Ion Channel Dysfunctions in Dilated Cardiomyopathy in Limb-Girdle Muscular Dystrophy

Ibrahim El-Battrawy; Zhihan Zhao; Huan Lan; Xin Li; Gökhan Yücel; Siegfried Lang; Katherine Sattler; Jan-Dierk Schünemann; Wolfram-Hubertus Zimmermann; Lukas Cyganek; Jochen Utikal; Thomas Wieland; Karen Bieback; Ralf Bauer; Antonius Ratte; Regina Pribe-Wolferts; Kleopatra Rapti; Daniel Nowak; Janina Wittig; Dierk Thomas; Patrick Most; Hugo A Katus; Ursula Ravens; Constanze Schmidt; Martin Borggrefe; Xiao-Bo Zhou; Oliver J Müller; Ibrahim Akin

doi:10.1161/CIRCGEN.117.001893

Ion Channel Dysfunctions in Dilated Cardiomyopathy in Limb-Girdle Muscular Dystrophy

Circ Genom Precis Med. 2018 Mar;11(3):e001893. doi: 10.1161/CIRCGEN.117.001893.

Authors

Ibrahim El-Battrawy¹, Zhihan Zhao¹, Huan Lan¹, Xin Li¹, Gökhan Yücel¹, Siegfried Lang¹, Katherine Sattler¹, Jan-Dierk Schünemann¹, Wolfram-Hubertus Zimmermann¹, Lukas Cyganek¹, Jochen Utikal¹, Thomas Wieland¹, Karen Bieback¹, Ralf Bauer¹, Antonius Ratte¹, Regina Pribe-Wolferts¹, Kleopatra Rapti¹, Daniel Nowak¹, Janina Wittig¹, Dierk Thomas¹, Patrick Most¹, Hugo A Katus¹, Ursula Ravens¹, Constanze Schmidt¹, Martin Borggrefe¹, Xiao-Bo Zhou², Oliver J Müller¹, Ibrahim Akin¹

Affiliations

¹ From the First Department of Medicine, Faculty of Medicine (I.E.-B., Z.Z., H.L., X.L., G.Y., S.L., K.S., J.-D.S., M.B., X.-B.Z., I.A.) and Department of Dermatology, Venereology and Allergology (J.U.), University Medical Centre Mannheim, University of Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen (I.E.-B., Z.Z., H.L., G.Y., S.L., W.-H.Z., L.C., J.U., T.W., R.B., A.R., D.T., P.M., H.A.K., C.S., M.B., X.-B.Z., O.J.M., I.A.); Institute of Pharmacology and Toxicology, University of Göttingen, Germany (W.-H.Z.); Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Germany (L.C.); Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg (J.U.); Institute of Experimental and Clinical Pharmacology and Toxicology (T.W.) and Department of Hematology and Oncology (D.N., J.W.), Medical Faculty Mannheim, University of Heidelberg, Germany; Institute for Transfusion Medicine and Immunology, Mannheim, Germany (K.B.); Internal Medicine III, University Hospital Heidelberg, Germany (R.B., A.R., R.P.-W., K.R., D.T., P.M., H.A.K., C.S., O.J.M.); Institute of Experimental Cardiovascular Medicine, University Heart Centre Freiburg, Germany (U.R.); Medical Faculty, University of Freiburg, Germany (U.R.); and Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China (H.L., X.-B.Z.).
² From the First Department of Medicine, Faculty of Medicine (I.E.-B., Z.Z., H.L., X.L., G.Y., S.L., K.S., J.-D.S., M.B., X.-B.Z., I.A.) and Department of Dermatology, Venereology and Allergology (J.U.), University Medical Centre Mannheim, University of Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Partner Sites, Heidelberg-Mannheim and Göttingen (I.E.-B., Z.Z., H.L., G.Y., S.L., W.-H.Z., L.C., J.U., T.W., R.B., A.R., D.T., P.M., H.A.K., C.S., M.B., X.-B.Z., O.J.M., I.A.); Institute of Pharmacology and Toxicology, University of Göttingen, Germany (W.-H.Z.); Stem Cell Unit, Clinic for Cardiology and Pneumology, University Medical Center Göttingen, Germany (L.C.); Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg (J.U.); Institute of Experimental and Clinical Pharmacology and Toxicology (T.W.) and Department of Hematology and Oncology (D.N., J.W.), Medical Faculty Mannheim, University of Heidelberg, Germany; Institute for Transfusion Medicine and Immunology, Mannheim, Germany (K.B.); Internal Medicine III, University Hospital Heidelberg, Germany (R.B., A.R., R.P.-W., K.R., D.T., P.M., H.A.K., C.S., O.J.M.); Institute of Experimental Cardiovascular Medicine, University Heart Centre Freiburg, Germany (U.R.); Medical Faculty, University of Freiburg, Germany (U.R.); and Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China (H.L., X.-B.Z.). Xiaobo.zhou@medma.uni-heidelberg.de.

PMID: 29545480
DOI: 10.1161/CIRCGEN.117.001893

Abstract

Background: Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis.

Methods: Dermal fibroblasts obtained from a patient with LGMD2I harboring a fukutin-related protein gene mutation (826C>A; Leu276Ile) and 3 healthy donors were reprogrammed to hiPSCs. The hiPSCs were differentiated into cardiomyocytes and used for biological and electrophysiological studies.

Results: Compared with hiPSC cardiomyocytes from the healthy donors, the hiPSC cardiomyocytes from the patient exhibited abnormal action potentials characterized by reduced amplitude and upstroke velocity. The peak and late Na channel currents (I_Na) as well as the peak L-type calcium channel currents were significantly reduced. The expression of SCN5A and CACNA1C was reduced in DCM cardiomyocytes, consistent with reduction of I_Na and L-type calcium channel currents. In addition, the rapidly activating delayed rectifier potassium current (I_Kr) was reduced, whereas the transient outward current (I_to) and slowly activating delayed rectifier potassium current (I_Ks) were similar in DCM and control cardiomyocytes. Finally, a significant reduction of systolic and diastolic intracellular Ca²⁺ concentrations was detected in DCM cardiomyocytes.

Conclusions: This study demonstrates that patient-specific hiPSC cardiomyocytes can recapitulate some phenotypic properties of LGMD2I with DCM and provide a platform for studies on the cardiac events in LGMD.

Keywords: action potentials; calcium channels, L-type; cardiomyopathy, dilated; induced pluripotent stem cells; muscular dystrophies, Limb-Girdle.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials
Calcium Channels, L-Type / genetics
Calcium Channels, L-Type / metabolism
Cardiomyopathy, Dilated / complications
Cardiomyopathy, Dilated / diagnosis*
Cardiomyopathy, Dilated / genetics
Fibroblasts / cytology
Fibroblasts / metabolism
Humans
Induced Pluripotent Stem Cells / cytology
Male
Microscopy, Fluorescence
Middle Aged
Muscular Dystrophies, Limb-Girdle / complications
Muscular Dystrophies, Limb-Girdle / diagnosis*
Muscular Dystrophies, Limb-Girdle / genetics
Myocytes, Cardiac / cytology
Myocytes, Cardiac / metabolism
NAV1.5 Voltage-Gated Sodium Channel / genetics
Patch-Clamp Techniques
Pentosyltransferases
Phenotype
Polymorphism, Single Nucleotide
Proteins / genetics

Substances

CACNA1C protein, human
Calcium Channels, L-Type
NAV1.5 Voltage-Gated Sodium Channel
Proteins
SCN5A protein, human
FKRP protein, human
Pentosyltransferases

Supplementary concepts

Muscular Dystrophy, Limb-Girdle, Type 2I