Using left atrial appendage (LAA) tissues from surgical patients, we have obtained RNAseq (mRNA and miRNA) and genotype data from 265 subjects. These studies reveal that atrial gene expression is significantly altered by history of AF. Mitochondrial dysfunction was identified by pathway analysis of both genes and pathways differentially co-expressed between subjects with vs. without a history of AF, and the genes coexpressed with AF risk loci. Precision medicine for AF treatment will require patient-specific targets to prevent progression of AF from a paroxysmal to persistent state. Two aims are proposed to enhance understanding of relationships between gene expression, atrial structure, function, and response to drugs that may help to prevent AF or minimize its burden. Aim 1 will integrate genomic, proteomic, and histologic signatures of AF progression in human left atrial samples from patients with paroxysmal vs. persistent AF. Aim 2 will create inducible pluripotent stem cells (iPSCs) from 40 AF patients with implanted cardiac devices in a clinical trial in which the patients are randomized to either metformin (MET), or MET plus aggressive risk factor modification. Epidemiologic data suggest that MET lowers the risk of AF. iPSCs will be differentiated to an atrial-like phenotype (a-iPS-CMs), and electrophysiologic (EP) and mRNA gene expression profiles will be assessed prior to and following rapid pacing in the presence of MET. In preliminary studies, we found that MET enhanced the heat shock response and preserved sodium and calcium channel expression. We will compare in vitro results with the cell donor response to MET in the clinical trial. These studies will enhance our understanding of the links between atrial gene expression, mitochondrial function and atrial EP. They will synergize with the clinical and basic projects in our proposal, and create a platform for systematic evaluation of patient-specific upstream interventions to prevent AF or reduce its burden.
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2018 → 06/30/2022|