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， 心肌梗死、充血性心力衰竭和中风。百岁老人和他们的后代 心血管疾病的负担比他们的同龄人通常长寿。由于胆固醇和脂质沉积 是钙化的一个有力的触发因素，有可能改善胆固醇从心脏组织的释放， 血清可能是特别长寿个体的保护机制。胆固醇外流是 胆固醇和磷脂从细胞膜向贫脂载脂蛋白受体的运动， 胆固醇逆向转运的第一步拟议的研究建立在申请人以前和正在进行的 通过利用LonGenity研究来研究冠状动脉和主动脉瓣钙化的决定因素， 减少钙化，改善胆固醇流出能力，并确定遗传 这些表型背后的变异。具体来说，这项横断面研究旨在增加一个 通过计算机断层扫描（CT）和胆固醇测量冠状动脉和主动脉瓣钙化 外排到LonGenity，一项对多达1400名遗传同质的老年德系犹太人的纵向队列研究 成年人，其中一半是非常长寿的父母的后代，对病理性心血管疾病有抵抗力。 父母之子，父母之子，父母之子。LonGenity队列是这项研究的理想选择，因为 队列年龄较大，具有表型和基因型特征，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，特别长寿的父母的后代的主动脉瓣钙化- 正常生活父母的匹配同龄人（目标1）;胆固醇流出与心脏钙化的关系， 特别长寿的后代组（目标2）;与胆固醇增加相关的候选基因 流出和减少心脏钙化（目的3）。本研究响应NHLBI的战略研究 冠状动脉和心脏瓣膜钙化的病理生物学优先，NIA的重点是识别 对疾病的抵抗力的决定因素LonGenity在解决钙化是否是 如果胆固醇流出减少，则在生命后期几乎没有钙化的对病理性衰老有弹性的个体中减少， 一种针对主动脉瓣钙化的潜在保护机制（其中这种流出相关蛋白具有 已确定），以及是否主要候选基因参与这些过程。这些发现可能导致 确定可以用小分子靶向以防止钙化的关键途径， 为预防目前缺乏医学治疗的疾病提供了新的方法。重要的是通过 由多学科导师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奖将推动候选人的进展， 作为一个以病人为导向的分子流行病学和转化研究的研究人员的独立性。

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.