Case Reports

. 2018 Mar;11(3):e001893.

doi: 10.1161/CIRCGEN.117.001893.

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

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

Case Reports

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

Ibrahim El-Battrawy et al. Circ Genom Precis Med. 2018 Mar.

. 2018 Mar;11(3):e001893.

doi: 10.1161/CIRCGEN.117.001893.

Authors

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.

PubMed Disclaimer

Comment in

Modeling Cardiomyopathy and Arrhythmias in Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
Chen SN, Taylor MRG, Mestroni L. Chen SN, et al. Circ Genom Precis Med. 2018 Mar;11(3):e002088. doi: 10.1161/CIRCGEN.118.002088. Circ Genom Precis Med. 2018. PMID: 29545481 Free PMC article. No abstract available.

Cited by

TRPV1 activation and internalization is part of the LPS-induced inflammation in human iPSC-derived cardiomyocytes.
Sattler K, El-Battrawy I, Cyganek L, Lang S, Lan H, Li X, Zhao Z, Utikal J, Wieland T, Borggrefe M, Zhou X, Akin I. Sattler K, et al. Sci Rep. 2021 Jul 19;11(1):14689. doi: 10.1038/s41598-021-93958-3. Sci Rep. 2021. PMID: 34282193 Free PMC article.
Electrocardiographic Parameters Associated with Adverse Outcomes in Children with Cardiomyopathies.
Luczak-Wozniak K, Obsznajczyk K, Niszczota C, Werner B. Luczak-Wozniak K, et al. J Clin Med. 2022 Nov 24;11(23):6930. doi: 10.3390/jcm11236930. J Clin Med. 2022. PMID: 36498505 Free PMC article.
Modeling Cardiomyopathy and Arrhythmias in Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
Chen SN, Taylor MRG, Mestroni L. Chen SN, et al. Circ Genom Precis Med. 2018 Mar;11(3):e002088. doi: 10.1161/CIRCGEN.118.002088. Circ Genom Precis Med. 2018. PMID: 29545481 Free PMC article. No abstract available.
miR-454-3p and miR-194-5p targeting cardiac sarcolemma ion exchange transcripts are potential noninvasive diagnostic biomarkers for childhood dilated cardiomyopathy in Egyptian patients.
Fayez AG, Esmaiel NN, Salem SM, Ashaat EA, El-Saiedi SA, El Ruby MO. Fayez AG, et al. Egypt Heart J. 2022 Sep 8;74(1):65. doi: 10.1186/s43044-022-00300-x. Egypt Heart J. 2022. PMID: 36076093 Free PMC article.
iPSCs as a Platform for Disease Modeling, Drug Screening, and Personalized Therapy in Muscular Dystrophies.
Ortiz-Vitali JL, Darabi R. Ortiz-Vitali JL, et al. Cells. 2019 Jan 3;8(1):20. doi: 10.3390/cells8010020. Cells. 2019. PMID: 30609814 Free PMC article. Review.

See all "Cited by" articles

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Supplementary concepts

Actions

LinkOut - more resources

Full Text Sources
- Atypon
- Ovid Technologies, Inc.
Other Literature Sources
- scite Smart Citations
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Affiliations

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

Authors

Affiliations

Abstract

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

Supplementary concepts

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous

Abstract

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

Supplementary concepts

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous