Cardiometabolic diseases (CMD) are a major cause of morbidity and mortality, especially among African Americans. CMD originates in youth, focusing prevention to the earliest stages before clinically overt cardio-vascular disease (CVD) or its risk factors develop. We have established that (1) subclinical CVD is present in children and young adults and forecasts long-term adverse CVD outcomes; (2) adverse CMD trajectories ap-pear in youth and are associated with mid-life CVD, specifically in African Americans. Here, we extend this pre-liminary work to identify molecular biomarkers in young adulthood that reflect cardiometabolic health transitions through life and how they impact long-term CMD and CVD risk phenotypes. Given their ability to reflect metabolism at a cellular level, we have chosen to perform metabolite profiling and quantification of extracellular RNAs (ex-RNAs) in a large NHLBI cohort. While specific changes in circulating metabolite patterns (e.g., branched chain amino acids) discriminate long-term diabetes risk in large studies, no studies have included a large num-ber of African Americans or younger individuals (before clinical CMD/CVD develops), and have not examined subclinical CMD/CVD phenotypes. In addition, we recently demonstrated circulating ex-RNAs associated with CMD (insulin resistance, hepatic/visceral fat) in older Caucasians in the Framingham Heart Study (FHS; via UH2-TR000921). We and others have demonstrated that ex-RNAs are associated with insulin resistance and adverse metabolite profile (branched chain amino acid) in children, and may regulate formation of these metabolites. While these data suggest an early clinical and functional role for metabolites and ex-RNAs in CMD, lack of large studies in young populations including African Americans, detailed CMD/CVD phenotypes, and long-term follow-up limit their translation. Here, we will directly address this limitation by performing metabolite profiling and RNA quantification in 2,400 biracial participants of the Coronary Artery Risk Development in Youth (CARDIA) study (at Year 7 Exam; mean age 32). We hypothesize that metabolites and ex-RNAs in early adult-hood are associated with long-term risk of CMD/CVD outcomes >20 years later. We will determine metabolite profiles in early adulthood that identify individuals in poorer lifetime CMD trajectories and how these profiles im-pact long-term risk of CMD (e.g., visceral/hepatic adiposity and metabolic syndrome; SA1). We will investigate how early adverse metabolite profiles impact mid-life subclinical CVD (cardiac hypertrophy, coronary and aor-tic calcification, fitness; SA2). Finally, following our results in FHS, we will determine whether circulating ex-RNAs differ in CARDIA participants across CMD trajectories and how ex-RNAs impact the metabolome (SA3). Our multidisciplinary team of investigators experienced in CMD and large cohort molecular profiling in conjunc-tion with phenotyping within CARDIA will address a central strategic goal of NHLBI by identifying early bi-omarkers of lifetime CMD trajectories. Successful completion will provide a publically available resource to a broader scientific community for investigation of CVD in a young, biracial population at high lifetime risk.
|Effective start/end date||3/1/20 → 2/28/22|
- Massachusetts General Hospital (230189//5R01HL136685-04)
- National Heart, Lung, and Blood Institute (230189//5R01HL136685-04)