JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
12, 2023
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VOL. 81, NO.
ª 2023 PUBLISHED BY ELSEVIER ON BEHALF OF THE
AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ORIGINAL INVESTIGATIONS
Changes in Cardiorespiratory Fitness and
Survival in Patients With or
Without Cardiovascular Disease
Peter Kokkinos, PHD,a,b,c Charles Faselis, MD,c,d Immanuel Babu Henry Samuel, PHD,e,f Carl J. Lavie, MD,g
Jiajia Zhang, PHD,h Jose D. Vargas, MD,a Andreas Pittaras, MD,a,c Michael Doumas, MD,i Pamela Karasik, MD,d
Hans Moore, MD,a Michael Heimal, BS,a Jonathan Myers, PHDj,k
ABSTRACT
BACKGROUND The association between cardiorespiratory fitness (CRF) and mortality risk is based mostly on 1 CRF
assessment. The impact of CRF change on mortality risk is not well-defined.
OBJECTIVES This study sought to evaluate changes in CRF and all-cause mortality.
METHODS We assessed 93,060 participants aged 30-95 years (mean 61.3
9.8 years). All completed 2 symptom-
limited exercise treadmill tests, 1 or more years apart (mean 5.8
3.7 years) with no evidence of overt cardiovascular
disease. Participants were assigned to age-specific fitness quartiles based on peak METS achieved on the baseline exercise
treadmill test. Additionally, each CRF quartile was stratified based on CRF changes (increase, decrease, no change)
observed on the final exercise treadmill test. Multivariable Cox models were used to estimate HRs and 95% CIs for all-
cause mortality.
RESULTS During a median follow-up of 6.3 years (IQR: 3.7-9.9 years), 18,302 participants died with an average yearly
mortality rate of 27.6 events per 1,000 person-years. In general, changes in CRF $1.0 MET were associated with inverse
and proportionate changes in mortality risk regardless of baseline CRF status. For example, a decline in CRF of >2.0 METS
was associated with a 74% increase in risk (HR: 1.74; 95% CI: 1.59-1.91) for low-fit individuals with CVD, and 69% in-
crease (HR: 1.69; 95% CI: 1.45-1.96) for those without CVD.
CONCLUSIONS Changes in CRF reflected inverse and proportional changes in mortality risk for those with and
without CVD. The impact of relatively small CRF changes on mortality risk has considerable clinical and public health
significance. (J Am Coll Cardiol 2023;81:1137–1147) © 2023 Published by Elsevier on behalf of the American College of
Cardiology Foundation.
From the aDepartment of Cardiology, Washington, DC, Veterans Affairs Medical Center, Washington, DC, USA; bDepartment of
Kinesiology and Health, School of Arts and Sciences, Rutgers University, New Brunswick, New Jersey, USA; cSchool of Medicine
and Health Sciences, George Washington University, Washington, DC, USA; dWashington, DC, Veterans Affairs Medical Center,
Washington, DC, USA; e
War Related Illness and Injury Study Center, Washington, DC, Veterans Affairs Medical Center,
Washington, DC, USA; fThe Henry Jackson Foundation for the Advancement of Military Medicine, Bethesda, Maryland, USA;
g
John Ochsner Heart and Vascular Institute, Ochsner Clinical School–The University of Queensland School of Medicine, New
Orleans, Louisiana. USA; hAristotle University of Thessaloniki, Thessaloniki, Greece; iDepartment of Epidemiology and Biosta-
tistics, University of South Carolina, Columbia, South Carolina, USA; jVeterans Affairs Palo Alto Health Care System, Palo Alto,
California, USA; and the kDepartment of Cardiology, Stanford University, Stanford, California, USA.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.
Manuscript received December 6, 2022; revised manuscript received January 6, 2023, accepted January 18, 2023.
ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2023.01.027
1138 Kokkinos et al
Fitness Changes and Mortality
A
ABBREVIATIONS plethora of evidence from large and
AND ACRONYMS well-designed epidemiologic studies
supports an inverse and graded asso-
BMI = body mass index
ciation between exercise capacity or cardio-
CRF = cardiorespiratory fitness
respiratory fitness (CRF) assessed
CVD = cardiovascular disease
objectively by a standardized exercise tread-
ETT = exercise treadmill test mill test (ETT) and all-cause mortality. 1-10
Q = quartile This association is robust, and independent
VA = Veterans Affairs of comorbidities 1-10
or documented cardio-
vascular disease (CVD) 9 across the age, sex, and race
spectra. 1,2 When compared to individuals with
CRF <5 METS, a decline in risk of approximately
20% is observed with a CRF that exceeds 5-7 METs,
progressively reaching an asymptote of an approxi-
mately 50%-75% decline with additional increases in
CRF regardless of age. 1,6-9,11
However, current con-
cepts of the CRF-risk association are based almost
exclusively on 1 CRF assessment and assume that
changes in CRF are commensurate with changes in
risk.
Limited evidence derived from relatively small
studies indicates that improvements in CRF assessed
objectively by sequential standardized ETTs are also
associated with favorable health outcomes in rela-
tively healthy populations, 11-17
and in patients with
coronary artery disease. 18
However, it is not known
whether changes in CRF are associated with recip-
rocal changes in mortality risk for patients with CVD.
Furthermore, the magnitude of CRF change necessary
to affect mortality risk or whether the impact of CRF
changes varies according to the initial CRF of an in-
dividual is not known. Quantifying CRF changes at
this granular level would require comparatively large
samples within each of several fitness categories and
serial measurements of CRF over an extended period.
To our knowledge, such an analysis across the fitness
spectrum has not been previously performed.
SEE PAGE 1148
In the current study, we evaluated the association
between changes in CRF and mortality risk among
U.S. veterans with and without CVD, taking into
consideration the initial CRF of each subject. For this
analysis, we obtained sequential CRF evaluations by
standardized ETTs at least 1 year apart. The analysis
was made possible by the large cohort (>93,000) and
the electronic health care database available within
the Veterans Affairs (VA) Health Care System that
facilitates risk-adjustment models, thereby
increasing the accuracy in determining health out-
comes.19 In addition, the equal access to medical care
offered by the VA Health Care System regardless of a
patient’s financial status provided a unique oppor-
tunity to assess the CRF–mortality risk association
JACC VOL. 81, NO. 12, 2023
MARCH 28, 2023:1137–1147
while minimizing the influence of disparities in
medical care. 20,21
METHODS
The sample of the current study was derived from the
ETHOS (Exercise Testing and Health Outcomes
Study), a large cohort (n ¼ 750,302) based at the VA
Medical Center in Washington, DC. The selection of
the ETHOS cohort is described in detail elsewhere.1
Briefly, all participants completed an ETT evaluation
within the U.S. VA Medical Centers across the United
States between 1999 and 2020 using the Bruce pro-
tocol. Subjects between the ages of 30-95 years who
completed the ETT and achieved $2.0 METS were
selected. To lower the likelihood of including in-
dividuals with overt heart disease, we excluded those
who met the following conditions within 6 months
post the initial ETT: 1) those who underwent coronary
artery bypass graft; 2) those who had a history of
percutaneous transluminal coronary angioplasty or
percutaneous coronary intervention; and 3) those
who had a myocardial infarction or a diagnosis of
chronic heart failure. The study was approved by the
Institutional Review Board at the Washington, DC, VA
(protocol # 0069).
CURRENT STUDY POPULATION. From the ETHOS
cohort, we identified 93,060 (87,998 male and 5,062
female participants) who were eligible and were
enrolled in the current study. Of those, 50,481 had
history of CVD documented at least 6 months prior to
their last ETT, including myocardial infarction, coro-
nary artery bypass graft, chronic heart failure, stroke
(all), and peripheral vascular disease, and 42,579 had
no history of CVD. All completed 2 ETT evaluations at
least 1 year apart (mean 5.8
3.7 years) without evi-
dence of overt disease during both ETT assessments.
PROCEDURES. Detailed information on relevant de-
mographic, clinical, and medication information; risk
factors; and comorbidities as defined by International
Classification of Diseases-9th Revision (ICD-9) and
International Classification of Diseases-10th Revision
(ICD-10) coding, with at least 2 recordings at least
6 months apart, were obtained for all participants
from the VA Computerized Patient Record System.
The VA records have high sensitivity for incidence of
chronic conditions.22,23 Data and analyses are pre-
sented according to the STROBE (Strengthening the
Reporting of Observational Studies in Epidemiology)
reporting guideline for cohort studies.24
Historical information included previous cardiac
procedures; myocardial infarction; coronary artery
bypass graft; chronic heart failure; peripheral
JACC VOL. 81, NO. 12, 2023 Kokkinos et al 1139
MARCH 28, 2023:1137–1147 Fitness Changes and Mortality

