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Cardiovascular Fitness as a Predictor of Mortality in Men
Jari A. Laukkanen, MD;
Timo A. Lakka, MD, PhD;
Rainer Rauramaa, MD, PhD, MSc;
Raimo Kuhanen, MSc;
Juha M. Venäläinen, MD;
Riitta Salonen, MD, PhD;
Jukka T. Salonen, MD, PhD, MScPH
Arch Intern Med. 2001;161:825-831.
ABSTRACT
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Objective To examine the relations of cardiorespiratory fitness, as measured by
maximal oxygen uptake and exercise test duration at the initiation of the
study, with overall, cardiovascular disease (CVD)–related, and non–CVD-related
mortality.
Methods A population-based cohort study of 1294 men with no CVD, pulmonary disease,
or cancer at baseline in Kuopio and surrounding communities in eastern Finland.
During an average follow-up of 10.7 years, there were 124 overall, 42 CVD-related,
and 82 non–CVD-related deaths.
Results The relative risk of overall death in unfit men (maximal oxygen uptake
<27.6 mL/kg per minute) was 2.76 (95% confidence interval, 1.43-5.33) (P = .002), and the relative risk of CVD-related death was
3.09 (95% confidence interval, 1.10-9.56) (P = .05),
compared with fit men (maximal oxygen uptake >37.1 mL/kg per minute) after
adjusting for age, examination years, smoking, and alcohol consumption. The
relative risk of non–CVD-related death in unfit men was almost the same
magnitude as for overall death. Furthermore, adjustment for serum lipid levels,
blood pressure, plasma fibrinogen level, diabetes, and fasting serum insulin
level did not weaken these associations significantly. Exercise test duration
also had a strong inverse relation to overall, CVD-related, and non–CVD-related
mortality. Poor cardiorespiratory fitness was comparable with elevated systolic
blood pressure, smoking, obesity, and diabetes in importance as a risk factor
for mortality.
Conclusions Cardiorespiratory fitness had a strong, graded, inverse association
with overall, CVD-related, and non–CVD-related mortality. Maximal oxygen
uptake and exercise test duration represent the strongest predictors of mortality.
INTRODUCTION
PHYSICAL INACTIVITY, as measured objectively by low cardiorespiratory
fitness, has been estimated to account for 12% of all deaths in the United
States.1 Thus, it is considered to be one of
the most crucial public health problems. Low cardiorespiratory fitness2-9
has consistently been associated with an increased risk of premature death
in prospective population-based studies. This has been mainly due to reduced
cardiovascular disease (CVD)–related mortality,2, 4-5
but also to some extent to reduced cancer-related mortality,4
in fit individuals. Indeed, low cardiorespiratory fitness has been found to
be as strong a predictor of mortality as the conventional modifiable risk
factors, such as cigarette smoking, hypercholesterolemia, and hypertension.7, 9
Recommendations concerning the specific quantity and intensity of physical
activity and the level of cardiorespiratory fitness needed to reduce premature
mortality are based on a few prospective population-based studies.10-11 Maximal oxygen uptake ( O2max), as a measure of cardiorespiratory fitness, provides a quantifiable
measurement of the level of physical exercise in addition to its genetic component.
Directly measured O2max is a gold standard for assessing
the amount of oxygen consumption in maximal effort.12
Maximal oxygen uptake during exercise represents cardiac, circulatory, and
respiratory function and muscle oxygen use under physiological stress conditions.
The present study examines the associations of cardiorespiratory fitness,
as indicated by directly measured O2max,13
and exercise test duration with mortality not only from CVDs but also from
other causes, in a population-based sample of men from eastern Finland.
SUBJECTS AND METHODS
SUBJECTS
Subjects were participants in the Kuopio Ischaemic Heart Disease Risk
Factor Study.14 This study was designed to
investigate risk factors for CVD, atherosclerosis, and related outcomes in
a population-based, randomly selected sample of men in eastern Finland.14 Of the 3433 men aged 42, 48, 54, or 60 years who
resided in the town of Kuopio or its surrounding rural communities, 198 were
excluded because of death, serious disease, or migration away from area, and
of the remaining men, 2682 (83%) agreed to participate in the study. Baseline
examinations were conducted between March 20, 1984, and December 5, 1989.
