Context Individual contributions of obesity and physical fitness (physical activity
and functional capacity) to risk of coronary heart disease in women remain
unclear.
Objective To investigate the relationships of measures of obesity (body mass index
[BMI], waist circumference, waist-hip ratio, and waist-height ratio) and physical
fitness (self-reported Duke Activity Status Index [DASI] and Postmenopausal
Estrogen-Progestin Intervention questionnaire [PEPI-Q] scores) with coronary
artery disease (CAD) risk factors, angiographic CAD, and adverse cardiovascular
(CV) events in women evaluated for suspected myocardial ischemia.
Design, Setting, and Participants The National Heart, Lung, and Blood Institute–sponsored Women's
Ischemia Syndrome Evaluation (WISE) is a multicenter prospective cohort study.
From 1996-2000, 936 women were enrolled at 4 US academic medical centers at
the time of clinically indicated coronary angiography and then assessed (mean
follow-up, 3.9 [SD, 1.8] years) for adverse outcomes.
Main Outcome Measures Prevalence of obstructive CAD (any angiographic stenosis ≥50%) and
incidence of adverse CV events (all-cause death or hospitalization for nonfatal
myocardial infarction, stroke, congestive heart failure, unstable angina,
or other vascular events) during follow-up.
Results Of 906 women (mean age, 58 [SD, 12] years) with complete data, 19% were
of nonwhite race, 76% were overweight (BMI ≥25), 70% had low functional
capacity (DASI scores <25, equivalent to ≤7 metabolic equivalents [METs]),
and 39% had obstructive CAD. During follow-up, 337 (38%) women had a first
adverse event, 118 (13%) had a major adverse event, and 68 (8%) died. Overweight
women were more likely than normal weight women to have CAD risk factors,
but neither BMI nor abdominal obesity measures were significantly associated
with obstructive CAD or adverse CV events after adjusting for other risk factors
(P = .05 to .88). Conversely, women with lower DASI
scores were significantly more likely to have CAD risk factors and obstructive
CAD (44% vs 26%, P<.001) at baseline, and each
1-MET increase in DASI score was independently associated with an 8% (hazard
ratio, 0.92; 95% confidence interval, 0.85-0.99; P =
.02) decrease in risk of major adverse CV events during follow-up.
Conclusions Among women undergoing coronary angiography for suspected ischemia,
higher self-reported physical fitness scores were independently associated
with fewer CAD risk factors, less angiographic CAD, and lower risk for adverse
CV events. Measures of obesity were not independently associated with these
outcomes.
Obesity is increasingly recognized as a public health epidemic and modifiable
risk factor for coronary heart disease (CHD).1,2 Among
adult US women and men, nearly two thirds are overweight and more than one
third are obese, and these proportions are rapidly increasing.1,3 Numerous
studies have shown that anthropometric indices including body mass index (BMI),
waist circumference, waist-hip ratio, and waist-height ratio are associated
with CHD risk factors or adverse events.4-9 Previous
reports have documented that increased cardiovascular (CV) risk associated
with being overweight is partially explained by its association with numerous
risk mediators, including traditional atherosclerotic risk factors, insulin
resistance, inflammation, and endothelial dysfunction.4-7,10
Most obesity studies, however, have not adequately measured physical
activity and functional capacity, which are also known to predict risk for
CHD.5,11-13 Some
studies show physical activity and fitness to be predictive of CV risk incrementally
and independent of anthropometric indices and traditional CV risk factors.14-18 Moreover,
many studies of physical activity and fitness have excluded women with known
or suspected CHD.7,16,19-21 Roles
of obesity and fitness as independent risk factors for CHD and adverse events
in women remain unresolved. Therefore, we investigated the relationships of
physical fitness and obesity measures with CHD risk factors, coronary angiographic
findings, and adverse events among a group of women undergoing coronary angiography
to evaluate suspected ischemia.
