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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
VOL. 66, NO. 25, 2015
ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
PUBLISHED BY ELSEVIER INC.
http://dx.doi.org/10.1016/j.jacc.2015.10.047
REVIEW TOPIC OF THE WEEK
Obesity, Exercise, Obstructive Sleep
Apnea, and Modifiable Atherosclerotic
Cardiovascular Disease Risk Factors
in Atrial Fibrillation
Jared D. Miller, MD, Konstantinos N. Aronis, MD, Jonathan Chrispin, MD, Kaustubha D. Patil, MD,
Joseph E. Marine, MD, Seth S. Martin, MD, MHS, Michael J. Blaha, MD, MPH, Roger S. Blumenthal, MD,
Hugh Calkins, MD
ABSTRACT
Classically, the 3 pillars of atrial fibrillation (AF) management have included anticoagulation for prevention of thromboembolism, rhythm control, and rate control. In both prevention and management of AF, a growing body of evidence
supports an increased role for comprehensive cardiac risk factor modification (RFM), herein defined as management of
traditional modifiable cardiac risk factors, weight loss, and exercise. In this narrative review, we summarize the evidence
demonstrating the importance of each facet of RFM in AF prevention and therapy. Additionally, we review emerging data
on the importance of weight loss and cardiovascular exercise in prevention and management of AF. (J Am Coll Cardiol
2015;66:2899–906) © 2015 by the American College of Cardiology Foundation.
A
trial fibrillation (AF) is the most common
prevention efforts by focusing on risk modification”
sustained
a
as a key research focus (6). Of note, there are
rapidly growing epidemic (1). It is projected
numerous other risk factors for AF, such as valvular
that the prevalence will rise from 5.2 million in
heart disease, thyroid disease, or chronic obstruc-
2010 to 12.1 million in 2030, driven primarily by
tive pulmonary disease, which are not thought of as
our aging population (2). AF is associated with
classical risk factors for atherosclerotic heart dis-
increased morbidity, mortality, and rising health
ease. Such conditions also have known causal
care–associated expenses (3,4).
relationships with AF and also have implications for
Unsurprisingly,
arrhythmia
many
and
modifiable
represents
risk
factors
management strategies. These other AF risk factors
associated with atherosclerotic cardiovascular dis-
warrant investigation in the work-up of new di-
ease (ASCVD) have also been associated with AF
agnoses of AF.
(Central Illustration). Although the most recent AF
practice guidelines acknowledge these risk factors,
OBESITY AND WEIGHT LOSS
they provide no evidence-based recommendations
Listen to this manuscript’s
audio summary by
on diet, exercise, and lifestyle changes in AF pri-
The rise in prevalence of obesity has been well
mary and secondary prevention (5). In 2013, the
documented, particularly in the United States, where
Heart Rhythm Society recognized “advancing AF
an estimated one-third of adults are obese (7). During
JACC Editor-in-Chief
Dr. Valentin Fuster.
From the Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. Dr.
Calkins is a consultant for Boehringer Ingelheim, Medtronic, and Atricure. All other authors have reported that they have no
relationships relevant to the contents of this paper to disclose.
Manuscript received October 5, 2015; accepted October 8, 2015.
2900
Miller et al.
JACC VOL. 66, NO. 25, 2015
DECEMBER 29, 2015:2899–906
Risk Factor Modification in AF
ABBREVIATIONS
the past 5 years, a number of studies have
13.5 years of follow-up, increased total body fat
AND ACRONYMS
established that obesity is closely linked to
mass assessed by bioelectrical impendence was
AF risk. Body mass index (BMI) is part of
associated with higher incidence of AF (16).
