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.


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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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