JACC: Heart Failure Vol. 2, No.

3, 2014
 2014 by the American College of Cardiology Foundation ISSN 2213-1779/$36.00
Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jchf.2014.01.004

CLINICAL RESEARCH

Association of Cardiorespiratory Fitness

With Left Ventricular Remodeling and
Diastolic Function
The Cooper Center Longitudinal Study
Stephanie K. Brinker, MD,* Ambarish Pandey, MD,* Colby R. Ayers, MS,*
Carolyn E. Barlow, MS,y Laura F. DeFina, MD,y Benjamin L. Willis, MD, MPH,y
Nina B. Radford, MD,z Ramin Farzaneh-Far, MD, MAS,* James A. de Lemos, MD,*
Mark H. Drazner, MD, MSC,* Jarett D. Berry, MD, MS*
Dallas, Texas

Objectives This study sought to compare the cross-sectional associations between fitness and echocardiographic measures of
cardiac structure and function.

Background Cardiorespiratory fitness is inversely associated with heart failure risk. However, the mechanism through which
fitness lowers heart failure risk is not fully understood.

Methods We included 1,678 men and 1,247 women from the Cooper Center Longitudinal Study who received an
echocardiogram from 1999 to 2011. Fitness was estimated by Balke protocol (in metabolic equivalents) and also
categorized into age-specific quartiles, with quartile 1 representing low fitness. Cross-sectional associations between
fitness (in metabolic equivalents) and relative wall thickness, left ventricular end-diastolic diameter indexed to body
surface area, left atrial volume indexed to body surface area, left ventricular systolic function, and E/e0 ratio were
determined using multivariable linear regression analysis.

Results Higher levels of mid-life fitness (metabolic equivalents) were associated with larger indexed left atrial volume (men:
beta ¼ 0.769, p < 0.0001; women: beta ¼ 0.879, p value 0.0001) and indexed left ventricular end-diastolic
diameter (men: beta ¼ 0.231, p < 0.001; women: beta ¼ 0.264, p < 0.0001). Similarly, a higher level of fitness
was associated with a smaller relative wall thickness (men: beta ¼ –0.002, p ¼ 0.04; women: beta ¼ –0.005,
p < 0.0001) and E/e0 ratio (men: beta ¼ –0.11, p ¼ 0.003; women: beta ¼ –0.13, p ¼ 0.01). However, there was no
association between low fitness and left ventricular systolic function (p ¼ NS).

Conclusions Low fitness is associated with a higher prevalence of concentric remodeling and diastolic dysfunction, suggesting
that exercise may lower heart failure risk through its effect on favorable cardiac remodeling and improved diastolic
function. (J Am Coll Cardiol HF 2014;2:238–46) ª 2014 by the American College of Cardiology Foundation

Higher levels of self-reported physical activity and measured
fitness are associated with a lower risk for heart failure that is
independent of established heart failure risk factors such as
obesity, diabetes, and hypertension (1–4). Whereas the
From the *Division of Cardiology, University of Texas Southwestern Medical Center,
Dallas, Texas; yThe Cooper Institute, Dallas, Texas; and zThe Cooper Clinic, Dallas,
Texas. Dr. de Lemos receives consulting fees from Roche Diagnostics, Abbott
Diagnostics, and Diadexus; and grant support from Abbott Diagnostics. Dr. Berry
receives funding from the Dedman Family Scholar in Clinical Care endowment at
University of Texas–Southwestern Medical Center; grant K23 HL092229 from the
National Heart, Lung, and Blood Institute; and grant 13GRNT14560079 from the
American Heart Association; and is a member of the Speakers’ Bureau for Merck &
Co. All other authors have reported that they have no relationships relevant to the
contents of this paper to disclose.
Manuscript received October 7, 2013; revised manuscript received January 2, 2014,
accepted January 10, 2014.
potential mechanisms through which exercise might lower
heart failure risk are not completely understood, multiple
lines of evidence suggest that higher levels of exercise might
have a direct effect on cardiac structure and function. In
particular, individuals who report high levels of exercise
across the lifespan have more compliant left ventricles than
sedentary, age-matched control subjects do (5,6). These
See page 247
findings suggest the hypothesis that higher levels of exercise
may lower the risk for heart failure with preserved ejection
fraction (HFpEF). Given the failure of numerous therapies
for the treatment and prevention of HFpEF, this would
JACC: Heart Failure Vol. 2, No. 3, 2014 Brinker et al. 239
June 2014:238–46 Echocardiographic Associations With Low Fitness

represent an important observation that could have signifi- After excluding 14 participants Abbreviations
cant public health implications (7). with severe valvular disorders, we and Acronyms
The associations between intense physical activity and included 1,678 men and 1,247
BSA = body surface area
fitness and physiologic cardiac remodeling and improved women in the final study sample
early diastolic filling are well established in elite athletes who received an echocardiogram BMI = body mass index