AF = atrial fibrillation
prediction models for new-onset AF (8). The
ASCVD = atherosclerotic
Several
mechanisms
underlie
the
association
connection between obesity and AF has been
between obesity and AF. In a sheep model fed a high-
shown to occur independently of the many
caloric diet, obesity was associated with left atrial
comorbidities associated with obesity (9,10).
enlargement and fibrosis, atrial inflammatory, and
In the ARIC (Atherosclerosis Risk In Com-
lipid infiltration, as well as changes in atrial elec-
munities) study (N ¼ 14,598), 17% of AF risk
trophysiological properties, ultimately leading to
was attributed to obesity or overweight sta-
increased rates of spontaneous and induced AF (17). In
PVI = pulmonary vein isolation
tus (11). In the WHS (Women’s Health Study)
an ovine model of obesity sustained for 8 months,
RFM = risk factor modification
(N ¼ 34,309), for every 1 kg/m2 increase in
obesity was associated with infiltration of the left atrial
BMI, the relative AF risk increased by 5% (10). In the
posterior myocardium by epicardial fat and reduced
Women’s Health Initiative cohort of 93,676 females,
endocardial voltage, representing a potential substrate
for every 1 kg/m 2 increase in BMI, AF relative risk
for AF (18).
cardiovascular disease
BMI = body mass index
HTN = hypertension
MET = metabolic equivalent
OSA = obstructive sleep apnea
increased by 12%. (12). Interestingly, higher levels of
In humans, increased BMI has been associated
physical activity attenuated the AF risk conferred by
with increased left atrial size (19), which, in turn, is
obesity (13). BMI >35 kg/m 2 was also associated with
associated with higher AF risk (20). Increased peri-
increased AF risk by a hazard ratio of 3.50 in young,
cardial fat volume has also been described in obese
healthy women (14).
individuals and is related to the presence, severity,
In a recent meta-analysis of 51 studies and 626,603
and post-ablation recurrence of AF, independent of
patients, for every 5 kg/m 2 increase in BMI, there was
BMI, suggesting a local pathogenic effect of pericar-
a 10% to 29% higher relative risk for new-onset or
dial fat (21). Obesity has also been associated with
post-operative AF (15). In a subanalysis of 16 studies
increased epicardial fat thickness, which may lead to
and 5,864 patients undergoing AF ablation, the risk of
altered atrial electrophysiology and sympathovagal
AF recurrence increased by 13% for every 5 kg/m2
imbalance of the atria (22–24). Clinically, epicardial
increase in BMI (15). Adiposity measures other than
fat has been associated with AF (25). Lastly, obesity is
BMI have also been associated with increased AF
a state of chronic, low-grade, systemic inflammation
risk. In a Danish registry of 55,273 participants and
(26). Systemic inflammation has a key role in
C EN T RA L IL LUSTR AT I ON
RFM in AF: The Associations Between Cardiometabolic RFs and AF
Risk Factor Modification in Atrial Fibrillation (AF)
Atrial electroanatomic
remodeling
AF risk factor (RF)
Modifiable:
Obesity
Hypertension
Hyperlipidemia
Diabetes mellitus
Low cardiorespiratory fitness
Obstructive sleep apnea
Coronary artery disease
Nonmodifiable:
Age
Genetics
AF
AF outcomes
Recurrence of AF
AF-related symptoms
Impaired quality of life
RF prevention
and management
Weight loss through
light to moderate exercise
(not high-intensity exercise)
and management of
modifiable RFs
Stroke and
systemic thromboembolism
Increased mortality
Increased morbidity
Rising health careassociated expenses
Miller, J.D. et al. J Am Coll Cardiol. 2015; 66(25):2899–906.
Cardiometabolic risk factors contribute to the development and consequences of atrial fibrillation (AF) and can be modified by weight loss, exercise, and management of
comorbid cardiac risk factors. RF ¼ risk factor; RFM ¼ risk factor modification.
Miller et al.
JACC VOL. 66, NO. 25, 2015
DECEMBER 29, 2015:2899–906
Risk Factor Modification in AF
initiation and perpetuation of AF and may contribute
loss and AF therapy is likely multifactorial, because
to the association of obesity with AF (27).
routine RFM and weight-loss counseling result in
Recent clinical trials demonstrate that weight
improvement in other comorbid conditions that are
reduction, in the context of a comprehensive risk
also independently associated with AF. However,
factor modification (RFM) plan, has an important role
weight loss does result in atrial structural changes,
in AF management (Table 1). In a single-center ran-
supporting a direct link between weight loss and
domized trial, 150 overweight patients with symp-
improved AF outcomes (34). Currently, the body of
tomatic AF were randomized to weight management
evidence is enough to strongly recommend weight
versus lifestyle advice, in addition to standard ther-
loss for both prevention and management of AF.
