ASPIRIN AND RECURRENT CARDIOVASCULAR DISEASE EVENTS IN HIGH RISK SIBSHIPS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目前，小剂量阿司匹林(ASA)被认为对心血管疾病(CVD)的二级预防具有成本效益和有效性，包括1)急性冠状动脉疾病(CAD)综合征，如心肌梗死(MI)。急性血栓性卒中(CVA)和3.周围血管疾病(PVD)。人们普遍认为，在接受预防性阿司匹林治疗的同时经历复发的心血管事件代表了阿司匹林抵抗的一种形式。由于长期或强烈的环境暴露(吸烟、饮食、运动)、生物因素(糖尿病、抑郁、高血压、肥胖)和/或遗传易感性，血小板聚集性增加被认为是反复发生血栓性心血管事件的主要机制。心脑血管疾病患者服用阿司匹林的益处归因于抑制血栓素依赖的血小板活化。阿司匹林引起血小板环氧合酶1的乙酰化，从而抑制血栓素的释放，并在体外减少激动剂诱导的血小板激活。作为第一步，我们将研究血小板聚集、影响血小板聚集的环境和生物变量，以及最终的基因效应，以及与目前正在接受ASA预防的约翰·霍普金斯兄弟姐妹研究原始队列中受影响的兄弟姐妹复发心血管事件相关的基因-环境相互作用。最初，我们将重点研究血小板表型的变化，以确定是否可以确定服用ASA的人中没有预期的血小板抑制的子集，我们将确定这可能是环境和生物变量的函数。在第一年，我们还将专注于识别候选基因和单核苷酸多态，这些基因和单核苷酸多态可能与观察到的任何阿司匹林“抵抗”有关。受影响的兄弟姐妹包括1)那些在最初的研究中患有冠状动脉疾病的先证者，2)在基线时受到心血管疾病影响的其他兄弟姐妹，以及3)在基线时没有受到影响但后来发生了心血管疾病的兄弟姐妹。这是一项前瞻性的观察性研究，我们假设服用ASA的人中存在的特定血小板表型将与高复发率的CVD事件、更多的复发性事件和更多的血管床相关。最终的长期目标是确定环境和生物变量对血小板表型的影响，然后研究相关基因型和基因-环境交互作用对该高危人群5年内复发事件发生率的影响。了解可逆风险因素、基因决定因素和/或基因环境交互作用对ASA充分抑制血小板聚集性的能力的可能机制，对于学习如何在既往有CVD事件的高危个体中定制二级预防治疗可能是极其重要的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Currently, low dose aspirin (ASA) therapy is considered cost effective and efficacious for the secondary prevention of cardiovascular disease (CVD) including 1) acute coronary artery disease (CAD) syndromes like myocardial infarction (MI), 2.) acute thrombotic strokes (CVA), and 3.) peripheral vascular disease (PVD). It is generally accepted that experiencing a recurrent CVD event while taking prophylactic ASA therapy represents a form of aspirin resistance. Increased platelet aggregability, as a function of a chronic or intensive environmental exposure (cigarette smoking, diet, exercise), biological factors (diabetes, depression, hypertension, obesity) and/or a genetic predisposition, are thought to be the principal mechanisms for a recurrent thrombotic CVD event. The benefit of ASA in populations with CVD has been attributed to inhibition of thromboxane-dependent platelet activation. Aspirin causes acetylation of platelet cyclooxygenase 1, resulting in inhibition of thromboxane release, and a reduction in agonist-inducible platelet activation in vitro. We will examine platelet aggregation, environmental and biological variables that influence platelet aggregation as a first step, and ultimately the gene effects, and gene-environment interactions related to recurrent CVD events in affected siblings from the original cohort of The Johns Hopkins Sibling Study who are currently taking ASA prophylaxis. Initially we will focus on variations in the platelet phenotypes to determine if we can identify a subset of people taking ASA who do not have expected suppression of platelets, and we will determine the extent to which this may be a function of environmental and biological variables. In Year 1, we will also concentrate on identifying candidate genes and single nucleotide polymorphisms that might be related to any aspirin "resistance" observed. The affected siblings include 1) those who were the probands with coronary disease in the original study, 2) other siblings who were affected with CVD at baseline, and 3) siblings who were unaffected at baseline but who have since developed CVD. This is a prospective observational study where we hypothesize that specific platelet phenotypes present in people who are taking ASA , will be associated with a high rate of recurrent CVD events, a larger number of recurrent events, and more affected vascular beds. The ultimate long-term goal is to determine the impact of environmental and biological variables on platelet phenotypes and then to study the effect of related genotypes, and gene-environment interactions, on recurrent event rates over 5 years in this high risk population Understanding putative mechanisms of reversible risk factors, genetic determinants, and/or gene environment interactions on the capacity of ASA to adequately suppress platelet aggregability may be extremely important in learning how to tailor secondary prevention therapy in high risk individuals with a prior CVD event.