(8–10), but the effects of exercise on cardiac structure and within 3 months of their exami- EF = ejection fraction

function within the continuum of normal fitness levels are nation and measured fitness at HFpEF = heart failure with
preserved ejection fraction
not known. Echocardiography represents a valuable poten- the clinic. There was a low prev-
tial intermediate phenotype that can provide important in- alence of low ejection fraction LA Vol = left atrial volume

sights into cardiac structure and both systolic and diastolic (EF) and abnormal stress echo in LA Vol/BSA = left atrial
function. The presence of pathologic ventricular remodeling the study cohort, and those sub- volume indexed to body
surface area
patterns (11–13) have been identified as important inter- jects were included in the final
LV = left ventricular
mediates in the pathway to heart failure. Ventricular analysis. Finally, because tissue
remodeling is associated with increased volume and altered Doppler was incorporated into LVEDD = left ventricular end-
diastolic diameter
chamber geometry that develops in response to a myocar- the standard echocardiographic
LVEF = left ventricular
dial injury and increased wall stress. Three patterns of examination at the Cooper Clinic
ejection fraction
left ventricular (LV) remodeling have been identified on the in 2003, 42% of the participants
LVMI = left ventricular mass
basis of the measures of LV mass index and relative wall were missing tissue Doppler data. index
thickness (RWT): concentric remodeling (normal LV mass Therefore, we included 1,235
PWT = posterior wall
index and increased RWT); eccentric hypertrophy participants for the tissue Doppler thickness
(increased LV mass index and normal RWT); and analyses.
Q = quartile
concentric hypertrophy (increased LV mass index and Data collection. Details of the
RWT = relative wall
increased RWT) (14). Similarly, subclinical systolic and clinical examination for CCLS thickness
diastolic dysfunction has been shown to be an important participants have been reported
SWT = septal wall thickness
determinant of adverse cardiovascular outcomes (15–18). previously (19,20). Medical his-
Specifically, subclinical systolic dysfunction carries increased tory of diabetes, hypertension,
risk of heart failure with reduced ejection fraction and coronary artery disease, smoking history, fasting blood
asymptomatic diastolic dysfunction increases the risk of glucose, blood pressure, and body mass index (BMI)
future HFpEF (15–18). (calculated from weight and height) were collected during
The purpose of this study was to characterize the association the physical examination. Medications were extracted from
between measured cardiorespiratory fitness and cardiac the medical record. Hypertension was defined as either a
structure and function in the Cooper Center Longitudinal systolic blood pressure >140 mm Hg, self-reported hyper-
Study. We hypothesized that higher fitness levels would be tension, or use of antihypertensive drug. Diabetes was
associated with a lower prevalence of diastolic dysfunction and defined as the presence of a fasting blood sugar 126 mg/dl,
a lower prevalence of concentric remodeling/hypertrophy. self-reported diabetes, or use of antihyperglycemic drug.
We further hypothesized that there would be no association Echocardiographic data. All echocardiograms were per-
between fitness and systolic function. formed using a GE Vivid 7 (Milwaukee, Wisconsin) and
were read by a staff cardiologist at the clinic at the time the
echocardiogram was done. The following variables were
Methods
gathered from the resting echocardiograms, including the
Study participants. The CCLS (Cooper Center Longitu- indication for the echocardiogram, left ventricular end-
dinal Study) is an ongoing study derived from patients at the diastolic diameter (LVEDD), left ventricular end-systolic
Cooper Clinic, a preventive health clinic in Dallas, Texas, diameter, posterior wall thickness (PWT), septal wall
and has previously been well described (19,20). All partici- thickness (SWT), left atrial diameter, left ventricular ejec-
pants are either self-referred to the clinic or are referred by tion fraction (LVEF), valvular stenosis/regurgitation,
their employer or personal physician. They are predomi- mitral inflow Doppler (E-wave, A-wave, and deceleration
nantly Caucasian and from the middle to upper socioeco- time), and tissue Doppler (e0 ) of the lateral mitral annulus.
nomic strata. For the present study, we included patients The following echocardiographic variables were defined in
from the CCLS who received both a clinically indicated accordance with standard definitions: LVEF: (LV end-
echocardiogram at the clinic between 1999 and 2011 and a diastolic volume – LV end-systolic volume) O LV end-
standardized medical examination by a physician including a diastolic volume, where both the LV end-diastolic volume
maximal treadmill exercise test. Echocardiograms were and LV end-systolic volume were estimated using the
performed for a broad range of indications (Online Table). modified Simpson rule (biplane method of disks): LV
This study was approved by both the Cooper Institute and mass (indexed to body surface area) [0.8  {1.04
the University of Texas Southwestern Institutional Review (LVEDD þ PWT þ SWT)3 – (LVEDD)3} þ 0.6 g];
Boards. RWT (2  PWT/LVEDD). Left atrial volume (LA Vol)
240 Brinker et al. JACC: Heart Failure Vol. 2, No. 3, 2014
Echocardiographic Associations With Low Fitness June 2014:238–46