T A B L E 1 Clinical Characteristics of the Entire Cohort and According to Quartiles of CRF

All Q1 Q2 Q3 Q4

Men 87,998 (94.6) 23,153 (92.1) 24,646 (94.4) 23,873 (95.5) 16,326 (97.1)
Women 5,062 (5.4) 1,994 (7.9) 1,460 (5.6) 1,121 (4.5) 487 (2.9)
Age, y 61.2
7.5 61.0
7.5 61.6
8.0 61.5
7.7 60.4
7.5
Body weight, kg 92.6
16.8 95.7
18.8 93.5
16.8 91.6
15.5 88.1
13.9
BMI, kg/m2 29.7
3.7 30.7
5.4 29.9
4.6 29.3
4.1 28.4
3.7
Peak METS—initial ETT 8.0
2.6 8.2
2.6 7.2
2.5 6.4
2.5 9.1
2.5
Peak METS—final ETT 8.0
2.6 9.1
2.6 9.7
2.5 11.0
2.5 8.0
2.5
ETT to ETT time, y 5.4
3.6 5.1
3.4 5.4
3.6 5.3
3.6 5.7
3.5
Ethnicity
White 66,659 (72.0) 17,761 (70.6) 19,002 (72.8) 18,127 (72.5) 12,069 (71.8)
Black 18,390 (19.7) 5,522 (22.0) 4,841 (18.5) 4,759 (19.0) 3,268 (19.4)
Hispanic 4,842 (5.2) 1,101 (4.4) 1,389 (5.3) 1,329 (5.3) 1,023 (6.1)
Native American 7,551 (1.9) 430 (1.7) 544 (2.1) 498 (2.0) 279 (1.7)
Other 1,118 (1.2) 333 (1.3) 330 (1.3) 281 (1.1) 174 (1.0)
CVD 19,778 (21.3) 5,718 (22.7) 5,409 (20.7) 2,209 (20.8) 3,442 (20.5)
Type 2 diabetes 33,697 (36.2) 11,451 (45.5) 10,057 (38.5) 8,244 (33.0) 3,945 (23.5)
Hypertension 73,571 (79.1) 21,360 (84.9) 21,215 (81.3) 19,295 (77.2) 11,701 (69.6)
Smoking 29,134 (31.3) 9,303 (37.0) 8,015 (30.7) 7,312 (29.3) 4,504 (26.8)
Dyslipidemia 76,680 (82.4) 21,212 (84.4) 21.744 (83.3) 20,538 (82.2) 13,186 (78.4)
Sleep apnea 35,080 (37.7) 10,188 (40.5) 9,708 (37.2) 9,415 (37.7) 5,769 (34.3)
CKD 8,793 (9.4) 3,140 (12.5) 2,591 (9.9) 2,015 (8.1) 1,047 (6.2)
All cancer 8,642 (9.3) 2,473 (9.8) 2,546 (9.8) 2,228 (8.9) 1,395 (8.3)
Antihypertensive/cardiac medication 75,584 (81.2) 22,256 (88.5) 21,838 (83.7) 19,761 (79.1) 11,729 (69.8)
Hypoglycemics 23,953 (25.7) 8,900 (35.4) 7,099 (27.2) 5,492 (22.0) 2,462 (14.6)
Statins 50,583 (54.4) 15,779 (62.7) 14,462 (55.4) 12,776 (51.1) 7,566 (45.0)

