JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 75, NO.

13, 2020

ª 2020 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

Relevance of Fitness to
Mortality Risk in Men Receiving
Contemporary Medical Care
Stephen W. Farrell, PHD,a Laura F. DeFina, MD,a Nina B. Radford, MD,b David Leonard, PHD,a
Carolyn E. Barlow, PHD,a Andjelka Pavlovic, PHD,a Benjamin L. Willis, MD,a William L. Haskell, PHD,c I-Min Lee, MDd

ABSTRACT

BACKGROUND An inverse association between cardiorespiratory fitness and mortality was robustly demonstrated 3
decades ago.

OBJECTIVES The purpose of this study was to determine whether significant advances in disease prevention, detection,
and treatment since that time have modified this association.

METHODS A total of 47,862 men completed baseline examinations, including a maximal treadmill test. Cohort 1
(n ¼ 24,475) was examined during 1971 to 1991 and followed for mortality through 1992. Cohort 2 (n ¼ 23,387) was
examined during 1992 to 2013 with follow-up through 2014. Men were categorized as low fit, moderate fit, or high fit
using Cooper Clinic normative data. Hazard ratios (HRs) for all-cause, cardiovascular disease, and cancer mortality were
determined across fitness categories in the 2 cohorts.

RESULTS A significant inverse trend between fitness categories and all-cause (HR: 1.0, 0.60, and 0.53 in cohort 1 and
HR: 1.0, 0.76, and 0.52 in cohort 2) and cardiovascular disease mortality (HR: 1.0, 0.55, and 0.43 in cohort 1 and HR:
1.0, 0.84, and 0.52 in cohort 2) was observed (p trend <0.001 for all). The trend across fitness categories and cancer
mortality was significant for cohort 1 (HR: 1.0, 0.62, and 0.48; p < 0.001), but not for cohort 2 (HR: 1.0, 1.08, and 0.74;
p ¼ 0.19). HRs for all-cause mortality were 0.86 (95% confidence interval: 0.82 to 0.90) and 0.87 (95% confidence
interval: 0.83 to 0.91) per 1-MET increment in fitness for cohorts 1 and 2, respectively (p < 0.001 for both). Similar values
were seen for cardiovascular disease and cancer mortality.

CONCLUSIONS Despite significant advances in disease prevention, detection, and treatment since fitness was
first shown to be associated with mortality, the inverse association between fitness and mortality remains
consistent in a contemporary cohort of men. (J Am Coll Cardiol 2020;75:1538–47) © 2020 by the American College
of Cardiology Foundation.

F or the past half-century, cardiovascular dis-

ease (CVD) and cancer have remained the lead-
ing causes of mortality among U.S. men.
During this time, diagnostic criteria for and preva-
United States have declined by 43% (11). Much of
this mortality reduction can be attributed to a
sharp decrease in CVD mortality, with 67% and 77%
decreases in coronary heart disease and stroke mor-
lence of risk factors have changed (1–6), disease pre- tality rates, respectively (12). This is likely due to
vention guidelines (4,7) as well as dietary guidelines decreased prevalence of tobacco use, new and more
(8) have been updated, and new and more effective effective treatments for chronic disease, and new
treatments for chronic conditions have emerged drugs for the treatment of hypertension and hyperlip-
Listen to this manuscript’s
(4,9,10). Since 1969, all-cause mortality rates in the idemia (9).
audio summary by
Editor-in-Chief
Dr. Valentin Fuster on
JACC.org.
From the aResearch Division, The Cooper Institute, Dallas, Texas; bDepartment of Cardiovascular Medicine, Cooper Clinic, Dallas,
Texas; cDepartment of Medicine, Stanford University, Palo Alto, California; and the dDepartment of Epidemiology, Harvard
Medical School, Boston, Massachusetts. The authors have reported that they have no relationships relevant to the contents of this
paper to disclose.

