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Accepted Manuscript

The Joint Association of Fitness and Fatness on Cardiovascular


Disease Mortality: A Meta-Analysis

Vaughn W. Barry, Jennifer L. Caputo, Minsoo Kang

PII: S0033-0620(18)30131-2
DOI: doi:10.1016/j.pcad.2018.07.004
Reference: YPCAD 902
To appear in: Progress in Cardiovascular Diseases
Received date: 2 July 2018
Accepted date: 2 July 2018

Please cite this article as: Vaughn W. Barry, Jennifer L. Caputo, Minsoo Kang , The Joint
Association of Fitness and Fatness on Cardiovascular Disease Mortality: A Meta-Analysis.
Ypcad (2018), doi:10.1016/j.pcad.2018.07.004

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Title

The Joint Association of Fitness and Fatness on Cardiovascular Disease Mortality: A Meta-

Analysis

Author Names

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Vaughn W. Barry1, PhD; Jennifer L. Caputo1, PhD; Minsoo Kang2, PhD

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Affiliations
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Health and Human Performance

Middle Tennessee State University


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Murfreesboro, TN

Institution where work was completed


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2
Exercise Science and Recreation Management

The University of Mississippi


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Oxford, Mississippi
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Corresponding Author Information

Vaughn W. Barry, PhD

Middle Tennessee State University

1301 East Main Street

P. O. Box 96

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Murfreesboro, TN 37132

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Phone: (615) 898-5535

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Fax: (615) 898-5550

Vaughn.Barry@mtsu.edu

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Abbreviation and Acronyms

ACLS = Aerobic Center Longitudinal Study

BMI = body mass index

CCLS = Cooper Clinic Longitudinal Study

CRF = cardiorespiratory fitness

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CVD = cardiovascular disease

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NOS = Newcastle-Ottawa Scale

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Abstract

The joint association between cardiorespiratory fitness (CRF) and body mass index

(BMI) on cardiovascular disease (CVD) mortality was determined. PubMed and CINAHL were

searched following PRISMA guidelines. Included studies were prospective, had objective

assessments of maximal CRF and BMI, and compared the joint impact of CRF and BMI on CVD

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mortality risk to normal weight, fit referents. Pooled hazard ratios and 95% confidence intervals

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were calculated from eight articles with nine independent groups using a random effects model.

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Unfit individuals had two to three times the risk of mortality across all levels of BMI.

Overweight and obese-fit individuals had 25% and 42% increased mortality risk, respectively,

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compared to normal weight-fit individuals. However, for the obese-fit group, a one study
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removed analysis for five studies resulted in non-significant changes in mortality risk.

Researchers, clinicians, and public health officials are encouraged to employ CRF interventions
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to reduce CDV mortality risk.


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Keywords: Cardiorespiratory fitness, body mass index, cardiovascular disease mortality


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Introduction

While significant decreases in cardiovascular disease (CVD) mortality have occurred

overtime (1), CVD mortality remained the leading cause of death in the US in 2015, accounting

for nearly a quarter (i.e. 23.4%) of all deaths nation-wide (2). Because of the significant health

and economic burdens related to CVD death, the need for primary and secondary interventions

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remains.

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Obesity, often illustrated at the population level by body mass index (BMI), is a noted

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risk factor for CVD. Based on BMI, 37.7% of US adults are considered obese (3) and annual

heath care costs for obesity-related health issues ranges from $147 - $220 billon (4-5). However,

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the relationship of BMI to CVD mortality has been challenged in the literature (6-8). Because of
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the magnitude of the problem and the dichotomy of research outcomes relating BMI to CVD

mortality (6-10), more research is needed to understand this relationship.


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Cardiorespiratory fitness (CRF) is also related to CVD mortality (11-12). While this
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relationship is not under debate in the literature, the magnitude is being investigated. Several

researchers have shown higher CRF levels associated with lower CVD mortality (3-4, 6, 13-15).
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Further, after adjusting for or jointly assessing BMI levels, the relationship between CRF and
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CVD mortality remains (3-4, 6, 13, 15).

