JACC: CARDIOVASCULAR IMAGING

VOL. 7, NO. 12, 2014

ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 1936-878X/$36.00

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http://dx.doi.org/10.1016/j.jcmg.2014.07.017

Visceral Adiposity and the Risk of Metabolic Syndrome Across Body Mass Index The MESA Study Ravi V. Shah, MD,* Venkatesh L. Murthy, MD, PHD,y Siddique A. Abbasi, MD,z Ron Blankstein, MD,z Raymond Y. Kwong, MD, MPH,z Allison B. Goldfine, MD,x Michael Jerosch-Herold, PHD,z João A.C. Lima, MD, MBA,k Jingzhong Ding, PHD,{ Matthew A. Allison, MD, MPH#

JACC: CARDIOVASCULAR IMAGING CME CME Editor: Ragavendra R. Baliga, MD

CME Objective for This Article: After reading this article, the reader should be able to: 1) explain the relationship between visceral and subcutaneous

This article has been selected as this issue’s CME activity, available online

adiposity measures and weight or BMI; 2) discuss the impact of visceral

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and subcutaneous adiposity on metabolic risk, including metabolic syn-

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drome; 3) explain the importance of changes in weight and fat distribution in addition to overall weight changes in metabolic syndrome risk; and 4) describe imaging methods used to assess adiposity distribution for

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research and clinical applications. CME Editor Disclosure: JACC: Cardiovascular Imaging CME Editor Ragavendra R. Baliga, MD, has reported that he has no relationships to disclose. Author Disclosures: Dr. Shah has received consulting fees from Novartis. Dr. Murthy has minor stock in General Electric. Dr. Abbasi has received research support from T32-HL094301. Dr. Goldfine was supported by P30-DK036836 from the National Institutes of Health; has received materials for investigator-initiated research from Amneal

Method of Participation and Receipt of CME Certificate

Pharmaceuticals, Johnson & Johnson, Novo Nordisk, Nestle Inc., and Mercodia; and has served as a consultant to Novo Nordisk. Dr. Allison

To obtain credit for this CME activity, you must:

was supported by funding for the MESA Abdominal Body Composition

1. Be an ACC member or JACC: Cardiovascular Imaging subscriber.

Ancillary study from the National Heart, Lung, and Blood Institute

2. Carefully read the CME-designated article available online and in this

(R01-HL088451). All other authors have reported that they have no

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relationships relevant to the contents of this paper to disclose. Medium of Participation: Print (article only); online (article and quiz).

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CME Term of Approval Issue Date: December 2014 Expiration Date: November 30, 2015

From the *Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; yDepartment of Medicine (Cardiovascular Medicine Division) and Department of Radiology (Nuclear Medicine and Cardiothoracic Imaging Divisions), University of Michigan, Ann Arbor, Michigan; zNon-Invasive Cardiovascular Imaging, Brigham and Women’s Hospital, Boston, Massachusetts; xJoslin Diabetes Center, Boston, Massachusetts; kDivision of Cardiology, Johns Hopkins Medical Institute, Baltimore, Maryland; {Department of Medicine, Wake Forest Baptist Medical Center, Winston-Salem, North Carolina; and the #Department of Family and Preventative Medicine, University of California–San Diego, San Diego, California. MESA was supported by contracts NO1-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute. Dr. Shah has received consulting fees from Novartis. Dr. Murthy has minor stock in General Electric. Dr. Abbasi has received research support from T32-HL094301. Dr. Goldfine was supported by P30-DK036836 from the National Institutes of Health; has

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Shah et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 7, NO. 12, 2014 DECEMBER 2014:1221–35

