Mediterranean diet, Metabolites, and cardiovascular Disease

描述(申请人提供)：在美国，每三例死亡中就有一例可归因于心血管疾病。健康的饮食和生活方式对预防心血管疾病至关重要。传统的地中海饮食模式因其对心血管疾病风险的潜在益处而受到越来越多的关注。最近，具有里程碑意义的PREDIMED随机试验(n=7,447名参与者在基线时没有被诊断为心血管疾病)表明，在中位数4.8年的随访期后，地中海饮食模式加上初榨橄榄油或坚果，与对照饮食相比，显著降低了重大临床心血管事件的风险约30%。该项目的目标是检验随机的PreEDIMED饮食干预对血浆代谢物水平的影响，并确定这些由此产生的代谢谱是否中介了干预措施对心血管疾病风险的益处。将使用嵌套病例队列设计，纳入所有288例心血管疾病事件和745例(10%)随机选择的试验参与者作为基线。在基线和试验第一年收集的储存空腹血液样本将使用由麻省理工学院和哈佛大学开发的最先进的LC-MS技术，为一个由约300种代谢物组成的经过充分验证的小组进行测量。我们将重点关注与心脏代谢风险有关的代谢物类别。我们的项目包括三个具体目标：1)在745名随机选择的试验参与者中，检查从基线到第一年的随机饮食干预对血浆代谢物水平变化的影响；2)使用有效的病例队列设计，检查血浆代谢物水平的一年变化是否中介了随机饮食干预对随后第二年到第五年的临床心血管疾病结果的影响；以及3)使用病例队列设计，检查基线代谢产物水平是否改变了随机饮食干预对心血管疾病风险的影响。作为第二个目标，我们将在745名随机选择的试验参与者中，检查代谢产物一年的变化是否中介了饮食干预对随后发生的代谢综合征的好处。PREDIMED是第一个评估地中海式饮食干预对硬性心血管疾病终点的影响的随机初级预防试验。目前的提案概述了一项极其高效和创新的研究，该研究将最先进的代谢组学技术应用于严格进行的饮食干预试验。这项研究提供了一个发现饮食影响心血管疾病风险的新途径的理想机会，可以获得基线和后续的存档血浆样本，有良好记录的心血管疾病终点，以及具有良好遵从性的长期随机干预。《2010年美国人饮食指南》已将地中海饮食模式与阻止高血压的饮食方法(DASH)一起确认为预防心血管疾病的健康饮食。这项研究的结果将提供进一步的证据，支持饮食预防心血管疾病的公共卫生建议。

DESCRIPTION (provided by applicant): In the U.S., one in every three deaths is attributable to cardiovascular disease (CVD). Healthy diet and lifestyle are crucial for CVD prevention. The traditional Mediterranean dietary pattern has received increasing attention because of its potential beneficial effects on CVD risk. Recently, the landmark PREDIMED randomized trial (n=7,447 participants free of diagnosed CVD at baseline) demonstrated that a Mediterranean dietary pattern, supplemented with either virgin olive oil or tree nuts, significantly reduced the risk of major clinical CVD events by ~30%, compared to a control diet, after a median follow-up of 4.8 years. The goal of this project is to examine the effects of the randomized PREDIMED dietary interventions on plasma levels of metabolites, and to determine whether these resulting metabolic profiles mediate the interventions' benefits on CVD risk. A nested case-cohort design will be used, incorporating all 288 incident cases of CVD and 745 (10%) randomly selected trial participants at baseline. Stored fasting blood specimens collected at baseline and at year 1 of the trial will be measured for a well-validated panel of ~300 metabolites, using the state-of-the-art LC-MS technology developed by the Broad Institute of MIT and Harvard. We will focus on classes of metabolites that have been implicated in cardio-metabolic risk. Our project includes three specific aims: 1) To examine the effects of the randomized dietary interventions on changes in plasma levels of metabolites from baseline to year 1 in 745 randomly selected trial participants; 2) To examine whether 1-year changes in plasma levels of metabolites mediate the effect of the randomized dietary interventions on subsequent clinical CVD outcomes from years 2 to 5, using the efficient case-cohort design; and 3) To examine whether baseline metabolite levels modify the effects of the randomized dietary interventions on CVD risk, using a case-cohort design. As a secondary aim, we will examine whether 1-year changes in metabolites mediate the benefits of dietary interventions on subsequent occurrence of the metabolic syndrome, among 745 randomly selected trial participants. The PREDIMED is the first randomized primary prevention trial to evaluate the effects of Mediterranean-style dietary interventions on hard CVD endpoints. The current proposal outlines an extremely efficient and innovative study that applies the state-of-the-art metabolomics technology to a rigorously conducted dietary intervention trial. This study provides an ideal opportunity to discover novel pathways through which diet influences CVD risk, with access to archived plasma samples at baseline and follow-up, well-documented CVD endpoints, and long-term, randomized interventions with excellent compliance. The 2010 Dietary Guidelines for Americans has recognized the Mediterranean dietary pattern, along with the Dietary Approaches to Stop Hypertension (DASH) diet, as a healthy diet for CVD prevention. Results from this study will provide further evidence to support public health recommendations for dietary prevention of CVD.