Values are n (%) or mean
SD.

BMI ¼ body mass index; CKD ¼ chronic kidney disease; CRF ¼ cardiorespiratory fitness; CVD ¼ cardiovascular disease; ETT ¼ exercise treadmill test; Q ¼ quartile.

vascular disease; stroke; hypertension
pressure $140/90 mm Hg); type 2 diabetes mellitus;
renal disease; hypercholesterolemia; cancer (all);
smoking status (current and past); aspirin; and use of
antihypertensive, hypoglycemic, or cardiac medica-
tions. Peak METS for each participant was estimated
by standardized American College of Sports Medicine
equations based on treadmill speed grade and exer-
cise time.25
MET EXTRACTION. A detailed MET extraction pro-
cess for the ETHOS cohort was described elsewhere.1
Briefly, we used natural language processing to
identify the cohort. We randomly selected 3,000
samples of physician clinical notes on ETTs from the
data set and identified METs manually. This anno-
tated data set was used to train the natural language
processing models. In the preprocessing phase, we
removed special characters (eg, $, &) and restricted
the note to 30 characters before and after the words
METS or MET. These words (METS or MET) were then
replaced with a special character to identify their
location within the clinical notes. Spacy software was
then used to convert the resulting string into word
tokens and then to a vector of numbers. The labels
(blood created were such that 1 corresponded to a token that
contained a MET value and 0 to a token not con-
taining (missing) a MET value. A 2-layer convolu-
tional neural network using the TensorFlow software
library was used to predict the probable location of
METS in the note. The model was trained over 100
epochs. Once METS were extracted, the MET data
were manually checked for errors and systematic
inaccuracies. MET values that exceeded physiologic
criteria were excluded. The model accuracy on the
test data set was 97%.
INITIAL CRF CATEGORIES. Age-specific CRF cate-
gories for those with and without CVD were estab-
lished based on methods described in our previous
work. 26 Briefly, we first stratified the cohort into 5 age
categories (30-49, 50-59, 60-69, 70-79, and 80-95
years). Then, we identified those with a MET level
achieved during the initial ETT that corresponded to
the 25th to 75th percentiles within their respective
age category and stratified the cohort accordingly.
We combined the respective quintiles to form 4 age-
and-sex-specific CRF quartiles (Q) for the entire
cohort, ranging from the least fit (Q1) to highly
fit (Q4).
1140 Kokkinos et al
Fitness Changes and Mortality
F I G U R E 1 Mortality Risk According to Baseline CRF Categories
1.2
CVD (n = 50,481)
1.00
1.0
0.8 * *
Relative Risk
0.68 * 0.69
0.6 0.57
* *
0.44
0.4
0.2
0.0
4.8 ± 1.2 7.2 ± 0.8 9.5 ± 0.9 12.0 ± 1.6
Peak METs
Bars within the (left) cardiovascular (CVD) and (right) no CVD cohorts represent the cardiorespiratory fitness (CRF) categories based on the age-specific peak METS
achieved on the initial exercise treadmill test. The mortality risk associated with the CRF categories is depicted by the HRs (numbers) above each bar. *P < 0.001.
CRF CATEGORIES BASED ON CHANGES IN EXERCISE
CAPACITY. To assess the association between change
in CRF and mortality risk, we formed 5 categories
within each fitness quartile (Q1 to Q4) as follows: In-
dividuals with a peak METS that deviated from the
initial METS by <0.1 METS formed the referent (no-
change) group. We then formed 2 groups representing
an increase of 0.1-2.0 METS (mean change 1.0
0.5);
and >2.0 METS (mean change 4.0
1.7), and 2 groups
representing a decrease by 0.1-2.0 METS (mean 1.0

