Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by the lack of functional dystrophin. DMD is associated with progressive dilated cardiomyopathy, eventually leading to heart failure as the main cause of death in DMD patients. Although several molecular mechanisms leading to the DMD cardiomyocyte (DMD-CM) death were described, mostly in mouse model, no suitable human CM model was until recently available together with proper clarification of the DMD-CM phenotype and delay in cardiac symptoms manifestation. We obtained several independent dystrophin-deficient human pluripotent stem cell (hPSC) lines from DMD patients and CRISPR/Cas9-generated DMD gene mutation. We differentiated DMD-hPSC into cardiac cells (CC) creating a human DMD-CC disease model. We observed that mutation-carrying cells were less prone to differentiate into CCs. DMD-CCs demonstrated an enhanced cell death rate in time. Furthermore, ion channel expression was altered in terms of potassium (Kir2.1 overexpression) and calcium handling (dihydropyridine receptor overexpression). DMD-CCs exhibited increased time of calcium transient rising compared to aged-matched control, suggesting mishandling of calcium release. We observed mechanical impairment (hypocontractility), bradycardia, increased heart rate variability, and blunted β-adrenergic response connected with remodeling of β-adrenergic receptors expression in DMD-CCs. Overall, these results indicated that our DMD-CC models are functionally affected by dystrophin-deficiency associated and recapitulate functional defects and cardiac wasting observed in the disease. It offers an accurate tool to study human cardiomyopathy progression and test therapies in vitro.

1st Department of Internal Medicine Cardioangiology Faculty of Medicine Masaryk University Brno Czechia

2nd Clinic of Internal Medicine Masaryk University of Brno Brno Czechia

CEITEC Masaryk University Brno Czechia

Department of Biochemistry Faculty of Science Masaryk University Brno Czechia

Department of Biology Faculty of Medicine Masaryk University Brno Czechia

Department of Clinical Biochemistry St Anne's University Hospital of Brno Brno Czechia

International Clinical Research Center ICRC St Anne's University Hospital Brno Brno Czechia

PhyMedExp University of Montpellier INSERM CNRS Montpellier France

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Acimovic I., Refaat M. M., Moreau A., Salykin A., Reiken S., Sleiman Y., et al. . (2018). Post-translational modifications and diastolic calcium leak associated to the novel RyR2-D3638A mutation lead to CPVT in patient-specific hiPSC-derived cardiomyocytes. J. Clin. Med. 7:423. 10.3390/jcm7110423 PubMed DOI PMC

Amedro P., Vincenti M., De La Villeon G., Lavastre K., Barrea C., Guillaumont S., et al. . (2019). Speckle-tracking echocardiography in children with duchenne muscular dystrophy: a prospective multicenter controlled cross-sectional study. J. Am. Soc. Echocardiogr. 32, 412–422. 10.1016/j.echo.2018.10.017 PubMed DOI

Andersson D. C., Marks A. R. (2010). Fixing ryanodine receptor Ca leak - a novel therapeutic strategy for contractile failure in heart and skeletal muscle. Drug Discov. Today Dis. Mech. 7, e151–e157. 10.1016/j.ddmec.2010.09.009 PubMed DOI PMC

Andersson D. C., Meli A. C., Reiken S., Betzenhauser M. J., Umanskaya A., Shiomi T., et al. . (2012). Leaky ryanodine receptors in β-sarcoglycan deficient mice: a potential common defect in muscular dystrophy. Skelet. Muscle 2:9. 10.1186/2044-5040-2-9 PubMed DOI PMC

Armstrong L., Tilgner K., Saretzki G., Atkinson S. P., Stojkovic M., Moreno R., et al. . (2010). Human induced pluripotent stem cell lines show stress defense mechanisms and mitochondrial regulation similar to those of human embryonic stem cells. Stem Cells 28, 661–673. 10.1002/stem.307 PubMed DOI