was determined by the biplane area-length method. LV
filling pressures were estimated by calculating the ratio of
the LV early diastolic filling wave (mitral inflow Doppler
E-wave velocity) to the early diastolic velocity of the lateral
mitral valve annulus (lateral e0 -wave velocity). An E/e0 ratio
>10 was used as a cutpoint for diastolic dysfunction of
indeterminate grade as this indicates elevated LV filling
pressure (16,21–23).
Remodeling patterns. Four LV remodeling pattern groups
were created using standard definitions: Normal geometry was
defined as a left ventricular mass index (LVMI) 95 g/m2 for
women or 115 g/m2 for men and a RWT 0.42; concentric
remodeling, a LVMI 95 g/m2 for women or 115 g/m2 for
men and a RWT >0.42; eccentric hypertrophy, a LVMI >95
g/m2 for women or >115 g/m2 for men and a RWT 0.42;
and concentric hypertrophy, a LVMI >95 g/m2 for women or
>115 g/m2 for men and a RWT >0.42.
Exercise testing. As reported previously (19,20), fitness
was measured in the CCLS cohort by a maximal treadmill
exercise test using a Balke protocol. In this protocol,
treadmill speed is set initially at 88 m/min. In the first min,
the grade is set at 0%, followed by 2% in the second min,
and an increase of 1% for every min thereafter. After 25 min,
the grade remains unchanged but the speed is increased by
5.4 m/min for each additional min until the test is termi-
nated. Participants were encouraged not to hold onto the
railing and were given encouragement to exert maximal
effort. The test was terminated by volitional exhaustion re-
ported by the participant or by the physician for medical
reasons. As described previously, the test time using this
protocol correlates highly with directly measured maximal
oxygen uptake (r ¼ 0.92) (24).
Statistical analysis. In accordance with standard ap-
proaches to the analysis of fitness data, treadmill times were
categorized into quartiles using age- and sex-specific
thresholds of treadmill performance. This allows each
participant to be categorized into 1 of 4 mutually exclusive
fitness categories that is independent of age and sex, with
quartile 1 (Q1) as the lowest fit group and Q4 as the highest
fit. In addition, treadmill times from the Balke protocol can
also be used to estimate continuous measures of fitness
(metabolic equivalents) (24).
Baseline characteristics and echocardiographic parameters
collected were stratified by sex and then compared across
quartiles of fitness using the Jonckheere-Terpstra trend test
for all continuous variables and the Cochran-Armitage trend
test for categorical variables. The association between fitness
and echocardiographic parameters (indexed LA volume
[LAVol/BSA], indexed LVEDD [LVEDD/BSA], RWT,
EF, E/e0 ratio) were estimated using linear regression with
fitness (metabolic equivalents) entered as a continuous in-
dependent variable in both age-adjusted and multivariable
models adjusted for age, BMI, hypertension, and diabetes.
All statistical analyses were performed using SAS for
Windows (release 9.2, SAS Institute, Inc. Cary, North
Carolina).
Results
The baseline characteristics of the study cohort are shown in
Table 1, demonstrating a low prevalence of previous coro-
nary artery disease and a low prevalence of traditional risk
factors for structural heart disease. As expected, higher
fitness was associated with a lower BMI, lower blood