Manuscript received November 5, 2019; revised manuscript received January 10, 2020, accepted January 27, 2020.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2020.01.049

JACC VOL. 75, NO. 13, 2020 Farrell et al. 1539
APRIL 7, 2020:1538–47 Fitness and Mortality in Men During 2 Different Eras

Similarly, a marked reduction in overall cancer age-predicted maximal heart rate (n ¼ 1,514) ABBREVIATIONS

mortality and an improvement in 5-year survival were excluded from the analyses. To AND ACRONYMS

rates occurred over the past five decades. Specifically, decrease the likelihood of reverse causation,
BMI = body mass index
yearly cancer mortality rates have decreased from we also excluded those with prevalent self-
CI = confidence interval
approximately 200 deaths per 100,000 persons in reported CVD, cancer, or diabetes (n ¼ 2,775);
CVD = cardiovascular disease
1975 to 159 deaths per 100,000 persons in 2015 (13). abnormal electrocardiogram (n ¼ 3,750); body
Five-year survival rates for all races and both sexes 2
mass index (BMI) <18.5 kg/m (n ¼ 111); or HR = hazard ratio

increased from 49% in 1975 to 68% in 2013 (13). <1 year of follow-up (n ¼ 3,920). This resulted ICD = International
Classification of Diseases
Changes in screening recommendations, early detec- in a sample size of 47,862 men for the
MET = metabolic equivalent
tion, marked decreases in smoking prevalence, and present study. The majority of participants
improved treatment regimens are likely responsible self-reported that they were white and NHANES = National Health and
Nutrition Examination Survey
for these improvements (14). college-educated.
Cardiorespiratory fitness (fitness) is 1 modifiable MEASUREMENTS. After receiving written informed
risk factor related to all-cause, CVD, and cancer consent from each participant, a clinical evaluation
mortality risk, and has received substantial attention was performed and included a physician examina-
over the past several decades (15-17). In 1989, Blair tion, fasting blood chemistry assessment, personal
et al. (16) published the first major study to show a and family health history, anthropometry, resting
strong and inverse relationship between fitness and blood pressure and electrocardiogram, and a maximal
subsequent all-cause mortality in a large, generally graded treadmill exercise test. Smoking history was
healthy cohort from the ACLS (Aerobics Center Lon- obtained from a standardized questionnaire and
gitudinal Study). Other prospective studies have grouped categorically for analysis (never, past, cur-
provided additional support to these findings (18–20). rent smoker). BMI was calculated as weight in kilo-
Recently, decades of scientific study documenting grams divided by height in meters squared. Fitness
the many health benefits of fitness were summarized was quantified as the duration of a maximal treadmill
by the American Heart Association in their scientific exercise test using a modified-Balke protocol as
statement calling for the inclusion of fitness as a described elsewhere (16). To standardize exercise test
clinical vital sign (21). Whether the development of performance, maximal metabolic equivalents (METs)
significant advances in disease prevention, detection, (1 MET ¼ 3.5 ml O 2 uptake/kg/min) levels of fitness
and treatment since the seminal paper of Blair et al. based on the final treadmill speed and grade were
(16) has modified the association between fitness and computed (22). Men were classified into 1 of 3 age-
mortality is unknown. Thus, the purpose of this study specific categories of fitness based on CCLS tread-
was to determine if the inverse association between mill time normative data. Category 1 was designated
fitness and mortality persists in the current medical low fitness, while categories 2 to 3 and 4 to 5 were
era of aggressive screening, risk factor modification, designated as moderate and high fitness, respec-
and newer treatment options. tively (23).

SEE PAGE 1548 COHORT SELECTION. Patients were then divided

into 1 of 2 cohorts. Cohort 1 included patients who
METHODS were examined during 1971 to 1991 and followed for
mortality through 1992. Cohort 2 included patients
STUDY PARTICIPANTS. The CCLS (Cooper Center who were examined during 1992 to 2013 and followed
Longitudinal Study) is an updated continuation of the for mortality through 2014. The time periods for these
previously mentioned ACLS, with additional clinical 2 cohorts were chosen for the following reasons. First,
measures and mortality follow-up added to the important interventions aimed at the prevention and
database. The aim of the CCLS is to examine pro- treatment of CVD became available near the end of
spectively the association of health behaviors and the cohort 1 examination period, and thus would be
chronic disease biomarkers with clinical outcomes in available for participants in cohort 2. These de-
adult men and women. The present study began with velopments included FDA approvals of the first statin
a total sample size of 59,932 men between the ages of medication and first thrombolytic therapy drug in
20 and 80 years who completed maximal treadmill 1987 (24) as well as the publication of the first na-
exercise testing during baseline preventive exami- tional clinical practice guideline for acute myocardial
nations at The Cooper Clinic in Dallas, Texas, be- infarction care in 1990 (25). Second, during the time
tween 1971 and 2013. To prevent misclassification period of cohort 1 examinations, interventions aimed
of fitness, those who did not achieve at least 85% of at cancer prevention and treatment were in
1540 Farrell et al. JACC VOL. 75, NO. 13, 2020