0.5); and >2.0 METS (mean change 3.0
0.8).
ASCERTAINMENT OF DEATH. The primary outcome
was all-cause mortality. Dates of death were verified
from the VA Beneficiary Identification and the Record
Locator System File. This system is used to determine
benefits to survivors of veterans. It is 95% complete
and accurate and is comparable to the Social Security
27,28
Administration. Vital status was determined as of
September 30, 2021.
STATISTICAL ANALYSIS. Continuous variables are
presented as mean
SD and categorical variables as
relative frequencies. Baseline associations between
categorical variables were tested with the Pearson
chi-square test. One-way analysis of variance was
used to evaluate mean differences of normally
distributed variables across CRF categories. We tested
the assumption of the equality of variances between
JACC VOL. 81, NO. 12, 2023
MARCH 28, 2023:1137–1147
No CVD (n = 42,579)
1.00
*
0.55
0.43
5.7 ± 1.4 8.3 ± 1.2 10.2 ± 1.0 12.7 ± 1.7
Peak METs
groups by Levene test and the assumption of
normality with probability-probability plots.
Cox proportional hazard models were constructed
to calculate HRs for all-cause mortality across the CRF
categories (quartiles) for the entire cohort and for
those with and without CVD. The follow-up time was
calculated from the last ETT date to the date of death
or the last date of VA care, or the end of the follow-up
period (September 30, 2021). Follow-up time is pre-
sented as mean
SD or median (IQR). The mortality
rates were calculated as the ratio of events to person-
years of follow-up.
To evaluate the mortality risk across the CRF
quartiles, we used the least fit category (Q1) as the
referent. To evaluate the association between
changes in CRF and mortality risk, we calculated HRs
for the 5 CRF subcategories within each CRF quartile.
For these models, we used the no-change group
within each CRF quartile as the referent. All analyses
were adjusted for age, body mass index (BMI), ethnic
origin, sex, and time (years) between the 2 ETTs (for
CRF change assessments). We also adjusted the
models for CVD, traditional CVD risk factors (hyper-
tension, type 2 diabetes mellitus, dyslipidemia, and
smoking), chronic kidney disease, cancer (all), and
current use of cardiac/antihypertensive medications
( b -blockers, calcium-channel blockers, angiotensin-
converting enzymes/angiotensin receptor blockers,
JACC VOL. 81, NO. 12, 2023 Kokkinos et al 1141
MARCH 28, 2023:1137–1147 Fitness Changes and Mortality

C ENTR AL I LL U STRA T I O N Mortality Risk According to Changes in Cardiorespiratory Fitness Categories

Q1 (Least-Fit) Q2 (Low-Fit)
2.0 2.0
* *
1.60 1.76

1.5 * 1.5 *
1.25
* 1.15
1.00 1.00 *
HR

HR
1.0 0.90 * 1.0 0.86 *
0.67 0.64
0.5 0.5

0.0 0.0
No Change Increase Increase Decrease Decrease No Change Increase Increase Decrease Decrease
0.1-2.0 METs >2.0 METs 0.1-2.0 METs >2.0 METs >0.1-2.0 >2.0 METs 0.1-2.0 METs >2.0 METs
METs

Q3 (Moderate-Fit) Q4 (High-Fit)
2.0 2.0
*
1.55 *
1.5 1.5
1.27
1.00 1.07 1.00
* 0.96
HR

0.90
HR

1.0 1.0
0.79 * *
0.61 0.57
0.5 0.5

0.0 0.0
No Change Increase Increase Decrease Decrease No Change Increase Increase Decrease Decrease
0.1-2.0 >2.0 METs 0.1-2.0 >2.0 METs 0.1-2.0 METs >2.0 METs 0.1-2.0 METs >2.0 METs
METs METs

Kokkinos P, et al. J Am Coll Cardiol. 2023;81(12):1137–1147.

Bars represent the change in fitness within cardiorespiratory fitness (CRF) categories for the entire cohort. CRF categories were based on the age-specific peak METS
achieved on the initial exercise treadmill test. Changes in fitness were defined as changes in peak METS from the initial to the final exercise treadmill test. The
mortality risk associated with the change in CRF (METS) is depicted by the HRs (numbers) above each bar. *P < 0.001. Q ¼ quartile.

diuretics, aspirin), insulin, metformin, sulfonylureas,
and statins that were identified prior to the first and
second evaluations.
The assumption of proportionality for all Cox pro-
portional hazard analyses was tested graphically, by
plotting the logarithm of cumulative hazards with
respect to each covariate separately. The propor-
tionality assumption was fulfilled for each model.
All hypotheses were 2-sided, and P < 0.05 was
deemed statistically significant. We performed all
statistics with SPSS version 26.0 (IBM Corp).
RESULTS
PATIENT DEMOGRAPHICS. We assessed
people for eligibility and enrolled 93,060 U.S. veter-
ans (88,597 men, mean age 61.4
7.7 years; 5,011
women, mean age 57.1
6.9 years) with at least 2 ETT
assessments at least 1 year apart. Of those, 66,959
were White (72.0%); 18,390 African American (19.8%);
4,842 Hispanic (5.2%); 1,751 Native-American, Asian,
or Hawaiian (1.9%); and 1,118 (1.2%) declined
to report.
The follow-up time ranged from 1.0 to 20.5 years
(mean 7.1
4.7 years) and a median of 6.3 years (IQR:
3.7-9.9 years), providing 663,522.0 person-years.
There were 18,302 deaths (19.7%) with an average
annual mortality rate of 27.6 events per 1,000 person-
years. CRF remained unchanged in 25.1% of the
cohort (n ¼ 23,389), increased in 29.3% (n ¼ 27,250),
and decreased in 45.6% (n ¼ 42,421). The mean time
between the 2 ETT assessments for the entire cohort
was 5.8
3.7. The trend was similar for those with
750,302 and without CVD.
Demographic and clinical characteristics across the
CRF quartiles are presented in Table 1. We observed
significant differences across the CRF categories
among all variables examined. In general, body
1142 Kokkinos et al JACC VOL. 81, NO. 12, 2023