Table 1 Baseline Characteristics Among Men and Women by Fitness Quartiles

Q1: Low Fitness Q2 Q3 Q4: High Fitness p Value

Men 425 424 387 452
Age, yrs 56.0  12.0 55.8  12.4 56.0  11.8 54.9  10.6 0.49
Body mass index, kg/m2 30.1  5.1 27.3  3.2 26.3  2.6 25.0  2.4 <0.0001
Systolic blood pressure, mm Hg 129  16 127  16 128  15 125  15 0.002
Diastolic blood pressure, mm Hg 84  11 83  10 82  10 81  9 <0.001
Hypertension 280 (69) 217 (52) 189 (50) 170 (38) <0.001
Diabetes 32 (8) 15 (4) 4 (1) 3 (1) <0.001
Coronary artery disease 35 (8) 29 (7) 32 (8) 24 (5) 0.14
Current smoker 54 (15) 36 (10) 32 (10) 24 (6) 0.0001
Women 315 284 358 290
Age, yrs 53.4  12.0 52.1  12.3 52.8  10.7 51.3  11.1 0.15
Body mass index, kg/m2 27.7  6.0 24.6  4.0 23.2  2.8 21.9  3.0 <0.0001
Systolic blood pressure, mm Hg 123  18 119  18 118  16 116  16 <0.0001
Diastolic blood pressure, mm Hg 80  10 78  10 78  9 77  9 <0.0001
Hypertension 148 (47) 88 (32) 126 (36) 61 (22) <0.0001
Diabetes 25 (8) 11 (4) 6 (2) 2 (1) <0.0001
Coronary artery disease 2 (0.6) 4 (1) 6 (2) 4 (1) 0.37
Current smoker 16 (6) 4 (1) 11 (4) 5 (2) 0.051

Values are n, mean  SD, or n (%). Values of p < 0.05 are statistically significant. Hypertension: blood pressure >140/90 mm Hg, self-report of hypertension or use of antihypertensive medication.
Diabetes: fasting blood glucose >126 mg/dl, self-report of diabetes or use of antidiabetic drug.
Q ¼ quartile.
JACC: Heart Failure Vol. 2, No. 3, 2014 Brinker et al. 241
June 2014:238–46 Echocardiographic Associations With Low Fitness

pressure, and a lower prevalence of diabetes and hyperten-
sion (Table 1).
Heart size, concentricity, and function across the fitness
quartiles. In men, compared with high fitness (Q4), low
fitness (Q1) was associated with smaller heart size (LA Vol/
BSA: 25.4 mm vs. 22.7 mm; p < 0.0001 and LVEDD: 48.5
mm vs. 49.9 mm; p < 0.0001), lower LV mass (LVMI: 84.3
g/m2 vs. 91.9 g/m2; p < 0.0001), and a higher RWT (RWT:
0.42 vs. 0.39; p < 0.0001). Lower fitness was also associated
with a higher E/e0 ratio (E/e0 : 6.6 vs. 5.3; p < 0.0001). In
contrast, there was no association between fitness and LVEF
(LVEF: 60.1 vs. 60.9; p ¼ 0.32). Overall, a similar pattern of
results was observed in women except there was no apparent
association between fitness and LVMI in women (68.2 g/m2
vs. 68.9 g/m2; p ¼ 0.688) (Table 2).
Prevalence of remodeling patterns by fitness quartile.
There was nearly twice the prevalence of concentric
remodeling among the lowest quartile compared with the
highest quartile of fitness (38% vs. 21%, Q1 vs. Q4; p <
0.0001). In addition, despite a low overall prevalence of
either concentric or eccentric hypertrophy in our cohort,
lower fitness was associated with a numerically higher
prevalence of concentric hypertrophy and a numerically
lower prevalence of eccentric hypertrophy (Fig. 1).
Prevalence of diastolic dysfunction. The overall preva-
lence of diastolic dysfunction was low (5%, 63 of 1,235),
which is consistent with the healthy nature of the cohort.
Nevertheless, lower fitness was associated with an increased
prevalence of diastolic dysfunction (8.9% vs. 2.2%, Q1 vs.
Q4; p < 0.0001) (Fig. 2).
The association of fitness with heart size, concentricity,
and diastolic function. After adjustment for age, BMI,
hypertension, and diabetes, cardiorespiratory fitness sig-
nificantly predicted indexed LAVol, indexed LVEDD,
RWT, and E/e0 ratio in both men and women. Higher
fitness levels (in metabolic equivalents) were associated

