Metal-nutrient mixtures in epidemiologic and toxicologic studies of cardiovascular disease

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Abstract This proposal is designed to extend and complement our R01-funded case-cohort study of cadmium (Cd) and acute myocardial infarction (AMI). Herein we will add arsenic (As), calcium (Ca), and magnesium (Mg) to our case-cohort study and include epidemiologic and toxicologic mixtures analyses. The four elements we have selected are compelling for their independent role in cardiovascular disease (CVD) and as a mixture. As increases plaque formation and adhesion to endothelium and Cd also induces endothelial dysfunction and atherosclerosis; yet it is not clear if the effects of As and Cd are synergistic or competing. To potentially counteract these processes, Mg is important for modulating endothelial function. While Ca’s role is equivocal, its role in calcification of the arteries is undeniable, making it important to consider as well. Our efficient case-cohort study design includes 810 cases of AMI and a comparison subcohort of 600 men and 600 women selected randomly from never smokers at risk of AMI at the start of follow-up, leveraging the prospective population-based Danish Diet Cancer and Health Cohort. We are already funded to measure Cd, creatinine, osmolality, and cotinine in baseline urine samples. We now propose to additionally analyze As species, Mg, and Ca in urine among ~2000 participants selected into this case-cohort study, along with pre-existing food frequency questionnaire data on Mg and Ca. In Aim 1 we will evaluate the association between each of As, Ca, and Mg, and incidence of AMI. This will be one of the largest prospective studies of these elements in relation to AMI. In Aim 2 we will apply mixtures methods (Bayesian kernel machine regression, weighted quantile sum regression, random forests) to evaluate the interactive and joint effects of Cd, As, Ca, and Mg in relation to AMI risk. In Aim 3 we will apply in vitro and in vivo approaches to study combined effects of exposure to these elements to investigate the toxicologic mechanisms and pathways of activity. Each Aim is independently compelling and will provide important scientific contributions but together the complementary approaches have the potential to provide evidence of consistency in findings across the distinct approaches. Triangulating data across in vitro, in vivo and epidemiologic analyses represents a translational bridge as depicted in the NIEHS translational research framework. The scope of this virtual consortium will enrich our understanding of the relationships between Cd, As, Mg, Ca, and CVD. Other innovative features of our study include leveraging an existing efficient case-cohort design, large sample size, a large number of incident AMI events, controlling for tobacco smoking, in vitro assays of pro-atherogenic mechanisms, and in vivo studies of atherosclerosis. Sources of exposure to these elements are well known, therefore the identification of mixtures of these elements as cardiovascular risk/protective factors can have major implications for the prevention and control of CVD.