New and old cardiovascular risk factors: C-reactive protein, homocysteine, cysteine and von Willebrand factor increase risk, especially in smokers

The relative importance of new risk factors for heart disease singly or in combination is uncertain. We assessed relationships between C-reactive protein, homocysteine, cysteine, von Willebrand factor, activated factor XII and stable heart disease, as well as interaction with established risk factors. A case-control study of 260 cases of stable heart disease from the Irish component of the European Action on Secondary Prevention through Intervention to Reduce Events (EUROASPIRE) II cohort and 260 age, sex-matched controls. C-reactive protein, homocysteine, cysteine, von Willebrand factor, activated factor XII and conventional risk factors were assayed or recorded. Interaction effects between new and conventional factors were assessed using additive and multiplicative models. C-reactive protein, homocysteine, cysteine and von Willebrand factor were significantly higher in cases than controls. Comparing the top fifth with the bottom four-fifths showed independent associations between heart disease and C-reactive protein [odds ratio (OR) 1.79; 95% confidence interval (CI) 1.12-2.86; P = 0.01], cysteine (OR 2.00; 95% CI 1.25-3.20; P = 0.004), von Willebrand factor (OR, 3.0; 95% CI 1.9-4.8; P < 0.0001). For homocysteine, the association was independent comparing the top tenth to the bottom nine-tenths (OR 1.95; 95% CI 1.02-3.41; P = 0.04). Activated factor XII was not associated with risk. The association between C-reactive protein and disease was U-shaped and a graded association existed between homocysteine, cysteine, von Willebrand factor and disease. C-reactive protein, homocysteine, cysteine and von Willebrand factor considerably increased risk associated with other factors, particularly smoking. Independent associations exist between stable heart disease and C-reactive protein, homocysteine, cysteine and von Willebrand factor. Strong combined effects were observed between these and conventional risk factors, particularly smoking. Smoking cessation may profoundly reduce risk associated with other risk factors. We found no evidence of a relationship between activated factor XII and disease.