The Women's Ischemia Syndrome Evaluation (WISE) is a multicenter study
sponsored by the National Heart, Lung, and Blood Institute and designed to
improve diagnostic testing for coronary artery disease (CAD) in women. Details
of the WISE design and methods have been published.22 Briefly,
between 1996 and 2000, 936 women with chest discomfort, suspected myocardial
ischemia, or both were enrolled at the time of referral for clinically indicated
coronary angiography. Each WISE site obtained consent for patient testing
through its institutional review board. Each woman provided written informed
consent to have the testing performed and to be contacted during follow-up.
Baseline evaluation included collection of demographic, symptom, cardiac
risk factor, medical history, physical activity, physical examination, and
laboratory data. Participants classified their race/ethnicity during completion
of the baseline form with the nurse coordinator or physician using US Census
Bureau standard categories. Race/ethnicity was assessed to investigate racial
differences in women with CAD and to allow this variable to be controlled
for in future analyses if informative. Some of the women underwent additional
diagnostic testing, such as exercise treadmill testing and coronary vasoreactivity
testing, based on the site of enrollment as previously described.22 Quantitative and qualitative analyses of CAD were
performed by the WISE angiographic core laboratory.23 Blood
lipid and inflammatory marker levels were quantified by WISE core laboratories.24,25
Body mass index was defined as weight in kilograms divided by the square
of height in meters, with normal weight defined as BMI less than 25, overweight
as BMI 25 through 29, and obese as BMI 30 or greater. Waist circumference
was measured at the umbilicus, with normal defined as 88 cm or less.5 Waist-hip ratio was calculated as 100 × (maximal
waist circumference in centimeters/maximal hip circumference in centimeters),
with normal defined as less than 80.26 Waist-height
ratio was calculated as maximal waist circumference in centimeters/height
in meters, with normal defined as less than 50.26
To evaluate physical fitness, we used the Duke Activity Status Index
(DASI) questionnaire, an assessment of functional capacity derived from self-reported
ability to perform various activities that correlates with exercise treadmill
results.27 Positive response scores are summed
to get a total score that is an estimate of maximal oxygen consumption, which
ranges from 0 to 58.2 mL/kg per minute. This total score can be divided by
3.5 to estimate metabolic equivalent tasks (METs). A score of at least 25
(≥7 METs) was defined as normal. This level approximates completion of
the second stage of a Bruce treadmill protocol (roughly equivalent to being
able to walk at 5 mph, jog, or participate in many noncontact sports) and
was significantly related to lower rates of CAD and risk factors in previous
WISE analyses.18
To evaluate physical activity, a contributor to fitness, we used the
Postmenopausal Estrogen-Progestin Intervention questionnaire (PEPI-Q), a self-reported
estimate of average physical activity level at home, work, and leisure.28 If question 1 regarding activity at work was answered
"not applicable," the PEPI-Q was adjusted by using the average of the other
2 answers as the third value. No validated threshold for PEPI-Q categories
is available, so PEPI-Q was used as a continuous variable.
Scores for both the DASI and the PEPI-Q have been correlated with treadmill
functional capacity measured in METs (r = 0.31, P<.001 and r = 0.27, P = .001, respectively) and validated within a representative
subset of the WISE cohort.18
Follow-up data were collected in person or by telephone interview by
an experienced nurse, physician, or both at 6 weeks after enrollment and then
yearly. Participants were queried for occurrence of adverse events, and referring
physicians were contacted for confirmation, dates, and documentation when
an adverse event was identified. In the event of death, a death certificate
was obtained.
Angiographically determined obstructive CAD was protocol-specified22 as any luminal diameter stenosis of 50% or greater;
severe CAD was defined as any luminal diameter stenosis of 70% or greater.
A prospectively developed WISE CAD severity score has been described in detail23 and was assigned based on angiographic severity of
stenoses, location of stenoses, and presence of partial or complete collateral
flow, with a range of 5.0 to 88.5. The metabolic syndrome was defined by Adult
Treatment Panel III criteria as participants' having at least 3 of the following:
(1) waist circumference of 88 cm or greater or BMI of 30 or greater; (2) systolic
blood pressure of 130 mm Hg or greater and diastolic blood pressure of 85
mm Hg or greater; (3) triglyceride level of 150 mg/dL or greater; (4) fasting
blood glucose level of 110 mg/dL or greater; or (5) high-density lipoprotein
cholesterol level less than 50 mg/dL.29
Prior CAD was defined as history of myocardial infarction (MI), percutaneous
coronary intervention, or coronary artery bypass graft surgery. All adverse
events were defined as all-cause death or hospitalization for nonfatal MI,
stroke, congestive heart failure, unstable angina, or other vascular events.
