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

摘要 这项建议旨在扩大和补充我们的R01资助的镉(Cd)病例队列研究和 急性心肌梗死(AMI)。在这里我们将添加砷(As)、钙(Ca)和镁(Mg)到我们的 病例队列研究，包括流行病学和毒物混合物分析。我们拥有的四个要素 被选中的药物因其在心血管疾病(CVD)中的独立作用和作为混合物而引人注目。AS 增加斑块的形成和与内皮的黏附，镉也会导致内皮功能障碍和 动脉粥样硬化；然而，尚不清楚砷和镉的作用是协同作用还是相互竞争。潜在地 抵消这些过程，镁对调节内皮功能是重要的。虽然钙的角色是模棱两可的，但它的 动脉钙化的作用是不可否认的，因此也要考虑到这一点。我们高效的病例队列 研究设计包括810例急性心肌梗死患者和由600名男性和600名女性组成的对比亚队列 从从不吸烟者中随机抽取有急性心肌梗死风险的人进行随访，利用基于预期人群的 丹麦饮食、癌症和健康队列。我们已经得到了资金来测量镉、肌酐、渗透压和 基线尿样中的可替宁。我们现在建议另外分析尿液中的砷、镁和钙 在被选入这项病例队列研究的约2000名参与者中，以及先前存在的食物频率 关于镁和钙的问卷调查数据。在目标1中，我们将评估As、Ca和Mg之间的关联， 和急性心肌梗死的发生率。这将是关于这些因素与急性心肌梗死关系的最大前瞻性研究之一。在……里面 目的2我们将应用混合方法(贝叶斯核机回归，加权分位数和回归， 随机森林)，以评估镉、砷、钙和镁与急性心肌梗死风险的相互作用和联合作用。在AIM 3我们将应用体外和体内方法来研究暴露于这些元素的联合影响 研究其毒理机制和活性途径。每个目标都是独立的、令人信服的和意志的 提供了重要的科学贡献，但结合起来，互补的方法有可能 提供证据，证明不同方法的结果是一致的。在体外对数据进行三角测量 活体和流行病学分析代表了NIEHS翻译的桥梁 研究框架。这个虚拟联盟的范围将丰富我们对这些关系的理解 Cd、As、Mg、Ca与CVD之间的关系。我们研究的其他创新特征包括利用现有的高效 病例队列设计，大样本量，大量急性心肌梗死事件，控制吸烟， 促动脉粥样硬化机制的体外分析和动脉粥样硬化的体内研究。接触的来源 这些元素是众所周知的，因此将这些元素的混合物识别为心血管 风险/保护因素可对预防和控制心血管疾病产生重大影响。

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.