Fitness and Mortality in Men During 2 Different Eras APRIL 7, 2020:1538–47

T A B L E 1 Baseline Characteristics of 47,862 Cooper Center Longitudinal Study Men Seen From 1971–2013 by Era of Medical Care and Fitness Level

Cohort 1* Cohort 2†

Category 1 Category 2-3 Category 4-5 Category 1 Category 2-3 Category 4-5
(Low Fit) (Moderate Fit) (High Fit) (Low Fit) (Moderate Fit) (High Fit)
(n ¼ 4,498) (n ¼ 10,081) (n ¼ 9,896) (n ¼ 3,097) (n ¼ 9,412) (n ¼ 10,878)

Age, yrs 41.5  8.5 42.4  9.2 42.1  9.8 44.1  8.6 45.7  8.9 46.3  9.1
Body mass index, kg/m2 28.7  4.8 26.3  3.1 24.6  2.4 32.3  5.6 28.3  3.6 25.9  2.7
Fitness, maximal METs 8.7  1.1 10.8  1.1 13.9  1.9 8.5  1.1 10.6  1.1 13.2  1.7
Systolic blood pressure, mm Hg 123.6  13.8 120.4  12.9 119.6  12.7 126.0  13.4 122.9  12.6 121.1  12.6
Diastolic blood pressure, mm Hg 83.1  9.8 80.8  9.4 78.8  8.9 86.1  10.0 83.6  9.4 81.0  9.1
Cholesterol, mg/dl 221.0  41.1 215.4  40.2 204.9  38.3 206.4  40.7 202.5  38.3 194.1  35.9
High-density lipoprotein, mg/dl 39.9  10.5 43.3  10.8 48.8  12.2 41.7  10.3 45.6  11.3 51.0  12.6
Low-density lipoprotein, mg/dl 146.6  37.5 143.5  36.1 135.1  34.7 129.3  35.0 127.6  33.6 121.0  31.7
Triglycerides, mg/dl 183.2 147.3 143  101.9 103.6  71.0 187.7  133.7 150.7  98.7 112.3  73.8
Triglyceride:HDL ratio 5.7  7.3 4.0  4.8 2.4  2.5 5.1  5.7 3.8  3.4 2.5  2.4
Glucose, mg/dl 102.5  19.2 99.8  13.1 97.9  10.5 103.5 21.8 99.1  17.7 96.5  9.8
Waist circumference, cm 101.3  20.6 92.9  17.8 85.6  18.0 106.7  13.2 97.2  9.8 89.7  8.3
Metabolic syndrome 1,562 (34.7) 2,290 (22.7) 980 (9.9) 1,743 (56.3) 3,020 (32.1) 1,293 (11.9)
Current smoker 1,514 (33.7) 2,202 (21.8) 993 (10) 680 (22.0) 1,657 (17.6) 1,189 (10.9)
ASCVD 10-yr risk, % 5.2  5.4 4.1  4.7 2.9  3.9 4.7  4.7 4.4  4.6 3.6  4.1

Values are mean  SD or n (%). *Cohort 1 examined 1971 to 1991, mortality follow-up through 1991. †Cohort 2 examined 1992 to 2013, mortality follow-up through 2014. Contemporary care including
prevention, updated guidelines, statin use, and modern cardiovascular and cancer interventions.
ASCVD ¼ atherosclerotic cardiovascular disease; MET ¼ metabolic equivalent.