Asp M. L., Martindale J. J., Heinis F. I., Wang W., Metzger J. M. (2013). Calcium mishandling in diastolic dysfunction: mechanisms and potential therapies. Biochim. Biophys. Acta 1833, 895–900. 10.1016/j.bbamcr.2012.09.007 PubMed DOI PMC

Blake D. J., Weir A., Newey S. E., Davies K. E. (2002). Function and genetics of dystrophin and dystrophin-related proteins in muscle. Physiol. Rev. 82, 291–329. 10.1152/physrev.00028.2001 PubMed DOI

Bondue A., Arbustini E., Bianco A., Ciccarelli M., Dawson D., De Rosa M., et al. . (2018). Complex roads from genotype to phenotype in dilated cardiomyopathy: scientific update from the working group of myocardial function of the european society of cardiology. Cardiovasc. Res. 114, 1287–1303. 10.1093/cvr/cvy122 PubMed DOI PMC

Bristow M. R., Ginsburg R., Minobe W., Cubicciotti R. S., Sageman W. S., Lurie K., et al. . (1982). Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N. Engl. J. Med. 307, 205–211. 10.1056/NEJM198207223070401 PubMed DOI

Caluori G., Pribyl J., Pesl M., Jelinkova S., Rotrekl V., Skladal P., et al. . (2019). Non-invasive electromechanical cell-based biosensors for improved investigation of 3D cardiac models. Biosens. Bioelectron. 124–125, 129–135. 10.1016/j.bios.2018.10.021 PubMed DOI

Carnwath J. W., Shotton D. M. (1987). Muscular dystrophy in the mdx mouse: histopathology of the soleus and extensor digitorum longus muscles. J. Neurol. Sci. 80, 39–54. 10.1016/0022-510X(87)90219-X PubMed DOI

Chenard A. A., Becane H. M., Tertrain F., de Kermadec J. M., Weiss Y. A. (1993). Ventricular arrhythmia in duchenne muscular dystrophy: prevalence, significance and prognosis. Neuromuscul. Disord. 3, 201–206. 10.1016/0960-8966(93)90060-W PubMed DOI

Choi B.-R., Burton F., Salama G. (2002). Cytosolic Ca2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome. J. Physiol. 543, 615–631. 10.1113/jphysiol.2002.024570 PubMed DOI PMC

Clarac F., Massion J., Smith A. M. (2009). Duchenne, charcot and babinski, three neurologists of la salpetrière hospital, and their contribution to concepts of the central organization of motor synergy. J. Physiol. Paris 103, 361–376. 10.1016/j.jphysparis.2009.09.001 PubMed DOI

Corrado G., Lissoni A., Beretta S., Terenghi L., Tadeo G., Foglia-Manzillo G., et al. . (2002). Prognostic value of electrocardiograms, ventricular late potentials, ventricular arrhythmias, and left ventricular systolic dysfunction in patients with Duchenne muscular dystrophy. Am. J. Cardiol. 89, 838–841. 10.1016/S0002-9149(02)02195-1 PubMed DOI

Coulton G. R., Morgan J. E., Partridge T. A., Sloper J. C. (1988). The mdx mouse skeletal muscle myopathy: I. A histological, morphometric and biochemical investigation. Neuropathol. Appl. Neurobiol. 14, 53–70. 10.1111/j.1365-2990.1988.tb00866.x PubMed DOI

Culligan K., Banville N., Dowling P., Ohlendieck K. (2002). Drastic reduction of calsequestrin-like proteins and impaired calcium binding in dystrophic mdx muscle. J. Appl. Physiol. 92, 435–445. 10.1152/japplphysiol.00903.2001 PubMed DOI

Danialou G., Comtois A. S., Dudley R., Karpati G., Vincent G., Des Rosiers C., et al. . (2001). Dystrophin-deficient cardiomyocytes are abnormally vulnerable to mechanical stress-induced contractile failure and injury. FASEB J. 15, 1655–1657. 10.1096/fj.01-0030fje PubMed DOI

de Lucia C., Eguchi A., Koch W. J. (2018). New insights in cardiac β-adrenergic signaling during heart failure and aging. Front. Pharmacol. 9:904. 10.3389/fphar.2018.00904 PubMed DOI PMC