The joint association between CRF and BMI relative to all-cause mortality has been
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highlighted (16-18). In a recent meta-analysis on this joint association, a change in CRF

impacted all-cause mortality risk while altering BMI did not (16). While the joint association of

CRF and BMI on CVD mortality has been investigated (3-6, 13-15, 19-20), a summary of

existing literature was not found. Therefore, the purpose of this manuscript was to jointly assess

the relationship of CRF and of BMI on CVD mortality using meta-analytical techniques.
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Methods

Literature Search

The PRISMA guidelines were followed during manuscript preparation (21). The

literature was reviewed using PubMed and CINAHL search engines using the following terms:

((“Cardiorespiratory fitness” OR “fitness” OR “maximal oxygen consumption” OR “VO2 max”

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OR “maximal oxygen uptake” OR “stress test” OR “maximal treadmill test”) AND (“Body

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composition” OR “BMI” OR “body mass index” OR “obesity” OR “adiposity”) AND (“diabetes

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mellitus” OR “chronic disease” OR “cancer” OR “cardiovascular” OR “cerebrovascular” OR

“Metabolic” OR “Cardiorespiratory” AND (“mortality” OR “mortalities” OR “death” OR

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“fatality” OR “fatal”)). The search was further limited by three criteria: 1) published between
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January 1989 and December 2017, 2) population was adult humans, and 3) written in English

language. During the literature search, articles were included if they were prospective,
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cardiorespiratory fitness was objectively measured through a maximal exercise test, height and
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body mass were measured with a stadiometer and a scale, respectively, and the joint impact of

CRF and BMI on cardiovascular disease mortality or a specific subtype of CVD (i.e. heart
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failure) was analyzed. Finally, the reference group for all studies was normal weight, fit
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individuals.

During the first stage of the literature search, 1,018 and 543 titles and abstracts from
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CINAHL and PubMed were assessed, respectively. Two researchers independently assessed all

of these titles and/or abstracts and any duplicate articles between the lists were removed, leaving

a combined pool of 22 articles. Next, the references pages of these sources were assessed to

document additional titles. Upon further review of the content of each article for the inclusion
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criteria and an attempt to contact one author for eligibility dependent information, a final pool of

8 articles was included in the meta-analysis (see Figure 1).

Article Quality

The Newcastle-Ottawa Scale (NOS) for Nonrandomized Studies (22) was used to assess

the quality of the studies in the meta-analysis. This validated scale is used to assess three

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components of research articles: selection (four questions), comparability (two questions), and

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outcome (three questions). A point was available for each question, with a total of nine possible

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points. A study was considered to have moderate to high quality if it received ≥ 6 points and low

quality if it received < 6 points.

Data Analysis
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Data within the eligible articles were categorized into fitness (i.e. fit and unfit) and BMI

(i.e. normal weight, overweight, and obese) categories by the respective study authors.
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Subgroups within the fitness and the fatness categories were combined into five comparison
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groups: unfit and normal weight, fit and overweight, unfit and overweight, fit and obese, and

unfit and obese. Hazard ratios and 95% confidence intervals were recorded from each study. In
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two articles, low, moderate, and high fitness levels were included in the analyses (6, 15).
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However, a dichotomous fitness variable (i.e. fit and unfit) was used in the meta-analysis.

Therefore, the Hamling method was used to combine the hazard ratios and 95% confidence
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intervals for the moderate and high fitness categories from these two studies (23).

The Comprehensive Meta-Analysis software (Comprehensive Meta-Analysis,

Englewood, New Jersey), version 2.2.064, was used to calculate a pooled hazard ratio and 95%

confidence intervals using a random-effects model for each comparison group (i.e. unfit and

normal weight, fit and overweight, unfit and overweight, fit and obese and unfit and obese). An
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I2 statistic was reported for each analysis to assess heterogeneity among study findings. To assess

publication bias across studies, the Egger test was completed (24). To assess the sensitivity of the

study outcomes, a one study removed analysis was completed. In this analysis, the data were

reanalyzed with each study in the total pool removed from the analysis. This allowed the

determination of the impact of individual studies to the overall analysis. Finally, a moderator

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analysis was completed to assess the effects of differing study characteristics on study outcomes.