Men who had a history of CVD, including coronary heart disease diagnosed
by angina pectoris, myocardial infarction, use of medications for coronary
heart disease, and myocardial ischemia in an exercise test (n = 766); cardiac
insufficiency (n = 194); claudication (n = 108); stroke (n = 69); cardiomyopathy
(n = 55); arrhythmias (n = 26); other CVDs (n = 103); cancer (n = 46); or
pulmonary diseases, including chronic obstructive pulmonary disease (n = 197),
pulmonary tuberculosis (n = 104), and asthma (n = 96) were excluded as these
conditions might have affected their physical exercise and cardiorespiratory
fitness. Some men had 2 or more of these diseases. Subjects (56 men with and
13 men without disease) whose O2max was less than 15.75
mL/kg per minute, corresponding to 4.5 metabolic equivalents (METs) (METs
of oxygen consumption), were also excluded, as a low O2max
may be an indicator of an underlying but yet undiagnosed disease. An exercise
capacity of 5 METs or less is related to poor prognosis in subjects younger
than 65 years.12 After these exclusions, complete
data on O2max and exercise test duration were available
for 1294 of the remaining men.
ASSESSMENT OF CARDIORESPIRATORY FITNESS
Cardiorespiratory fitness was assessed with a maximal, symptom-limited
exercise tolerance test on an electrically braked bicycle ergometer at the
initiation of the study. For 307 men examined before May 8, 1986, the testing
protocol comprised a 3-minute warm-up at 50 W followed by a step-by-step increase
in the workload of 20 W/min. The remaining 987 men were tested with a linear
increase in the workload of 20 W/min. The electrocardiogram was registered
continuously during the exercise stress test.
Maximal oxygen uptake and exercise test duration were used as measures
of cardiorespiratory fitness. A detailed description of the measurement of
O2max has been given elsewhere.13
In short, respiratory gas exchange was measured for the first 307 men by the
mixing-chamber method, and for the other 987 men by a breath-by-breath method. Maximal oxygen uptake was defined as the highest value
for or the plateau of oxygen uptake. Maximal oxygen uptake was also expressed
in METs. The MET is the ratio of the metabolic rate
during exercise to the metabolic rate at rest. One MET corresponds to an oxygen
uptake of 3.5 mL/kg per minute.
The most common reasons for stopping the exercise test were leg fatigue
(n = 735); exhaustion (n = 207); breathlessness (n = 155); and pain in the
leg muscles, joints, or back (n = 50). The test was discontinued because of
cardiorespiratory symptoms or abnormalities in 86 men. These included arrhythmias
(n = 36), a marked change in systolic (n = 8) or diastolic (n = 24) blood
pressure, dizziness (n = 7), chest pain (n = 7), or ischemic electrocardiographic
changes (n = 4).
ASSESSMENT OF OTHER RISK FACTORS
Assessments of smoking, alcohol consumption, physical activity, and
blood pressure13, 15-16
were performed as described previously. The collection of blood specimens15 and the measurement of serum lipids and lipoproteins,17-18 insulin,18
plasma fibrinogen,19 and glucose15
have been described elsewhere. Body mass index was computed as weight in kilograms
divided by the square of height in meters, and waist-hip ratio as the ratio
of the circumference of the waist to that of the hip.
ASCERTAINMENT OF FOLLOW-UP EVENTS
Deaths were ascertained by linkage to the national death registry using
the Finnish social security number. There were no losses to follow-up. All
deaths that occurred between study enrollment (from March 20,1984, to December
5, 1989) and December 31, 1997, were included. Deaths that were coded with
the International Classification of Diseases, Ninth Revision (ICD-9),20
codes 390 to 459 were included in the analyses of CVD-related deaths. All
other deaths were non–CVD-related deaths. The average time to any death
or the end of follow-up was 10.7 years (range, 0.8-13.8 years). In the present
sample, there were 124 deaths during the follow-up period, 42 from CVD-related
causes and 82 from non–CVD-related causes.