Dumont N. A., Wang Y. X., von Maltzahn J., Pasut A., Bentzinger C. F., Brun C. E., et al. . (2015). Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. Nat. Med. 21, 1455–1463. 10.1038/nm.3990 PubMed DOI PMC

Dvorak P., Dvorakova D., Koskova S., Vodinska M., Najvirtova M., Krekac D., et al. . (2005). Expression and potential role of fibroblast growth factor 2 and its receptors in human embryonic stem cells. Stem Cells 23, 1200–1211. 10.1634/stemcells.2004-0303 PubMed DOI

Eisen B., Ben Jehuda R., Cuttitta A. J., Mekies L. N., Shemer Y., Baskin P., et al. . (2019). Electrophysiological abnormalities in induced pluripotent stem cell-derived cardiomyocytes generated from duchenne muscular dystrophy patients. J. Cell. Mol. Med. 23, 2125–2135. 10.1111/jcmm.14124 PubMed DOI PMC

Engelhardt S., Hein L., Wiesmann F., Lohse M. J. (1999). Progressive hypertrophy and heart failure in beta1-adrenergic receptor transgenic mice. Proc. Natl. Acad. Sci. U.S.A. 96, 7059–7064. 10.1073/pnas.96.12.7059 PubMed DOI PMC

Fauconnier J., Thireau J., Reiken S., Cassan C., Richard S., Matecki S., et al. . (2010). Leaky RyR2 trigger ventricular arrhythmias in duchenne muscular dystrophy. Proc. Natl. Acad. Sci. U.S.A. 107, 1559–1564. 10.1073/pnas.0908540107 PubMed DOI PMC

Fayssoil A., Nardi O., Orlikowski D., Annane D. (2010). Cardiomyopathy in duchenne muscular dystrophy: pathogenesis and therapeutics. Heart Fail Rev. 15, 103–107. 10.1007/s10741-009-9156-8 PubMed DOI

Finsterer J., Stöllberger C. (2003). The heart in human dystrophinopathies. Cardiology 99, 1–19. 10.1159/000068446 PubMed DOI

Gerke V., Creutz C. E., Moss S. E. (2005). Annexins: linking Ca2+ signalling to membrane dynamics. Nat. Rev. Mol. Cell Biol. 6, 449–461. 10.1038/nrm1661 PubMed DOI

Hajjar R. J., Liao R., Young J. B., Fuleihan F., Glass M. G., Gwathmey J. K. (1993). Pathophysiological and biochemical characterisation of an avian model of dilated cardiomyopathy: comparison to findings in human dilated cardiomyopathy. Cardiovasc. Res. 27, 2212–2221. 10.1093/cvr/27.12.2212 PubMed DOI

He J.-Q., Ma Y., Lee Y., Thomson J. A., Kamp T. J. (2003). Human embryonic stem cells develop into multiple types of cardiac myocytes: action potential characterization. Circ. Res. 93, 32–39. 10.1161/01.RES.0000080317.92718.99 PubMed DOI

Hess G. P. D., Horsch A. D., Zdunek D. D. (2008). Means and Methods for Optimization of Diagnostic and Therapeutic Approaches in Chronic Artery Disease Based on the Detection of Troponin T and NT-proBNP. Available online at: https://patents.google.com/patent/EP1925943A1/en/en22 (accessed December 14, 2019).