apy for AF (28). The weight management consisted of
a prescribed exercise routine and a low-calorie diet,
EXERCISE AND FITNESS
with improvement in BMI from 32.8 to 27.2 kg/m2 at
15 months versus no change for the control group. At
The benefits of routine exercise in improving ASCVD
15 months, the weight management group had
risk factors have been well established, and guide-
reduced frequency of AF episodes, reduced duration
lines recommend regular brisk exercise for this
in AF, and lower symptom severity scores.
purpose (35). Observational studies have shown
Goal
increased risk of AF in young athletes or in those
Directed Weight Management on Atrial Fibrillation
performing endurance training (36,37). A common
Cohort: A 5 Year Follow-Up Study) study investigated
theme in these studies is involvement in regular long-
the impact of RFM and weight loss in longer-term AF
duration endurance training that is well beyond the
management (30). Patients with a BMI $27 kg/m 2 and
scope of what would be practiced by the typical pa-
AF (N ¼ 825) were offered weight management and
tient with AF and other comorbidities.
The
LEGACY-AF
(Long-Term
Effect
of
standard therapy for AF at the discretion of the
In the Cardiovascular Health Study, the incidence
treating physician. At 5-year follow-up, a dose–
of AF was lower in individuals performing light-
response relationship was seen, with greater weight
to-moderate exercise compared with those per-
loss resulting in reduced AF burden and symptoms.
forming no exercise (38). There was no difference in
Weight loss $10% was associated with >6-fold
AF incidence between individuals performing high-
decrease in arrhythmia-free survival. Fluctuations of
intensity exercise versus no exercise. Among those
weight >5% within the study time period offset some,
who walked for exercise, walking greater distances
but not all, of the benefits of weight loss.
or at a faster pace was associated with a greater
Weight loss has also been demonstrated to reduce
reduction in incident AF. In the Women’s Health
AF recurrence after ablation procedures. In the
Initiative study, increased physical activity was
ARREST-AF (Aggressive Risk Factor Reduction Study
associated with less incident AF and appeared to
for Atrial Fibrillation and Implications for the Outcome
mediate some of the relationship between obesity
of Ablation), patients with AF and obesity undergoing
and AF (13). Two meta-analyses examining the
catheter ablation were offered the chance to partici-
relationship of routine nonendurance exercise and
pate in a group in a nonrandomized fashion (29). At a
AF reported no association between exercise and AF
mean follow-up of 42 months after catheter ablation,
risk (39,40).
patients in the RFM group had significant reductions in
In a cohort of 64,561 adults with a mean follow-up
weight, blood pressure, and lipid profile, and improved
of 5.4 years, for each 1 metabolic equivalent (MET)
glycemic control. There was a significant decrease in
achieved during treadmill stress testing, there was a
AF frequency, duration, symptoms, and arrhythmia-
7% decreased relative risk for AF development (41). In
free survival with the RFM group. Additionally, obese
the recent CARDIO-FIT (Impact of CARDIOrespiratory
patients have been observed to receive at least a 2-fold
FITness on Arrhythmia Recurrence in Obese In-
higher
dividuals with Atrial Fibrillation) study, 308 obese
effective
radiation
dose
compared
with
nonobese patients during an AF ablation (33).
(BMI $27 kg/m 2) patients with AF were enrolled in a
The epidemiological link between obesity and AF is
tailored exercise program. Patients that had high
clear, and there is increasing understanding of the
cardiorespiratory fitness had greater arrhythmia-free
pathophysiology linking the 2 conditions. Recent data
survival with and without rhythm-control strategies.
support the importance of weight loss in AF man-
Patients who improved their fitness level by $2 METs
agement. Of note, weight loss did not occur in isola-
had a 2-fold higher probability of AF-free survival, as
tion in the studies discussed earlier, but rather
well as lower AF burden and symptom severity
included components of exercise, diet, and modifi-
compared with those that improved their fitness
cation of other risk factors. The link between weight
by <2 METs (32).
2901
2902
Year
Design
Patient Population
Sample Size
Intervention
Results (Intervention vs.
