LEGACY Scientific Aims
Current Scientific Aims for the FHS LEGACY Program
The FHS LEGACY program is an actively funded National Heart, Lung, and Blood Institute grant, under Drs. Jessica Fetterman and Deepa Gopal.
The FHS Cardiovascular Biobank is an unprecedented opportunity to advance our understanding of how lifelong CVD risk factors relate to cardiovascular tissue transcriptomics in humans. We hypothesize that CVD risk factor exposures during the lifespan relate to cardiovascular tissue cell types and transcriptomic signatures that differ by anatomic site. We propose to:
Aim 1A: Create a biobank of cardiac biosamples collected from FHS participants.
We will solicit the FHS cohorts (n=4,444) to discuss the new cardiac donation program. Whole hearts with major blood vessel sampling (proximal aorta, pulmonary arteries and veins, coronaries) will be procured rapidly after death. Using a standardized, methodologically rigorous, published protocol, all biosamples will be dissected to maintain spatial orientation and preserved using the PAXgene system and flash freezing for histology and multiomics. To facilitate expansion of the biobank in the future, other NHLBI cohorts (MESA) with greater racial diversity than FHS will be surveyed to evaluate participant interest and identify potential barriers/facilitators to heart donation.
Aim 1B: Build the infrastructure for cataloging and requesting biosamples and cardiac data access.
A web-based portal (FHS Cardiovascular Atlas) will be created to catalog biospecimens and data. We will utilize a transparent review process by an external committee to facilitate global research community access to available samples and data. All data generated using the FHS Cardiovascular Biobank will be cataloged back into the FHS Cardiovascular Atlas and deposited into dbGaP and the NHLBI BioData Catalyst to foster scientific productivity, innovation, and broad utilization of this unique resource.
Aim 2: Relate CVD risk factors to cell type proportions and transcriptomic signatures of the human heart and proximal vessels.
As a first use case, we will perform single-nucleus RNA-seq from the left atrium, left ventricle, and pulmonary vein samples obtained in Aim 1A. In cross-sectional analyses, we will evaluate the association of CVD risk factors (hypertension, body mass index, fasting blood glucose, LDL levels, smoking) with cell type proportions and gene expression patterns. RNAscope and immunostaining will be used to validate cell types and transcript/protein levels of differentially expressed genes in top pathways associated with CVD risk factors. We hypothesize that premortem CVD risk factors affect the cell type proportions and phenotypes present and that CVD risk factor-related gene expression patterns differ by anatomic site.