STATISTICAL ANALYSIS
The associations of O2max and exercise test duration
with the risk factors for death were examined using covariate analysis. The
levels of O2max and exercise test duration were entered
as dummy variables into forced Cox proportional hazards regression models
using Statistical Package for the Social Science software (SPSS Inc, Chicago,
Ill).21 In these models, O2max and exercise test duration were categorized according to quartiles.
If possible, covariates were entered uncategorized into the Cox proportional
hazards regression models. Three different sets of covariates were used: (1)
age and examination years (1985, 1986, 1987, 1988, and 1989); (2) age, examination
years, cigarette smoking, and alcohol consumption; and (3) in the case of
overall and CVD-related mortality, age, examination years, cigarette smoking,
alcohol consumption, systolic blood pressure, diabetes, fasting serum insulin
level, plasma fibrinogen level, serum high- and low-density lipoprotein cholesterol
levels, and triglycerides level. Relative hazards, adjusted for risk factors,
were estimated as antilogarithms of coefficients from multivariate models.
Their confidence intervals (CIs) were estimated under the assumption of asymptotic
normality of the estimates. All tests for statistical significance were 2-sided.
The fit of the proportional hazards regression models was examined by plotting
the hazard functions in different categories of risk factors over time. The
results indicated that the application of the models was appropriate. All
statistical analyses were performed using Statistical Package for the Social
Science software for Windows. To reduce the possibility of self-selection
bias, these data were reanalyzed by excluding men who had died during the
first 3 years of follow-up.
RESULTS
BASELINE CHARACTERISTICS
At the beginning of the follow-up, the mean age of the subjects was
52.1 years (range, 42.0-61.3 years). The mean O2max was
32.7 mL/kg per minute (range, 16.0-65.4 mL/kg per minute), and the mean exercise
test duration was 9.7 minutes (range, 2.9-19.9 minutes). Maximal oxygen uptakewas
associated directly with serum high-density lipoprotein cholesterol level
and exercise test duration and inversely with cigarette smoking, alcohol consumption,
body mass index, waist-hip ratio, systolic and diastolic blood pressure, diabetes,
fasting serum insulin level, plasma fibrinogen level, serum total and low-density
lipoprotein cholesterol level, and triglycerides level (Table 1).
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Table 1. Characteristics of 1294 Men in Eastern Finland Who Reported
Having No Cardiovascular or Pulmonary Disease or Cancer at Baseline According
to Quartiles of Maximal Oxygen Uptake*
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CARDIORESPIRATORY FITNESS AND OVERALL MORTALITY
Low cardiorespiratory fitness was related to increased risk of overall
mortality (Table 2). Low O2max (<27.6 mL/kg per minute) was associated with a 2.76-fold (95%
CI, 1.43-5.33) (P = .002) risk of overall mortality
after adjusting for age, examination years, smoking, and alcohol consumption
(P<.001 for linear trend). Also, a short exercise
test duration was associated with an increased risk of overall mortality (Table 2). The relative risk (RR) of overall
death was 2.72 (95% CI, 1.37-5.42) (P = .004) in
men whose exercise test duration was less than 8.2 minutes (lowest quartile)
compared with men whose exercise test duration was more than 11.2 minutes
(highest quartile) after adjusting for age, examination years, smoking, and
alcohol consumption (P = .007 for linear trend).
Additional adjustment for serum triglycerides level, high- and low-density
lipoprotein cholesterol levels, systolic blood pressure, diabetes, fasting
serum insulin level, and plasma fibrinogen level did not change the associations
of O2max and exercise test duration with overall mortality
significantly.
