13 January, 2020: 

Summary

A recent study by Chen et al. (1) analyzed a sample of 2,683 postmenopausal women from the Women’s Health Initiative (WHI) cohort, with normal body mass index (BMI; 18.5 to <25 kg/m2), no known cardiovascular disease (CVD), and for whom data was available on body composition, as determined by dual-energy X-ray absorptiometry (DXA). After a median follow-up of 17.9 years, there were 291 cases of CVD (coronary heart disease [CHD], stroke, or the combination of both). After adjusting for confounding factors (i.e., demographics, lifestyle, clinical factors), neither whole-body fat mass nor fat percentage was found to be related to CVD risk. Higher percent trunk fat and leg fat were associated with an increased and decreased risk of CVD, respectively. The association of trunk fat with CVD risk was attenuated but remained significant even after adjusting for waist circumference or waist-to-hip ratio. A combination of higher trunk and lower leg fat was linked to a higher CVD risk. The authors concluded that, in postmenopausal women with normal BMI, both elevated trunk and reduced leg fat increase the risk of CVD.

Commentary

After menopause, there is an increase in cardiovascular risk (CVR), basically due to the rise in body weight (2). Despite BMI being an indicator of adiposity, and thus a marker of CVR, its predictive value for CVR or CVD is limited (3). An important related aspect is that, during the menopausal transition, women develop increased adiposity mainly at the waist. Indeed, many women with abdominal obesity have a healthy BMI. In the present study, the authors tested the hypothesis that among postmenopausal women with normal BMI, regional body fat deposits, as determined by DXA (trunk or leg fat), would be related to CVD. The fat mass gain in peri- and young postmenopausal women may determine either of two phenotypes: the “apple” shape due to fat accumulation in the abdomen or the “pear” shape due to accumulation in the buttocks. These phenotypes confer different pathophysiological metabolic alterations and, as observed in the paper by Chen et al. (1), various cardiovascular risks. The study by Chen et al. (1) provides evidence that even in non-obese women, “regional” fat deposition produces various inflammatory changes, endothelial alterations, and probably insulin resistance. However, delineating the possible implicated pathways still requires appropriately designed studies in non-obese women (normal BMI). A variability in fat distribution in age-matched women has been previously described. A higher risk of type 2 diabetes (the final and more manifest outcome of insulin resistance), hypertension, and hypercholesterolemia have been associated with the “apple” phenotype (4). An aspect that requires adequate research, which is not defined in the paper by Chen et al., is the level of physical activity in women with both phenotypes that would allow checking for insulin sensitivity as related to regular physical activity/week. Programmed regular exercise may be an antidote to the increasing insulin resistance and altered cholesterol metabolism (6). Also, the study did not mention the prevalence of polycystic ovary syndrome (PCOS) in the study population, which is estimable at about 10% but can vary according to ethnicity (7). PCOS may contribute to the pattern of fat accumulation in this reported non-obese population. Non-obese PCOS women may display a trend towards sub-clinical atherosclerosis due to visceral fat deposition, which is the principal predictor of this phenomenon in PCOS women ( 8). A third aspect lacking in the Chen et al. (1) publication is the history of hypertensive disorders of pregnancy or preeclampsia, which may be associated with a variety of metabolic alterations that may persist after pregnancy, or surge after the menopause in obese and non-obese women. Meta-research indicates that women who have suffered preeclampsia are at increased risk of CVD (9) and diabetes years after pregnancy (10). A recent meta-analysis has also demonstrated that in the intermediate to long term follow up period, women with preeclampsia/eclampsia still have worse metabolic and biochemical profiles than those who did not suffer the syndrome (11). The study has its strengths, such as its prospective design, long-term follow-up, repeated DXA scans to measure body composition, registry of CVD events, and the assessment of several serum biomarkers that provide biological plausibility for a mechanistic link between regional body fat and the development of CVD. However, it is limited, as stated by the authors, by its cross-sectional nature that does not provide a causal relationship between regional body fat and CVD risk. Despite this, studies focused on weight-loss have determined that a reduction of trunk fat can result in an improvement of cardiometabolic indicators, while increasing leg fat may lead to a decrease in CVD (3). As stated by the authors, there is a need for more clinical trials to better determine the causal relationship between regional body fat and CVD, including a better determination of ethnicity (basically Caucasian in the WHI cohort). Indeed, reports indicate that CVD may vary according to race; hence future studies should control for this factor.

Peter Chedraui

Director, Instituto de Investigación e Innovación en Salud Integral, Facultad de Ciencias Médicas, Universidad Católica de Santiago de Guayaquil, Guayaquil, Ecuador

References

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