Cardiac Calcification and Cholesterol Efflux in Older Adults

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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.