Table 2 Echocardiographic Characteristics by Fitness Quartile

Q1: Low Fitness Q2 Q3 Q4: High Fitness p Value

Men 425 424 387 452
MET 8.5  1.4 10.4  1.2 11.6  1.2 13.8  1.8 <0.0001
LA Vol/BSA 22.8  7.2 22.5  6.5 23.9  6.4 25.4  7.1 <0.001
LV geometry
LV mass/BSA, g/m2 84.3  22.0 84.4  19.9 87.3  18.2 91.9  43.2 <0.0001
LVEDD, mm 48.5  5.2 48.6  5.2 48.7  4.6 49.9  4.8 <0.0001
PWT, mm 10.1  1.8 9.8  1.4 9.8  1.5 9.6  1.3 <0.0001
SWT, mm 10.5  1.9 10.3  1.9 10.4  1.7 10.3  3.5 0.045
RWT 0.42  0.09 0.41  0.08 0.41  0.09 0.39  0.08 <0.0001
Systolic function
LVEF 60  6 61  5 61  4 61  4 0.319
Diastolic function
Mitral E/A 1.15  0.42 1.19  0.43 1.24  0.44 1.33  0.43 <0.0001
Lateral e0 , cm/s 0.11  0.03 0.11  0.03 0.11  0.03 0.12  0.03 <0.0001
E/e0 6.6  2.8 5.9  1.7 5.9  1.8 5.3  1.5 <0.0001
Deceleration time, ms 204  45 208  43 209  38 209  47 0.084
Women 315 284 358 290
MET 7.1  1.1 8.7  1.1 9.7  1.1 11.7  1.5 <0.0001
LA Vol/BSA 19.7  5.3 19.0  5.3 19.6  5.5 22.0  6.1 0.001
LV geometry
LV mass/BSA, g/m2 68.2  15.4 68.1  15.5 66.4  13.4 68.9  14.4 0.688
LVEDD, mm 43.7  4.9 44.4  4.1 44.2  3.9 44.8  4.2 0.005
PWT, mm 8.6  1.4 8.2  1.6 8.0  1.2 7.9  1.2 <0.0001
SWT, mm 9.0  1.7 8.4  1.5 8.2  1.3 8.3  1.3 <0.0001
RWT 0.4  0.09 0.37  0.09 0.37  0.07 0.35  0.07 <0.0001
Systolic function
LVEF 62  5 62  5 62  4 62  4 0.326
Diastolic function
Mitral E/A 1.24  0.42 1.36  0.51 1.43  0.56 1.5  0.54 <0.0001
Lateral e0 , cm/s 0.11  0.03 0.12  0.03 0.12  0.03 0.12  0.03 0.0001
E/e0 7.0  2.5 6.7  2.3 6.54  2.1 6.0  1.8 0.001
Deceleration time, ms 196  42 191  41 196  37 195  37.6 0.498

