Unlike BMI, a higher WC in our post-hoc analysis of patients with PPMs was associated with a higher risk of cardiovascular death. This relationship was observed only in men patients.
To the best our knowledge, this is the first study to specifically examine the association between WC and clinical outcomes (cardiovascular death and all-cause mortality), focusing on the role and impact of the sex difference on the association between abdominal obesity and cardiovascular death in patients with PPMs. Our findings added further knowledge on the evidence provided by previous studies on CIEDs recipients.
Earlier studies conducted in this field have focused on obese patients with ICD, and their results revealed an “obesity paradox” (6, 7, 17). In the study of Hsu et al., patients with ICD and with a BMI ≤ 18.5 kg/m2 experienced a 2-fold increase in the odds of in-hospital death, whereas patients with a BMI ≥ 30 kg/m2 did not have an increased risk of adverse events (6). In a similar study, Echouffo et al. found that ≥ 65-year-old patients with CRT-D in the underweight population (BMI: 25 − 29.9 kg/m2) had greater risks of mortality and hospitalization, whereas the overweight (BMI ≥ 30 kg/m2) or obese patients had a lower mortality risk than the normal-weight individuals (17). In our study, BMI showed no association with cardiovascular death. This result was consistent with the findings of a previous study, in which Gregory et al. investigated the cases of 8,079 patients undergoing coronary angiography in the APPROACH-NL database and found no significant association between BMI and all-cause or cardiac-specific mortality after adjustments for potential confounders (18). Moreover, other studies also showed that cardiovascular risks are linked to body fat storage but not to BMI itself (19–22). Therefore, results in which BMI has been used as a criterion for obesity determination should be evaluated in the context of the inherent limitations of BMI as an index of adiposity. Furthermore, methodological biases and the presence of confounding factors, such as physical activity, smoking, and cardiorespiratory fitness, may have resulted in erroneous findings (8, 23–25).
In contrast, WC measurement and evaluation is a clinically-valuable and easy-to-perform method for central obesity assessments, which has been shown to indicate an excellent correlation of abdominal imaging and cardiovascular disease risk and mortality (26, 27), with or without adjustment for BMI (28, 29). Recently, a consensus statement from the International Atherosclerosis Society (IAS) and the International Chair on Cardiometabolic Risk (ICCR) Working Group suggested that BMI alone is insufficient to properly assess adiposity in patients, and WC evaluation should be adopted as a routine measure in clinical practice alongside BMI to classify obesity (30). In addition, WC is easier to measure and more intuitive than BMI for the determination of a patient's health status.
Although the mechanism underlying the association between WC and cardiovascular death has not been elucidated, several factors have been suggested to explain their association. First, abdominal fat affects inflammation more significantly than the fat stored in other parts of the body (2). Further, inflammatory markers such as C-reactive protein have been recently reported to be associated with sudden cardiac death (31). Second, abdominal visceral adiposity is associated with impaired inhibition of adipocyte lipolysis and elevated levels of non-esterified fatty acids or free fatty acids, leading to vascular endothelial dysfunction (2). Third, the adipose tissue also releases a variety of cytokines, such as leptin, adiponectin, and interleukin-6, which results in insulin resistance and thereby causes hypercholesterolemia and glucose intolerance (32).
In our study, we also found that WC had a strong positive association with cardiovascular death only in men but not in women patients. This result is consistent with that of a previous investigation, where Xing et al. (33) found that higher WC in male T2DM patients alone was significantly associated with a higher risk of cardiovascular events. Similarly, Song et al. (34) used data from four European national registries to estimate cardiovascular death in relation to obesity and sex, and established that men had higher cardiovascular death than women when obesity was defined by WC. Importantly, these associations remained statistically significant even after adjustment for other cardiac risk factors. In a prospective study conducted in Korea, 23,263,878 subjects were followed up for a period of six years via the National Insurance Service health checkup system. The authors found that WC increased all-cause mortality and men had higher HRs for mortality than women (35).
The observed sex differences in the association between WC and mortality in patients with PPMs may be related to the following factors. First, there are significant sex differences in the body fat content and fat distribution. Women have more subcutaneous adipose tissue, whereas men have predominantly visceral adipose tissue (36). Additionally, the higher amount of visceral adipose tissue in men is associated with elevated postprandial insulin and higher free fatty acid and triglyceride levels (37). In women, the greater quantity of subcutaneous adipose tissue is associated with very little inflammation during obesity and is characterized by a higher capacity to absorb circulating free fatty acids and triglycerides, thereby providing a protective effect against obesity-related diseases (38). Second, sex hormones may also be critically involved in the susceptibility to cardiovascular disease. Specifically, the higher total testosterone in males is associated with an increased risk of coronary heart disease, whereas the higher estradiol levels in females are correlated with a lower risk (39).
With the extended life expectancy and technology advancements, the speed of CIEDs utilization increases annually. Recently, a worldwide report showed that nearly 40,728 patients per year were treated with PPMs implantation, and, in China, this number was larger than that of any other CIEDs (40). Therefore, it is important to effectively perform health management and accurately assess the cardiovascular risk in these patients. Obesity is one of the most important indicators of cardiovascular health. However, most medical institutions still use BMI as the main criterion for obesity assessment and classification. Therefore, on the ground of our findings using the conventional BMI-based approach can lead to a missed diagnostic opportunity to detect neglected high-risk patients (i.e., those with a high WC but a normal BMI).