Major adverse events were defined as death, nonfatal MI, or nonfatal stroke.
Myocardial infarction was defined by elevation of creatine kinase-MB isoenzyme
level at least 5 times the upper limit of the reference range. Other vascular
events included primarily peripheral arterial or venous events, such as carotid
endarterectomy or deep venous thrombosis.
Data are summarized as mean (SD) or percentages as indicated. To ascertain
trends in baseline characteristics across categories of BMI (Table 1), we used Mantel-Haenszel tests for frequencies; for continuous
data we used Jonkheere-Terpstra tests (a nonparametric method to detect ordered
differences in distributions of continuous variables across ordered groups).
We also compared the same characteristics for DASI categories (Table 1) using logistic regression analysis, with P values adjusted for age. Adverse events were evaluated as all adverse
events and as major adverse events. We used χ2 analysis to
evaluate the incidence of events across the 4 categories of obesity/fitness
and Kaplan-Meier plots to evaluate event-free survival during follow-up.
Standard multivariate logistic regression techniques were used to assess
obstructive CAD, and multivariate Cox regression models were used to assess
adverse events. We performed multivariate modeling in 2 steps. The first was
to develop a basic risk model for each outcome using forward stepwise logistic
or Cox regression techniques. Characteristics in Table 1, except fitness or obesity variables, with P values less than .10 for univariate associations with obstructive
CAD or adverse events were considered for inclusion in each model. Notably,
both obstructive CAD (ie, any angiographic stenosis ≥50%) and WISE CAD
severity score were assessed for multivariate relationships with adverse events.
Significant predictors that remained in each model are listed in the appropriate
paragraph in the "Results" section and in the footnote to each multivariate
model table.
The second step of multivariate modeling was to separately add DASI
scores, PEPI-Q scores, and the obesity variables to this basic risk model.
Because of strong correlations among the fitness and obesity variables, their
predictive ability was evaluated in separate models, each time adjusting for
the same set of significant covariates. The final models were evaluated for
other linear relationships among variables in the model (collinearity), which
have the potential of rendering significance testing unreliable. Using standard
diagnostic techniques, all models presented were found to be free from collinearity
(tolerance, 0.64-0.97). All tests were 2-sided, and a P value less than .05 was considered statistically significant. Data
were analyzed using SAS version 8.2 (SAS Institute Inc, Cary, NC).
Among 906 women (mean age, 58 [SD, 12] years) with complete data, 19%
were nonwhite, 24% had a history of diabetes mellitus, 59% of hypertension,
55% of dyslipidemia, 20% currently smoked, and 53% had a history of smoking.
Angiographically, 349 (39%) of the women had obstructive CAD (50% luminal
diameter stenosis), including 216 (24%) with severe CAD (≥70% luminal diameter
stenosis).
Of the 906 women, 693 (76%) were overweight (BMI ≥25), and 374 (41%)
were obese (BMI ≥30). When analyzed by categories of BMI (Table 1), higher BMI was significantly associated with nonwhite
race and higher prevalence of hypertension, diabetes, and dyslipidemia. Higher
BMI was also associated with lower average age, less current smoking, higher
systolic and diastolic blood pressure, lower levels of high-density lipoprotein
cholesterol, higher levels of fasting blood glucose and triglycerides, higher
levels of high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6),
and higher prevalence of the metabolic syndrome. Body mass index strongly
correlated with other anthropometric indices. Higher BMI was associated with
lower DASI and PEPI-Q scores. However, despite this preponderance of CAD risk
factors associated with higher BMI, there was no difference in presence or
severity of angiographic CAD among the BMI categories (Table 1).
