Significant gaps remain in our understanding of the molecular, structural, and electrophysiological connections that promote the development and progression of atrial fibrillation (AF) and adverse atrial remodeling. The limitations in our ability to prevent AF, despite medical and ablative approaches, and disappointing results from prospective randomized studies of conventional upstream therapies, highlight the need for the identification and development of novel upstream therapies for the primary and secondary prevention of AF. The overall goal of this Center is to accelerate translation of molecular research in AF to address these critical gaps in AF patient care. The Center will leverage molecular data, including genomic, transcriptomic, and proteomic data that provide more logical selection of upstream targets for study. These data may facilitate better stratification of AF phenotypes that could drive personalized targeting of preventive therapies. The proposed projects will utilize multi-pronged basic and translational investigations to build support and identify novel therapies for testing in an efficient clinical trial infrastructure designed to test effects on AF burden and progression. The basic project will explore gene-aging-metabolism interactions in AF pathogenesis; studies are expected to yield several novel AF targets. The clinical project will test our initial upstream targets focused on the metabolic derangements associated with AF in a clinical trial. The trial will test patient-specific lifestyle and risk factor modification, the upstream therapy with the best supporting outcomes reported to date, but which has significant barriers to implementation in the U.S., in conjunction with a potentially synergistic re-purposed drug, metformin, which targets important upstream metabolic pathways, mitochondrial dysfunction, and derangements in protein handling indicated by genomic analyses to be operative in AF pathophysiology. This project will provide a platform for testing other novel upstream therapies and will demonstrate an individualized, patient-specific sustainable upstream lifestyle/weight loss strategy for AF that can be scaled to expanded populations. A population/translational project will characterize AF phenotypes, using a multi-'omics approach, utilize longitudinal samples and cells from the clinical project to dissect patient-specific response mechanisms to the upstream therapies with an overall aim of personalizing AF treatment.
|Program type||Strategically Focused Research Network|
|Effective start/end date||07/01/2018 → 06/30/2022|