Himmrich E., Popov S., Liebrich A., Rosocha S., Zellerhoff C., Nowak B., et al. . (2000). [Hidden intracardiac conduction disturbances and their spontaneous course in patients with progressive muscular dystrophy]. Z Kardiol. 89, 592–598. 10.1007/s003920070208 PubMed DOI

Hwang H. S., Kryshtal D. O., Feaster T. K., Sánchez-Freire V., Zhang J., Kamp T. J., et al. . (2015). Comparable calcium handling of human iPSC-derived cardiomyocytes generated by multiple laboratories. J. Mol. Cell. Cardiol. 85, 79–88. 10.1016/j.yjmcc.2015.05.003 PubMed DOI PMC

Inomata K., Aoto T., Binh N. T., Okamoto N., Tanimura S., Wakayama T., et al. . (2009). Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation. Cell 137, 1088–1099. 10.1016/j.cell.2009.03.037 PubMed DOI

International Stem Cell Initiative. Adewumi O., Aflatoonian B., Ahrlund-Richter L., Amit M., Andrews P. W., et al. . (2007). Characterization of human embryonic stem cell lines by the international stem cell initiative. Nat. Biotechnol. 25, 803–816. 10.1038/nbt1318 PubMed DOI

Jelinkova S., Fojtik P., Kohutova A., Vilotic A., Marková L., Pesl M., et al. . (2019a). Dystrophin deficiency leads to genomic instability in human pluripotent stem cells via NO synthase-induced oxidative stress. Cells 8:53. 10.3390/cells8010053 PubMed DOI PMC

Jelinkova S., Markova L., Pesl M., Valáškova I., Makaturová E., Jurikova L., et al. . (2019b). Generation of two duchenne muscular dystrophy patient-specific induced pluripotent stem cell lines DMD02 and DMD03 (MUNIi001-A and MUNIi003-A). Stem Cell Res. 40:101562. 10.1016/j.scr.2019.101562 PubMed DOI

Johnson D. M., Heijman J., Bode E. F., Greensmith D. J., van der Linde H., Abi-Gerges N., et al. . (2013). Diastolic spontaneous calcium release from the sarcoplasmic reticulum increases beat-to-beat variability of repolarization in canine ventricular myocytes after β-adrenergic stimulation. Circ. Res. 112, 246–256. 10.1161/CIRCRESAHA.112.275735 PubMed DOI

Jung C., Martins A. S., Niggli E., Shirokova N. (2008). Dystrophic cardiomyopathy: amplification of cellular damage by Ca2+ signalling and reactive oxygen species-generating pathways. Cardiovasc. Res. 77, 766–773. 10.1093/cvr/cvm089 PubMed DOI

Kajimoto H., Ishigaki K., Okumura K., Tomimatsu H., Nakazawa M., Saito K., et al. . (2006). Beta-blocker therapy for cardiac dysfunction in patients with muscular dystrophy. Circ. J. 70, 991–994. 10.1253/circj.70.991 PubMed DOI

Kamdar F., Garry D. J. (2016). Dystrophin-deficient cardiomyopathy. J. Am. Coll. Cardiol. 67, 2533–2546. 10.1016/j.jacc.2016.02.081 PubMed DOI

Koenig X., Dysek S., Kimbacher S., Mike A. K., Cervenka R., Lukacs P., et al. . (2011). Voltage-gated ion channel dysfunction precedes cardiomyopathy development in the dystrophic heart. PLoS ONE 6:e20300. 10.1371/journal.pone.0020300 PubMed DOI PMC

Koenig X., Rubi L., Obermair G. J., Cervenka R., Dang X. B., Lukacs P., et al. . (2014). Enhanced currents through L-type calcium channels in cardiomyocytes disturb the electrophysiology of the dystrophic heart. Am. J. Physiol. Heart Circ. Physiol. 306, H564–H573. 10.1152/ajpheart.00441.2013 PubMed DOI PMC

Krutá M., Bálek L., Hejnová R., Dobšáková Z., Eiselleová L., Matulka K., et al. . (2013). Decrease in abundance of apurinic/apyrimidinic endonuclease causes failure of base excision repair in culture-adapted human embryonic stem cells. Stem Cells 31, 693–702. 10.1002/stem.1312 PubMed DOI

