In normal BMI post-menopausal women, trunk fat was associated with higher and leg fat with lower CVD risk
Introduction and methods
Although body mass index (BMI) is widely used in clinical practice and research, the limitations of its use as a proxy for adiposity are well known. BMI cannot distinguish well between fat mass and fat-free mass. As a consequence, individuals in the same BMI category can have very different fat distribution and thereby different health risks. For instance, among people with normal BMI, those with higher waist circumference have higher CVD risk [1-3].
The biological function of adipose tissue depends on the location, with opposing effects seen in upper- and lower-body fat, namely detrimental vs. beneficial. This affects various metabolic processes, such as glucose regulation and lipid storage [4-6]. Accumulating evidence suggests that trunk fat mass is a strong predictor of unfavourable metabolic features that increase CVD risk. Increased leg fat, on the other hand, may be associated with lower risk of metabolic disturbances [7-10].
Metabolic alterations are seen in postmenopausal women, partly due to a shift from subcutaneous to intra-abdominal visceral fat . No studies have investigated the impact of regional fat accumulation in normal BMI postmenopausal women. This study therefore examined the associations of whole-body fat, upper-body (trunk) fat and lower-body (leg) fat with risk of CVD among postmenopausal women with normal BMI, using body composition data as defined by dual energy X-ray absorptiometry (DXA) in a subset of the Women’s Health Initiative (WHI). 11393 Women underwent whole body DXA scans at enrolment (1993-1998), of whom 3464 participants had normal BMI (18.5 to <25 kg/m²). 781 Of those were excluded because of reporting a CV condition at study entry, or having incomplete data, leaving 2683 individuals eligible for the current analysis. Over a median 17.9 years of follow-up (40421 person-years), 291 incident CVD cases occurred (202 CHD and 105 stroke, 16 women had both outcomes).
- Both trunk and leg fat were correlated with whole-body fat, and they correlated positively with each other (r=0.39).
- After adjustment for age and race/ethnicity, whole-body fat was not significantly related to CVD risk (P-trend >0.05).
- Trunk fat was positively associated with risk of CVD (P-trend <0.001), and leg fat inversely (P-trend =0.003). Further adjustment for demographic, lifestyle and clinical risk factors gave similar results.
- Comparing the highest with the lowest quartile yielded 1.91 (95% CI 1.33–2.74; P-trend<0.001) for % trunk fat and 0.62 (95% CI 0.43–0.89; P-trend=0.008) for % leg fat. Similar results were seen for absolute trunk or leg fat mass.
- Each SD increment in % trunk fat mass gave a 32% higher risk in the more adjusted model (95%CI: 1.16-1.51), and for % leg fat mass a 15% lower risk of CVD was seen (95%CI: 0.76-0.96).
- Higher ratio of trunk-to-leg fat mass was associated with a higher risk of CVD (HR: 1.99, 95%CI: 1.39-2.85, P-trend <0.001). Per SD increase in the ratio, risk increased by 31% (95%CI: 1.19-1.46).
- Combining the regional fat measures showed that women with the highest %trunk fat and the lowest % leg fat had a particularly higher risk of CVD (HR: 3.33, 95%CI: 1.46-7.63), compared to those in the opposite extreme tertiles of both measures.
This analysis of data of US postmenopausal women with normal BMI shows that total body fat was not substantially associated with CVD risk. Upper-body and lower-body fat, however, showed contrasting associations with CVD risk, with trunk fat being related to higher CVD risk and higher leg fat with lower CVD risk. The combination of high trunk fat and low leg fat put women at a three-fold increased risk of CVD as compared to those with low trunk and high leg fat.
In their editorial comment  Blüher and Laufs note that several lines of evidence have pointed in the direction that fat distribution determines CV morbidity and mortality more strongly than increased fat mass. The current study by Chen and colleagues provides further support for the importance of fat distribution as a determinant of ASCVD risk. Blüher and Laufs note that ‘the study may inspire novel concepts of how a dysbalance between “atherogenic” and “anti-atherogenic” fat depots may indirectly contribute to vascular damage.’
Various studies have shed light on different aspects of the relation between cardiometabolic factors and CVD risk, both in non-overweight, overweight and obese individuals. Data suggest that the importance of mechanisms linking adverse effects of abdominal fat and potential positive effects of leg fat to increased ASCVD risk are particularly pronounced in individuals with low BMI. In those with higher total body fat mass and associated adverse factors, effects of these mechanisms may be attenuated.
Blüher and Laufs then consider the question whether trunk fat is dangerous and leg fat is protective. They propose that subcutaneous leg fat may function as a metabolically ‘inert’ sink, which does not induce harmful adipose tissue dysfunction. Also, leg fat may release lower concentrations of potentially harmful metabolites such as free fatty acids. Furthermore, they hypothesize that leg fat may directly protect against ASCVD through anti-atherogenic and anti-inflammatory factors. Ectopic fat deposition may develop as a compensatory mechanism if excess energy cannot be sufficiently stored in healthy fat depots. Thus, Blüher and Laufs conclude that an adverse fat distribution may increase CVD risk independently of body fat mass. An intact balance between potentially harmful ectopic fat depots and safer or even beneficial fat storage may therefore be cardioprotective. It remains to be elucidated how the adverse fat distribution may develop, and how it is linked to atherosclerosis.