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In completing this analysis, length of follow-up (> 14 years), baseline health status (lack of

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chronic disease), and confounder control (accounted for ≥ 3 cardiovascular disease risk factors;

(25), were assessed as dichotomous variables (yes or no). Additionally, a meta-regression was

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completed to assess the effect of age. An α level of 0.05 was used to indicate statistical
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significance.
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Results
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All eight articles scored ≥ 6 on the NOS scale, an indication of high quality. There was

no publication bias across studies as assessed by the Egger test, for each of the five comparison
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groups (see Table 1). The hazard ratios, 95% confidence intervals, forest plots, and pooled ratios
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for the five comparison groups relative to the reference group of normal weight, fit are displayed

in Figures 2, 3, and 4. In addition, the relative weight of each study is indicated within each
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figure. The risk of CVD death for normal weight, unfit individuals was twice as high relative to

the reference group, i.e. normal weight, unfit individuals (see Figure 2). A one study removed

sensitivity analysis did not significantly alter the pooled hazard ratio. Furthermore, the three

dichotomous moderator analyses (follow-up, baseline health status, confounder control) did not

significantly affect the main outcome, nor did age influence this relationship.
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There was an additional increased risk of death due to CVD for the overweight groups

(see Figure 3). Specifically, the risk for those who were overweight and unfit was doubled

whereas the risk for overweight and fit relative to the normal weight fit reference was only 25%

elevated. The sensitivity analysis did not significantly alter the pooled hazard ratios for the

overweight groups. Further, the dichotomous moderator analyses did not significantly alter the

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outcomes. However, age had a significant inverse effect (slope coefficient [se] = -0.07 [0.03]) on

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CVD mortality risk in the overweight, unfit group (model Q = 4.22, df = 1, p = 0.04).

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Figure 4 shows the elevated risk of CVD mortality for the obese groups. Again, there was

a higher elevation in risk for the obese unfit group (tripled) than for the obese fit group

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(increased by 42%). However, the significance of the obese fit data was changed as multiple
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analyses were completed with each study removed. This one study removed sensitivity analysis

resulted in a lack of significant increase in the hazard ratio for this group, when five of the
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articles in the total pool were individually removed, one at a time, and the analyses re-run (4, 6,
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13, 15, 19). The one study removed analysis did not significantly affect findings for the obese,

unfit group. The three dichotomous moderator analyses did not affect the main outcomes for the
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obese groups, while the age meta-regression showed an inverse relationship (slope coefficient
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[se] = -0.09 [0.03]) between age and risk of CVD mortality only in the unfit obese group (model

Q = 8.24, df = 1, p = 0.004).
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Discussion

Observational studies, in which the joint impact of CRF and BMI on CVD mortality was

determined, were analyzed using meta-analytical techniques. After assessing publication bias and

moderator analyses and jointly assessing CRF and BMI, both variables (i.e. decreases in CRF
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and increases in BMI) increased CVD mortality risk. However, the data suggest that low CRF is

a stronger predictor of CVD mortality risk (more than double), than elevated BMI. In fact, a

significant increase in CVD mortality risk occurred, for all unfit groups, in every article included

in the meta-analysis, regardless of BMI. This is compelling evidence of the significant mortality

risk associated with having low CRF. While CVD death risk significantly increased in fit

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overweight and obese individuals, a one study removed analysis in the obese, fit group reduced

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the CVD mortality risk to non-significant levels when each of five articles were removed (4, 6,

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13, 15, 19). Therefore, CRF is a powerful predictor of CVD mortality risk.