When categorized by DASI score less than 25 (approximately 7 METs),
631 women (70%) had low functional capacity (Table 1). Women with low functional capacity were older and less
likely to be white or using hormone therapy. Women with low functional capacity
were more likely to have a history of hypertension, diabetes, dyslipidemia,
menopause, or smoking. They had significantly higher mean anthropometric measurements,
systolic blood pressures, triglyceride levels, IL-6 levels, and prevalence
of the metabolic syndrome. Furthermore, women with lower DASI scores had significantly
higher WISE CAD severity scores and were significantly more likely to have
both obstructive and severe angiographic CAD (Table 1).
Both DASI and PEPI-Q scores were significantly lower for women with
the metabolic syndrome or diabetes across all categories of BMI (data not
shown), suggesting that women with these dysmetabolic conditions were significantly
less active or had lower functional capacities than women with normal metabolic
status, regardless of weight. Additionally, DASI score as a continuous variable
was inversely correlated with blood levels of hs-CRP (r = −0.19, P<.001), IL-6 (r = −0.14, P<.001), and serum amyloid
A (r = −0.10, P =
.01). Furthermore, women with a history of ever smoking had significantly
lower mean (SD) DASI scores (18.7 [14.8] vs 21.4 [14.6], P = .007) and PEPI-Q scores (7.1 [2.0] vs 7.5 [2.0], P = .001) than women with no history of smoking.
Table 2 summarizes the independent
predictive ability of anthropometric measures as well as DASI and PEPI-Q scores
in separate models adjusted for other significant predictors of CAD in the
WISE cohort (age, diabetes, dyslipidemia, use of hormone therapy, pulse pressure,
hs-CRP level, triglyceride level, fasting blood glucose level, and aspirin
use). We found no significant relationships between the proportion of women
with obstructive CAD and any categorical (data not shown) or continuous anthropometric
measurement (Table 2), except
for a trend toward lower likelihood of obstructive CAD with increasing BMI
(P = .05). In contrast, even after adjusting for
other significant predictors of CAD, we found significant associations between
risk of obstructive CAD and PEPI-Q score (Table 2) as well as both continuous (Table 2) and categorical DASI score: a DASI score less than 25 was
associated with more than a 2-fold risk of having obstructive CAD (hazard
ratio [HR], 2.21; 95% confidence interval [CI], 1.62-3.01; P = .01).
Complete follow-up data were available for 880 (97%) of the 906 women.
Overall, after a mean follow-up time of 3.9 (SD, 1.8) years, 337 (38%) of
the women had experienced a first adverse event, 118 (13%) a major adverse
event, and 68 (8%) had died. Table 3 summarizes
the adverse events and their associations with categories of BMI or DASI scores. Table 4 summarizes the univariate associations
of measures of obesity and fitness with all adverse events, major adverse
events, and all-cause mortality.
Categorically or continuously, BMI was not associated with risk of all
adverse events, major adverse events, or all-cause mortality (P>.10 for all) in univariate analyses. In contrast, risks of all adverse
events and major adverse events were associated with categorical (P<.05 for all, data not shown) and continuous waist circumference,
waist-hip ratio, and weight-height ratio, before adjusting for other predictors
(Table 4). No anthropometric measurement
was associated with all-cause mortality (P≥.10
for all). Furthermore, after adjusting for significant risk factors for all
adverse events (race; history of dyslipidemia, diabetes, or smoking; prior
CAD; diastolic blood pressure; and WISE CAD severity score) or major adverse
events (history of diabetes or smoking, prior CAD, hs-CRP level, hemoglobin
level, and WISE CAD severity score), no significant relationships were found
between anthropometric measures and all adverse events or major adverse events
(Figure 1).