Visceral Adiposity and Metabolic Syndrome

Visceral Adiposity and the Risk of Metabolic Syndrome Across Body Mass Index The MESA Study ABSTRACT OBJECTIVES This study sought to evaluate differential effects of visceral fat (VF) and subcutaneous fat and their effects on metabolic syndrome (MetS) risk across body mass index (BMI) categories. BACKGROUND The regional distribution of adipose tissue is an emerging risk factor for cardiometabolic disease, although serial changes in fat distribution have not been extensively investigated. VF and its alterations over time may be a better marker for risk than BMI in normal weight and overweight or obese individuals. METHODS We studied 1,511 individuals in the MESA (Multi-Ethnic Study of Atherosclerosis) with adiposity assessment by computed tomography (CT). A total of 253 participants without MetS at initial scan underwent repeat CT (median interval 3.3 years). We used discrete Cox regression with net reclassification to investigate whether baseline and changes in VF area are associated with MetS. RESULTS Higher VF was associated with cardiometabolic risk and coronary artery calcification, regardless of BMI. After adjustment, VF was more strongly associated with incident MetS than subcutaneous fat regardless of weight, with a 28% greater MetS hazard per 100 cm2/m VF area and significant net reclassification (net reclassification index: 0.44, 95% confidence interval [CI]: 0.29 to 0.60) over clinical risk. In individuals with serial imaging, initial VF (hazard ratio: 1.24 per 100 cm2/m, 95% CI: 1.08 to 1.44 per 100 cm2/m, p ¼ 0.003) and change in VF (hazard ratio: 1.05 per 5% change, 95% CI: 1.01 to 1.08 per 5% change, p ¼ 0.02) were associated with MetS after adjustment. Changes in subcutaneous fat were not associated with incident MetS after adjustment for clinical risk and VF area. CONCLUSIONS VF is modestly associated with BMI. However, across BMI, a single measure of and longitudinal change in VF predict MetS, even accounting for weight changes. Visceral adiposity is essential to assessing cardiometabolic risk, regardless of age, race, or BMI, and may serve as a marker and target of therapy in cardiometabolic disease. (J Am Coll Cardiol Img 2014;7:1221–35) © 2014 by the American College of Cardiology Foundation.

V

an

otherwise “obese”

isceral adipose tissue is a relevant, pro-

dysfunction—hallmarks of

inflammatory endocrine tissue and may ac-

phenotype—regardless of adiposity status (1). Never-

count for an increased cardiometabolic risk

theless, several questions critical to using BMI and

across body mass index (BMI) (1). A recent report in

adiposity in cardiovascular risk remain. Whether

obese individuals demonstrated that a single mea-

standard metrics of adiposity used in the clinic

surement of visceral fat (VF) was associated with

(weight or BMI and waist circumference) adequately

risk of dysglycemia, independent of weight or meta-

reflect pathologic visceral (or subcutaneous) fat and

bolic

associated

the subsequent risk of metabolic syndrome (MetS) is

with an adverse cardiometabolic profile, including

important. Whether weight gain alone explains most

inflammation, insulin resistance, and myocardial

of the hazard of incident MetS—regardless of whether

risk

(2).

Visceral

adiposity

is

received materials for investigator-initiated research from Amneal Pharmaceuticals, Johnson & Johnson, Novo Nordisk, Nestle Inc., and Mercodia; and has served as a consultant to Novo Nordisk. Dr. Allison was supported by funding for the MESA Abdominal Body Composition Ancillary study from the National Heart, Lung, and Blood Institute (R01-HL088451). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Shah and Murthy have contributed equally to this work. Manuscript received May 22, 2014; revised manuscript received July 21, 2014, accepted July 24, 2014.

Shah et al.

JACC: CARDIOVASCULAR IMAGING, VOL. 7, NO. 12, 2014 DECEMBER 2014:1221–35

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Visceral Adiposity and Metabolic Syndrome

it is gained in the visceral or subcutaneous depot—

“baseline” examination as the first examina-

ABBREVIATIONS

will not only provide valuable translation of the mo-

tion at which the CT scan was performed

AND ACRONYMS

lecular and physiological importance of visceral

(either examination 2 or 3). Of this initial

adiposity, but will also inform clinical assessments

cohort with both baseline subcutaneous and

of risk with weight reduction.

VF data (n ¼ 1,687), we excluded participants with: 1) missing data for BMI at baseline ex-

SEE PAGE 1236

BMI = body mass index CT = computed tomography HR = hazard ratio

amination (n ¼ 1); or 2) any history of cirrhosis,

MetS = metabolic syndrome

To date, most reports on large, community-based

cancer, or self-reported renal disease at index

SQ = subcutaneous fat

studies have used a single measure of VF to fore-

examination (to limit confounding by chronic

VF = visceral fat

cast long-term risk (2–4) or are limited to 1 ethnic

illness and inflammation; n ¼ 175). The final popula-

background

im-

tion was composed of 1,511 individuals with baseline

portant gap by studying participants in MESA

measures for visceral adiposity. Of this subcohort, 253

(Multi-Ethnic Study of Atherosclerosis) with VF

participants without MetS or dysglycemia (impaired

(5,6).