While there are several pertinent review articles showing strong effects of CRF on

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mortality while concurrently assessing BMI levels (26, 27, 28, 29), a numerical assessment of
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these effects was only available for all-cause mortality (16). These prior all-cause mortality

analyses produced similar findings in that unfit individuals had at least twice the risk of death
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from all causes compared to fit counterparts. Interestingly, there was a greater risk of CVD
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mortality in the current meta-analysis for all fitness and fatness groups, suggesting that fitness

and, to an extent, fatness are greater predictors of CVD mortality than all-cause mortality.
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Age was the only moderator that was statistically significant. In the unfit and fat groups
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(those at highest risk), age was inversely related to CVD mortality risk. Younger, unfit,

overweight or obese individuals had a higher CVD mortality risk than older individuals in these
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groups. While an inverse relationship seems counterintuitive, specific factors may have

contributed to this outcome: 1) a survivor bias may have occurred in which unfit and overweight

or obese individuals were preselected to survive and 2) the baseline age range within the

included studies was limited (< 10 years).


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There is controversy within the literature surrounding the use of BMI as an indicator of

risk. While other anthropometric measures provide an assessment of body composition, BMI

simply measures body mass standardized to height. With the current anthropometric paradigm, it

seems logical for body fat percentage and possibly waist circumference to be better assessments

of CVD mortality risk. While a direct comparison of these exposure variables on CVD mortality

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was not found in the literature, a review article showed mortality risk was not elevated in fit and

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obese individual, regardless of anthropometric method (30). Furthermore, recent research

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demonstrated independent association between fat free mass and mortality in obese individuals

(31). The fact that BMI, as a measure of body mass, includes both fat and fat free mass, may

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improve its prognostic effect on cardio metabolic risk.
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All studies included in this analysis were longitudinal studies with one exposure

assessment at baseline. While the current study design provided powerful information on CVD
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mortality risk relative to fitness and fatness, changes in the exposure variables (i.e. fitness and
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BMI) and their effect on CVD death were not assessed. A recent study by Lee et al. (2011)

assessed the combined association of changes in fitness and BMI and the impact on CVD
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mortality. Lee et al. showed fitness gains stabilized CVD mortality risk while fitness loss
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increased CVD mortality risk, regardless of BMI changes. This suggests better CVD mortality

prognoses in individuals who improve CRF compared to those who reduce their BMI (32).
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It is important to note, the data in the studies in the meta-analysis were drawn from three

sources, the Aerobic Center Longitudinal Study (ACLS) and the Cooper Clinic Longitudinal

Study (CCLS) databases, an independent sample of men from the United States, and an

independent sample of men from Russia. However, the ACLS database name was changed to the

CCLS in 2006. Therefore, these databases were considered the same source for this analysis,
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resulting in three total sources. This may result in concern of population overlap, specifically

among the ACLS and CCLS studies. However, many of the study samples were from disease-

specific populations within the ACLS and CCLS databases, minimizing this concern. It is also

important to consider how BMI and CRF exposure variables are expressed. As shown in Table 2,

there was variability among studies. Due to this, not all studies were included in every analysis.

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Also pertinent, is that only eight articles were included in the meta-analysis. However, tens of

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thousands of individuals were included in the analyzed samples. In future studies, the joint

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association between CRF and BMI on CVD mortality risk in women needs to be investigated as

only ~2,000 women were in this meta-analysis.

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In conclusion, CRF is a powerful predictor of CVD mortality risk. Individuals who are
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unfit are at twice the risk of death compared to their fit counterparts, regardless of BMI.

Individuals who are obese and unfit have the highest mortality risk (tripled) compared to normal
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weight, fit individuals. While an elevated BMI was associated with CVD mortality risk, being fit
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nearly eliminated this risk in overweight and obese individuals. Therefore, CRF needs to be a

central component in interventions aimed at reducing the health and economic burdens related to
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CVD mortality.
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Statement of Conflict of Interest


The authors declare there are no conflicts of interest.

