Interaction between subclinical carotid atherosclerosis endotype and biological sex: a study from IMPROVE cohort

Abstract Background Carotid-intima media thickness (c-IMT) is a measure of subclinical carotid atherosclerosis and a predictor of future atherosclerotic cardiovascular events (ASCVD). We have recently generated, using an artificial intelligence approach, four endotypes (E) of subclinical atherosclerosis, i.e. subgroups of individuals predisposed to both c-IMT progression and ASCVD. Each E is defined by a set of demographic, clinical, and molecular data and characterize individuals with a low (E1), intermendiate (E2), high (E3) and very high (E4) cardiovascular risk profile. We observed an unbalanced distribution of males and females across the 4 endotypes, with a higher prevalence of female in the low risk E1. Purpose To estimate the interaction between biological sex and the 4 endotypes on measures of c-IMT progression and ASCVD risk. Methods We performed our study on 3121 individuals from the IMPROVE cohort, which includes participants with at least three ASCVD risk factors. We estimated the interaction between biological sex and the endotypes generated in the IMPROVE on (1) c-IMT and carotid plaque measurements after 30 months of follow-up (c-IMTfastest-progr, Area of plaquesbulb-progr) by linear regression (β, SE) and (2) with the 3-year ASCVD risk by Cox [hazard ratio (HR), 95% confidence interval (CI)] regression model. Crude estimates were adjusted by batch effect for biomarker measurement, geographical region and/or baseline ultrasonographic measures. Adjusted models further included ASCVD common risk factors. Results As shown in Figure 1, we did not observe any significant interaction between endotypes and biological sex on 30-month carotid ultrasound progression measures, and 3-year-ASCVD risk. In both the crude and adjusted models on c-IMTfastest-progr, Area of plaquesbulb-progr, and 3-year ASCVD, the p-value for interaction ranged from 0.18 to 0.98. While E4 was associated with the strongest cardiovascular risk profile in both males and females. Conclusions Our results indicate that the association between endotypes and progression of subclinical atherosclerosis and ASCVD risk mirrors a specific risk profile not entirely explained by differences in biological sex.