Prospective Phenotyping for Genetic Subtypes of Early-onset Atrial Fibrillation

This study will address the hypothesis that re-phenotyping patients with AF and pathogenic arrhythmia/CM variants will identify unrecognized underlying genetic disease. The investigators will recruit from participants sequenced as part of our prospective clinical registries and participants cared for in the Vanderbilt Genetic Arrhythmia Clinic or Meharry Arrhythmia Clinic and enrolled in the Vanderbilt Early-onset Atrial Fibrillation Registry (IRB #201666). Eligible participants will have pathogenic/likely pathogenic (P/LP) rare variants (or matched controls) and will undergo prospective cardiac phenotyping, which will include a cardiac MRI, rest/stress/signal averaged ECGs, blood work, and ambulatory ECG monitoring. A subset of patients will also undergo a procainamide drug challenge. If an inherited arrhythmia/CM syndrome is diagnosed, guideline-directed changes to medical care will be recommended. This study will define the cardiac phenotype of individuals with AF who have a P/LP rare variant in an inherited arrhythmia or CM disease gene and compare to controls. Participants with a P/LP variant in a cardiomyopathy gene or arrhythmia gene (N=150) will be compared to controls (N=75). Controls will have no P/LP variant and be balanced for sex, race, and ethnicity. The association between P/LP variants and the following endpoints will be tested: 1) imaging and ECG-derived measurements (e.g., ventricular size, function, fibrosis, ectopy); 2) diagnoses (e.g., arrhythmogenic cardiomyopathy (AC), hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), Long QT Syndrome (LQTS), Short QT Syndrome (SQTS), Brugada Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), Progressive Cardiac Conduction Disease (PCCD); and 3) management changes including new medical therapy, activity restrictions, implantable cardioverter-defibrillator use, or cascade screening. Sample sizes per group have been selected to power the diagnostic and management endpoints. An Adjudication Committee with arrhythmia, CM, and genetics expertise will determine if diagnostic criteria are met and make management recommendations.