Values are n or mean  SD. Values of p < 0.05 are statistically significant.
E/e0 ¼ mitral peak Doppler E-wave to peak mitral annulus velocity ratio; Lateral e0 ¼ peak velocity of the lateral mitral annulus; LA Vol/BSA ¼ left
atrial volume indexed to body surface area; LV ¼ left ventricular; LVEDD ¼ left ventricular end-diastolic diameter; LVEF ¼ left ventricular ejection
fraction; LV mass/BSA: left ventricular mass indexed to body surface area; MET ¼ maximal workload in metabolic equivalents achieved in a Balke
protocol treadmill stress test; Mitral E/A ¼ mitral peak velocity of early filling (E) to mitral peak velocity of late filling (A); PWT ¼ posterior wall
thickness; RWT ¼ relative wall thickness; Q ¼ quartile; SWT ¼ septal wall thickness.
242 Brinker et al.
Echocardiographic Associations With Low Fitness
Association Between Fitness and
Figure 1
Remodeling Patterns (n ¼ 2,815)
Concentric remodeling: LVMI 95 g/m2 for women or 115 g/m2 for men and a
RWT >0.42. Eccentric hypertrophy: LVMI >95 g/m2 for women or >115 g/m2 for
men and a RWT 0.42. Concentric hypertrophy: LVMI >95 g/m2 for women or
>115 g/m2 for men and a RWT >0.42. P-trend < 0.0001 for concentric remod-
eling; p value for trend ¼ 0.293 for eccentric hypertrophy; p value for trend ¼ 0.071
for concentric hypertrophy. LVMI ¼ left ventricular mass index; Q ¼ quartile.
with larger indexed LA Vol (men: beta ¼ 0.769, p <
0.0001; women: beta ¼ 0.879, p  0.0001) and indexed
LVEDD (men: beta ¼ 0.231, p < 0.001; women:
beta ¼ 0.264, p < 0.0001). Similarly, a higher level of fitness
was associated with a smaller RWT (men: beta ¼ –0.002,
p ¼ 0.04; women: beta ¼ –0.005, p < 0.0001) and E/e0 ratio
(men: beta ¼ –0.111, p ¼ 0.003; women: beta ¼ –0.13, p ¼
0.01) (Table 3). In additional sensitivity analyses performed
excluding participants with a low EF or abnormal stress test,
a similar pattern of results were observed (data not shown).
Left atrial size and diastolic function. Among participants
with low fitness, LA Vol/BSA positively correlated with
increased E/e0 (rho ¼ 0.29, p < 0.0001), however, we
observed no apparent association between LA Vol/BSA and
E/e0 among participants with high fitness (rho ¼ 0.036, p ¼
0.55) (Fig. 3). These data suggest that the association bet-
ween LA Vol and filling pressures differ according to fitness
status and therefore, the observed association between higher
fitness and higher LA Vol is unrelated to diastolic function.
Discussion
We observed 2 important findings in this study. First, in a
low-risk cohort with a low prevalence of cardiovascular
disease and traditional risk factors, we observed that low
fitness was independently associated with smaller heart size
and a pattern of concentric remodeling. Second, although we
observed that higher fitness was associated with a lower
prevalence of diastolic dysfunction, there was no apparent
association between fitness and systolic function. Taken
JACC: Heart Failure Vol. 2, No. 3, 2014
June 2014:238–46
Association Between Fitness and
Figure 2
Diastolic Dysfunction (n ¼ 1,235)
Diastolic dysfunction is defined as E/e0 10. p value for trend <0.0001.
together, these data suggest that diastolic dysfunction might
play a significant role in predisposing subjects with low mid-
life fitness to a higher risk for HFpEF at a later age.
Whereas self-reported physical activity has previously
been associated with higher LV mass and larger LV end-
diastolic volume (25–28), there are few studies that have
comprehensively addressed the association between mea-
sured fitness and echocardiographic measures of LV struc-
ture and function in middle-aged adults (29). To our
knowledge, this is the first paper to examine the association
between measured cardiorespiratory fitness and echocardio-
graphic measures of both LV structure and function in a
large cohort of healthy, asymptomatic, middle-aged adults
not referred for exercise testing. In previous reports from the
Mayo Clinic among patients referred for exercise stress
echocardiography, higher fitness levels were observed to
be inversely proportional to diastolic function. However,
because of the higher prevalence of disease in a symptomatic
population (49% of this cohort was referred for shortness
of breath or chest pain), diastolic dysfunction was potentially
a cause rather than an effect of lower fitness levels (30). In
a smaller study from this same cohort, exercise capacity
was inversely associated with RWT and LV mass index.
Lower exercise tolerance in these patients was also associated
with a higher prevalence of pathologic remodeling pheno-
types (31). We extend these findings by examining a subset
of patients at the Cooper Clinic who underwent fitness
testing for screening purposes and received echocardio-
graphic testing for reasons largely unrelated to symptoms.
Previous studies have observed that physical activity and
fitness are inversely associated with the risk of heart failure
independent of established heart failure risk factors such as
obesity, diabetes, and hypertension (1–4). However, the
JACC: Heart Failure Vol. 2, No. 3, 2014 Brinker et al. 243
June 2014:238–46 Echocardiographic Associations With Low Fitness

mechanisms through which exercise might lower heart

<0.0001
0.0002
p Value

<0.001
0.009

0.003

0.486
0.004
failure risk remain poorly understood. Data from animal

0.06
0.08

0.01
models suggest that exercise has a direct effect on both

Values of p < 0.05 are statistically significant. Hypertension: blood pressure >140/90 mm Hg, self-reported hypertension or use of antihypertensive medication. Diabetes: fasting blood glucose >126 mg/dl, self-reported diabetes or use of antidiabetic drug.
cardiac structure and function (32,33). For example, exercise
training in hypertensive rats not only attenuates the devel-

