title: hiPSC-derived cardiomyocytes from Brugada Syndrome patients without identified mutations do not exhibit clear cellular electrophysiological abnormalities.
abstract: Brugada syndrome (BrS) is a rare cardiac rhythm disorder associated with sudden cardiac death. Mutations in the sodium channel gene SCN5A are found in ~20% of cases while mutations in other genes collectively account for <5%. In the remaining patients the genetic defect and the underlying pathogenic mechanism remain obscure. To provide insight into the mechanism of BrS in individuals without identified mutations, we here studied electrophysiological properties of cardiomyocytes (CMs) generated from human induced pluripotent stem cells (hiPSCs) from 3 BrS patients who tested negative for mutations in the known BrS-associated genes. Patch clamp studies revealed no differences in sodium current (INa) in hiPSC-CMs from the 3 BrS patients compared to 2 unrelated controls. Moreover, action potential upstroke velocity (Vmax), reflecting INa, was not different between hiPSC-CMs from the BrS patients and the controls. hiPSC-CMs harboring the BrS-associated SCN5A-1795insD mutation exhibited a reduction in both INa and Vmax, demonstrating our ability to detect reduced sodium channel function. hiPSC-CMs from one of the BrS lines demonstrated a mildly reduced action potential duration, however, the transient outward potassium current (Ito) and the L-type calcium current (ICa,L), both implicated in BrS, were not different compared to the controls. Our findings indicate that ion channel dysfunction, in particular in the cardiac sodium channel, may not be a prerequisite for BrS.
authors.affiliation: Heart Centre, Department of Experimental and Clinical Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Christiaan C
authors.initials: CC
authors.lastname: Veerman
authors.affiliation: Heart Centre, Department of Experimental and Clinical Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Isabella
authors.initials: I
authors.lastname: Mengarelli
authors.affiliation: Department of Cardiology and Pneumonology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Kaomei
authors.initials: K
authors.lastname: Guan
authors.affiliation: Department of Cardiology and Pneumonology, Georg-August-University Göttingen, Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Stauske
authors.affiliation: Heart Centre, Department of Experimental and Clinical Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|l'institut du thorax, INSERM, CNRS, Université de Nantes, Nantes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Barc
authors.affiliation: Heart Centre, Department of Experimental and Clinical Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Hanno L
authors.initials: HL
authors.lastname: Tan
authors.affiliation: Heart Centre, Department of Experimental and Clinical Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Arthur A M
authors.initials: AA
authors.lastname: Wilde
authors.affiliation: Department of Anatomy, Embryology and Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.affiliation: Heart Centre, Department of Experimental and Clinical Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Connie R
authors.initials: CR
authors.lastname: Bezzina
mesh_terms: D053840:Brugada Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics / Q000378:metabolism
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human