Cardiac Calcification and Cholesterol Efflux in Older Adults

冠状动脉和主动脉瓣钙化在老年人中普遍存在，并与 心肌梗塞、充血性心力衰竭和中风。百岁老人及其后代的 心血管疾病负担比平时长寿的同龄人要长。因为胆固醇和脂肪沉积 是钙化的有效触发因素，可能是促进心脏组织胆固醇释放到 对于特别长寿的人来说，血清可能是一种保护机制。胆固醇外流是 胆固醇和磷脂从细胞膜转移到低脂载脂蛋白受体， 胆固醇反向运输的第一步。拟议的研究建立在申请人先前和正在进行的研究的基础上 利用Long Genity研究探讨冠状动脉和主动脉瓣钙化的决定因素 通过减少钙化、改善胆固醇流出能力和识别基因来延长寿命 这些表型背后的变异。具体地说，这项横断面研究旨在增加一个 冠状动脉和主动脉瓣钙化的CT和胆固醇测量 Exlux to LonGenity--一项对多达1400名基因相同的年长德系犹太人的纵向队列研究 成年人，其中一半是特别长寿的父母的后代，他们对病理性心血管疾病具有弹性 年事已高的父母中有一半是正常生活的父母的后代。LonGenity队列是这项研究的理想选择，因为 队列年龄较大，具有表型和基因特征，其同质群体使 更有效地检测遗传变异。本研究旨在评估冠心病的患病率和严重程度。 与年龄和性别相比，超长寿父母的后代中的主动脉瓣钙化- 正常生活父母的配对同龄人(目标1)；胆固醇外流与心脏钙化和 超长寿后代组(目标2)；与胆固醇增加相关的候选基因 外流和减少心脏钙化(目标3)。这项研究响应了NHLBI的战略研究 冠状动脉和心脏瓣膜钙化的优先病理生物学和NIA的重点识别 疾病复原力的决定因素。LonGenity在解决钙化是否 抗病理性衰老的人晚年几乎没有钙化，如果胆固醇外流是 对主动脉瓣钙化的潜在保护机制(在这种机制中，这种外流相关蛋白具有 已确定)，以及主要候选基因是否参与这些过程。这些发现可能会导致 识别可被小分子靶向以防止钙化的关键途径， 为预防目前缺乏治疗的疾病提供新的方法。重要的是，通过 由多学科指导团队指导的研究经验，以及基因组学和 心脏计算机断层扫描，拟议的K23奖将使候选人的进步提前到 作为一名以患者为中心的分子流行病学和转化性研究的独立研究人员。

Calcification of the coronary arteries and aortic valve is prevalent in older adults and associated with myocardial infarction, congestive heart failure and stroke. Centenarians and their offspring have a lower burden of cardiovascular disease than their peers with usual longevity. Since cholesterol and lipid deposition are a potent trigger for calcification, it is possible that improved release of cholesterol from cardiac tissues to serum may be a protective mechanism in exceptionally long-lived individuals. Cholesterol efflux is the movement of cholesterol and phospholipid out of cell membranes to lipid-poor apolipoprotein acceptors, the first step in reverse cholesterol transport. The proposed study builds on the applicant’s previous and ongoing work into the determinants of coronary and aortic valve calcification by leveraging the LonGenity study to relate longevity with reduced calcification, improved cholesterol efflux capacity, and identify genetic variants underlying these phenotypes. Specifically, this cross-sectional study is designed to add a measurement of coronary artery and aortic valve calcification by computed tomography (CT) and cholesterol efflux to LonGenity, a longitudinal cohort study of up to 1400 genetically homogenous older Ashkenazi Jewish adults, of whom half are the offspring of exceptionally long-lived parents resilient to pathologic cardiovascular aging and half are the offspring of usual-lived parents. The LonGenity cohort is ideal for this study because the cohort is older, characterized phenotypically and genotypically, and its homogeneous population makes detecting genetic variants more efficient. This study aims to assess the prevalence and severity of coronary and aortic valve calcification in the offspring of exceptionally long-lived parents as compared to age and sex- matched peers of usual-lived parents (Aim 1); the association of cholesterol efflux with cardiac calcification and the exceptional-longevity offspring group (Aim 2); and candidate genes associated with increased cholesterol efflux and decreased cardiac calcification (Aim 3). This study responds to the NHLBI’s strategic research priority on pathobiology of calcification of the coronary arteries and heart valves and NIA’s focus on identifying determinants of resiliency to disease. LonGenity has advantages for addressing whether calcification is reduced in individuals resilient to pathologic aging who have little calcification late in life, if cholesterol efflux is a potential protective mechanism against aortic valve calcification (in which such efflux-related proteins have been identified), and if major candidate genes are involved in these processes. These findings could lead to identification of key pathways that could be targeted with small molecules to protect against calcification, offering new approaches to prevention of disorders that currently lack medical treatment. Importantly, through a mentored research experience by a multi-disciplinary mentorship team, and formal training in genomics and cardiac computed tomography, the proposed K23 award will advance the candidate’s progression to independence as a patient-oriented researcher in molecular epidemiology and translational research.