Cardiac Calcification and Cholesterol Efflux in Older Adults

老年人的心脏钙化和胆固醇流出

• 批准号: 10554167
• 负责人: Anna E Bortnick
• 金额: $ 19.02万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-15 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554167
• 关键词: Address; Adult; Affect; Agatston Score; Age; Aging; American; Apolipoproteins; Ashkenazim; Biological; Biological Markers; Candidate Disease Gene; Cardiac; Cardiac health; Cardiovascular Diseases; Cardiovascular system; Cell membrane; Centenarian; Cessation of life; Cholesterol; Cholesterol Esters; Cohort Studies; Congestive Heart Failure; Coronary; Coronary artery; Cross-Sectional Studies; Data; Deposition; Disease; Drug Design; Elderly; Founder Generation; Functional disorder; Future; Genes; Genetic; Genomics; Genotype; Goals; Heart; Heart Diseases; Heart Valve Diseases; Heart Valves; Heritability; High Density Lipoproteins; Human; Incidence; Individual; Inherited; Knowledge; Life; Link; Lipids; Lipoproteins; Longevity; Longitudinal cohort study; Measurement; Medical; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Mission; Molecular Epidemiology; Morbidity - disease rate; Movement; Myocardial Infarction; National Heart, Lung, and Blood Institute; Operative Surgical Procedures; Parents; Pathologic; Pathway interactions; Persons; Phenotype; Phospholipids; Population; Population Study; Prevalence; Prevention; Prevention approach; Process; Prospective, cohort study; Proteins; Research; Research Personnel; Research Priority; Research Project Grants; Resistance; Serum; Severities; Stroke; Testing; Tissues; Training; Translational Research; Work; X-Ray Computed Tomography; aortic valve; calcification; cardiovascular disorder risk; cohort; coronary artery calcification; coronary plaque; coronary sinus valve structure; density; design; disorder prevention; epidemiology study; experience; follow-up; follower of religion Jewish; frailty; genetic resistance; genetic variant; healthspan; human old age (65+); improved; mortality; multidisciplinary; novel; novel strategies; offspring; pathological aging; patient oriented; peer; pharmacologic; prevent; protective pathway; resilience; resilience research; reverse cholesterol transport; secondary analysis; sex; small molecule; therapeutic target; translational goal; variant detection

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.

冠状动脉和主动脉瓣的钙化在老年人中很普遍，并且与 心肌梗塞，充血性心力衰竭和中风。百岁老人和他们的后代较低 心血管疾病的负担比通常长寿的同龄人的负担。由于胆固醇和脂质沉积 是计算的潜在触发因素，可以改善胆固醇从心脏组织释放到 血清可能是异常长寿命的受保护机制。胆固醇外排是 将胆固醇和磷脂从细胞膜中移出到脂质贫民蛋白受体，即 反向胆固醇运输的第一步。拟议的研究基于申请人以前的和正在进行的 通过利用纵向研究与冠状动脉和主动脉瓣计算的确定剂进行工作 通过减少计算，提高胆固醇外排的寿命，并确定通用 这些表型背后的变体。特别是，该横断面研究旨在添加一个 通过计算机断层扫描（CT）和胆固醇计算冠状动脉和主动脉瓣的测量 对纵向的排出，一项纵向队列研究多达1400个通常同质的老年ashkenazi犹太人 成年人，其中一半是异常长寿的父母的后代 衰老和一半是通常的父母的后代。长度队列是这项研究的理想选择，因为 队列年龄较大，表征性和遗传性的特征，其同质种群使得 检测遗传变异更有效。这项研究旨在评估冠状动脉的患病率和严重程度 与年龄和性别相比 匹配通常的父母的同龄人（AIM 1）；胆固醇外排与心脏钙化和 杰出的朗格维特后代小组（AIM 2）；和与胆固醇升高有关的候选基因 外排和改善心脏钙化（AIM 3）。这项研究对NHLBI的战略研究做出了回应 优先考虑冠状动脉和心脏瓣膜钙化病理生物学以及NIA专注于识别 对疾病弹性的决定因素。纵向具有解决钙化是否为 减少对病理衰老的弹性，他们在生命后期几乎没有计算，如果胆固醇外排为 对主动脉瓣钙化的潜在保护机制（这种与外排相关的蛋白质具有 被鉴定出来），如果主要候选基因参与这些过程。这些发现可能导致 识别可以用小分子靶向的关键途径以防止钙化， 提供预防目前缺乏医疗疾病的新方法。重要的是，通过 多学科心态团队的心理研究经验，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高到 独立于分子流行病学领域的患者研究人员，并翻译了研究。