Control Group)
Comparison
Follow-up
General lifestyle
advice
15 months
Greater weight loss (14.3 vs. 3.6 kg)
Reduced AF burden and severity scores
(11.8 vs. 2.6 points and 8.4 and 1.7 points,
respectively)
Less frequent AF episodes
Reduced cumulative AF duration (692 min
reduction vs. 419 min increase)
Reduced IVS and LAA
42 months
Greater reductions in weight and blood pressure,
as well as improved glycemic control and lipid
profile.
Decreased AF frequency, duration, symptoms, and symptom severity.
Improved arrhythmia-free survival after a
single or multiple procedures (with or
without the use of anti-arrhythmic agents)
No control arm
46–48 months
Decreased AF burden and symptom severity
in patients that lost $10% of their weight
compared to those that lost <10%
Weight loss $10% was associated with a
6-fold greater probability of arrhythmiafree survival
Fluctuations of weight >5% offset some,
but not all, benefits of weight loss
Standard
strategy
(HbA1c:
7.0%–7.9%)
4.7 yrs
There was no difference in AF incidence
between the 2 groups
Patients with DM and new-onset AF had a
hazard ratio of 2.65 for all-cause mortality
No control arm
49 months
Greatest arrhythmia-free survival (with and
without rhythm control strategies) was
observed in patients with high
cardiorespiratory fitness compared with
adequate or low cardiorespiratory fitness
Decreased AF burden and symptom severity
in patients with cardiorespiratory fitness
gain $2 METs, compared with <2 METs
2-fold greater probability of arrhythmiafree survival in patients with
cardiorespiratory fitness gain $2 METs,
compared with <2 METs
Obesity
Abed et al. (28)
2013
Single-center,
Overweight and
partially blinded,
obese ambulatory
RCT (weight-loss
patients with
counselors were
symptomatic AF
not blinded)
150
(I ¼ 75;
C ¼ 75)
Weight management
Pathak et al. (29)
2014
Single-center,
nonrandomized,
placebocontrolled
trial
Consecutive patients
with BMI $27 kg/m2 and $1 RF
(HTN, glucose intolerance/DM,
HLD, OSA, smoking, or alcohol
excess) undergoing initial catheter
ablation for symptomatic AF,
despite the use of antiarrhythmic
medication
149
(I ¼ 61;
C ¼ 88)
RFM by a physician-led
Information on
clinic (HTN control,
RFM was
provided
weight management,
lipid management,
glycemic control, OSA
management,
smoking and alcohol
counseling)
Pathak et al. (30)
2015
Single-center,
single-arm,
study
Consecutive patients with
symptomatic paroxysmal or
persistent AF and BMI $27 kg/m2
355
Weight management
2014
Multicentric,
RCT
Patients with CVD or aged 55 to 79 yrs
and had anatomic evidence of
significant ASCVD, albuminuria,
LVH, or $2 additional RFs (HLD,
HTN, current smoking status, or
obesity)
Miller et al.
First Author
(Ref. #)
Risk Factor Modification in AF
T A B L E 1 Interventional Studies Assessing the Effect of RFM on AF Outcomes
Diabetes
Fatemi et al. (31)
10,251
(I ¼ 5,040;
C ¼ 5,042)
Intensive glucose
control
(HbA1c <6.0%)
Exercise and cardiorespiratory fitness
Pathak et al. (32)
2015
Single-center,
single-arm
study
Consecutive patients with
symptomatic paroxysmal or
persistent AF and BMI $27 kg/m2
308
Weight and risk
factor management
program, structured
exercise program
JACC VOL. 66, NO. 25, 2015
DECEMBER 29, 2015:2899–906
AF ¼ atrial fibrillation; ASCVD ¼ atherosclerotic cardiovascular disease; BMI ¼ body mass index; C ¼ sample size of the control group; CVD ¼ cardiovascular disease; DM ¼ diabetes mellitus; HLD ¼ hyperlipidemia; HTN ¼ hypertension; I ¼ sample size of the intervention
group; IVS ¼ intraventricular septum thickness; LAA ¼ left atrial area; LVH ¼ left ventricular hypertrophy; METs ¼ metabolic equivalents; OSA ¼ obstructive sleep apnea; RCT ¼ randomized controlled trial; RF ¼ risk factors; RFM ¼ risk factor management.
Miller et al.
