Urine Cadmium and Risk of Cardiovascular Disease

摘要 心血管疾病（CVD）是美国和全球发病率和死亡率的主要原因。尽管 虽然心血管疾病的危险因素已经确定，但许多病例仍然无法解释。镉是一种重金属 显示在动物中损伤血管组织、诱导内皮功能障碍和促进动脉粥样硬化， 机械研究。流行病学研究已经将镉与心血管终点联系起来， 高血压、外周动脉疾病和心血管死亡率。将镉作为一种 然而，由于缺乏前瞻性发病率研究，心血管危险因素的研究受到限制。此外 很少有研究有足够的统计能力来调查从不吸烟者与吸烟的关系。 缓解对吸烟可能造成混淆的严重担忧。建议的目标 本研究旨在调查心血管事件与镉暴露之间的关系， 与一般人群中从不吸烟者相关的水平。人体接触镉 主要是通过不同的食物类型和香烟烟雾。摄入后，镉主要储存在 肾，在肾中保留数十年（半衰期：10-30年）。一小部分镉会慢慢排出体外， 尿液中的镉，使尿镉长期暴露的一个公认的生物标志物。我们将利用 来自19，000多名从不吸烟的参与者的现有样本和数据， 丹麦饮食癌症和健康队列，招募1993-1997年的参与者，并收集当时的尿液。 我们将包括人口统计学，行为和临床数据，从长达20年的随访，以前瞻性 评估镉暴露与临床心血管事件之间的关系。使用病例队列 研究设计：我们将选择卒中（N=549）、急性心肌梗死（N=641）和心力衰竭病例 （N=761），以及600名男性和600名女性的比较子队列。微量金属、肌酸酐、渗透压摩尔浓度和 将在基线尿样中分析可替宁。作为次要目标，我们将应用中介分析 使用基于反事实框架的方法来估计镉对环境的影响程度， 中风、心力衰竭和急性心肌梗死可能通过高血压介导， 高胆固醇血症和糖尿病。中介分析的结果可能有助于确定其他目标 干预以及帮助理解镉在这些CVD的病理生理学中的作用 事件我们提出的研究将是首批量化镉与 在一项针对从不吸烟队列的纵向研究中，镉的来源 众所周知，环境中的镉，包括磷肥;由于广泛的镉暴露， 通过食物接触镉可以通过控制肥料来降低， 心血管危险因素对心血管疾病的预防和控制具有重要意义。

Abstract Cardiovascular disease (CVD) is the major cause of morbidity and mortality in the US and globally. Despite established risk factors for CVD, many cases remain unexplained. Cadmium is a heavy metal that has been shown to damage vascular tissues, induce endothelial dysfunction and promote atherosclerosis in animal and mechanistic studies. Epidemiologic studies have linked cadmium to cardiovascular endpoints such as hypertension, peripheral arterial disease, and cardiovascular mortality. Establishing cadmium as a cardiovascular risk factor, however, has been limited by the lack of prospective incidence studies. In addition few studies have had sufficient statistical power to investigate the association among never smokers to alleviate serious concerns about potential confounding by tobacco smoking. The objective of this proposed study is to investigate the association between incident cardiovascular outcomes and cadmium exposure at levels that are relevant to the general population among never-smokers. Human exposure to cadmium occurs primarily via diverse food types and cigarette smoke. Following intake, cadmium is stored predominantly in the kidney, where it remains for decades (half-life: 10-30 years). A small portion of cadmium is slowly excreted in the urine, making urinary cadmium a well-established biomarker of long-term exposure. We will leverage existing samples and data from the 19,000+ never-smoking participants in the prospective population-based Danish Diet Cancer and Health Cohort which recruited participants 1993-1997 and collected urine at that time. We will include demographic, behavioral, and clinical data from up to 20 years of follow-up to prospectively evaluate the association between cadmium exposure and clinical cardiovascular events. Using a case-cohort study design we will select cases of stroke (N=549), acute myocardial infarction (N=641), and heart failure (N=761), and a comparison subcohort of 600 men and 600 women. Trace metals, creatinine, osmolality, and cotinine will be analyzed in baseline urine samples. As a secondary Aim, we will apply mediation analyses using a counterfactual framework based approach to estimate the extent to which cadmium’s influence on stroke, heart failure, and acute myocardial infarction might be mediated via hypertension, hypercholesterolemia, and diabetes. Results from the mediation analysis may help to identify additional targets for intervention as well as aid in understanding the role of cadmium in the pathophysiology of these CVD events. Our proposed research will be one of the first studies to quantify the association between cadmium and incidence of cardiovascular disease in a longitudinal study with a never-smoking cohort. Sources of cadmium in the environment are well known, including phosphate fertilizers; given widespread cadmium exposure, and that cadmium exposure via food can be lowered by regulating fertilizer, the identification of cadmium as a cardiovascular risk factor can have major implications for the prevention and control of cardiovascular disease.