Obesity and Cardiovascular Risk: Sex Matters
Obesity, traditionally measured using body mass index (BMI), has been the cornerstone for predicting cardiometabolic and cardiovascular (CV) risk. With the prevalence of obesity in the United States approaching 50%,1 national guidelines recommend adults who are overweight or obese by BMI criteria to participate in lifestyle interventions for weight loss, although no sex-specific BMI cutoff values exist.2 Interestingly, BMI has not consistently predicted adverse CV risk – also known as the obesity paradox3 – and BMI has not been included in estimations of 10-year atherosclerotic CV risk.4 Importantly, BMI is unable to differentiate between subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and sex differences in regional adipose tissue distribution have been well documented.5 Over the last three decades, increasing evidence has linked visceral adiposity to CV risk independently of BMI,6 and thus these more precise measures of obesity may be needed to better estimate sex-specific CV risk and determine preventive strategies.
Recently, Kammerlander et al. described sex differences in the associations of computed tomography (CT) – based versus anthropometric measures of adiposity with cardiometabolic and CV risk in 3,482 Framingham Heart Study (FHS) participants.7 The authors found that men had higher amounts of VAT but lower amounts of SAT compared with women, and mean BMI and waist circumference were higher in men compared with women. Over a mean follow-up of 12.7 years, anthropometric measures adequately captured risk of incident cardiometabolic risk factors and CV events in men. In women, however, VAT demonstrated much stronger associations with cardiometabolic and CV outcomes compared with BMI or waist circumference. This study highlights the importance of studying sex-specific differences in the role of various measures in predicting cardiometabolic and CV risk.
The mechanisms explaining these differences lie in the functional difference between SAT and VAT, as well as sex-specific differences in body fat distribution. Increased concentrations of circulating pro-inflammatory markers including interleukin 6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNF- α), known as adipokines, are present in VAT and are associated with increased systemic inflammation, contributing to insulin resistance and cardiometabolic disease.8 Compared to SAT, VAT has also been linked with systemic endothelial dysfunction and more atherogenic gene expression profiles, related to greater expression of pro-inflammatory and oxidative stress-related genes.9 Both VAT and SAT increase with age; however, different trends are observed in males and females during and after puberty, where males deposit more VAT in the abdominal region and females deposit preferentially SAT in the extremities. This is thought to be secondary to estrogen's role in enhancing the expandability of adipocytes in the subcutaneous depot and inhibiting it in the visceral depot. This distribution of body fat changes in females during and post-menopause as the deposition of body fat shifts from subcutaneous tissue to visceral resulting in an increased VAT to SAT ratio and a parallel increase in metabolic risk similar to that seen in men.10
While the FHS study is the first to report sex-differences in VAT and SAT versus BMI in predicting CV events, other studies have evaluated sex-differences in the relationship between body fat distribution and metabolic risk factors. The Jackson Heart Study observed that VAT was more strongly associated with cardiometabolic risk factors than SAT in women than men, although men had higher volume of VAT than women, supporting similar sex interactions with abdominal VAT with cardiometabolic risk in African-Americans.11 The Multiethnic Study of Atherosclerosis (MESA) demonstrated that visceral adiposity is associated with greater cardiometabolic risk regardless of BMI, and suggested that BMI may not fully capture cardiometabolic risk due to variability in both SAT and VAT stores over time, with changes in VAT associated with a greater incidence of metabolic syndrome than changes in SAT.12 However, MESA did not find evidence of modification of the association between visceral or subcutaneous adiposity and incident metabolic syndrome by sex.
Nevertheless, other studies are consistent in demonstrating the shortcomings of BMI in assessing CV risk in women. The Nurses' Health Study found that both waist-hip ratio (WHR) and waist circumference were significantly associated with increased risk of coronary heart disease, even after controlling for BMI.13 The Nurses' Health Study underscored the heterogeneity of obesity: coronary risk of overweight/obese women who were not abdominally obese was similar to the coronary risk of nonobese women with higher levels of abdominal fat, lending to the notion that VAT is more directly associated with coronary heart disease in women. The Women's Ischemia Syndrome Evaluation (WISE) has similarly highlighted the limitations of BMI in predicting CV risk in women with suspected ischemia, demonstrating an inverse relationship between obesity (as defined by BMI) with long-term CV outcomes in physically fit women.14 Furthermore, women with elevated BMI ≥25 but without metabolic syndrome had lower mortality than women with normal BMI but with metabolic syndrome.15 These studies indicate that physical fitness and other metabolic factors may explain the obesity paradox.
Advanced imaging can now provide additional insight into coronary risk related to visceral adiposity, such as epicardial adipose tissue, pericoronary adipose tissue, and other ectopic fat depots. Studies indicate that epicardial adipose tissue is a biologically active organ that increases over time and is associated with increased cardiovascular risk, including the development of coronary atherosclerotic plaque16-20 and adverse coronary events.21 The Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research (EISNER) demonstrated that increased epicardial adipose tissue volume and decreased epicardial adipose tissue attenuation were independently associated with adverse coronary event risk in both asymptomatic men and women.21 Suggested mechanisms include the secretion of pro-inflammatory adipokines that interact with coronary vasculature or adjacent myocardium via paracrine and "vasocrine" signalling.22 Cardiac CT can quantify not only epicardial adipose tissue but also pericoronary adipose tissue, a surrogate measure of coronary inflammation associated with coronary artery disease and adverse CV outcomes.23
With increasing availability of rapid, robust, and fully automated quantification of VAT and epicardial adipose tissue,24-26 future studies focusing on the feasibility and possible implementation of visceral fat measurements into clinical practice and risk calculators should be a priority, as the obesity epidemic continues to grow. Sex differences in adiposity and CV risk should be included in the development of obesity-related CV risk assessment tools and interventions.