–0.111 (–0.184 to –0.038)

opment of heart failure without decreasing blood pressure,

0.013 (–0.023 to 0.049)

–0.13 (–0.23 to –0.031)

0.059 (0.045 to 0.073)
0.385 (0.094 to 0.675)

0.069 (0.054 to 0.084)

0.646 (0.306 to 0.985)

1.123 (0.369 to 1.876)

0.66 (–0.088 to 1.407)
E/e’

0.04 (0.002 to 0.076) but it also appears to result in reduced concentric remodeling
Beta (95% CI)

of the left ventricle (32). Similarly, among athletes and in-

dividuals engaged in lifelong training, higher self-reported
exercise levels have been associated with a larger heart size
and improved early diastolic filling (5,8–10,34–36). The
present study significantly extends the available published
data, including a large number of healthy subjects with
objectively measured fitness and echocardiographic exami-
<0.0001
<0.0001
0.0001

<0.0001
<0.0001
<0.0001

<0.0001
p Value

0.646
0.042

0.255

nations and observing a strong inverse association between

fitness and concentric remodeling and diastolic dysfunction.
The benefits of exercise have also been observed among
higher-risk individuals with concentric hypertrophy and
–0.005 (–0.028 to 0.017)

–0.005 (–0.007 to 0.002)

0.001 (0.001 to 0.001)
0.019 (0.011 to 0.028)
0.002 (0.001 to 0.004)

0.001 (0.001 to 0.002)

0.024 (0.015 to 0.034)
0.002 (0.001 to 0.003)
0.013 (–0.01 to 0.036)
RWT

–0.002 (–0.004 to 0)

HFpEF. For example, 16 weeks of exercise training in

Beta (95% CI)

46 men with poorly controlled hypertension was associated

with a decrease in wall thickness, suggesting that regular
physical exercise may be protective against concentric LV
hypertrophy (37). However, the effects of exercise training
among patients with known HFpEF are not well under-
stood. Exercise training improved heart failure symptoms
(38,39) and diastolic function (38) among HFpEF patients
<0.0001

<0.0001

<0.0001

<0.0001
p Value

0.004
0.549

0.215

0.246
0.179

0.586

in some studies but failed to show any favorable effects in

others (40).
Measures of cardiac structure and function represent an
important intermediate phenotype in the natural history of
LVEDD/BSA

–0.242 (–0.279 to –0.206)

–0.009 (–0.024 to 0.006)
–0.217 (–0.254 to –0.18)

structural heart disease and symptomatic heart failure.

–0.079 (0.335 to 0.178)

0.439 (–0.255 to 1.133)

0.213 (–0.555 to 0.981)

0.231 (0.164 to 0.298)

–0.218 (–0.536 to 0.1)

0.018 (0.005 to 0.03)

0.264 (0.17 to 0.358)

Pathologic remodeling patterns are poor prognostic in-

Beta (95% CI)

dicators for all-cause mortality, cardiovascular events, and

heart failure (11–13), and asymptomatic systolic LV dys-
BMI ¼ body mass index; CI ¼ confidence interval; HTN ¼ hypertension; other abbreviations as in Table 2.

function represents a strong predictor of systolic heart failure

in individuals without previous myocardial infarction or
valvular disease (15). Similarly, recent data has shown 1 in
4 persons with moderate to severe asymptomatic diastolic
Multivariable Analysis of LVEDD, RWT, and E/e0

dysfunction will progress to HFpEF (16–18). In the present

<0.0001

<0.0001

<0.0001

<0.0001

<0.0001
p Value

0.182
0.139
0.777

0.411

0.298

study, we observed a consistent association between low

fitness and both concentric remodeling and diastolic
dysfunction in a cohort of healthy adults not referred
for exercise testing. The effect of fitness on E/e0 is notable
LA Vol/BSA

–1.185 (–3.414 to 1.045)

0.107 (–0.034 to 0.249)
0.385 (–2.282 to 3.052)

0.415 (–0.574 to 1.404)

0.161 (0.116 to 0.205)

0.879 (0.591 to 1.167)

0.728 (–0.34 to 1.796)
0.239 (0.189 to 0.29)

