Abstract 247: LMNA Mutation-induced Endothelial Dysfunction Contributes To The Pathogenesis Of Atrial Fibrillation

Introduction: The genetic basis of atrial fibrillation (AF), a commonly encountered arrhythmia in clinical practice, is well established. Clinical and epidemiologic studies have implicated endothelial dysfunction in early-onset AF; however, the molecular mechanisms underlying this association remain unclear. Early-onset AF is a common occurrence in Lamin A/C ( LMNA ) cardiomyopathy and usually precedes DCM. As variants in LMNA can cause endothelial dysfunction, we have explored the mechanistic link between endothelial dysfunction and early onset AF using human induced pluripotent stem cell -derived atrial cardiomyocytes (iPSC-aCMs) and iPSC-endothelial cells (ECs) generated from the proband of an affected family harboring a pathogenic LMNA -S143P mutation ( Figure 1 ). Hypothesis: LMNA -S143P mutation causes endothelial dysfunction which leads to ion channel and structural remodeling generating an arrhythmic substrate for AF. Methods: Human iPSC-aCMs and iPSC-ECs were generated from the wildtype (WT) and LMNA -S143P mutation proband. Electrophysiological assessment was performed in matured iPSC-aCMs by optical voltage mapping and measuring calcium transients. EC function was assessed by angiogenesis assay. Results: The LMNA -S143P-iPSC-ECs exhibited impaired angiogenesis compared to WT-iPSC-ECs. The action potential duration at 90% repolarization (APD90) was prolonged in LMNA -S143P-iPSC-aCMs compared to WT-iPSC-aCMs ( Figure 1 ). LMNA -S143P-iPSC-aCMs had irregular calcium transients resembling triggered delayed afterdepolarizations. Conclusions: We showed ion channel remodeling and abnormal calcium homeostasis as a potential mechanistic link between endothelial dysfunction and triggered AF due to a pathogenic LMNA -S143P mutation. Our findings suggest that treatment of endothelial dysfunction with calcium channel blockers and/or statins may prevent the progression of early-onset AF associated with LMNA variants.