Creation of the Framingham Heart Study Cardiovascular Biobank and Atlas - Abstract Cardiovascular risk factor burden heavily impacts most cardiovascular disease (CVD) events. A longer duration of CVD risk factor exposure is associated with elevated risk of CVD and reduced longevity. The complex phenotypic variation and duration of multimorbidity in individuals results in unique challenges in understanding the underlying pathobiology of CVD. Currently, our knowledge of human cardiac tissue biology in CVD is based upon small numbers of chamber biopsies or postmortem sampling in select diseases, and are largely restricted to White individuals, limiting generalizability. Human cardiovascular tissue multiomics paired with longitudinal clinical, imaging, and CVD risk factor data are currently unavailable. Consequently, the effect of CVD risk factors on human cardiovascular tissues is largely unknown. To address these gaps, we propose to create the Framingham Heart Study (FHS) Cardiovascular Biobank and Atlas. The FHS investigators have collected clinical, biomarker, and omics data longitudinally across 3 generations and 2 non-European ancestral cohorts. We propose to create the FHS Cardiovascular Biobank consisting of a systematic and detailed postmortem cardiac and blood vessel tissue repository from consented FHS participants (n=208, Aim 1A). A survey of interest and of potential barriers and facilitators for cardiac donation in NHLBI participants with diverse genetic ancestries (FHS, including Omni 1 & 2, MESA) will be conducted. Community engagement events in MESA will enable future expansion. A web-based portal, the FHS Cardiovascular Atlas, will be created to digitally catalog the cardiac biospecimens, provide information regarding biospecimen and data availability, and transparency on the review process for global research community access via review and approval through an external biorepository committee (Aim 1B). In Aim 2, single-nucleus RNA-Seq will be performed in biospecimens from 3 cardiovascular sites (left atrium and ventricle, pulmonary vein) obtained in Aim 1A. In cross-sectional analyses, we will evaluate the association of the cell type proportions and transcriptomic signatures with individual CVD risk factors by anatomic site. We will perform RNAscope and immunofluorescence staining to validate the cell types and transcript/protein levels of differentially expressed genes in top pathways associated with the CVD risk factors. We hypothesize that premortem CVD risk factors affect the cell type proportions present and that CVD risk factor-related gene expression patterns will differ by anatomic site. Use of induced pluripotent stem cell-derived cardiovascular cells, generated from the same individuals of biobank cardiovascular samples, will allow novel mechanistic inquiries that underlie cardiac tissue phenotypes in the future. The FHS Cardiovascular Biobank and Atlas will advance our understanding of the relation of cardiovascular risk factors and disease with cardiovascular structure/phenotype and enable us to identify new biomarker signatures and mechanisms of CVD in an unprecedented and systematic manner. Gopal-Fetterman 1