Before adjusting for other significant predictors, both DASI and PEPI-Q
scores were significantly associated with risks of all adverse events, major
adverse events, and all-cause mortality (P<.01
for all). After adjusting for the other significant predictors of all adverse
events, categorical DASI score less than 25 was associated with 46% increased
risk of all adverse events (HR, 1.46; 95% CI, 1.10-1.94; P = .008). Furthermore, both DASI and PEPI-Q scores remained significant
independent predictors of the risk of all adverse events and major adverse
events (Figure 1) but not all-cause
mortality (PEPI-Q: HR, 0.88; 95% CI, 0.74-1.03; P =
.11; DASI METs: HR, 0.93; 95% CI, 0.87-1.01; P =
.12), even after adjusting for significant risk predictors for adverse events
(as listed above) including CAD severity score.
When divided into groups by categories of BMI and physical activity
(Figure 2), women who had a BMI
less than 30 and a DASI score of 25 or greater had the lowest proportion of
all adverse events (23.9%, P = .001) or major adverse
events (5.6%, P = .002) during follow-up. Women with
a DASI score less than 25 had the highest risk of all adverse events or major
adverse events regardless of BMI category. When these category groups were
analyzed for survival free of all adverse events using Kaplan-Meier methods
(Figure 3), women who had DASI scores
of 25 or greater had significantly greater event-free survival than women
with DASI scores less than 25, both for all adverse events and for major adverse
events, regardless of BMI category.
When women with obstructive CAD were excluded from the adverse event
analyses or when other anthropometric measures were used to categorize obesity
(eg, waist-hip ratio), these categorical and continuous relationships with
adverse events remained significant and relatively unchanged (data not shown).
Likewise, when only women with severe CAD were analyzed, none of the anthropometric
measures were related to adverse events, but DASI and PEPI-Q scores were still
significant univariate predictors of all adverse events and major adverse
events (data not shown).
Most studies of BMI and other measures of obesity have not adequately
accounted for physical fitness, a known modifier of weight status and a potential
mediator of the effects of obesity on CAD and adverse CV outcomes.5,11-13 Therefore,
the independent contributions of BMI and fitness to CV health or disease have
been unclear. Our study indicates that data from simple, self-reported questionnaires
that estimate average physical activity and functional capacity are significantly
associated with objective CV outcomes, including presence of angiographic
CAD as well as risk of adverse CV events. Moreover, these associations are
independent of anthropometric measurements and other CV risk predictors, including
prior CAD or severity of angiographic CAD.
Thus, our findings suggest that self-reported level of physical activity
and functional capacity are more important than weight status or body habitus
for CV risk stratification in women. Although physical fitness was not directly
measured in most women, the DASI and PEPI-Q scores have been shown in a WISE
cohort substudy to correlate with fitness directly measured as exercise capacity
by treadmill testing.18 Our data support previous
studies showing that functional capacity appears to be more important than
BMI for all-cause and CV mortality, especially in women,17 and
we extend the predictive importance of fitness in women to include other adverse
events including nonfatal MI and stroke in addition to mortality. Notably,
adverse event rates in the WISE cohort are much higher than in the general
population, as 8% of the women died, 13% had a major adverse CV event, and
38% had some adverse CV event during an average follow-up of less than 4 years.
Obesity is increasingly recognized as a public health epidemic and modifiable
risk factor for CHD,1 but the prevalence of
obesity has only increased in recent decades.1,3 Numerous
studies that have not adequately measured fitness have shown that anthropometric
indices are independently related to risk of CHD and CV events,4-9 and
BMI in particular has become commonly used in clinical practice. We found
that, despite its association with numerous CV risk factors including hypertension,
diabetes, and the metabolic syndrome, BMI was a poor predictor of both baseline
angiographic CAD as well as prospective risk of adverse events. When compared
with BMI, indices of abdominal adiposity were all stronger predictors of obstructive
angiographic CAD and risk of adverse events, consistent with prior studies.5,19 However, in contrast to DASI and PEPI-Q
scores, anthropometric indices were not independently associated with obstructive
CAD or adverse events after adjusting for other CV risk predictors. While
our findings may underestimate the impact of obesity on CV risk because it
is mediated by these other CV risk predictors, the self-reported fitness scores
provided significant independent measures for risk stratification.
