Red Blood Cell Fatty Acid Biomarkers and Cardiovascular Disease Risk

描述（由申请人提供）：Omega-3脂肪酸（n-3 FAs）被认为可以降低心血管疾病（CVD）的风险，尤其是心源性猝死和充血性心力衰竭（CHF）。然而，流行病学仍然存在争议，膳食n-3脂肪酸的作用机制仍然是推测性的。心率的降低、心率变异性的增加和内皮功能的改善都与较高水平的n- 3fa生物标志物有关。这些可能是由膜结构/功能和/或类二十烷或细胞因子诱导的炎症蛋白的变化介导的。红细胞（RBC） n- 3fa含量最近被证明是人类心肌n- 3fa水平的有效替代生物标志物。除了更客观（相对于基于饮食问卷的测量），RBC n-3 FAs可能比血浆FAs水平更可取，因为它们反映了几周内的组织FA水平，并且变化较小（类似于评估平均血糖水平的血红蛋白A1C）。之前没有研究评估红细胞n-3 FAs（或FA模式）与心血管结局和血管危险标志物之间的关系。为了解决这些知识上的空白，我们建议在两个弗雷明汉心脏研究队列（后代研究和少数，Omni研究）中测量RBC FA组成。RBC n- 3fa含量将结合已收集的丰富数据集进行分析，这些数据集包括经典和新出现的危险因素、亚临床左心室（LV）重塑、血管僵硬和内皮功能。这些受试者还受到心血管疾病和心力衰竭发展情况的持续监测。我们提出以下三个目标：目标1。红细胞n-3FAs与临床相关。在社区样本中定义横断面临床相关性、遗传性和RBC n- 3fa含量的稳定性。目标2。红细胞n-3 FAs与血管和心室重构。探讨RBC n-3 FAs与a)微循环功能和导管动脉硬度（使用血压计），b)内皮功能（使用基于超声的肱动脉血流介导扩张）和c)左室重构指标（使用超声心动图）的横断面关系。目标3。红细胞n-3 FAs与心血管疾病危险因素的发展及心血管疾病的发生。探讨红细胞n- 3fa含量与心血管疾病危险因素演变及心血管事件发生率的关系。这些数据不仅将为未来评估RBC FAs对CVD的预测价值的研究提供信息，还将为这些FAs可能调节的其他疾病（如痴呆、关节炎、黄斑变性等）提供信息。公共健康相关性：人们对鱼油对心脏健康的影响越来越感兴趣，尤其是它们所含的omega-3脂肪酸（EPA和DHA）。虽然我们现在知道，给心脏病高危人群服用鱼油补充剂似乎可以降低他们患心脏病的风险，但我们不知道这些天然油是如何帮助心脏的，也不知道血液水平的正常变化在多大程度上与心脏病风险因素有关。这项研究将试图揭示血液中omega-3含量与人们患高血压的速度、血管的柔韧性（即健康）、心脏泵血的活力或动脉的炎症程度等因素之间迄今未知的联系。所有这些因素在确定心脏病发作和中风的风险方面都很重要，因此了解ω -3脂肪酸是如何影响它们的，将有助于我们设计新的治疗策略，以降低美国这些主要疾病的风险。

DESCRIPTION (provided by applicant): Omega-3 fatty acids (n-3 FAs) are believed to reduce risk for cardiovascular disease (CVD), especially sudden cardiac death, and for congestive heart failure (CHF). The epidemiology, however, remains conflicted, and the mechanisms by which dietary n-3 FAs operate remain speculative. A decrease in heart rate, an increase in heart rate variability, and improved endothelial function have all been associated with higher levels of n-3 FA biomarkers. These may be mediated by changes in membrane structure/function and/or eicosanoids or cytokine- induced inflammatory proteins. Red blood cell (RBC) n-3 FA content has recently been shown to be a valid surrogate biomarker of human myocardial n-3 FA levels. In addition to being more objective (relative to dietary questionnaire-based measures), RBC n-3 FAs may be preferable to plasma levels of FAs because they reflect tissue FA levels over several weeks and are less variable (analogous to hemoglobin A1C in the assessment of average blood glucose levels). No prior studies have evaluated the relationships between RBC n-3 FAs (or FA patterns) on cardiovascular outcomes and vascular risk markers. To address these gaps in knowledge, we propose to measure RBC FA composition in two Framingham Heart Study cohorts (the Offspring Study and the minority, Omni Study). The RBC n-3 FA content will be analyzed in conjunction with the rich dataset already collected on these subjects which includes classical and emerging risk factors, subclinical left ventricular (LV) remodeling, vascular stiffness, and endothelial function. These subjects are also under continuous surveillance for the development of CVD and CHF. We propose the following 3 aims: Aim 1. RBC n-3FAs and clinical correlates. To define the cross-sectional clinical correlates, the heritability and the stability of RBC n-3 FA content in a community-based sample. Aim 2. RBC n-3 FAs and vascular & ventricular remodeling. To examine the cross-sectional relations of RBC n-3 FAs to a) microcirculatory function and conduit artery stiffness (using tonometry), b) endothelial function (using ultrasound-based brachial artery flow-mediated dilation), and c) indexes of LV remodeling (using echocardiography). Aim 3. RBC n-3 FAs and the development of CVD risk factors & incident CVD. To investigate prospectively the relations of RBC n-3 FA content to longitudinal tracking of the evolution of CVD risk factors and of the incidence of CVD events. These data will not only inform future studies assessing the predictive value of RBC FAs for CVD, but also for other diseases (e.g., dementia, arthritis, macular degeneration, etc.) potentially modulated by these FAs. PUBLIC HEALTH RELEVANCE: There has been increasing interest in the heart-healthy effects of fish oils, especially the omega-3 fatty acids (EPA and DHA) that they contain. While we now know that giving fish oil supplements to people who are at high risk for heart attacks seems to reduce their risk for heart disease, we don't know how these natural oils work to help the heart, nor do we know the degree to which normal variations in blood levels are related to heart disease risk factors. This study will attempt to uncover heretofore unknown links between blood omega-3 levels and such things as how fast people develop high blood pressure, how flexible (i.e., healthy) the blood vessels are, how vigorously the heart pumps blood, or how inflamed the arteries are. All of these factors are important in determining risk for heart attacks and strokes, and so learning how they are affected by omega-3 fatty acids will help us devise new treatment strategies to reduce risk for these major diseases in the US.