development. For example, in the 1970s, antismoking used to estimate all-cause, CVD, and cancer mortality
regulations were instituted affecting tobacco expo- hazard ratios for fitness by cohort. One set of models
sure in public places and the workplace. Adjuvant was adjusted for age and current smoking; another
cancer chemotherapy was shown to have survival was additionally adjusted for BMI, glucose, total
benefit in 1975 (26). As a consequence of these de- cholesterol, and systolic blood pressure and used to
velopments and others, cancer mortality began to estimate 10-year cumulative all-cause mortality inci-
decline in 1990 (27), just prior to the time the early dence as well as hazard ratios (HRs) with 95% confi-
cohort 2 examinations were performed. Finally, the 2 dence intervals (CIs). Fitness was entered as a
cohorts would share similar sample sizes and periods cohort  fitness interaction to estimate and test
of examination time and follow-up, with no overlap cohort-specific HRs for fitness. Deaths and survival
in mortality surveillance. The total sample size con- times of the 1971 to 1991 cohort were censored at
sisted of 24,475 men in cohort 1 and 23,387 men December 31, 1992, while deaths and survival times of
in cohort 2. the 1992 to 2013 cohort were censored at December 31,
OUTCOMES. The National Death Index Plus service 2014, the latest date of National Death Index Plus
was used to determine vital status. CVD deaths were follow-up for the more contemporary cohort. In
identified using the International Classification of models with continuous fitness as the independent
Diseases (ICD)-9th revision (codes 410.0 to 414.9 and variable, HRs with 95% CIs for all-cause, CVD, and
429.2) for deaths occurring before 1999, and 10th cancer mortality were calculated per 1-MET incre-
revision (codes C00 to C97 for deaths during 1999 to ment. Additionally, Kaplan-Meier failure curves were
2014). Similarly, cancer deaths were classified with developed for both cohorts for all-cause, CVD, and
ICD-9 codes (140 to 239) and ICD-10 codes (C00 cancer mortality, stratified by cohort and fitness. All
to C97). analyses were programmed in SAS/STAT version 9.4
(SAS Institute, Inc., Cary, North Carolina).
STATISTICAL METHODS. Descriptive statistics on
demographic and other clinical characteristics of RESULTS
participants at baseline were compiled by cohort.
Cohort differences of demographic and clinical DESCRIPTIVE CHARACTERISTICS. The mean dura-
characteristics at baseline were tested using tion of follow-up for cohorts 1 and 2 was 10.5  5.3
likelihood-ratio chi-square statistics for categorical years and 12.1  5.6 years, respectively. Baseline
characteristics and rank-sum statistics for continuous characteristics of men in both cohorts by fitness cat-
characteristics. Proportional hazards models were egories are presented in Table 1. Men in cohort 2 were
JACC VOL. 75, NO. 13, 2020 Farrell et al. 1541
APRIL 7, 2020:1538–47 Fitness and Mortality in Men During 2 Different Eras

