Heart failure (HF), atrial fibrillation (AF), and peripheral artery disease (PAD) have emerged as important cardiovascular diseases (CVDs) contributing to the increasing burden of chronic diseases and escalating health care costs in the United States and globally. Recent advances in metabolomics have allowed investigators to assay hundreds of metabolites from a small volume of blood, providing a comprehensive picture of an individual’s metabolic status that may underlie the effects of diet on disease risk. However, few studies have assessed the association between metabolite profiles and risk of HF, AF, and PAD. In this competing rewewal application, we propose a nested case-control design to conduct targeted and untargeted metabolomics analyses of incident cases of HF (n=332), AF (n=594), and PAD (n=196) and matched controls in a cohort of 7,447 participants during the active intervention and extended follow-up periods (2003-2018) in the PREDIMED trial. Our specific aims are: 1). To examine the associations between approximately 400 known metabolites at baseline and risk of HF, AF, and PAD, using a nested case-control design. 2). To conduct pathway analysis and agnostic network modeling that integrate non-targeted metabolites with known metabolites to identify novel metabolomic signatures of risk of HF, AF, and PAD. 3). To assess whether the randomized dietary interventions modify the effect of baseline metabolite profiles on HF, AF, and PAD risk. In addition, we will explore both unique and common metabolites and metabolic pathways associated with incident HF, AF, and PAD and will replicate novel metabolites identified in the PREDIMED cohort in the Atherosclerosis Risk in Communities (ARIC) study, an independent multi-ethnic cohort in the US. This competing renewal application represents an extension of our long-standing research on the Mediterranean diet and CVD to new clinical endpoints in the context of the landmark PREDIMED trial. This research has important implications for the US population because the current Dietary Guidelines for Americans recommend the Mediterranean diet as one of healthy dietary patterns for CVD prevention. The current cycle of the grant has been highly productive with 11 papers published or submitted, contributing to new knowledge about mechanisms underlying diet and CVD and new statistical methods for analyzing nutritional metabolomics data. This competing renewal, built on the numerous strengths of the PREDIMED trial and a multi-disciplinary and cohesive team, has the potential to advance our understanding of CVD pathophysiology and produce knowledge that can directly inform specific dietary interventions to prevent overall CVD and its subtypes.