Sex differences in compositional plaque volume progression in patients with coronary artery disease

OBJECTIVES This study sought to explore sex-based differences in total and compositional plaque volume (PV) progression. BACKGROUND It is unclear whether sex has an impact on PV progression in patients with coronary artery disease (CAD). METHODS The study analyzed a prospective multinational registry of consecutive patients with suspected CAD who underwent 2 or more clinically indicated coronary computed tomography angiography (CTA) at $ 2-year intervals. Total and compositional PV at baseline and follow-up were quantitatively analyzed and normalized using the analyzed total vessel length. Multivariate linear regression models were constructed. RESULTS Of the 1,255 patients included (median coronary CTA interval 3.8 years), 543 were

C ardiovascular disease (CVD) remains a leading cause of mortality and morbidity in both women and men, but the overall CVD mortality has dramatically declined over recent decades as a result of preventive strategies (1). However, the decline in CVD mortality has been far less significant for women (1)(2)(3), and they continue to have higher mortality rates than men, although women generally present with smaller plaque burden and less obstructive coronary artery disease (CAD) (4)(5)(6)(7)(8)(9). Pathologic and invasive angiographic evidence has also suggested sex-specific differences in atherosclerotic plaque profiles, with plaque erosion more frequently observed in women and plaque rupture more frequent in men (4,5,9). Overall, these findings To address these issues, evaluation of the atherosclerotic burden and its changes over the entire coronary artery, instead of visualizing a few selected lesions or segments, is mandatory, as CAD is a dynamic disease with plaques at various stages that can coexist in a single patient, whereby 1 plaque may just be developing while another is stabilizing or even regressing (10). In this regard, coronary computed tomography angiography (CTA) may represent an optimal imaging modality, as it allows not only simplified detection of the presence of CAD, but also quantification of the composition within plaques and detection of its changes across the entire coronary vasculature (11). Recent studies have also demonstrated a direct association between the overall atherosclerotic burden and characteristics of individual plaques assessed by coronary CTA and clinical outcomes (12)(13)(14).
Hence, we explored the sex differences in overall and compositional atherosclerotic burden according to age group and evaluated whether the total and compositional plaque volume (PV) progression rate also differed according to sex in patients with CAD from a large multicenter registry of serial coronary CTAs. Coronary CTA datasets were transferred to a core laboratory for analysis by Level III experienced readers using semi-automated plaque analysis software (QAngioCT Research Edition v2.1.9.1, Medis Medical Imaging Systems, Leiden, the Netherlands) with manual correction as described previously (18,19).

METHODS
Briefly, for the determination of atherosclerotic plaque burden across the entire coronary tree, all coronary segments and lesions with diameters $2 mm were evaluated for every coronary artery and its branches using a modified 17-segment American Heart Association model (17,20). The presence of an atherosclerotic plaque was defined as any tissue $1 mm 3 within or adjacent to the lumen that could be discriminated from the surrounding pericardial tissue, epicardial fat, or lumen, and identified in $2 planes (17,20). For serial comparisons of coronary CTAs, coronary segments and lesions were coregistered between the coronary CTA-1 and coronary CTA-2 evaluations using fiduciary landmarks, including the distance from the ostium and the branch vessels.
To determine the overall atherosclerotic plaque burden of a patient, total PV (mm 3 ) was determined by summing the PVs of each segment (21 To account for the difference in the total vessel length between patients, particularly between women and men, and to provide equal weighting of Propensity score matching between women and men in 1:1 manner using same variables used in the multivariate linear regression analysis was performed to assess the contribution of each plaque compositions to every 100 mm 3 total PV progression (28).
A 2-tailed p value <0.05 was considered statistically significant. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, North Carolina) and R 3.3.0 (R Foundation for Statistical Computing, Vienna, Austria).

STUDY POPULATION AND BASELINE CHARACTERISTICS.
Overall, 543 women and 712 men were included in the study ( Table 1). Women were about 3 years older and had a lower body mass index than men (61. 9  to 109.14 mm 3 ]; p < 0.001) and all of its constituents.
There was no difference in calcified PV (p ¼ 0.106).
Total and compositional PVs showed an exponential increase in both women and men when stratified according to age group ( Figure 2 and all of its components. The progression rate of calcified PV did not differ between sexes (p ¼ 0.670).
Upon stratifying according to age groups ( Figure 2), the progression rate of total PV was relatively parallel between women and men. The annual total PV Values are mean AE SD or n (%).
ACC ¼ American College of Cardiology; CAD ¼ coronary artery disease; CTA ¼ computed tomography angiography; CTA-2 ¼ follow-up coronary computed tomography angiography; HDL ¼ high-density lipoprotein; LDL ¼ low-density lipoprotein. Compositional Plaque Progression on the Basis of Sex change rate of men at 54 years of age, in which the total PV reached 100 mm 3 , was similar to women at 64 years of age, demonstrating a similar age gap as that of the total PV. The progression rate of calcified PV was similar for women and men throughout the age group, but the noncalcified PV progression rate continued to be higher in men.
In multivariate analysis adjusting for age, risk factors, lipid level, statin use, and total PV at baseline, there was no effect of female sex on the total PV progression rate (p ¼ 0.677) ( Table 3). However, women were associated with greater calcified PV progression (b ¼ 2.832; p ¼ 0.004) but slower noncalcified PV progression (b ¼ -3.387; p ¼ 0.008) than men. Women were also associated with less devel- including low-attenuation plaques and spotty calci- When PVs were stratified according to age group after propensity score matching using the same variables adjusted for in the multivariate linear regression analysis, including total PV at baseline (Supplemental Table 2  Values are median (interquartile range) or n (%). *High-risk plaque is defined as a lesion with $2 features indicative of positive arterial remodeling, low-attenuation plaque, or spotty calcification. †Noncalcified PV is the summation of fibrous, fibrofatty, and necrotic core PV.
Moreover, once the total PV was matched in women and men, the progression rate of total PV showed no sex differences, and female sex had no effect on total PV progression rate in multivariate analysis. These  Values are n (%) or median (interquartile range). *High-risk plaque is defined as a lesion with $2 features indicative of positive arterial remodeling, low-attenuation plaque, or spotty calcification. †Noncalcified PV is the summation of fibrous, fibrofatty, and necrotic core PV.
Abbreviations as in Table 2.
CACS ¼ coronary artery calcium score; other abbreviations as in Table 2.
Lee et al.   Compositional Plaque Progression on the Basis of Sex