older than cohort 1 and had less healthy characteris-

T A B L E 2 Crude Rates* for All-Cause, CVD, and Cancer Mortality in 47,862 Cooper Clinic
tics with regard to BMI, resting blood pressure, tri- Longitudinal Study Men
glycerides, prevalence of metabolic syndrome, and
Cohort 1 Cohort 2
Atherosclerotic Cardiovascular Disease Score. How-
Number of Follow-Up Number of Follow-Up
ever, cohort 2 had healthier characteristics than Deaths (yrs) Rate Deaths (yrs) Rate
cohort 1 with regard to total cholesterol, high- and All-cause mortality 646 257,597 2.51 526 282,169 1.86
low-density lipoprotein cholesterol level, triglyceride CVD mortality 190 0.74 109 0.39
to high-density lipoprotein cholesterol ratio, fasting Cancer mortality 265 1.03 222 0.79
glucose, and smoking prevalence. Mean fitness levels
*Rates expressed as number of deaths per 1,000 man-years of data.
were similar (11.7  2.5 and 11.5  2.2 METs in cohorts CVD ¼ cardiovascular disease.
1 and 2, respectively). Medication use data for cohort 1
men was unavailable. Medication use data was
available on two-thirds of cohort 2 (n ¼ 15,578), with moderate (categories 2 and 3), and high (categories 4
12.1% of cohort 2 reporting statin use at the time of and 5) fitness. Failure trends for all-cause, cardio-
their examination. vascular (CVD), and cancer mortality are more
prominent in the early exam-year cohort, but are
MORTALITY. Total deaths in cohorts 1 and 2 were 646
statistically significant in both exam-year cohorts (all
and 526, respectively. Deaths from CVD and cancer
p < 0.03).
combined accounted for 70.4% and 62.9% of deaths
in each cohort, respectively. Crude rates for all-cause, DISCUSSION
CVD, and cancer mortality were 2.51, 0.74, and 1.03
deaths per 1,000 person-years, respectively, for The purpose of the present study was to determine
cohort 1, and 1.86, 0.39, and 0.79 deaths per 1,000 whether the association between fitness and mor-
person-years, respectively, for cohort 2 (Table 2). tality in an early cohort of men (1971 to 1991) per-
Adjusted HRs with 95% CIs for all-cause, CVD, and sisted when evaluated in a more contemporary
cancer mortality across ordered fitness categories in cohort of men (1992 to 2013) with exposure to ad-
each cohort are presented in Table 3. A significant vances in the prevention, detection, and treatment
inverse relationship between ordered fitness cate- of disease. In addition to all-cause mortality, CVD
gories and all-cause mortality (p trend <0.001 for and cancer mortality were examined due to the fact
both cohorts) and CVD mortality (p trend <0.001 for that they not only represent the 2 leading causes of
both cohorts) was observed. The trend across ordered mortality in U.S. men, but also because they share
fitness categories and cancer mortality was significant the common risk factor of low fitness/physical inac-
for cohort 1 (p < 0.001), but not for cohort 2 (p ¼ 0.19). tivity (28). An inverse trend was observed across
Our overall findings regarding the association of ordered fitness categories for all-cause and cardio-
fitness with all-cause mortality in the 2 cohorts are vascular mortality risk in both cohorts. For each
shown in the Central Illustration. 1-MET increment in fitness, there was a significantly
When expressed as a continuous variable decreased risk of all-cause, CVD, and cancer mortal-
(Table 3), HRs for all-cause mortality were 0.86 ity in both cohorts. When comparing crude mortality
(95% CI: 0.82 to 0.90) and 0.87 (95% CI: 0.83 to 0.91) rates between cohorts, all-cause, CVD, and cancer
per 1-MET increment in fitness for cohorts 1 and 2, mortality rates were shown to be substantially lower
respectively (p < 0.001 for both). Corresponding in the contemporary cohort versus the earlier cohort.
values for CVD mortality were 0.82 (95% CI: 0.75 to This finding is consistent with the decline in mor-
0.89) and 0.84 (95% CI: 0.76 to 0.93) per 1-MET tality reported for U.S. men over the same time
increment for cohorts 1 and 2, respectively (p # period (11), likely due to advancements in screening
0.002), whereas those for cancer mortality were 0.85 and treatment, as well as a marked reduction in to-
(95% CI: 0.80 to 0.91) and 0.91 (95% CI: 0.85 to 0.97) bacco use. Importantly, the current study demon-
per 1-MET increment for cohorts 1 and 2, respectively strates that fitness remains strongly associated with
(p # 0.01 for both). Thus, the overall inverse rela- all-cause, CVD, and cancer mortality in this era of
tionship between fitness and mortality remains in enhanced medical care.
cohort 2. Abundant published data has shown that fitness is
Kaplan-Meier failure curves for all-cause, CVD, and an independent risk factor for all-cause, CVD, and
cancer mortality by fitness categories within cohort cancer mortality in diverse populations. In an anal-
are presented in Figure 1, and illustrate the decreasing ysis of a Veterans Affairs–based population, there
failure gradient across low (CCLS fitness category 1), was a 12% improvement in mortality with each
1542 Farrell et al. JACC VOL. 75, NO. 13, 2020

Fitness and Mortality in Men During 2 Different Eras APRIL 7, 2020:1538–47

T A B L E 3 Hazard Ratios With 95% CIs for All-Cause, CVD, and Cancer Mortality Across Fitness Categories and Per 1-MET Increment in Fitness in
47,862 CCLS Men by Era of Contemporary Medical Care

Cohort 1 (1971–1992) Cohort 2 (1993–2014)

