Gender disparities in the association between epicardial adipose tissue volume and coronary atherosclerosis: A 3-dimensional cardiac computed tomography imaging study in Japanese subjects

We recruited 119 consecutive subjects who underwent 256-slice MDCT coronary angiography between October 2009 and April 2011 at the Kawashima Hospital, Tokushima, Japan. The subjects underwent MDCT if they had atherosclerotic risk factors such as age ≥65 years [15], hypertension, smoking, diabetes mellitus, or dyslipidemia or symptoms suggestive of angina pectoris. According to the 2010 Appropriate Use Criteria for Cardiac Computed Tomography [16] guidelines, cardiac CT is not necessarily recommended for asymptomatic individuals with low-to-moderate CAD risk. However, the prevalence of CAD was not negligible even in asymptomatic subgroups [17]; hence, we employed MDCT in subjects with moderate-to-high CAD risk after they were informed of the radiation-exposure related risk, and they provided written informed consent. Coronary CT angiography was performed using a 256-slice scanner (Brilliance iCT, Philips Healthcare, Amsterdam, Netherlands), and the diagnostic accuracy of the coronary CT angiography for coronary luminal narrowing was validated by routine invasive coronary angiography. Exclusion criteria included a history of cardiac surgery, iodine-based contrast allergy, or renal failure (creatinine, >1.5 mg/dL). Hypertension was defined as a systolic blood pressure of ≥140 mm Hg and/or diastolic blood pressure of ≥90 mm Hg or as the current use of antihypertensive treatment. Diabetes was defined as fasting plasma glucose of ≥6.99 mmol/L (126 mg/dL) or the current use of hypoglycemic treatment. Hyperlipidemia was defined as fasting serum LDL-cholesterol of ≥3.62 mmol/L (140 mg/dL), HDL-cholesterol of <1.03 mmol/L (40 mg/dL), triglyceride of ≥1.58 mmol/L (140 mg/dL), and/or the current use of antihyperlipidemic treatment. The subjects were segregated into 2 groups: CAD group (presence of plaques resulting in >50% luminal narrowing in the major coronary arteries) and non-CAD group (no plaque or plaques resulting in ≤50% luminal narrowing). All subjects in the CAD and non-CAD groups were further segregated into younger (age, <65 years) and older subgroup (age, ≥65 years).

Of the 119 subjects who underwent cardiac MDCT, 29 were excluded from analysis. Among the men, 11 were excluded because of differences in slice levels and 2 because of insufficient image quality; among the women, 11 were excluded because of differences in slice levels and 5 because of insufficient image quality. A total of 90 subjects (men: n = 47; age = 63 ± 12 years; women: n = 43, age = 64 ± 12 years) were analyzed (Table 1). By using MDCT, 22 men and 16 women were segregated into the CAD group (>50% luminal narrowing), while 25 men and 27 women were segregated into the non-CAD group. Among the 47 men, 36 (77%) had normal weight (BMI < 25 kg/m²), 8 (17%) were overweight (BMI 25–30 kg/m²), and 3 (6%) were obese (BMI > 30 kg/m²). Among the 43 women, 33 (77%) had normal weight (BMI < 25 kg/m²), 7 (16%) were overweight (BMI 25–30 kg/m²), and 3 (7%) were obese (BMI > 30 kg/m²). When the non-CAD and CAD groups were combined, we found that the EATV was higher in men than in women (80 ± 33 vs. 65 ± 21 cm³; p = 0.0089), but the mean EATV/height and EATV/BSA were comparable (Table 1).

Numerous studies suggest that the role of coronary risk factors in the progression of coronary atherosclerosis differ in men and women [25‐27]. EAT volume is reported to be associated with visceral adipose tissue (VAT) volume but not with subcutaneous adipose tissue volume [2, 3]. Greater VAT volume is more prevalent in men and is strongly associated with metabolic syndromes [13, 14, 27, 28], suggesting that the gender differences in this syndrome may contribute to gender differences in CAD [19]. Park et al. [29] reported that echocardiographically determined EAT thickness, a surrogate marker of total EAT volume [30, 31], was significantly increased in patients with metabolic syndrome and CAD, but the power of EAT thickness to predict metabolic syndrome and CAD was stronger in patients with less BMI (<27 kg/m²). Associations between whole body fat distribution and EAT volume, in men and women, need to be clarified in future studies. EAT volume can be a mere marker of metabolic syndrome or a local stimulator of atherosclerotic lesions [1‐4, 12, 32]. Although EATV accounts for ~1% of the total body fat mass, EAT volume accounts for 15–20% of the total cardiac volume and covers ~80% of the total cardiac surface [2‐4]. Products secreted by EAT can be delivered to atherosclerotic plaques via the vasa vasorum [12, 32]. It has been reported that the expression of pro- and anti-inflammatory cytokines was attenuated in EAT near coronary atherosclerotic lesions [10, 11, 33, 34]. Zhou et al. reported that decreased adiponectin mRNA expression was associated with enhanced expression of cytokines IL-6, TNF-α, or TLR4 in EAT [33]. Gao et al. reported that mRNA and protein expression of chemerin, a novel adipocytokine regulating immune responses and glucose and lipid metabolism, are higher in EAT of Chinese patients with CAD [34]. They also showed that the severity of coronary atherosclerosis is positively correlated with the chemerin mRNA level in EAT rather than its circulating level [34]. We previously reported that the expression of pro-inflammatory cytokines was positively correlated, and the expression of anti-inflammatory cytokines was negatively correlated, with the ratio of M₁/M₂ macrophages in epicardial adipose tissue of CAD patients [10, 11]. Thus, locally produced adipocytokine could enhance the progression of coronary atherosclerosis in men.

Greater CAD event rates in men than in women could be a result of the differences in coronary artery plaque burden and composition [35, 36]. The coronary plaque burden is lower in women, and plaque morphology differs by age and gender [35]. Plaque rupture with a large necrotic core and disrupted fibrous cap infiltrated by macrophage and lymphocytes is common in men and older women, while plaque erosion with no fibrous cap but with intima consist of smooth muscle and proteoglycan is common in younger women. Women have relatively less calcified plaques and mixed plaques than men [36]. Taken together, coronary plaque lesions can be more strongly activated in men through inflammatory process which is enhanced in EAT with or without the underlying metabolic syndrome [10, 11]. Because no correlation was found between EATV/BSA and Agatston score in non-CAD and CAD groups (Figure 4, lower panel), gender difference in coronary calcified lesion may not be related to the impact of EATV/BSA on coronary atherosclerosis in our subjects.

Angina-like chest pain with angiographically normal coronary arteries affects women more frequently than men [37]. These individuals often show microvascular dysfunction as detected by reduced coronary blood flow reserve (CFR) [38]. In women with microvascular dysfunction, multivariate regression analysis revealed epicardial fat thickness as the only independent predictor of microvascular dysfunction (p < 0.0001), although traditional atherosclerotic risk factors such as age, hypertension, HOMA-IR, and menopause did not predict women with abnormal microvascular function [39]. The impact of EATV on coronary microvascular dysfunction in men and women should also be studied in future studies.