Fitness Changes and Mortality MARCH 28, 2023:1137–1147

T A B L E 2 Mortality Risk in All Participants According to Change in Exercise Capacity Within CRF Categories

CRF Categories Based on MET Change

Increase Increase Decrease Decrease

Referent #2.0 METS >2.0 METS #2.0 METS >2.0 METS

Q1 (n ¼ 25,147)
METS 5.4
1.5 6.6
1.4 9.2
2.0 4.9
1.4 3.5
1.1
Events 2,265/7,372 (30.8) 1,666/5,855 (28.5) 1,141/6,171 (18.5) 1,403/4,237 (33.1) 571/1,533 (37.2)
HR (95% CI) 1.00 0.91 (0.86-0.97) 0.68 (0.64-0.73) 1.17 (1.10-1.25) 1.60 (1.46-1.76)
Q2 (n ¼ 26,106)
METS 7.7
1.3 9.2
1.4 11.2
1.8 7.0
1.3 5.0
1.5
Events 1,542/7,480 (20.6) 803/4,852 (16.5) 337/2,845 (11.8) 1,509/6,695 (22.5) 1,151/4,234 (27.2)
HR (95% CI) 1.00 0.88 (0.80-0.95) 0.65 (0.57-0.73) 1.29 (1.20-1.38) 1.77 (1.63-1.91)
Q3 (n ¼ 24,994)
METS 9.8
1.1 10.8
1.2 13.2
1.6 8.8
1.3 6.4
1.5
Events 950/6,008 (15.8) 480/3,904 (12.3) 87/1,070 (8.1) 1,101/7,055 (15.6) 1,367/6,957 (19.6)
HR (95% CI) 1.00 0.78 (0.71-0.89) 0.61 (0.49-0.76) 1.09 (0.99-1.19) 1.56 (1.43-1.70)
Q4 (n ¼ 16,813)
METS 12.1
1.7 13.3
1.4 15.0
1.8 11.2
1.5 8.7
2.2
Events 325/2,550 (12.7) 186/1,918 (9.7) 40/635 (6.3) 451/4,494 (10.0) 927/7,216 (12.8)
HR (95% CI) 1.00 0.95 (0.79-1.14) 0.58 (0.41-0.80) 0.99 (0.86-1.15) 1.28 (1.13-1.46)

Values are mean
SD or n/N (%), unless otherwise indicated. The models were adjusted for age, BMI, the time between the 2 ETT assessments, ethnic origin, sex, hypertension,
CVD, type 2 diabetes mellitus, dyslipidemia, smoking, CKD, cancer (all), cardiac/antihypertensive medications (b-blockers, calcium channel blockers, angiotensin-converting
enzymes/angiotensin receptor blocker, diuretics, aspirin), statins, insulin, metformin, and sulfonylureas.
Abbreviations as in Table 1.

weight, BMI, CVD risk factors, and overall disease
burden were progressively more unfavorable for
those in the lowest CRF categories than for the in-
dividuals in the highest CRF categories. The differ-
ences tended to be more pronounced between Q1 and
Q2. Conversely, the use of all medications was pro-
gressively higher among those within the low CRF
categories (moving from Q4 to Q1 [P < 0.001]).
PREDICTORS OF ALL-CAUSE MORTALITY. In the
fully adjusted model, higher CRF was inversely
related to mortality risk for the entire cohort and for
those with and without CVD. Cumulative survival
rates across the 4 CRF categories based on METS
achieved at the initial assessment declined progres-
sively with increased fitness (Figure 1). Additional
significant predictors of all-cause mortality for pa-
tients with CVD were age (HR: 1.07; 95% CI: 1.06-1.08;
P < 0.001) and BMI (HR: 0.98; 95% CI: 0.97-0.99;
P < 0.001), chronic kidney disease (HR: 1.85; 95% CI:
1.77-1.93; P < 0.001), smoking (HR: 1.57; 95% CI: 1.82-
1.62; P < 0.001), type 2 diabetes mellitus (HR: 1.42;
95% CI: 1.38-1.47; P < 0.001), hypertension (HR:
1.39; 95% CI: 1.33-1.45; P < 0.001), cancers (HR: 1.37;
95% CI: 1.30-1.43; P < 0.001), and CVD (HR: 1.11;
95% CI: 1.07-1.15; P < 0.001).
assessments) for the entire cohort and for those with
and without CVD. To evaluate the impact of CRF
change may have on mortality risk for individuals
with varying baseline CRF status, we assessed CRF
changes within the initial CRF quartiles (Q1-Q4). The
no-change group within each CRF quartile was used
as the referent for these assessments.
In general, these analyses revealed a progressive
decline in mortality risk associated with graded in-
creases in CRF and a progressive increase in risk with
a decline in CRF within all fitness quartiles for the
entire cohort (Central Illustration, Table 2) and for
individuals with CVD (Figure 2, Table 3) and without
CVD (Figure 3, Table 4). However, for high-fit in-
dividuals with no CVD (Q4), changes in risk across
CRF categories were not statistically significant
(Table 4).
To account for the possibility that the higher
mortality rates and the decline in CRF were the out-
comes of underlying disease (reverse causality), we
excluded patients who exhibited a decline in CRF and
died within 2 years following the last ETT (n ¼ 371)
and repeated the analyses. The association between
changes in CRF and mortality risk did not change
substantially from that observed in the entire cohort.