Model 1* Model 2† Model 1* Model 2†

All-cause mortality
Category 1 (low fit) 1.0 1.0 1.0 1.0
Categories 2–3 (moderate fit) 0.57 (0.48–0.68) 0.60 (0.50–0.72) 0.73 (0.57–0.92) 0.76 (0.59–0.97)
Categories 4–5 (high fit) 0.49 (0.40–0.61) 0.53 (0.43–0.66) 0.48 (0.37–0.61) 0.52 (0.40–0.68)
p trend across fitness categories <0.001 <0.001 <0.001 <0.001
Fitness (per 1-MET increment) 0.85 (0.82–0.88) 0.86 (0.82–0.90) 0.86 (0.82–0.90) 0.87 (0.83–0.91)
p < 0.001 p < 0.001 p < 0.001 p < 0.001)
Cardiovascular disease mortality
Category 1 (low fit) 1.0 1.0 1.0 1.0
Categories 2–3 (moderate fit) 0.48 (0.35–0.65) 0.55 (0.40–0.77) 0.73 (0.44–1.20) 0.84 (0.50–1.41)
Categories 4–5 (high fit) 0.33 (0.22–0.49) 0.43 (0.28–0.65) 0.39 (0.23–0.67) 0.52 (0.29–0.92)
p trend across fitness categories <0.001 <0.001 <0.001 <0.001
Fitness (per 1-MET increment) 0.78 (0.72–0.84) 0.82 (0.75–0.89) 0.82 (0.75–0.90) 0.84 (0.76–0.93)
p < 0.001 p < 0.001 p < 0.001 p < 0.001
Cancer mortality
Category 1 (low fit) 1.0 1.0 1.0 1.0
Categories 2–3 (moderate fit) 0.58 (0.44–0.76) 0.62 (0.47–0.82) 0.98 (0.66–1.46) 1.08 (0.72–1.63)
Categories 4–5 (high fit) 0.42 (0.30–0.59) 0.48 (0.34–0.67) 0.62 (0.41–0.94) 0.74 (0.48–1.16)
p trend across fitness categories <0.001 <0.001 <0.001 0.19
Fitness (per 1-MET increment) 0.84 (0.78–0.89) 0.85 (0.80–0.91) 0.88 (0.82–0.94) 0.91 (0.85–0.97)
p < 0.001 p < 0.001) p < 0.001 p < 0.01

*Adjusted for age and smoking. †Adjusted for age, smoking, body mass index, glucose, cholesterol, and systolic blood pressure.
CCLS ¼ Cooper Center for Longitudinal Study; CI ¼ confidence interval; CVD ¼ cardiovascular disease; MET ¼ metabolic equivalent.

1-MET increase in exercise capacity in men with a environmental tobacco smoke has decreased signifi-
clinical indication for treadmill exercise testing (20). cantly due to legislation limiting smoking in public
In a more contemporary analysis of patients referred areas (31). Conversely, the current prevalence of
for clinically indicated stress testing, Mandsager obesity (36.3%), pre-diabetes (33.9%), diabetes
et al. (29) studied 122,007 patients between 1991 and (9.1%), and hypertension (34%) among adults repre-
2014 in whom a total of 13,637 all-cause deaths sents a marked increase during this time period
occurred during 8.4 years of follow-up. With each although a higher percentage of hypertensive in-
increment in fitness category, there was a corre- dividuals have their blood pressure under control
sponding significant decreased risk of all-cause (54.4%) compared with previous decades (6).
mortality (29). Further, a meta-analysis performed Mean levels of low-density lipoprotein cholesterol
in 2009 confirmed that higher fitness was associated have significantly decreased in the U.S. adult popu-
with lower all-cause, CVD, and coronary heart dis- lation since the advent of the statin era (32). Only 2%
ease mortality in men and women (15). Importantly, of the adult population reported use of a statin in the
none of these studies compared and contrasted the past 30 days during the 1988 to 1994 National Health
relationship between fitness and mortality in an and Nutrition Examination Survey (NHANES) III (33).
earlier versus a more recent cohort. In this study, we As data accumulated regarding the efficacy of statins
were able to explore the association of fitness with for primary and secondary prevention of CVD (34),
mortality in 2 eras with differing risk factor burden statin use increased to 27.8% of the adult population
and treatment opportunities. from 2012 to 2013 (35). Although medication data are
CHANGES IN PREVALENCE OF RISK FACTORS. The not available for cohort 1, it is reasonable to assume
prevalence of various risk factors for all-cause, CVD, that only a very small percentage of cohort 1 men
and cancer mortality has changed significantly over were taking a statin at the time of their examination
time in the United States as a whole, as well as in the for reasons previously mentioned. Cohort 2 had more
CCLS cohort. For example, the prevalence of cigarette favorable blood lipid values (vs. cohort 1), perhaps a
smoking among U.S. adults declined from 34% during result of the higher prevalence of statin use in this
1976 to 1980 to 15.1% currently (30). Exposure to era. Medication use data were available on two-thirds
JACC VOL. 75, NO. 13, 2020 Farrell et al. 1543
APRIL 7, 2020:1538–47 Fitness and Mortality in Men During 2 Different Eras

C EN T R A L IL L U ST R A T I O N Fitness and Mortality in Men During 2 Different Eras of Medical Care

10-Year Cumulative Incidence (per 1,000 Person-Years)

40

30

20

10

0
5 10 15
Cardiorespiratory Fitness (MET)
Year of Exam 1971-1991 1992-2013
Farrell, S.W. et al. J Am Coll Cardiol. 2020;75(13):1538–47.

