in physically active subjects. 28 Little information is available on the associations of various diseases with VO 2max. 4 The relative importance of health status as a determinant of VO 2max is greater in older subjects because of a higher prevalence of chronic diseases that limit cardiorespiratory capacity in these subjects. Based on our analyses, CHD and asthma are the most important diseases associated with low VO 2max in middle-aged men. In older men, prevalent cardiomyopathy and left ventricular hypertrophy also explained some of the variation in VO 2max. We found that waist-to-hip ratio was inversely associated with VO 2max, especially in older healthy men. Large adipose tissue mass and low fat-free weight have been associated with low VO 2max in older populations. 3,11 However, in our study total body weight had a direct association with VO 2max as expressed in liters per minute, most likely because heavier and more obese men also have a larger fat-free mass, including skeletal muscle. Thus, total oxygen uptake may be greater than in lighter men, although their functional capacity and VO 2max per kilogram of body weight or fat-free mass may be lower. Cardiorespiratory fitness was associated directly with intake of carbohydrates and inversely with fasting serum insulin. These relations may to some extent reflect the improved use of carbohydrates and insulin sensitivity in men with good cardiorespiratory fitness. The metabolic capacity of the body during endurance exercise is closely related to VO 2max. 25 Exercise increases the rate of use of all metabolic fuels and muscle oxidative enzyme activities. Dietary carbohydrates are potentially significant substrates to increase endurance performance and may increase VO 2max by maintaining the ability to oxidize carbohydrates at high rates. 29 Based on this cross-sectional population-based study, frequency, duration, and especially intensity of conditioning physical activity are associated directly with VO 2max in middle-aged men. This is in line with our previous findings showing the strong prognostic value of cardiorespiratory fitness. 13,30 However, factors other than physical activity, such as age, body composition, prevalent heart disease and obstructive pulmonary disease, cardiovascular and pulmonary functions, and carbohydrate use, appear to account for the variance in VO 2max. The relative importance of physical activity was higher in younger and healthy men, whereas other factors were more important in older men. 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