MORTALITY RISK ACCORDING TO CRF CHANGE. We DISCUSSION

also assessed mortality risk across the 5 CRF cate-
gories representing changes in aerobic capacity (peak The findings of this study demonstrated that changes
METS achieved from the initial to final ETT in CRF over time reflect reciprocal changes in
JACC VOL. 81, NO. 12, 2023 Kokkinos et al 1143
MARCH 28, 2023:1137–1147 Fitness Changes and Mortality

F I G U R E 2 Mortality Risk in Subjects With CVD

2.0 2.0
Q1 (Least-Fit) Q2 (Low-Fit) *
* 1.74
*P < 0.02 1.49 *P ≤ 0.002
1.5 * 1.5 *
1.14 1.23
*
1.00 1.00 *
HR

HR
1.0 0.91 * 1.0 0.85 *
0.67 0.62
0.5 0.5

0.0 0.0
No Change Increase Increase Decrease Decrease No Change Increase Increase Decrease Decrease
≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs
2.0 2.0
Q3 (Moderate-Fit) * Q4 (High-Fit)
1.50 *
1.5 *P < 0.02 1.5 *P ≤ 0.004 1.37
1.10
1.00 1.05 1.00
*
HR

HR
1.0 * 1.0 0.92
0.77 0.73 *
0.48
0.5 0.5

0.0 0.0
No Change Increase Increase Decrease Decrease No Change Increase Increase Decrease Decrease
≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs

Bars represent the change in fitness within the CRF categories. CRF categories were based on the age-specific peak METS achieved on the initial exercise treadmill test.
Changes in fitness were defined as changes in peak METS from the initial to the final exercise treadmill test. The mortality risk associated with the change in CRF (METS)
is depicted by the HRs (numbers) above each bar. Q ¼ quartile; other abbreviations as in Figure 1.

mortality risk independent of other comorbidities. In
general, an increase in CRF of approximately $1.0
MET from the initial evaluation was associated with a
progressively lower mortality risk regardless of CRF
status at baseline. Conversely, a decrease in CRF
by $1.0 MET from baseline was associated with a
progressive increase in mortality risk (Tables 2 and 3),
except in those with very high baseline CRF and no
CVD (Table 4). These findings strengthen previous
reports from comparatively small studies assessing
sequential CRF by a standardized ETT 11-18 and by a
recent large study using self-reported
assessments.29
There are several unique contributions of the cur-
rent study. First, the observation that changes in risk
are proportionate to changes in CRF have clinical and
public health significance because they support that
mortality risk can be significantly decreased by a $1.0
MET increase in CRF, regardless of initial CRF status.
Furthermore, it quantifies the CRF change needed to
modify mortality risk regardless of initial fitness sta-
tus. More importantly, it provides a practical guide
for clinicians, and the public in general, for improving
CRF to achieve more favorable health outcomes. In
this regard, we observed that most of the reduction in
all-cause mortality risk was associated with an
improvement in CRF >2.0 METS.
These findings further reinforce the concept that
regular physical activity is important to optimize
CRF.
Second, it is noteworthy that CRF increased by at
least 1 MET in approximately 29% of the participants
in the current study and decreased in approximately
46% of participants. This finding underscores the
need to promote physical activity to maintain or in-
fitness crease CRF levels in middle-aged and older in-
dividuals. 4 It also suggests that the impact of
relatively high CRF on health outcomes is under-
estimated when it is based on 1 assessment.
Our findings also enhance the understanding of the
independent or synergistic effects of CRF and genetic
factors on the CRF–mortality risk association, which
is yet to be fully determined. Although CRF is deter-
mined to some degree by genetic factors,30,31 im-
provements in aerobic capacity or CRF over time are
largely the outcomes of regular engagement in aero-
bic activities of adequate intensity and volume. 25,32
Conversely, a decline in CRF is likely the result of
1144 Kokkinos et al JACC VOL. 81, NO. 12, 2023

Fitness Changes and Mortality MARCH 28, 2023:1137–1147

T A B L E 3 Mortality Risk in Participants With CVD, According to Change in CRF

CRF Categories Based on MET Change

Increase Increase Decrease Decrease

Events Referent #2.0 METS >2.0-3.0 METS #2.0 METS >2.0 METS

Q1 (n ¼ 15,539) 4,183 (36.4)

