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.

Public Health Relevance

The landmark PREDIMED trial has demonstrated that a Mediterranean dietary pattern enriched with extra virgin olive oil or mixed nuts significantly reduced incidence of cardiovascular disease (CVD), compared to a control diet. The goal of this project is to identify novel metabolomic signatures of the risk of heart failure, atrial fibrillation, and pheripheral artery disease, and investigate whether the dietary interventions in the PREDIMED trial mitigate the adverse associations between certain plasma metabolites and the these diseases. The study has the potential to discover novel pathways through which diet influences CVD risk, and will provide further evidence to support public health recommendations for dietary prevention of overall CVD and its subtypes.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cancer, Heart, and Sleep Epidemiology B Study Section (CHSB)
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Wright, Jacqueline
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Harvard University
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Satija, Ambika; Hu, Frank B (2018) Plant-based diets and cardiovascular health. Trends Cardiovasc Med 28:437-441
Pan, An; Lin, Xu; Hemler, Elena et al. (2018) Diet and Cardiovascular Disease: Advances and Challenges in Population-Based Studies. Cell Metab 27:489-496
Razquin, Cristina; Liang, Liming; Toledo, Estefanía et al. (2018) Plasma lipidome patterns associated with cardiovascular risk in the PREDIMED trial: A case-cohort study. Int J Cardiol 253:126-132
Yu, Edward; Malik, Vasanti S; Hu, Frank B (2018) Cardiovascular Disease Prevention by Diet Modification: JACC Health Promotion Series. J Am Coll Cardiol 72:914-926
Guasch-Ferré, Marta; Hu, Frank B; Ruiz-Canela, Miguel et al. (2017) Plasma Metabolites From Choline Pathway and Risk of Cardiovascular Disease in the PREDIMED (Prevention With Mediterranean Diet) Study. J Am Heart Assoc 6:
Toledo, Estefanía; Wang, Dong D; Ruiz-Canela, Miguel et al. (2017) Plasma lipidomic profiles and cardiovascular events in a randomized intervention trial with the Mediterranean diet. Am J Clin Nutr 106:973-983
(2017) Erratum for Yu et al. Increases in plasma tryptophan are inversely associated with incident cardiovascular disease in the Prevención con Dieta Mediterránea (PREDIMED) Study. J Nutr 2017;147:314-22. J Nutr 147:1234
Ruiz-Canela, Miguel; Hruby, Adela; Clish, Clary B et al. (2017) Comprehensive Metabolomic Profiling and Incident Cardiovascular Disease: A Systematic Review. J Am Heart Assoc 6:
Yu, Edward; Ruiz-Canela, Miguel; Hu, Frank B et al. (2017) Plasma Arginine/Asymmetric Dimethylarginine Ratio and Incidence of Cardiovascular Events: A Case-Cohort Study. J Clin Endocrinol Metab 102:1879-1888
Yu, Edward; Ruiz-Canela, Miguel; Guasch-Ferré, Marta et al. (2017) Increases in Plasma Tryptophan Are Inversely Associated with Incident Cardiovascular Disease in the Prevención con Dieta Mediterránea (PREDIMED) Study. J Nutr 147:314-322

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