Mediterranean diet, Metabolites, and cardiovascular Disease

描述（由申请人提供）：在美国，三分之一的死亡可归因于心血管疾病。健康的饮食和生活方式对预防CVD至关重要。传统的地中海饮食模式由于其对CVD风险的潜在有益影响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名基线时未诊断出CVD的参与者）表明，与对照饮食相比，地中海饮食模式，补充初榨橄榄油或树坚果，在中位随访4.8年后，主要临床CVD事件的风险显着降低约30%。该项目的目标是检查随机PREDIMED饮食干预对血浆代谢物水平的影响，并确定这些代谢特征是否介导了干预对CVD风险的益处。将采用巢式病例队列设计，纳入所有288例CVD事件病例和745例（10%）随机选择的基线试验参与者。将使用由麻省理工学院布罗德研究所和哈佛开发的最先进的LC-MS技术，测量在基线和试验第1年采集的储存的空腹血液标本中约300种代谢物的经过充分验证的组。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随机饮食干预对血浆代谢物水平从基线到第1年变化的影响; 2）检查代谢物血浆水平的1年变化是否介导随机饮食干预对2至5年的后续临床CVD结果的影响，使用有效的病例队列设计;和3）使用病例队列设计，检查基线代谢物水平是否改变随机饮食干预对CVD风险的影响。作为次要目的，我们将在745名随机选择的试验参与者中研究代谢物的1年变化是否介导饮食干预对随后发生代谢综合征的益处。PREDIMED是第一个随机的一级预防试验，以评估地中海式饮食干预对硬CVD终点的影响。目前的提案概述了一项非常有效和创新的研究，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理想的机会来发现饮食影响CVD风险的新途径，可以在基线和随访时获得存档的血浆样本，记录良好的CVD终点，以及具有良好依从性的长期随机干预。2010年美国人膳食指南已经认识到地中海饮食模式，沿着的饮食方法来阻止高血压（DASH）饮食，作为一个健康的饮食预防心血管疾病。这项研究的结果将提供进一步的证据，以支持公共卫生建议的饮食预防心血管疾病。

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.