HR (95% CI) 1.00 0.91 (0.85-0.98) 0.67 (0.61-0.73) 1.14 (1.05-1.23) 1.49 (1.34-1.66)
METS 4.6
1.2 6.0
1.3 8.6
1.9 4.1
1.1 2.7
0.7
Q2 (n ¼ 14,504) 4,248 (27.9)
HR (95% CI) 1.00 0.85 (0.77-0.95) 0.62 (0.54-0.72) 1.23 (1.13-1.34) 1.74 (1.59-1.91)
METS 7.0
0.7 8.3
1.1 10.5
1.4 6.3
1.0 4.2
1.0
Q3 (n ¼ 12,793) 3,098 (20.4)
HR (95% CI) 1.00 0.77 (0.68-0.89) 0.73 (0.56-0.95) 1.05 (0.94-1.16) 1.50 (1.36-1.66)
METS 9.5
1.1 10.4
1.1 12.8
1.4 8.3
1.2 6.1
1.5
Q4 (n ¼ 7,645) 1,442 (16.7)
HR (95% CI) 1.00 0.92 (0.72-1.17) 0.48 (0.29-0.80) 1.10 (0.91- 1.32) 1.37 (1.16-1.61)
METS 11.6
1.6 12.8
1.3 14.7
1.4 10.7
1.4 8.1
2.2

Values are n (%) or mean
SD, unless otherwise indicated. The models were adjusted for age, BMI, the time between the 2 ETT assessments, ethnic origin, sex, hypertension,
type 2 diabetes mellitus, dyslipidemia, smoking, CKD, cancer (all), cardiac/antihypertensive medications (b-blockers, calcium channel blockers, angiotensin-converting en-
zymes/angiotensin receptor blocker, diuretics, aspirin), statins, insulin, metformin, and sulfonylureas.
Abbreviations as in Tables 1 and 2.

sedentary behavior, the onset of a chronic condition, high CRF (ie, the cardiorespiratory system) also
or aging.33-35 render the individual more resilient to injury and
Accordingly, it is plausible that inherently deter- disease, ultimately resulting in lower mortality rates.
mined structural and functional attributes that favor If this were entirely true, changes in CRF would not

F I G U R E 3 Mortality Risk in Subjects With No CVD

2.0 2.0
Q1 (Least-Fit) * Q2 (Low-Fit) *
1.83 1.69
*P < 0.03 *P < 0.01 *
1.5 * 1.5
1.30
1.18
* 1.00 *
1.00
HR

HR

1.0 0.87 * 1.0 0.87 *

0.69 0.67
0.5 0.5

0.0 0.0
No Change Increase Increase Decrease Decrease No Change Increase Increase Decrease Decrease
≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs

2.0 2.0
*
Q3 (Moderate-Fit) Q4 (High-Fit)
1.60
1.5 *P < 0.04 1.5
*
1.12 1.11
1.00 1.00
HR

HR

1.0 1.0 0.89

0.81 0.81
* 0.67
0.47
0.5 0.5

0.0 0.0
No Change Increase Increase Decrease Decrease No Change Increase Increase Decrease Decrease
≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs ≤2.0 METs >2.0 METs

Bars represent the change in fitness within CRF categories. CRF categories were based on age-specific peak METS achieved on the initial exercise treadmill test. Changes
in fitness were defined as changes in peak METS from the initial to the final exercise treadmill test. The mortality risk associated with the change in CRF (METS) is
depicted by the HRs (numbers) above each bar. Abbreviations as in Figures 1 and 2.
JACC VOL. 81, NO. 12, 2023 Kokkinos et al 1145
MARCH 28, 2023:1137–1147 Fitness Changes and Mortality

T A B L E 4 Mortality Risk in Participants Without CVD, According to Change in CRF

CRF Categories Based on MET Change

Increase Increase Decrease Decrease

Events Referent #2.0 METS >2.0-3.0 METS #2.0 METS >2.0 METS

Q1 (n ¼ 9,608) 1,767 (19.2)

HR (95% CI) 1.00 0.87 (0.76-0.99) 0.69 (0.60-0.79) 1.18 (1.03-1.35 1.83 (1.51-2.20)
METS 5.7
1.4 6.9
1.4 9.5
2.0 5.0
1.1 3.6
1.1
Q2 (n ¼ 11,602) 1,737 (13.0)
HR (95% CI) 1.00 0.87 (0.75-1.02) 0.67 (0.54-0.82) 1.30 (1.14-1.48) 1.69 (1.45-1.96)
METS 8.0
1.2 9.5
1.2 11.6
1.9 7.4
1.2 5.3
1.5
Q3 (n ¼ 12,201) 1,052 (10.2)
HR (95% CI) 1.00 0.81 (0.67-0.99) 0.47 (0.32-0.70) 1.12 (0.96-1.30) 1.60 (1.38-1.87)
METS 10.0
1.1 11.2
1.1 13.6
164 9.2
1.3 6.8
1.5
Q4 (n ¼ 9,368) 776 (8.1)
HR (95% CI) 1.00 0.89 (0.67-1.17) 0.67 (0.43-1.05) 0.81 (0.65- 1.02) 1.11 (0.99-1.36)
METS 12.3
1.7 13.4
1.5 15.5
1.8 11.2
1.5 9.0
2.3

Values are n (%) or mean
SD, unless otherwise indicated. The models were adjusted for age, BMI, the time between the 2 ETT assessments, ethnic origin, sex, hypertension,
type 2 diabetes mellitus, dyslipidemia, smoking, CKD, cancer (all), cardiac/antihypertensive medications (b-blockers, calcium channel blockers, angiotensin-converting
enzymes/angiotensin receptor blocker, diuretics, aspirin), statins, insulin, metformin, and sulfonylureas.
Abbreviations as in Tables 1 and 2.

