Although the accurate diagnosis and prevention of coronary artery disease (CAD), acute myocardial infarction (AMI) and death is a major public health issue, risk stratification for CAD with current diagnostic tools is not properly supporting clinical decision making. RiskyCADs overall goal is to identify novel biomarkers for asymptomatic patients in high risk of major coronary events, and develop new diagnostic tools and personalized therapeutic strategies for this selected group of patients. Taking advantage of the latest technologies, we will look into new biomarkers for asymptomatic patients in high risk of CAD using some of the finest cohorts (WP1), identify new molecules and develop new diagnostic kits that will be further validated in additional cohorts (WP6). We will generate reprogrammed iPS cell based human models for the study of metabolic aberrations in selected individual vulnerable CAD patients (WP2). We will identify defects, e.g. in liver lipid metabolism, in high risk CAD patients (WP3) and test targeted treatments in traditional and new preclinical animal models to provide proof-of-concept level evidence (WP4, WP5). As our approach is based on well characterized patients and phenotypes, we will generate clinically applicable stratification methods that will allow targeted treatment and patient enrichment for clinical trials (WP1). Unique predictive modelling and link identification platforms including Drug Repositioning will be used to select drugs or drug combinations that will best match the patients biomarker profile (WP7). The final (translational) outcomes of this project will be: (i) a set of distinct biomarker test(s) for asymptomatic patients in high risk of CAD that can be ordered both by primary care physicians and specialized cardiologists from routine clinical laboratories; (ii) new CAD risk estimation models; (iii) a set of repositioned drugs ready to be exploited further for the optimal treatment of patients in high risk of CA...