Krutá M., Šeneklová M., Raška J., Salykin A., Zerzánková L., Pešl M., et al. . (2014). Mutation frequency dynamics in HPRT locus in culture-adapted human embryonic stem cells and induced pluripotent stem cells correspond to their differentiated counterparts. Stem Cells Dev. 23, 2443–2454. 10.1089/scd.2013.0611 PubMed DOI PMC

Li Y., Zhang S., Zhang X., Li J., Ai X., Zhang L., et al. . (2014). Blunted cardiac beta-adrenergic response as an early indication of cardiac dysfunction in duchenne muscular dystrophy. Cardiovasc. Res. 103, 60–71. 10.1093/cvr/cvu119 PubMed DOI PMC

Lu S., Hoey A. (2000). Changes in function of cardiac receptors mediating the effects of the autonomic nervous system in the muscular dystrophy (MDX) mouse. J. Mol. Cell. Cardiol. 32, 143–152. 10.1006/jmcc.1999.1063 PubMed DOI

Mah J. K., Korngut L., Dykeman J., Day L., Pringsheim T., Jette N. (2014). A systematic review and meta-analysis on the epidemiology of duchenne and becker muscular dystrophy. Neuromuscul. Disord. 24, 482–491. 10.1016/j.nmd.2014.03.008 PubMed DOI

Manzur A. Y., Kinali M., Muntoni F. (2008). Update on the management of duchenne muscular dystrophy. Arch. Dis. Child. 93, 986–990. 10.1136/adc.2007.118141 PubMed DOI

Markham L. W., Michelfelder E. C., Border W. L., Khoury P. R., Spicer R. L., Wong B. L., et al. . (2006). Abnormalities of diastolic function precede dilated cardiomyopathy associated with Duchenne muscular dystrophy. J. Am. Soc. Echocardiogr. 19, 865–871. 10.1016/j.echo.2006.02.003 PubMed DOI

Matsumura T., Tamura T., Kuru S., Kikuchi Y., Kawai M. (2010). Carvedilol can prevent cardiac events in duchenne muscular dystrophy. Intern. Med. 49, 1357–1363. 10.2169/internalmedicine.49.3259 PubMed DOI

McNally E. M., Kaltman J. R., Benson D. W., Canter C. E., Cripe L. H., Duan D., et al. . (2015). Contemporary cardiac issues in duchenne muscular dystrophy. Circulation 131, 1590–1598. 10.1161/CIRCULATIONAHA.114.015151 PubMed DOI PMC

Meyers T. A., Heitzman J. A., Krebsbach A. M., Aufdembrink L. M., Hughes R., Bartolomucci A., et al. . (2019). Acute AT1R blockade prevents isoproterenol-induced injury in mdx hearts. J. Mol. Cell. Cardiol. 128, 51–61. 10.1016/j.yjmcc.2019.01.013 PubMed DOI PMC

Meyers T. A., Townsend D. (2019). Cardiac pathophysiology and the future of cardiac therapies in duchenne muscular dystrophy. Int. J. Mol. Sci. 20:4098. 10.3390/ijms20174098 PubMed DOI PMC

Oda T., Yang Y., Uchinoumi H., Thomas D. D., Chen-Izu Y., Kato T., et al. . (2015). Oxidation of ryanodine receptor (RyR) and calmodulin enhance Ca release and pathologically alter, RyR structure and calmodulin affinity. J. Mol. Cell. Cardiol. 85, 240–248. 10.1016/j.yjmcc.2015.06.009 PubMed DOI PMC

Panovský R., Pešl M., Holeček T., Máchal J., Feitová V., Mrázová L., et al. . (2019). Cardiac profile of the czech population of duchenne muscular dystrophy patients: a cardiovascular magnetic resonance study with T1 mapping. Orphanet J. Rare Dis. 14:10. 10.1186/s13023-018-0986-0 PubMed DOI PMC