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Figure 1. Selection of Articles for Meta-analysis; CVD, Cardiovascular disease; BMI, body

mass index; CRF, Cardiorespiratory fitness; HR, Hazard ratio; CI, Confidence interval.

Figure 2. Meta-analysis of CVD mortality for normal weight unfit individuals compared to

normal weight fit individuals; CVD, Cardiovascular disease; r, Russian males; u, United States

males.

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Figure 3. Meta-analysis of CVD mortality for unfit and fit overweight individuals compared to

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normal weight fit individuals; CVD, Cardiovascular disease.

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Figure 4. Meta-analysis of CVD mortality for unfit and fit obese individuals compared to normal

weight fit individuals; CVD, Cardiovascular Disease; r, Russian males; u, United States males.

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Conflict of interest: None.

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Table 1. Assessment of publication bias (Egger test) by comparison group*


Fit Unfit
Group t (df) t (df)
Normal weight Referent 1.00 (7)
Overweight 2.31 (5) 0.41 (5)
Obese 0.36 (6) 0.59 (7)
* All comparisons were non-significant (p < .05).

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Table 2. Characteristics of studies included in the meta-analysis

Follow-
Exposures
up Outcome
Age Baseline Study
Men (mean health data- (mean (No. of
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Article N (%) years) status base years) deaths) CRF BMI (kg/m )

Church et al. 2,316 100 49.3 Diabetes ACLS 15.9 179 F: upper 80% NW: 18.5-24.9
2005

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UF: lower 20% OW: 25-29.9

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OB: 30-34.9

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a
Farrell et al. 44,674 100 45 - CCLS 19.8 153 F: upper 80% NW: 18.5-24.9
2013

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UF: lower 20% OW: 25-29.9
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OB: ≥30

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Lee et al. 1998 21,865 100 43.9 - ACLS 8.1 144 F: upper 80% NW: 19-24.9
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UF: lower 20% OW: 25-27.7


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OB: ≥27.8
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McAuley et al. 13,155 100 62.4 HTN ACLS 12 355 F: upper 80% NW: 18.5-24.9
2009
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UF: lower 20% OW: 25-29.9

OB: ≥30
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McAuley et al. 9,563 100 43.9 CHD ACLS 13.4 348 F: upper 66.6% NW: 18.5-24.9
2012
UF: lower 33.3% OW: 25-29.9

OB: 30-34.9
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Table 2. Characteristics of studies included in the meta-analysis

Follow-
Exposures
up Outcome
Age Baseline Study
Men (mean health data- (mean (No. of
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Article N (%) years) status base years) deaths) CRF BMI (kg/m )

McAuley et al. 17,044 89 47.4 Pre- ACLS 13.9 246 F: upper 66.6% NW: 18.5-24.9
2014

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diabetes
UF: lower 33.3% OW: 25-29.9

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OB: ≥30

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a b
Stevens et al. 1,359 100 47.7 - LRCS 17.6 - F: upper 80% Non-OB: lower 80%
2004r

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UF: lower 20% OB: upper 20%
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a b
Stevens et al. 1,716 100 57.3 - LRCS 17.6 - F: upper 80% Non-OB: lower 80%
2004u
UF: lower 20% OB: upper 20%
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Wei et al. 1999 25,714 100 64.4 - ACLS 10.1 439 F: upper 80% NW: 18.5-24.9
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UF: lower 20% OW: 25-29.9


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OB: ≥30
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a b
: no specific baseline disease reported; :outcome not provided; r, Russian sample; u, United States sample; ACLS, Aerobic Center
Longitudinal Study; CCLS, Cooper Clinic Longitudinal Study; LRCS, Lipids Research Clinics Study; CRF, Cardiorespiratory Fitness;
BMI, Body Mass Index; F, Fit; UF, Unfit; NW, Normal Weight; OW, Overweight; OB, Obese. Note: The ACLS database is a subset of
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the CCLS database


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