- Ward ZJ, Bleich SN, Cradock AL, et al. Projected U.S. state-level prevalence of adult obesity and severe obesity. N Engl J Med 2019;381:2440-50.
- Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;140:e596-e646.
- Lavie CJ, Laddu D, Arena R, Ortega FB, Alpert MA, Kushner RF. Healthy weight and obesity prevention: JACC Health Promotion Series. J Am Coll Cardiol 2018;72:1506-31.
- Goff DC Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2935-59.
- Fox CS, Massaro JM, Hoffmann U, et al. Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 2007;116:39-48.
- Powell-Wiley TM, Poirier P, Burke LE, et al. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2021;143:e984-e1010.
- Kammerlander AA, Lyass A, Mahoney TF, et al. Sex differences in the associations of visceral adipose tissue and cardiometabolic and cardiovascular disease risk: the Framingham Heart Study. J Am Heart Assoc 2021;10:e019968.
- Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes 2007;56:1010-13.
- Parikh NI, Keyes MJ, Larson MG, et al. Visceral and subcutaneous adiposity and brachial artery vasodilator function. Obesity (Silver Spring) 2009;17:2054-59.
- Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol 2015;402:113-19.
- Liu J, Fox CS, Hickson DA, et al. Impact of abdominal visceral and subcutaneous adipose tissue on cardiometabolic risk factors: the Jackson Heart Study. J Clin Endocrinol Metab 2010;95:5419-26.
- Shah RV, Murthy VL, Abbasi SA, et al. Visceral adiposity and the risk of metabolic syndrome across body mass index: the MESA Study. JACC Cardiovasc Imaging 2014;7:1221-35.
- Rexrode KM, Carey VJ, Hennekens CH, et al. Abdominal adiposity and coronary heart disease in women. JAMA 1998;280:1843-48.
- Quesada O, Wei J, Suppogu N, et al. Role of physical fitness in the obesity paradox. Long-term major adverse cardiovascular events in the Women's Ischemia Syndrome Evaluation (WISE). Eur Heart J 2020;41:ehaa946.3023.
- Quesada O, Wei J, Suppogu N, et al. Is a normal body mass index protective in women with metaboilc syndrome and suspected myocardial ischemia? J Am Coll Cardiol 2020;75:2043.
- Nerlekar N, Thakur U, Lin A, et al. The natural history of epicardial adipose tissue volume and attenuation: a long-term prospective cohort follow-up study. Sci Rep 2020;10:7109.
- Cheng VY, Dey D, Tamarappoo B, et al. Pericardial fat burden on ECG-gated noncontrast CT in asymptomatic patients who subsequently experience adverse cardiovascular events. JACC Cardiovasc Imaging 2010;3:352-60.
- Nakanishi K, Fukuda S, Tanaka A et al. Persistent epicardial adipose tissue accumulation is associated with coronary plaque vulnerability and future acute coronary syndrome in non-obese subjects with coronary artery disease. Atherosclerosis 2014;237:353-60.
- Nerlekar N, Brown AJ, Muthalaly RG, et al. Association of epicardial adipose tissue and high-risk plaque characteristics: a systematic review and meta-analysis. J Am Heart Assoc 2017;6:e006379.
- Goeller M, Achenbach S, Marwan M, et al. Epicardial adipose tissue density and volume are related to subclinical atherosclerosis, inflammation and major adverse cardiac events in asymptomatic subjects. J Cardiovasc Comput Tomogr 2018;12:67-73.
- Eisenberg E, McElhinney PA, Commandeur F, et al. Deep learning-based quantification of epicardial adipose tissue volume and attenuation predicts major adverse cardiovascular events in asymptomatic subjects. Circ Cardiovasc Imaging 2020;13:e009829.
- Talman AH, Psaltis PJ, Cameron JD, Meredith IT, Seneviratne SK, Wong DTL. Epicardial adipose tissue: far more than a fat depot. Cardiovasc Diagn Ther 2014;4:416-29.
- Guglielmo M, Lin A, Dey D, et al. Epicardial fat and coronary artery disease: role of cardiac imaging. Atherosclerosis 2021;321:30-38.
- Parikh AM, Coletta AM, Yu ZH, et al. Development and validation of a rapid and robust method to determine visceral adipose tissue volume using computed tomography images. PLoS One 2017;12:e0183515.
- Commandeur F, Goeller M, Razipour A, et al. Fully automated CT quantification of epicardial adipose tissue by deep learning: a multicenter study. Radiol Artif Intell 2019;1:e190045.
- Hu HH, Chen J, Shen W. Segmentation and quantification of adipose tissue by magnetic resonance imaging. MAGMA 2016;29:259-76.
Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Noninvasive Imaging, Prevention, Sports and Exercise Cardiology, Atherosclerotic Disease (CAD/PAD), Computed Tomography, Nuclear Imaging, Stress, Sports and Exercise and Imaging
Keywords: Intra-Abdominal Fat, Body Mass Index, Interleukin-6, Waist Circumference, Adiposity, Insulin Resistance, Metabolic Syndrome, Weight Loss, Waist-Hip Ratio, Postmenopause, Adipokines, Subcutaneous Tissue, Coronary Artery Disease, Sex Characteristics, Prevalence, African Americans, Cardiovascular Diseases, Transcriptome, Feasibility Studies, Follow-Up Studies, Tissue Distribution, Risk Factors, Subcutaneous Fat, Obesity, Overweight, Atherosclerosis, Adipocytes, Tomography, X-Ray Computed, Risk Assessment, Extremities, Physical Fitness, Life Style, Inflammation, Myocardium, Ischemia, Oxidative Stress, Epidemics, Tomography
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