JACC VOL. 66, NO. 25, 2015
DECEMBER 29, 2015:2899–906
Risk Factor Modification in AF
Although there is a link between endurance exer-
of 6 randomized controlled trials involving 3,557 pa-
cise and AF, this represents a small fraction of
tients, statin therapy decreased the relative risk of
patients and a subgroup of people already at low risk
incident or recurrent AF by 61% compared with stan-
of developing AF. There are no data to suggest that
dard of care (52). In a subgroup analysis, the benefit
routine light or moderate exercise puts patients at
from statin use was limited to those with a previous
increased risk of AF, and there is evidence that
history of AF and those undergoing cardiac surgery or
light-to-moderate exercise may decrease incident AF.
treatment for ACS.
In addition, increased fitness is associated with
Prospective data on the role of fish oil in decreasing
reduced AF risk. Given the other cardiovascular
the incidence of AF are limited. Two randomized,
benefits of routine exercise, it is logical to recom-
double-blind, placebo-controlled trials of high-dose
mend regular, moderate exercise as part of routine AF
omega-3 (4 to 8 g/day) failed to show a reduction
prevention and management.
in AF recurrence among patients with a history
HYPERTENSION
Elevated blood pressure has consistently been one the
strongest predictors of the development of AF (42).
Even high-normal blood pressure has been linked with
increased risk of AF (43). The increased afterload leads
to both atrial and ventricular structural remodeling,
resulting in diastolic dysfunction and left atrial
enlargement and fibrosis (44,45). These changes in
turn lead to increased AF (45).
AF risk reduction via blood pressure control has
not been consistently shown. Therefore, control of
hypertension (HTN) in those without cardiovascular
disease is not currently recommended for prevention
of AF (5). However, HTN plays an important role in
the management of AF in regard to thromboembolic
risk. The presence of HTN is a risk factor for stroke in
patients with AF in both the CHADS2 and CHADS2 VASc risk stratification instruments (46). Control of
HTN with losartan has been associated with a 2-fold
reduction of stroke rates (47).
It is well-documented that HTN is associated with
increased risk of AF and increased risk of complications of AF, particularly stroke. Although treatment of
HTN has not been consistently shown to decrease AF
risk, it is an important component of reducing thromboembolic risk and of any AF management strategy.
CHOLESTEROL
of paroxysmal or persistent AF (53,54). In metaanalyses, fish oil supplementation was not associated with reduction of AF risk (55).
Statins are, however, associated with decreased risk
of post-operative AF. A meta-analysis of randomized
controlled and observational studies in cardiac surgery
including 17,643 patients demonstrated less postoperative AF with pre-operative statin use (56).
In total, the data linking abnormal lipid profiles
and incident AF has been mixed, as have been studies
of statins and fish oils in prevention of AF. On the
basis of the evidence, recommendations for use of
lipid-lowering agents for the purpose of preventing or
managing AF is limited to its role in cardiac surgery
patients.
DIABETES
Diabetes is an independent risk factor for AF (57,58).
This has been corroborated with long-term prospective population cohort studies. In the Framingham
Heart Study, diabetes was associated with 40% higher
risk of AF in men and 60% higher risk in women after
38 years of follow-up (59).
Regarding mechanisms underlying the association
of diabetes and AF, cardiac autonomic neuropathy
has been implicated by leading to sympathetic overactivity and neural remodeling (60,61). Dysfunctional
cardiac autonomic activity can trigger AF, especially
with changes in vagal tone (62).
Studies assessing associations between dyslipidemia
There are limited data on diabetes management and
and incident AF report variable results. Multiple
AF risk. The Action to Control Cardiovascular Risk in
studies have shown that low levels of high-density
Diabetes study randomized 10,251 patients to intense
lipoprotein cholesterol (<35 mg/dl) are associated
glycemic control (HbA 1c <6.0%) or a standard target
with increased risk of new-onset AF (48,49). How-
(7.0% to 7.9%). There was no difference in new-onset
ever, other studies have found no association
AF between the 2 arms (31). In a prospective study of
between high-density lipoprotein cholesterol and
263 consecutive patients undergoing first-time cath-
incident AF, and increased total cholesterol and low-
eter ablation for AF, there was no difference in AF
density lipoprotein cholesterol have been associated
recurrence between those patients with and without
with a lower incidence of AF (50,51).
diabetes; however, there was a significant increase in
A number of studies have evaluated the roles of
procedural complications including stroke, cardiac
statins and fish oil in AF prevention. In a meta-analysis
tamponade, and hematomas among those with
2903
2904
Miller et al.