Papa A. A., D'Ambrosio P., Petillo R., Palladino A., Politano L. (2017). Heart transplantation in patients with dystrophinopathic cardiomyopathy: review of the literature and personal series. Intractable Rare Dis Res. 6, 95–101. 10.5582/irdr.2017.01024 PubMed DOI PMC

Park K. C., Gaze D. C., Collinson P. O., Marber M. S. (2017). Cardiac troponins: from myocardial infarction to chronic disease. Cardiovasc. Res. 113, 1708–1718. 10.1093/cvr/cvx183 PubMed DOI PMC

Patrick Gonzalez J., Ramachandran J., Xie L.-H., Contreras J. E., Fraidenraich D. (2015). Selective connexin43 inhibition prevents isoproterenol-induced arrhythmias and lethality in muscular dystrophy mice. Sci. Rep. 5:13490. 10.1038/srep13490 PubMed DOI PMC

Pesl M., Acimovic I., Pribyl J., Hezova R., Vilotic A., Fauconnier J., et al. . (2014). Forced aggregation and defined factors allow highly uniform-sized embryoid bodies and functional cardiomyocytes from human embryonic and induced pluripotent stem cells. Heart Vessels 29, 834–846. 10.1007/s00380-013-0436-9 PubMed DOI

Pesl M., Jelinkova S., Caluori G., Holicka M., Krejci J., Nemec P., et al. . (2020). Cardiovascular progenitor cells and tissue plasticity are reduced in a myocardium affected by Becker muscular dystrophy. Orphanet J. Rare Dis. 15:65. 10.1186/s13023-019-1257-4 PubMed DOI PMC

Pesl M., Pribyl J., Acimovic I., Vilotic A., Jelinkova S., Salykin A., et al. . (2016). Atomic force microscopy combined with human pluripotent stem cell derived cardiomyocytes for biomechanical sensing. Biosens. Bioelectron. 85, 751–757. 10.1016/j.bios.2016.05.073 PubMed DOI

Peterson J. M., Wang D. J., Shettigar V., Roof S. R., Canan B. D., Bakkar N., et al. . (2018). NF-κB inhibition rescues cardiac function by remodeling calcium genes in a duchenne muscular dystrophy model. Nat. Commun. 9:3431. 10.1038/s41467-018-05910-1 PubMed DOI PMC

Pioner J. M., Guan X., Klaiman J. M., Racca A. W., Pabon L., Muskheli V., et al. . (2020). Absence of full-length dystrophin impairs normal maturation and contraction of cardiomyocytes derived from human-induced pluripotent stem cells. Cardiovasc. Res. 116, 368–382. PubMed PMC

Pribyl J., Pešl M., Caluori G., Acimovic I., Jelinkova S., Dvorak P., et al. . (2019). Biomechanical characterization of human pluripotent stem cell-derived cardiomyocytes by use of atomic force microscopy. Methods Mol. Biol. 1886, 343–353. 10.1007/978-1-4939-8894-5_20 PubMed DOI

Puzzo D., Raiteri R., Castaldo C., Capasso R., Pagano E., Tedesco M., et al. . (2016). CL316,243, a β3-adrenergic receptor agonist, induces muscle hypertrophy and increased strength. Sci. Rep. 5:37504. 10.1038/srep37504 PubMed DOI PMC

Qu C., Puttonen K. A., Lindeberg H., Ruponen M., Hovatta O., Koistinaho J., et al. . (2013). Chondrogenic differentiation of human pluripotent stem cells in chondrocyte co-culture. Int. J. Biochem. Cell Biol. 45, 1802–1812. 10.1016/j.biocel.2013.05.029 PubMed DOI

Rengo G., Lymperopoulos A., Koch W. J. (2009). Future g protein-coupled receptor targets for treatment of heart failure. Curr. Treat. Options Cardiovasc. Med. 11, 328–338. 10.1007/s11936-009-0033-5 PubMed DOI

