PO-01-108 ELUCIDATING THE MECHANISM OF ATRIAL FIBRILLATION IN LAMIN A/C HEART DISEASE USING HUMAN IPSC-DERIVED ATRIAL CARDIOMYOCYTES

Abstract

Mutations in the LMNA gene, encoding the nuclear envelope proteins lamin A/C, cause cardiac arrhythmias, conduction disease, and dilated cardiomyopathy. Malignant arrhythmias such as atrial fibrillation (AF) and ventricular tachycardia are common and pose an increased risk of stroke and sudden cardiac death. To investigate the etiological mechanisms by which a heterozygous pathogenic LMNA-S143P mutation causes early-onset AF using mature human iPSC-derived atrial cardiomyocytes (hiPSC-aCM) generated from a large kindred with a strong cardiac phenotype. Detailed phenotyping of a 4-generation family pedigree and generation of hiPSCs from the proband using a comprehensive approach for the differentiation of mature hiPSC-aCMs. Action potential duration was measured by optical voltage mapping. Calcium transients were measured by confocal microscopy. The proband (III-3) is a 42-year-old female of European and Asian descent who developed symptomatic early-onset AF at age 35. She underwent direct current cardioversion (DCCV), pulmonary vein isolation, and implantation of a biventricular pacemaker. Cardiac MRI showed an enlarged left atrium with preserved left ventricular systolic function (EF 56%). A detailed family history revealed early-onset AF and AV block, congestive heart failure (CHF), and sudden death (Fig. 1). Genetic testing of the proband revealed a pathogenic missense mutation in LMNA (c427T>Cp. Ser143Pro). Mature LMNA-S143P-hiPSC-aCMs displayed prolongation of the atrial action potential duration (APD90) with delayed afterdepolarizations, abnormal calcium transients, and AF as compared to wild-type hiPSC-aCMs. Detailed phenotyping of a large LMNA kindred revealed a phenotype of AF, cardiac conduction disease, dilated cardiomyopathy, and sudden death. Our hiPSC-aCM studies uncovered a triggered mechanism for the AF with ion channel remodeling and pave the way for targeting calcium handling proteins as a potential therapeutic strategy in LMNA associated arrhythmias.