likely coincide with changes in mortality risk. This is
not supported by our current findings, because
changes in risk were concomitant and proportional to
changes in CRF regardless of initial CRF status. An
alternative hypothesis is that the structural and
functional physiological changes
participation in aerobic activities render an individual
more resistant to injury or disease, ultimately
resulting in lower mortality rates independent of ge-
netic factors. Accordingly, the progressive changes in
mortality risk that parallel changes in CRF after ad-
justments for aging (time between the 2 ETTs) and
comorbidities make a persuasive argument that CRF
is a strong and independent determinant of all-cause
mortality risk and is independent of genetic factors as
suggested by others. 33 Emerging evidence supports
that: 1) exercise is a powerful modulator of the gene
expression profile; and 2) exercise-induced tissue-
specific epigenetic modifications lead to improve-
ments in metabolism, performance, and health
outcomes. 36-38
STUDY STRENGTHS. To our knowledge, this study is
the largest cohort with 2 sequential standardized
ETT-CRF assessments at least 1 year apart. Although
there are no widely accepted standards for the
classification of CRF based on ETT performance, we
followed the age- and-sex-specific methods for CRF
standardization proposed in our previous work.26
Access to care was independent of a patient’s
financial status because it was provided by the
Veterans Health Administration,
epidemiologic assessment while minimizing the ef-
fect of disparities in medical care.19-21 Equal access
to care, along with the existence of electronic
health records within the Veterans Health Admin-
istration system, enables the assessment of history
and alterations in health status to be analyzed in
detail. These factors, coupled with the similar
resulting from trends when we excluded individuals whose CRF
status declined and died during the first 2 years of
follow-up, reduce the effect of pre-existing disease
on our findings. Thus, reverse causality was less
likely, strengthening the validity of the association
between change in CRF and mortality risk.
We recognize that changes in CRF are in part age-
related.35 Hence, we considered an age-related
decline in CRF of 1% per year and classified CRF cat-
egories accordingly. 39,40 The findings between the 2
methods used to define CRF categories (an absolute
change in METS vs changes in METS per year between
the 2 assessments) were similar. Our decision to
define CRF categories according to an absolute
change in METS was based mainly on the practicality
and applicability of this approach for both clinicians
and the public. To account for the impact of aging on
CRF, we adjusted the model for the time (years) be-
tween the 2 CRF assessments.
STUDY LIMITATIONS. The retrospective nature of the
study does not prove causation, regardless of the
strong associations between CRF changes and mor-
tality risk. Accordingly, we cannot discern whether
reductions in CRF were the outcome of intentional
abstinence from physical activity, other lifestyle fac-
which enabled tors, or subclinical disease that underlies low CRF
(reverse causality), despite steps taken to minimize
the possible impact of reverse causality.
1146 Kokkinos et al JACC VOL. 81, NO. 12, 2023

Fitness Changes and Mortality MARCH 28, 2023:1137–1147

We also acknowledge that our cohort was drawn
from ETTs across the VA system, and whereas the
same protocol was used, some unknown differences
in ETT conduct may exist. We recognize that our
population (U.S. veterans referred for ETTs) may not
reflect the general population. In addition, the results
may have been influenced by factors that were
beyond the capacity of this study to account. We
cannot discern whether the favorable health out-
comes associated with CRF are exclusively the result
of increases in aerobic capacity or physical activities
(aerobic and anaerobic) of adequate and equivalent
caloric expenditure, independent of improvements in
aerobic capacity. We also acknowledge that in-
terventions, treatment, and risk status may have
changed during the follow-up, which may affect the
results. Moreover, we could not account for factors
that lead to subsequent ETTs. Thus, our results may
not be generalized to changes in CRF in the absence
of factors precipitating a second ETT. Lastly, the CRF
categories were not based on direct assessment of V O2
max, but on METS (an estimation of VO 2 max). Thus,
we acknowledge that our findings might vary if CRF
categories were based on direct assessment of VO2
max.
CONCLUSIONS
The salient and unique finding of the current study is
that it quantifies the volume of change in CRF needed
to alter mortality risk. Changes in CRF of $1.0 MET
(increases or decreases) were associated
concomitant and progressive changes in mortality
risk, whereas a major portion of the risk reduction
was noted with CRF changes of >2.0 METS. These
findings provide a guide for clinicians and the public
in general regarding CRF changes necessary to
improve CRF and health outcomes. Accordingly,
encouraging the public to improve CRF by at least 1.0
MET can have considerable clinical and public health
significance.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
The authors have reported that they have no relationships relevant to
the contents of this paper to disclose.
ADDRESS FOR CORRESPONDENCE: Dr Peter
Kokkinos, Veterans Affairs Medical Center, Cardiol-
ogy Division, 50 Irving Street NW, Washington, DC
20422, USA. E-mail: peter.kokkinos@va.gov.
PERSPECTIVES
COMPETENCY IN PATIENT CARE AND
PROCEDURAL SKILLS: Changes in CRF over time
are associated with graded changes in mortality
regardless of initial fitness.
TRANSLATIONAL OUTLOOK: More consistent
efforts are necessary to improve CRF in middle-aged
and older individuals by implementing current rec-
ommendations to engage in $150 minutes per week
of moderate (brisk walking or similar activities) or
75 minutes of higher intensity physical activity to
with
reduce mortality.

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KEY WORDS cardiovascular disease, fitness
change, mortality