Clinical Genetic Testing for Atrial Fibrillation: Are We There Yet?

Important progress has been made toward unravelling the complex genetics underlying atrial fibrillation (AF). Initial studies were aimed to identify monogenic causes; however, it has become increasingly clear that the most common predisposing genetic substrate for AF is polygenic. Despite intensive investigations, there is robust evidence for rare variants for only a limited number of genes and cases. Although the current yield for genetic testing in early onset AF might be modest, there is an increasing appreciation that genetic culprits for potentially life-threatening ventricular cardiomyopathies and channelopathies might initially present with AF. The potential clinical significance of this recognition is highlighted by evidence that suggests that identification of a pathogenic or likely pathogenic rare variant in a patient with early onset AF is associated with an increased risk of death. These findings suggest that it might be warranted to screen patients with early onset AF for these potentially more sinister cardiac conditions. Beyond facilitating the early identification of genetic culprits associated with potentially malignant phenotypes, insight into underlying AF genetic substrates might improve the selection of patients for existing therapies and guide the development of novel ones. Herein, we review the evidence that links genetic factors to AF, then discuss an approach to using genetic testing for early onset AF patients in the present context, and finally consider the potential value of genetic testing in the foreseeable future. Although further work might be necessary before recommending uniform integration of genetic testing in cases of early onset AF, ongoing research increasingly highlights its potential contributions to clinical care.

Electrophysiologic Characterization of Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Atrial Cardiomyocytes.

Human induced pluripotent stem cell (hiPSC)-derived atrial cardiomyocytes (CMs) hold great promise for elucidating underlying cellular mechanisms that cause atrial fibrillation (AF). In order to use atrial-like hiPSC-CMs for arrhythmia modeling, it is essential to better understand the molecular and electrophysiological phenotype of these cells. We performed comprehensive molecular, transcriptomic, and electrophysiologic analyses of retinoic acid (RA)-guided hiPSC atrial-like CMs and demonstrate that RA results in differential expression of genes involved in calcium ion homeostasis that directly interact with an RA receptor, chicken ovalbumin upstream promoter-transcription factor 2 (COUP-TFII). We report a mechanism by which RA generates an atrial-like electrophysiologic signature through the downstream regulation of calcium channel gene expression by COUP-TFII and modulation of calcium handling. Collectively, our results provide important insights into the underlying molecular mechanisms that regulate atrial-like hiPSC-CM electrophysiology and support the use of atrial-like CMs derived from hiPSCs to model AF.