The 10-year cumulative incidence of all-cause mortality versus cardiorespiratory fitness by examination-year cohort with 95% confidence
bands, Cooper Center Longitudinal Study, Men, 1971–2014. Incidence of all-cause mortality decreases across the range of cardiorespiratory
fitness regardless of examination-year cohort, as illustrated by 10-year cumulative incidence estimated using a proportional hazards
regression of all-cause mortality on fitness (in metabolic equivalents), adjusted for age, smoking, body mass index, glucose, cholesterol, and
systolic blood pressure. The estimates also illustrate the general reduction in incidence experienced by the later examination-year cohort.

of cohort 2 men, and showed that 12% of this severe coronary artery disease, statin and aspirin
contemporary cohort were using a statin at the time use for secondary prevention, as well as drug
of their baseline examination. treatment and device therapies to prolong life in the
With respect to lifestyle recommendations to setting of valvular heart disease, heart failure, and
improve risk, the 2018 Physical Activity Guidelines life-threatening arrhythmias (36–39). At the same
streamlined guidance for the general population. time, there has been an increase in the number of
For good health, 150 min or more of moderate-in- cardiac intensive care units, emergency medical
tensity aerobic activity per week is advocated in services, and rehabilitation programs for patients
addition to at least 2 days per week of muscle with myocardial infarction and stroke (40).
strengthening activities. In addition, the Dietary
Guidelines for Americans have increased their CORRELATION BETWEEN CVD AND CANCER. CVD
emphasis over time on reducing dietary saturated and some types of cancer share several common risk
and trans fat, sodium, and simple sugars, as well as factors, including age, tobacco use, obesity, diabetes,
increasing intake of whole grains, other plant-based hypertension, and physical inactivity (28). There
foods, as well as reduced-fat dairy, fatty fish, and may also be an overlap in terms of mechanisms, as
fiber (8). Further, there have been numerous ad- CVD and some cancers are influenced by chronic
vances in the treatment of CVD, such as thrombo- inflammation, oxidative stress, and cytokines. Thus,
lytic therapy and percutaneous coronary it was somewhat unexpected to find that ordered
intervention to treat acute myocardial infarction, categories of fitness were not significantly associated
coronary artery bypass grafts for the treatment of with cancer mortality in cohort 2. Because cancer is a
1544 Farrell et al. JACC VOL. 75, NO. 13, 2020

Fitness and Mortality in Men During 2 Different Eras APRIL 7, 2020:1538–47

F I G U R E 1 Kaplan-Meier Cumulative Event Rate Estimates for All-Cause, CVD, and Cancer Mortality by Examination-Year Cohort and Fitness Category
With Log-Rank Tests and Numbers at Risk, CCLS, Men, 1971–2014

Exam Years 1971-1991 Exam Years 1992-2013

Log-rank trend p ≤ 0.001 Log-rank trend p ≤ 0.001

All-Cause Mortality
10

0
Cumulative Event Rate (%)

4 Log-rank trend p ≤ 0.001 Log-rank trend p = 0.001

Cardiovascular Disease
3

Mortality
2

Log-rank trend p ≤ 0.001 Log-rank trend p = 0.029

6

Cancer Mortality
4

0
4,498 4,082 3,271 1,786 182 3,097 2,686 1,879 905 358
10,081 8,467 5,646 2,420 356 9,412 8,239 5,915 2,674 848
9,896 7,521 3,676 1,244 232 10,878 9,445 6,939 3,570 1,168

0 5 10 15 20 0 5 10 15 20
Follow-up Time (Years)

