The long-term impact of traditional risk factors for atherosclerosis: analysis by sex and by arterial territory

Abstract Background Risk factors for atherosclerosis have been associated with cardiovascular disease events (CVDE) in all arterial territories. However, these observations are limited by relatively short-term follow-up (i.e. ten years), focus on a limited number of outcome events and often lack sex- and territory specific analyses. We therefore investigated sex-stratified associations between risk factors for atherosclerosis and territory-specific CVDE in a large, prospective cohort with ≥20 years follow-up. Methods We included individuals without baseline CVD from the EPIC Norfolk prospective population cohort. To evaluate associations with the first occurrence of a CVDE, competing risk-adjusted regression analysis was conducted for three dichotomized risk factors: low-density lipoprotein cholesterol (LDL-C) 3 mmol/L, systolic blood pressure (SBP) 140 mmHg, and smoking. CVDE were defined as hospitalisation or death due to ischemic heart disease (IHD), ischemic stroke, haemorrhagic stroke, peripheral arterial disease (PAD), or aortic aneurysm (AA). Participants were followed-up until first event, non-CVD death (competing risk) or end of study (15-03-2018). In territory-specific analyses, first CVDE in other territories were considered competing risks. We stratified analyses by sex, and adjusted for age, diabetes, HDL-c, kidney function, and body mass index. Results We included 23,581 participants (56% women) with a median baseline age of 58 years interquartile range (IQR) 51-66. LDL-C was 3 mmol/L in 82% of participants, SBP was 140 mmHg in 36%, and 12% were smokers. During a median follow-up of 21.3 years (IQR 19.0-22.8), men had higher CVDE rates than women (33% vs. 22%, p0.001). Overall, the first event was IHD in 17%, ischemic stroke in 3.6%, haemorrhagic stroke in 1.4%, PAD in 3.1% and AA in 1.4%. In the sex-stratified analyses, elevated LDL-C was associated with increased total CVD risk in men, adjusted hazard ratio (aHR) 1.41, 95% confidence interval (CI) 1.26–1.58 mainly driven by IHD and PAD, whereas in women, LDL-C showed no significant association with events across any of the arterial territories (e.g. Total CVD: aHR 1.09, 95% CI 0.96–1.23). Elevated SBP was associated with total CVD risk in both men and women (aHR 1.29, 95% CI 1.20-1.39 and aHR 1.34, 95% CI 1.23-1.45), with a numerically stronger link to hemorrhagic stroke in men (aHR 1.61, 95% CI 1.20-2.18) than in women (aHR 1.17, 95% CI 0.89-1.53). Smoking was the strongest contributor to total CVD risk in both sexes (men: aHR 1.59, 95% CI 1.44–1.76; women: aHR 1.77, 95% CI 1.58–1.98), with no significant sex differences across arterial territories. Conclusion The impact of risk factors was consistent across arterial territories. There were however significant differences between men and women, particularly in the impact of LDL-c. This suggests sex-specific differences in pathophysiology. These findings support sex-specific approaches to CVD risk assessment and management.