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.
This study shows that common risk factors – high cholesterol, high blood pressure, and smoking – are linked to different first events of cardiovascular disease.Risk factors and first events of cardiovascular disease: Although there is overlap in how these risk factors contribute to different types of cardiovascular disease, the magnitude of their effects differs. For all cardiovascular events combined, smoking was the strongest risk factor. Smoking was especially strongly linked to abdominal aortic aneurysm, with greater impact than high cholesterol and high blood pressure combined. High blood pressure was the most important risk factor for both ischemic and haemorrhagic stroke. The risk of ischemic heart disease increased stepwise with each additional factor.Sex-Specific associations: High cholesterol was more strongly associated cardiovascular disease in men, while elevated systolic blood pressure was more strongly associated with events in women, particularly for ischemic heart disease and peripheral artery disease. These variations suggest underlying pathophysiological differences.
© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.