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Table 2. Relative Risks of Overall, CVD-Related, and Non-CVD-Related
Death According to Quartiles of Maximal Oxygen Uptake and Exercise Test Duration*
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CARDIORESPIRATORY FITNESS AND CVD-RELATED MORTALITY
Low cardiorespiratory fitness was associated with an increased risk
of CVD-related mortality (Table 2).
Men with a low O2max (<27.6 mL/kg per minute) had
a 3.09-fold (95% CI, 1.10-9.56) (P = .05) risk of
CVD-related death after adjusting for age, examination years, smoking, and
alcohol consumption compared with men with a high O2max
(>37.1 mL/kg per minute) (P = .01 for linear trend).
Further adjustment for serum triglycerides level, serum low- and high-density
lipoprotein cholesterol levels, systolic blood pressure, diabetes, fasting
serum insulin level, and plasma fibrinogen level slightly weakened these associations
(P = .05 for linear trend). There was little difference
in the risk between the first and second quartiles (Table 2).
Exercise test duration was related to an increased risk of CVD-related
mortality (Table 2). The RR of
CVD-related death was 3.44 (95% CI, 1.09-10.80) (P
= .04) in the lowest quartile compared with men in the highest quartile after
adjustment for age, examination years, smoking, and alcohol consumption (P = .01 for linear trend).
CARDIORESPIRATORY FITNESS AND NON–CVD-RELATED MORTALITY
Low cardiorespiratory fitness (O2max of <27.6
mL/kg per minute or an exercise duration of <10.2 minutes) was also associated
with an increased risk of non–CVD-related death (Table 2). The RR of non–CVD-related death in men with a low
O2max was 2.60 (95% CI, 1.16-5.83) (P = .02) after adjustment for age, examination years, smoking, and
alcohol consumption (P = .005 for linear trend).
Men whose exercise test duration was less than 10.2 minutes (lowest quartile)
had an increased risk of non–CVD-related death (RR, 2.46; 95% CI, 1.01-5.70; P = .05) compared with men with durations that were longer
than 13.2 minutes (highest quartile) after adjustment for age, examination
years, smoking, and alcohol consumption.
STRONGEST RISK FACTORS FOR DEATH
The associations of other risk factors with overall and CVD-related
mortality are presented in Table 3.
High systolic blood pressure, smoking, obesity, and diabetes were associated
with an increased risk of all-cause and CVD-related mortality. Men with the
highest systolic blood pressure (>143 mm Hg) had a 2.32-fold risk and men
with the highest waist-hip ratio (>0.98) had a 1.54-fold risk of overall death
(Table 3). The RR of CVD-related
death was 3.18 in hypertensive men (those with a systolic blood pressure of
>143 mm Hg) and 3.74 in obese men (those with a waist-hip ratio of >0.98).
Smokers had a 3.74-fold and diabetic men had a 2.38-fold risk of overall mortality,
whereas the RR of CVD-related death was 2.57 in smokers and 4.09 in diabetic
men (Table 3). Unfit men had RRs
of 3.85 for overall and 3.97 for CVD-related death, which are at least as
strong as the other risk factors presented in Table 3.
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Table 3. Relative Risks of Overall and CVD-Related Death According
to Systolic Blood Pressure, Obesity, Smoking, and Diabetes*
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COMMENT
In the present study, in middle-aged men, O2max
and exercise test duration had a strong, graded, and inverse association with
overall, CVD-related, and non–CVD-related mortality. In fact, O2max and exercise test duration were 2 of the strongest predictors for
mortality in the present unselected Finnish cohort. These findings support
US cohort studies7, 9 suggesting
that the risk of death associated with low cardiorespiratory fitness is comparable
with that of conventional risk factors, including smoking, hypertension, obesity,
and diabetes.
