Therapeutic Modulation of Atrial Remodeling

PROJECT SUMMARY Atrial fibrillation (AF) is a leading cause of stroke and a major cause of morbidity and mortality in the US. AF is highly associated with conditions that elevate intracardiac pressure, such as hypertension and heart failure. Cardiac pressure overload induces electrical and structural changes in the left atrium (LA) in a process known as atrial remodeling that creates the substrate for AF. There are currently no therapies that directly address the underlying atrial remodeling process. To address this critical unmet need, we focused on signaling pathways essential for atrial development to identify novel therapeutic targets. We found that all-trans retinoic acid (ATRA), a vitamin A derivative that is essential for atrial development, can prevent and reverse atrial remodeling in a cardiac pressure overload model. Comparative left atrial transcriptomic analysis revealed that ATRA treatment normalizes important metabolic pathways, atrial developmental pathways, rapid conduction genes, and reduces pro-inflammatory and pro-fibrotic pathways. Single nuclear sequencing analysis shows that ATRA changes the population of macrophages from a pro-inflammatory subtype to a reparative subtype. ATRA can also protect against atrial fibrosis in a non-pressure overload mouse model of AF. ATRA is FDA approved for the treatment of acute promyelocytic leukemia (APL). We found that ATRA therapy improves atrial conduction parameters in APL patients at one month of treatment. Our findings strongly support ATRA as a powerful new treatment that can reverse atrial remodeling for the prevention of AF.