Here,

we

address

this

measures at 2 time points and detailed metabolic,

fasting glucose $100 mg/dl or diabetes) at baseline

cardiac, and demographic phenotyping. We define a

were reimaged at examination 4 (median interval 3.2

relationship between visceral and subcutaneous

years, interquartile range [IQR]: 3.0 to 3.3 years) and

adiposity and BMI, their cross-sectional association

had complete data for subcutaneous and visceral

with incident MetS across BMI categories and race

adiposity.

independent of classic cardiometabolic risk factors,

Fasting blood samples collected at examination 3

and the longitudinal association of changes in each

were used to quantify selected adipokines reflecting

fat depot versus changes in weight with incident

insulin resistance and systemic inflammation (inter-

MetS.

leukin-6, high-sensitivity C-reactive protein [CRP], leptin, adiponectin, insulin, and tumor necrosis fac-

METHODS

tor- a ) as previously described (10,11). Protocols were approved by the Institutional Review Board at each

PARTICIPANT POPULATION. The overall design of

participating institution. All participants provided

the MESA study has been described previously (7). In

written informed consent.

brief, the MESA study consists of 6,814 men and

MEASUREMENT OF VISCERAL AND SUBCUTANEOUS

women of different ethnicities (white, African Amer-

ADIPOSITY. Electron-beam CT scanners were utilized

ican, Chinese American, and Hispanic) enrolled from

at Northwestern University and University of Cali-

6 different national sites, all of whom were free of

fornia, Los Angeles (Imatron C-150, Imatron Inc.,

clinical cardiovascular disease (history of myocardial

South San Francisco, California), with the following

infarction, angina pectoris, prior revascularization, heart failure, atrial fibrillation, stroke, or peripheral arterial disease) at the time of enrollment. Baseline demographics, medical history (including cardiac risk factors), medications (for hypertension, dyslipidemia, and diabetes), and physical examination were assessed at 5 clinic visits in MESA (examinations 1 to 5, between 2000 and 2011), as has been described (8). MetS was determined at each MESA clinic visit as defined by updated National Cholesterol Education Panel Adult Treatment Panel III guidelines (including abdominal obesity by waist circumference, serum triglyceride level, high-density lipoprotein [HDL] cholesterol, systolic and diastolic blood pressure, and fasting glucose) (9). At examinations 2 and 3, a random subset of 1,970 MESA participants underwent abdominal computed

F I G U R E 1 Diagram of Visceral and Subcutaneous Fat

tomography (CT) scans for aortic calcium that were

Compartments Analyzed by CT Imaging in MESA

subsequently used for quantifying visceral/subcutaneous fat mass: examination 2: n ¼ 756/n ¼ 577; examination 3: n ¼ 1,172/n ¼ 1,114, respectively. For the purposes of the current study, we defined the

A description of the delineation of these compartments is provided in the text. CT ¼ computed tomography; MESA ¼ MultiEthnic Study of Atherosclerosis.

High VF (n ¼ 99)

18 (20.7)

56 (13.7)

151 (37.0)

41 (10.0)

38 (9.3)

Former smoker

Current smoker

Metabolic syndrome

7 (1.7)

8 (2.0)

Stage 1 HTN

Stage 2 HTN

Stage 3 HTN

26 (6.4)

Treated diabetes

5.4 (5.2–5.8)

478.7 (335.6–636.5)

743.2 (571.2–967.6)

292.5 (200.9–384.3)

Visceral fat, cm2

Subcutaneous fat, cm2

Height-indexed visceral fat, cm2/m 598.5 (540.3–703.9)

754.6 (628.5–903.0)

1,004.1 (929.0–1,205.8)

54.3 (0.0–244.7)

5.4 (5.2–5.6)

0.0 (0.0–63.8)

88.0 (64.0–123.0)