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: 9892260
• 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/9892260
• 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; Gap Junctions; Genes; Genetic; Genomics; Genotype; Goals; Heart; Heart Diseases; Heart Valve Diseases; Heart Valves; Heritability; High Density Lipoproteins; Human; Incidence; Individual; Inherited; Knowledge; Lead; 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; Pharmacology; 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; Time; Tissues; Training; Translational Research; Variant; 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; prevent; resilience; reverse cholesterol transport; secondary analysis; sex; small molecule; therapeutic target

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钙化在老年人中普遍存在，并与 百岁老人及其后代的心肌梗死、充血性心力衰竭和中风的发生率较低。 由于胆固醇和脂质沉积，心血管疾病的负担比同龄人长寿。 是钙化的有效触发因素，可能会改善心脏组织中胆固醇的释放 血清可能是特别长寿个体的一种保护机制。 胆固醇和磷脂从细胞膜移出至缺乏脂质的载脂蛋白受体， 反向胆固醇转运的第一步。拟议的研究建立在申请人之前和正在进行的研究的基础上。 利用 LonGenity 研究来研究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遗传来延长寿命 具体来说，这项横断面研究旨在添加一个潜在的变异这些表型。 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 流出至 LonGenity，这是一项针对多达 1400 名基因同质的老年德系犹太人的纵向队列研究 成年人，其中一半是对病理性心血管疾病有抵抗力的特别长寿父母的后代 LonGenity 队列是这项研究的理想选择，因为其中一半是正常生活的父母的后代。 队列年龄较大，具有表型和基因型特征，并且其同质群体使得 更有效地检测遗传变异本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，长寿父母的后代的主动脉瓣钙化 与正常生活的父母的同龄人相匹配（目标 1）；胆固醇流出与心脏钙化的关系； 超长寿后代组（目标 2）和与胆固醇升高相关的候选基因； 流出和心脏钙化减少（目标 3）。 优先考虑冠状动脉和心脏瓣膜钙化的病理学，NIA 重点关注识别 LonGenity 在解决钙化问题方面具有优势。 如果胆固醇流出量减少，则在晚年几乎没有钙化的、能够抵抗病理性衰老的个体中，钙化程度会降低。 对抗主动脉瓣钙化的潜在保护机制（其中此类外排相关蛋白具有 已确定），并且如果主要候选基因参与这些过程，这些发现可能会导致。 识别可以用小分子靶向以防止钙化的关键途径， 重要的是，通过提供新的方法来预防目前缺乏治疗的疾病。 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 奖项将推动候选人的进展 作为分子流行病学和转化研究领域以患者为中心的研究者的独立性。