CCLS Fitness Category 1 2,3 4,5

Cumulative event rate probability estimates calculated using the Kaplan-Meier method illustrate the decreasing event rate gradient across low (CCLS
[Cooper Center Longitudinal Study] fitness category 1) moderate (2 to 3) and high (4 to 5) fitness. Event rate trends for all-cause, cardiovascular disease
(CVD), and cancer mortality are more prominent in the early examination-year cohort, but are statistically significant in both examination-year cohorts
(all p < 0.03). The estimates also illustrate the general reduction of mortality experienced by the later examination-year cohort.
JACC VOL. 75, NO. 13, 2020 Farrell et al. 1545
APRIL 7, 2020:1538–47 Fitness and Mortality in Men During 2 Different Eras

heterogeneous disease and different cancers have previously, it is likely that statin use was extremely
different etiologies, not all cancers are related to low among this group. Further, in cohort 2, statin
physical inactivity/low fitness. Thus, the association utilization status was missing in one-third
between fitness categories and all-cancer mortality (n ¼ 7,809) of the participants. Therefore, statin
may have been somewhat diluted. However, it is usage was not considered as a covariate, but rather
important to reinforce the point that when expressed accounted for by the categorization of the eras.
as a continuous variable (i.e., maximal METs), there
CONCLUSIONS
was a 9% lower cancer mortality risk per 1-MET
increment in fitness.
Despite substantial decreases in U.S. mortality rates
STUDY STRENGTHS AND LIMITATIONS. Among the over the past 3 decades, fitness remains significantly
strengths of the current study are a large and well- and inversely associated with mortality risk in a
characterized cohort of generally healthy men with contemporary cohort of men when compared with
objective measures of fitness, BMI, blood pressure, its impact in an earlier cohort. Each 1-MET incre-
blood lipids, and glucose. Protocols for data collec- ment in fitness was associated with a 13%, 16%, and
tion have remained consistent over time. For pur- 9% decreased risk of all-cause, CVD, and cancer
poses of generalizability, it is important to note that mortality, respectively, in the more contemporary
median estimated maximal oxygen consumption cohort. These results support the American Heart
values for CCLS men are very similar to those ob- Association Position Statement regarding the
tained during the 1998 to 2004 NHANES, which assessment of fitness as a clinical vital sign (21). The
used a stratified random sample of the apparently recommendation that men maintain a healthy
healthy U.S. population. For example, the median level of fitness by meeting current public health
estimated maximal oxygen consumption for CCLS guidelines for physical activity remains a relevant
versus NHANES men in the age 40 to 49 years group public health message in the setting of contempo-
is 40.1 and 40.9 ml/kg/min, respectively (41). Addi- rary disease prevention strategies, early disease
tionally, there is extensive follow-up with a large detection, and multimodality disease treatment op-
number of deaths for analysis in our cohort. The portunities (43).
percentage of deaths from CVD and cancer in our
ACKNOWLEDGMENTS The authors thank Kenneth H.
cohort are in accord with percentage of deaths from
Cooper, MD, MPH, for establishing the Cooper Center
CVD and cancer combined in the general U.S.
Longitudinal Study, as well as Cooper Clinic physi-
adult population (42). Finally, to decrease the like-
cians, patients, technicians, and The Cooper Institute
lihood of reverse causation, we excluded men
data entry staff.
with prevalent disease, abnormal electrocardiogram,
2
BMI <18.5 kg/m , and <1 year follow-up.
ADDRESS FOR CORRESPONDENCE: Dr. Stephen W.
Because of a much smaller sample size and
Farrell, The Cooper Institute, 12330 Preston Road,
limited number of deaths (n ¼ 87) among the female
Dallas, Texas 75230. E-mail: [email protected].
participants in the CCLS during the time frame
Twitter: @b2wright.
established for cohort 1, the current study focused
only on men. This cohort is primarily white and
from middle to upper socioeconomic strata, so our PERSPECTIVES
findings must be cautiously interpreted when
generalized to other populations. However, this
COMPETENCY IN MEDICAL KNOWLEDGE: An inverse as-
same limitation strengthens the internal validity of
sociation between fitness and mortality persists in a cohort of
our findings. We do not have complete data for
men with access to advanced levels of contemporary health care.
specific lifestyle habits (dietary intake, alcohol use),
medication use for primary or secondary prevention
TRANSLATIONAL OUTLOOK: Medical professionals should
of disease (aspirin, antihypertensive medications),
be familiar with the 2018 Physical Activity Guidelines for Amer-
and/or disease treatments (stents, rehabilitation,
icans, counsel patients on the benefits of physical activity, and
chemotherapy) to explore the contributions of each
measure or estimate fitness level during routine health
of these components to the differences in mortality
assessments.
incidence between the 2 cohorts. Statin use data is
unavailable for cohort 1, but as explained
1546 Farrell et al. JACC VOL. 75, NO. 13, 2020

Fitness and Mortality in Men During 2 Different Eras APRIL 7, 2020:1538–47

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