BACKGROUND: Conventional cardiac risk scores may not be completely accurate in predicting acute events because they only include factors associated with atherosclerosis, considered as the fundamental precursor of cardiovascular disease. In UK in 2006-2008 (Whitehall II study) we tested the ability of several risk scores to identify individuals with cardiac cell damage and assessed to what extent their estimates were mediated by the presence of atherosclerosis. METHODS: 430 disease-free, low-risk participants were tested for high-sensitivity cardiac troponin-T (HS-CTnT) and for coronary calcification using electron-beam, dual-source, computed tomography (CAC). We analysed the data cross-sectionally using ROC curves and mediation tests. RESULTS: When the risk scores were ranked according to the magnitude of ROC areas for HS-CTnT prediction, a score based only on age and gender came first (ROC area=0.79), followed by Q-Risk2 (0.76), Framingham (0.70), Joint-British-Societies (0.69) and Assign (0.68). However, when the scores were ranked according to the extent of mediation by CAC (proportion of association mediated), their order was essentially reversed (age&gender=6.8%, Q-Risk2=9.7%, Framingham=16.9%, JBS=17.8%, Assign=17.7%). Therefore, the more accurate a score is in predicting detectable HS-CTnT, the less it is mediated by CAC; i.e. the more able a score is in capturing atherosclerosis the less it is able to predict cardiac damage. The P for trend was 0.009. CONCLUSIONS: The dynamics through which cardiac cell damage is caused cannot be explained by 'classic' heart disease risk factors alone. Further research is needed to identify precursors of heart disease other than atherosclerosis.