Blair and coworkers4, 7 found
that moderate levels of cardiorespiratory fitness, defined by quintiles of
treadmill test time, were associated with reduced all-cause and CVD-related
mortality, while higher levels provided only little further reduction in the
risk of death. Sandvik and coworkers5 observed
that moderate levels (quartiles) of work capacity in the bicycle ergometer
test were associated with reduced CVD-related mortality, but there was some
further reduction in the risk at the highest levels. However, Ekelund and
coworkers2 showed a marked difference in CVD-related
mortality between high and low levels of cardiorespiratory fitness, assessed
by heart rate at a speed of 4 km/h (2.5 miles/h) on a treadmill. In our study,
O2max had a strong, graded, and inverse association with
overall, CVD-related, and non–CVD-related mortality through its whole
range. The mortality curves for the quartiles of O2max
continued to diverge during follow-up (Figure
1). The greatest excess of mortality was found at the lowest level
of O2max (<27.6 mL/kg per minute or 7.9 METs).
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Cumulative overall mortality up to 13.8 years of follow-up in men
according to quartiles (Qs) of maximal oxygen uptake (Q4 indicates <27.6
mL/kg per minute; Q3, 27.6-32.2 mL/kg per minute; Q2, 32.3-37.1 mL/kg per
minute; and Q1, >37.1 mL/kg per minute).
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The expert panel suggested that every US adult should accumulate 30
minutes or more of moderate-intensity physical activity on most, preferably
all, days of the week to promote health and to prevent chronic diseases.10 In a recent randomized trial,22
researchers estimated that an increase of 10% in cardiorespiratory fitness,
corresponding to a 1-MET increase in exercise capacity, can be achieved by
maintaining these exercise recommendations for 2 years. However, more intense
structured exercise could increase physical fitness by 1 MET in 6 months.22 Blair and coworkers6
reported that an increase of 2 METs in treadmill performance was related to
a reduction of 30% in mortality. Previous studies6, 8
have suggested that even a small improvement in cardiorespiratory fitness
can result in reduced all-cause and CVD-related mortality.
Some studies23-27
have suggested that physical exercise reduces the risk of prostate, breast,
and large-bowel cancer, but the evidence is inconclusive for other cancers.
However, little is known about the relation between cardiorespiratory fitness
and cancer risk. In a few previous studies, cardiorespiratory fitness has
been related inversely to mortality from cancer of combined sites4, 23 and of the prostate.24
In our study, cardiorespiratory fitness had a strong, graded, and inverse
association with non–CVD-related mortality, primarily due to cancers
and pulmonary diseases. It has been suggested that physical activity and good
cardiorespiratory fitness could reduce the risk of cancer through their beneficial
effects on energy balance, the digestive system (decreased intestinal transit
time), hormonal concentrations (a reduced testosterone level), changes in
prostaglandin levels, antioxidant enzyme activities, or body mass.23-25 However, these mechanisms
are largely speculative, whereas physiological and metabolic mechanisms underlying
the association of cardiorespiratory fitness with CVD-related mortality are
understood better.10-11
Maximal oxygen uptake, which is a product of cardiac output and maximal
arteriovenous oxygen difference, is determined by age; sex; the duration,
intensity, frequency, and type of physical activity; genetic factors; and
clinical or subclinical disease.2, 4, 7, 28
The genetic component of cardiorespiratory fitness is estimated to be 25%
to 40%.28 It is proposed that low cardiorespiratory
fitness reflects mainly physical inactivity. High-intensity exercise is more
effective than low-intensity exercise for improving O2max
in healthy persons, but lower-intensity physical activity may be sufficient
to improve O2max in high-risk persons.29
Therefore, the level of physical activity sufficient to improve cardiorespiratory
fitness probably depends on the initial health and fitness status, the length
of the previous training history, and the duration, frequency, and intensity
of the exercise. Maximal oxygen uptake usually decreases by 5% to 15% per
decade between the ages of 20 and 80 years, and the rate of decline in oxygen
uptake is directly related to maintenance of physical activity level, emphasizing
the importance of physical activity.12
The strength of our study is that we have a representative population-based
sample of middle-aged men in Finland. Second, the participation rate was high,
and there were no losses during follow-up. Third, we have reliable data on
mortality because deaths were ascertained by the Finnish National Death Registry
using social security number, supplemented with reliable data on health status
and risk factors that permit the control of potential confounders. Our study
also demonstrated that both of the measurements of cardiorespiratory fitness,
O2max and exercise test duration, were strong predictors
of mortality. The exercise test is readily available from any exercise laboratory,
and the duration of the test can be measured without any additional equipment.
