Differences in long-term impact of traditional risk factors for atherosclerosis on different arterial territories Insights from over 20 years of follow up in the EPIC-Norfolk prospective population study

Abstract Background and Aim The relative impact of risk factors for atherosclerosis on cardiovascular disease (CVD) events differs among arterial territories. Most studies investigating these associations comprised CVD patients, had short follow-up or lacked sex- and territory specific analyses. We therefore investigated associations between risk factors for atherosclerosis and territory-specific CVD in a large cohort with ≥20 years follow-up. Methods EPIC Norfolk participants without CVD were analysed for the association between first CVD event and three dichotomized risk factors: low-density lipoprotein cholesterol (LDL-C) 3 mmol/L, systolic blood pressure (SBP) 140 mmHg, and smoking, assessed individually and in clusters, with multivariable adjustment. Events included hospitalisation or death due to ischemic heart disease (IHD), ischemic stroke, haemorrhagic stroke, peripheral arterial disease (PAD) or aortic aneurysm (AA). Sex-specific estimates were obtained from interaction terms. Results In 23,581 participants (56% women, median age 58 (IQR 51-66)) with median follow-up 21.3 years, 26.4% experienced ≥1 CVD event. First CVD event incidence was 1.7 times higher in men. Total CVD was associated with LDL-C (aHR 1.35, 95%CI1.24-1.46), SBP (1.29, 1.22-1.37), and smoking (1.69, 1.56-1.82), with overlapping impact across territories. IHD risk increased with each additional factor (all three: aHR 2.86, 2.36-3.48). SBP was the most important risk factor for ischemic and haemorrhagic stroke (aHR 1.45, 1.29-1.64; 1.34, 1.10-1.64). Smoking was most strongly associated with AA (aHR 3.56, 2.93-4.34), exceeding the impact of LDL-C and SBP combined (aHR 1.78, 1.16-2.71). Associations of LDL-C with total CVD were stronger in men than in women (aHR 1.47, 1.19-1.80 vs 1.20, 1.06-1.35; p=0.018), while SBP showed stronger associations in women than in men for IHD (1.36, 1.24-1.50 vs 1.20, 1.02-1.40; p=0.037) and PAD (1.49, 1.26-1.76 vs 1.12, 0.86-1.47; p=0.008). Conclusions Risk factor impact was consistent across arterial territories, but variation in magnitude and sex differences suggest underlying pathophysiological distinctions.