JACC VOL. 66, NO. 25, 2015
DECEMBER 29, 2015:2899–906
Risk Factor Modification in AF
diabetes (63). Other studies have shown a greater atrial
There is clear evidence demonstrating OSA to be a
tachyarrhythmia recurrence rate following catheter
significant risk factor for AF. In addition, treatment of
ablation for AF in patients with diabetes (64,65).
OSA is an important component of AF management,
In summary, there is currently insufficient evi-
particularly when cardioversion or PVI is used. The
dence to suggest that any particular management
strength of the evidence warrants consideration of
strategy for diabetes directly affects the risk of
routine clinical screening for OSA prior to use of a
developing AF. However, it is reasonable to hypoth-
rhythm control strategy.
esize that optimal management of diabetes and
prevention of cardiovascular complications may
TOBACCO AND ALCOHOL
indirectly reduce risk of AF.
Studies yield conflicting results in regard to the
OBSTRUCTIVE SLEEP APNEA
association of tobacco use and incident AF (71–73).
Alcohol consumption has been associated with
Obstructive sleep apnea (OSA) is highly prevalent in
an increased risk of developing AF in a dose-
patients with AF. In a prospective analysis, approxi-
dependent manner
mately 50% of AF patients had OSA, as compared with
alcohol have been associated with increased risk of
32% of controls (66). After a multivariate analysis
AF, the effect of tobacco cessation or reduction in
looking at traditional risk factors for OSA, AF had
alcohol intake on management of AF is less clear.
a greater association with OSA than BMI, HTN, or
They are, therefore, components of a comprehen-
diabetes.
sive strategy to lower AF risk, but cannot be rec-
Mechanisms by which OSA contributes to AF
risk
include
intermittent
nocturnal
hypoxemia/
(74). Although tobacco
and
ommended specifically for the purpose of improving
AF outcomes.
hypercapnia, surges in sympathetic tone and blood
pressure during apneic episodes, and increased
CONCLUSIONS
inflammation (67,68). All of these factors may
contribute to left atrial remodeling and chamber dila-
In addition to anticoagulation, rhythm control, and
tion, contributing to perpetuation of AF.
rate control, a fourth pillar of AF management is
Rates of AF recurrence after electrical cardioversion
emerging. There is growing evidence supporting
are higher in patients with OSA who are not treated with
aggressive RFM, especially weight loss, in the
nocturnal positive-pressure therapy. In a prospective
context of a comprehensive RFM plan. These bene-
study of patients with OSA referred for electrical car-
fits are seen in AF prevention, success rates in AF
dioversion (N ¼ 39), the 12-month AF recurrence rate
management, and in reducing complications of AF,
was 82% in patients who were not appropriately
including stroke. Although fundamental in primary
receiving positive-pressure therapy versus 42% in pa-
care and cardiology for the management of ASCVD,
tients using appropriate OSA treatment (69).
RFM in AF deserves similar recognition. The current
In a prospective study of AF patients with OSA
body of evidence supports a comprehensive strategy
referred for index pulmonary vein isolation (PVI)
of weight loss, exercise, and fitness, screening for
procedure, arrhythmia-free survival at 1 year was
OSA, and treatment of traditional modifiable ASCVD
higher in those who were compliant with positive-
risk factors. Further research needs to be performed
pressure therapy (71.9%) compared with patients
before
who were not (36.7%) (70). Arrhythmia-free survival
guidelines on appropriate weight loss and fitness
after PVI in treated OSA patients was similar to
targets.
making
specific
recommendations
and
arrhythmia-free survival in patients who did not
have OSA. The risk of AF recurrence after PVI in
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
untreated OSA patients was the same as the risk of
Hugh Calkins, Division of Cardiology, Johns Hopkins
recurrence in OSA patients with AF who were medi-
Hospital, 1800 Orleans Street, Zayed Tower 7125R, Bal-
cally managed without PVI.
timore, Maryland 21287. E-mail: [email protected].
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KEY WORDS diabetes, hyperlipidemia,
hypertension