0.274 (0.167 to 0.38)

as it is a highly reproducible echocardiographic measure

0.769 (0.5 to 1.04)
Beta (95% CI)

strongly associated with adverse cardiac events (41). Taken

together, these findings suggest that higher fitness levels are
associated with a lower prevalence of concentric remodeling
and diastolic dysfunction, which could play an important
role in lowering the risk for heart failure, specifically HFpEF
at a later age.
It is well established that the LA enlarges in the setting
Diabetes, yes/no

Diabetes, yes/no

of increased filling pressures (42) and, therefore, LA size

Fitness, MET

Fitness, MET
HTN, yes/no

HTN, yes/no
BMI, kg/m2

BMI, kg/m2

is a good marker of diastolic dysfunction (43–45) and is

Age, yrs

Age, yrs
Table 3

strongly associated with cardiovascular events (46–49).

Women

Thus, we observed an apparent conflict between LA size

Men

and diastolic function, with higher fitness associated with

244 Brinker et al.
Echocardiographic Associations With Low Fitness
Figure 3 Correlation Between LA Vol/BSA and E/e0 According to Fitness Level
(A) Low fitness (quartile 1) (n ¼ 730; r ¼ 0.29, p < 0.0001); (B) high fitness (quartile 4) (n ¼ 742; r ¼ 0.036, p ¼ 0.55). LA Vol/BSA ¼ left atrial volume indexed to
body surface area.
both a lower prevalence of diastolic dysfunction and a
larger LA size. However, when we stratified our cohort
according to fitness levels, we observed 2 distinct patterns
of results. Among low fitness individuals, diastolic dys-
function was associated with a larger LA size (Fig. 3). In
contrast, we observed no apparent association between
diastolic dysfunction and LA size among high-fitness in-
dividuals. Our findings, as well as those reported by others
(50), suggest that the mechanisms of LA dilation may be
different among high- and low-fitness individuals, with a
larger LA in high-fitness individuals reflecting physiology
unrelated to diastolic function (i.e., greater cardiac output).
Study limitations. The present study is cross sectional in
nature and, therefore, we cannot completely exclude the
possibility of reverse causation, whereby subclinical dias-
tolic dysfunction promoted exercise intolerance. Although
possible, we believe that this is unlikely for several reasons.
First, we observe consistent, inverse associations between
fitness and subclinical measures of remodeling and diastolic
dysfunction within the normal range of fitness levels in
healthy adults, suggesting at a minimum that the presence
of subclinical heart failure represents an unlikely explana-
tion for the present findings. Second, the Cooper Clinic
population represents a healthy cohort of subjects who have
lower burden of traditional risk factors for heart failure and
normal exercise capacity levels than do the general popu-
lation (19,20,51). The prevalence of exercise intolerance
was very low in the study cohort with only 6% of subjects
with complaints of subjective shortness of breath. Further
studies looking at effects of longitudinal changes in fitness
on cardiac structure and function are needed to establish
a causal association between low fitness and diastolic
dysfunction.
A significant number of participants were referred for
either resting or stress echocardiogram for an abnormal ex-
ercise electrocardiogram. However, only 8 of 871 partici-
pants with stress echocardiograms had an abnormal stress
JACC: Heart Failure Vol. 2, No. 3, 2014
June 2014:238–46
echocardiogram. Furthermore, in sensitivity analyses where
these participants were excluded, we observed a similar
pattern of results between fitness and measures of cardiac
structure and function. Finally, in the present study, the
majority of subjects had a normal EF; therefore, the lack
of association with EF should be interpreted cautiously.
Conclusions
We observed that low fitness was associated with a smaller
heart size, increased concentricity, and diastolic dysfunction,
suggesting that exercise might reduce the risk of heart failure
through its favorable effects on cardiac remodeling and
diastolic function.
Acknowledgments
The authors thank Dr. Kenneth H. Cooper for establishing
the Cooper Center Longitudinal Study, the Cooper Center
staff for collecting clinical data, and the Cooper Institute for
maintaining the database. They also thank Christina Podias
(University of Texas Southwestern) for her role in the
management of the echocardiographic database.
Reprint requests and correspondence: Dr. Jarett D. Berry,
University of Texas Southwestern Medical Center, 5323 Harry
Hines Blvd, Dallas, Texas 75390-9047. E-mail: jarett.berry@
utsouthwestern.edu.
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