The treadmill test2, 4 and the
bicycle dynamometer test5 are useful and reliable
ways to define cardiorespiratory fitness status.
In this study, we used only a single measurement of O2max at baseline, but this is not a major limitation. Ideally, the measurement
of cardiorespiratory fitness should be repeated to investigate the effect
over time. However, it has been shown that the intraindividual variability
of O2max is low.30 In
fact, variation with time in cardiorespiratory fitness could underestimate
the real association between O2max and mortality. It
is impossible to know whether cardiorespiratory fitness decreased or increased
during follow-up because of the probable changes in the exercise and other
health habits of the subjects. We have no data on changes in cardiorespiratory
fitness during follow-up, which could affect mortality, as reported previously.6, 8
This prospective population study provides evidence that O2max is associated with an increased risk of death, although only a
randomized controlled trial of thousands of subjects could prove a causal
pathway between O2max and mortality. It is difficult
to distinguish an increased risk of death due to a low level of cardiorespiratory
fitness from an increased risk because of prevalent asymptomatic or preexisting
CVD or cancer. Thus, it is possible that the strength of the association of
cardiorespiratory fitness with mortality is exaggerated by such a bias. It
is unclear how long a lag time would be required to avoid any such possible
selection bias. However, the importance of the lag period diminishes with
longer follow-up, because any bias will be diluted by the increasing weight
of the unbiased cases. We excluded men who died during the first 3 years of
follow-up, but the results did not change markedly because of the few deaths
occurring in the first 3 years (Figure 1).
Furthermore, the careful exclusion of individuals with prevalent coronary
heart disease, stroke, cardiac insufficiency, cardiomyopathy, arrhythmias,
claudication, cancer, and pulmonary diseases and of persons with a low O2max means that a self-selection bias is an unlikely source of bias
in our study.
An increasing amount of epidemiologic data supports the measurement
of cardiorespiratory fitness in clinical practice. Based on the results in
our study, direct or indirect measurement of O2max, which
is available in most clinics, can provide a good estimate for cardiorespiratory
fitness level and prognosis. Poor cardiorespiratory fitness is an important
and independent risk factor for premature death, and can be considered to
be as important as smoking, hypertension, obesity, and diabetes.
AUTHOR INFORMATION
Accepted for publication October 3, 2000.
This study was supported by grants from the Finnish Academy, Helsinki;
the Ministry of Education of Finland; the city of Kuopio, Finland; the Yrjö
Jahnsson Foundation, Helsinki (Drs Laukkanen and Lakka); and the Juho Vainio
Foundation, Helsinki (Drs Laukkanen and Lakka), Finland.
We thank Esko Taskinen, MD, and Hannu Litmanen, MD, for supervising
the exercise tests; Kari Seppänen, MSc, and Kristiina Nyyssönen,
PhD, for supervising the laboratory measurements; and Sudhir Kurl, MD, and
Kimmo Ronkainen, MPH, for data management and analyses.
Corresponding author and reprints: Jukka T. Salonen, MD, PhD, MSPH,
Research Institute of Public Health, University of Kuopio, PO Box 1627, Harjulantie
1 B, 70211 Kuopio, Finland (e-mail: Jukka.Salonen{at}uku.fi).
From the Research Institute of Public Health (Drs Laukkanen, Lakka,
R. Salonen, and J. T. Salonen) and the Department of Community Health and
General Practice, University of Kuopio (Drs R. Salonen and J. T. Salonen);
Inner Savo Health Center (J. T. Salonen); and the Kuopio Research Institute
of Exercise Medicine (Drs Rauramaa and Venäläinen and Mr Kuhanen),
Kuopio, Finland.
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