Many theories have been proposed to explain increased CV risk associated
with obesity, such as the association of obesity with numerous risk mediators
including traditional CV risk factors, insulin resistance, inflammation, and
endothelial dysfunction.4-7,10,30 We
demonstrate that excess weight is also associated with reduced physical activity
and functional capacity, suggesting that the CV risk of obesity may be explained
in part by the adverse effects of low fitness. Both weight loss and exercise
have been shown to reduce levels of inflammatory markers in women and in patients
with CHD.31-34 We
found that higher physical fitness scores were related to lower levels of
insulin, triglycerides, hs-CRP, and IL-6, so inflammation and insulin resistance
could provide mechanistic links for the strong association of fitness with
adverse events in this population of women. Therefore, the DASI and PEPI-Q
provide simple, noninvasive assessments that encompass the interactions of
multiple CV risk mediators within individual patients and that independently
predict their CV outcomes.
Physical fitness has beneficial effects on numerous mediators of CV
risk including obesity,1 so increased physical
activity appears to be an ideal therapy for CHD. While weight loss has been
shown to improve multiple CV risk factors,35,36 the
direct benefit of weight reduction on CV risk remains unproven and unclear.37,38 However, physical activity has been
shown to reduce CV risk.16,39,40 Many
currently popular approaches to reduction of obesity, such as specific diets
or bariatric surgery, do not directly measure improvements in physical fitness.
Focusing on weight loss alone fails to directly address the related but more
important lack of physical fitness among overweight individuals. The latest
American Heart Association CV disease prevention guidelines for women have
made accumulating a minimum of 30 minutes of moderate-intensity physical activity
on most, and preferably all, days of the week a Class I recommendation for
all risk groups.2 Thus, physical fitness assessment
and intervention should be included in the management of all women at risk
for CHD.
Our prospective, observational study has inherent limitations regarding
assessment of causality. Specifically, our reported associations between measures
of fitness and adverse CV events may have been due to physical activity limitations
from the observed higher prevalence of obstructive CAD rather than due to
the low fitness levels, per se. However, our analyses showing DASI and PEPI-Q
scores to be signficant predictors despite adjusting for both prior CAD and
WISE CAD severity score argue against this possibility, and analyses excluding
patients with obstructive CAD continued to show the same relationships, although
significance was reduced mainly due to reduced numbers of adverse CV events
(data not shown).
We do not have access to more accurate indices of visceral adiposity
such as dual-energy x-ray absorptiometry or computed tomography scans, but
previous studies have shown that results of such scans are highly correlated
with measures such as waist circumference and waist-hip ratio.41,42 We
also do not have adequate dietary information to include in these analyses.
In addition, our lack of independent associations between measures of obesity
and CV outcomes may be confounded by adjusting for other independent predictors
that are actually mediators of adverse effects of obesity on CV outcomes.
Furthermore, we studied a relatively small population of symptomatic women,
and the DASI and PEPI-Q scores are self-reported measures with potential source
random error, although these scores have been validated in the WISE cohort.18 The PEPI-Q is a limited measure and could theoretically
be affected by patients' occupations or domestic situations, whereas the DASI
includes more generally applicable activities from daily living or common
recreation. Women lost to follow-up as result of an adverse event (eg, survival
bias) may have contributed to underestimation of long-term adverse event rates
and associations. Finally, our results using the DASI and PEPI-Q for CV risk
prediction need to be confirmed in other large cohorts.
Among women referred for coronary angiography to evaluate suspected
myocardial ischemia, we found that BMI, waist circumference, waist-hip ratio,
and waist-height ratio were not independently associated with angiographic
CAD or adverse CV events. However, lower self-reported physical fitness scores
were associated with higher prevalence of CHD risk factors and angiographic
CAD at baseline as well as higher risk of adverse events during intermediate-term
follow-up, independent of both traditional CV risk factors as well as anthropometric
indices. These results suggest that fitness may be more important than overweight
or obesity for CV risk in women. Evaluation of physical activity and functional
capacity using simple questionnaires should be an integral part of CV risk
stratification, and interventions aimed at increasing physical fitness levels
should be included in the management of all women at risk for CHD.
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