Imaging detected coronary and carotid atherosclerosis in the general population: is prevalence still different between sexes?

This editorial refers to ‘Sex differences in prevalence and characteristics of imaging-detected atherosclerosis: a population-based study’, by E. Swahn et al., https://doi.org/10.1093/ehjci/jeae217. Cardiovascular diseases are the most common cause of death in Europe, whereby age-standardized rates of both morbidity and death are significantly higher in men than in women.1 Consistent differences exist in epidemiology, pathophysiology, clinical manifestations, and outcomes of cardiovascular diseases between women and men.2 In men, coronary atherosclerosis is more likely to manifest by acute coronary syndromes, 10 years earlier as compared with women, largely as the result of both biological and sociocultural factors.2 However, in recent decades the occurrence of ischaemic heart disease events in younger women is increasing, indicating a potentially more aggressive course of disease once established.3 Sex-based differences in peripheral artery disease epidemiology are also evident, with a similar or higher prevalence of lower extremities artery disease4 and fewer carotid plaques in women than in men.5 At post-menopause, the risk of atherosclerotic diseases increases in women in relation to changes in cardiometabolic profiles, including lipid and glucose metabolism, and inflammation that are differently regulated by hormones in men and women.6 This highlights the importance of sex-specific medical strategies to improve prognosis and treatment outcomes. Moreover, consistent sex-related differences in the effectiveness of the diagnostic strategies for cardiovascular diseases should be also acknowledged. In patients with suspected ischaemic heart disease, a higher rate of non-diagnostic imaging findings and lower overall accuracy is observed in women than in men,7 whereby almost 80% of young women (below age 60) show normal coronary arteries at invasive coronary angiography, as compared with only 40% of men.8 Coronary computed tomography angiography (CCTA) allows the detection of earlier stages of atherosclerotic disease. CCTA imaging studies have highlighted differences in the plaque characteristics between sexes, with women showing less calcific and more fibrous plaques than men, which might not be identified by using other imaging approaches that focus on calcification, such as coronary calcium score (CACS).9,10 While several population studies have been conducted so far, the relative weight of either lifestyle, socioeconomic and conventional risk factors in predicting sex differences in the prevalence and characteristics of imaging-detected coronary and peripheral atherosclerosis has been loosely investigated. In this regard, the study by Swahn et al.11 evaluated the prevalence of any imaging finding of coronary and carotid atherosclerosis in a primary-prevention population including subjects between 50 and 65 years of age from the Swedish Cardiopulmonary Bioimage Study (SCAPIS).12 Patients underwent CCTA and carotid ultrasounds, primary aiming at determining the presence and magnitude of sex-related differences in the detection rate of atherosclerotic plaques. To avoid possible interference by major confounders, the magnitude of any association between sex, either carotid or coronary atherosclerosis was assessed after extensive multivariable adjustment for major cardiovascular risk factors, as well as relevant socioeconomic and lifestyle factors. While atherosclerosis was only categorized in a binary fashion (as the presence of any plaque at imaging assessment), for the coronary district three additional definitions were used to capture (to some extent) the severity of the vascular involvement (i.e. presence of coronary stenosis ≥ 50%, segment involvement score≥ 4, and CACS > 100). Of the > 30 k patients enrolled in the SCAPIS, a final population of roughly 25 k subjects with no history of atherosclerotic vascular disease and with paired CCTA and carotid ultrasounds data were selected (49% being male and 51% being female). At primary analysis, men had consistently more coronary and, to a lesser extent, carotid atherosclerosis than women. Specifically, while any coronary plaque was revealed in 56% of men, only 9% of them showed ≥ 50% stenosis, proportions dropping to 29 and 2% in women, respectively (P < 0.01). Similarly, a CACS > 0 and > 100 was detected in 56 and 18% of men, respectively, both proportions dropping to 27 and 5% in women (P < 0.01). Similar trends were revealed in all patients’ age classes and persisted even after multivariable adjustment, with men demonstrating approximately a 3-times higher rate of any coronary artery disease (CAD) and 1.5-times higher rate of coronary atherosclerosis. The highest prevalence of atherosclerosis in women occurred in the oldest age strata (≈ 50% rate of any CAD and ≈ 4% rate of ≥ 50% coronary stenosis) corresponding to 10 – 14 years younger men. Among major cardiovascular risk factors, only smoking interacted with sex in predicting a higher rate of atherosclerosis. The authors should be congratulated for having provided interesting data on a mostly low-risk population of patients (as demonstrated by the low prevalence of major cardiovascular risk factors), underrepresented in multimodality imaging studies. The study by Swahn et al.12 further extends the original results of the SCAPIS that had already reported a ≈ 2 times higher crude prevalence of CAD in randomly selected, primary prevention, middle-aged men vs. women. The central message of the present study is somehow in line with the general knowledge of an overall lower atherosclerotic risk in women than in men. However, a lower prevalence of CAD was also demonstrated in aged women than in matched men and this may seem at odds with solid epidemiological data showing an accrual of major cardiovascular risk factors and, hence, coronary events in elder women who currently represent most of the patients suffering an acute coronary syndrome after age 75.2 These apparently conflicting findings may result from some limitations of the SCAPIS protocol. The definition of vascular atherosclerosis that was used by Swahn et al.,11 whereby both carotid and coronary disease were defined in a dichotomous fashion (i.e. presence or absence of any plaque or stenosis), might have underestimated the real burden of atherosclerotic disease. Recent data underline how emerging cardiometabolic risk factors (i.e. high fasting plasma glucose, low high-density lipoprotein cholesterol, and high triglycerides), which more frequently manifest in post-menopausal women,6 are associated with whole heart coronary plaque volume at CCTA, and both are strong predictors of rapid coronary plaque progression and events at follow-up, independently of other risk factors and current treatments.13 The SCAPIS protocol did not include either quantitative and longitudinal assessment of coronary plaque extent, and this could have limited the recognition of a more diffuse and progressive disease in particular in older women. Moreover, only scant data were provided by Swahn et al. on the impact of sex on atherosclerotic plaque characteristics, which are relevant determinants of risk both in patients with carotid disease5 and coronary disease in whom plaque composition may also condition downstream myocardial perfusion abnormalities.14,15 Future observational CCTA studies focusing on quantification of coronary plaque burden and components might unveil the role of sex with its hormones and socioeconomic factors on plaque characteristics and their evolution over time. The authors should be also credited for having provided additional data on the impact of sex on CACS, whose use is supported by current guidelines for intermediate-risk patients’ characterization in conjunction with risk scores. However, recent data have questioned the possible role of CACS in patients at risk for CAD, since a non-negligible number of patients with a CACS = 0 have coronary plaques at CCTA, a finding of particular importance both in younger patients as well as in those at higher estimated baseline risk.12 While the present sub-analysis of the SCAPIS provided initial data on the impact of sex on the multisite vascular diseases, the lack of information on sex differences in the occurrence of lower extremities atherosclerotic disease, whose strong association with adverse coronary events has been repeatedly underlined,4 demands a dedicated assessment. The study by Swahn et al.11 provided an updated snapshot on sex differences in the prevalence of coronary and carotid plaques in a large population of presumably low-risk patients. While the study results may possibly aid in the risk stratification of primary-prevention patients, further analyses exploring the prevalence and characteristics of a more diffuse coronary atherosclerosis in elder women as compared with men and the predictors of (rapid) plaque progression in patients at risk of multisite vascular disease are eagerly awaited. None declared. No new data were generated or analysed in support of this paper.