Rossi D. J., Bryder D., Seita J., Nussenzweig A., Hoeijmakers J., Weissman I. L. (2007). Deficiencies in DNA damage repair limit the function of haematopoietic stem cells with age. Nature 447, 725–729. 10.1038/nature05862 PubMed DOI

Sadek A. A., Mahmoud S. M., El-Aal M. A., Allam A. A., El-Halim W. I. A. (2017). Evaluation of cardiac functions in children with duchenne muscular dystrophy: a prospective case-control study. Electron. Physician. 9, 5732–5739. 10.19082/5732 PubMed DOI PMC

Sato H., Shiraishi I., Takamatsu T., Hamaoka K. (2007). Detection of TUNEL-positive cardiomyocytes and c-kit-positive progenitor cells in children with congenital heart disease. J. Mol. Cell. Cardiol. 43, 254–261. 10.1016/j.yjmcc.2007.05.011 PubMed DOI

Shirokova N., Niggli E. (2013). Cardiac phenotype of duchenne muscular dystrophy: insights from cellular studies. J. Mol. Cell. Cardiol. 58, 217–224. 10.1016/j.yjmcc.2012.12.009 PubMed DOI PMC

Skeberdis V. A. (2004). Structure and function of beta3-adrenergic receptors. Medicina (Kaunas). 40, 407–413. PubMed

Stehlíková K., Skálová D., Zídková J., Haberlová J., Vohánka S., Mazanec R., et al. . (2017). Muscular dystrophies and myopathies: the spectrum of mutated genes in the czech republic. Clin. Genet. 91, 463–469. 10.1111/cge.12839 PubMed DOI

Tsurumi F., Baba S., Yoshinaga D., Umeda K., Hirata T., Takita J., et al. . (2019). The intracellular Ca2+ concentration is elevated in cardiomyocytes differentiated from hiPSCs derived from a duchenne muscular dystrophy patient. PLoS ONE 14:e0213768. 10.1371/journal.pone.0213768 PubMed DOI PMC

Villa Chet R., Czosek Richard J., Ahmed H., Khoury Philip R., Anderson Jeffrey B., Knilans Timothy K., et al. . (2015). Ambulatory monitoring and arrhythmic outcomes in pediatric and adolescent patients with duchenne muscular dystrophy. J. Am. Heart Assoc. 5:e002620. 10.1161/JAHA.115.002620 PubMed DOI PMC

Viollet L., Thrush P. T., Flanigan K. M., Mendell J. R., Allen H. D. (2012). Effects of angiotensin-converting enzyme inhibitors and/or beta blockers on the cardiomyopathy in duchenne muscular dystrophy. Am. J. Cardiol. 110, 98–102. 10.1016/j.amjcard.2012.02.064 PubMed DOI

Voigt N., Li N., Wang Q., Wang W., Trafford A. W., Abu-Taha I., et al. . (2012). Enhanced sarcoplasmic reticulum Ca2+-leak and increased Na+-Ca2+-exchanger function underlie delayed afterdepolarizations in patients with chronic atrial fibrillation. Circulation 125, 2059–2070. 10.1161/CIRCULATIONAHA.111.067306 PubMed DOI PMC

Vry J., Gramsch K., Rodger S., Thompson R., Steffensen B. F., Rahbek J., et al. . (2016). European cross-sectional survey of current care practices for duchenne muscular dystrophy reveals regional and age-dependent differences. J. Neuromuscul. Dis. 3, 517–527. 10.3233/JND-160185 PubMed DOI PMC

Wagner K. R., Lechtzin N., Judge D. P. (2007). Current treatment of adult duchenne muscular dystrophy. Biochim. Biophys. Acta 1772, 229–237. 10.1016/j.bbadis.2006.06.009 PubMed DOI

Weiss J. N., Garfinkel A., Karagueuzian H. S., Chen P.-S., Qu Z. (2010). Early afterdepolarizations and cardiac arrhythmias. Heart Rhythm. 7, 1891–1899. 10.1016/j.hrthm.2010.09.017 PubMed DOI PMC

Williams I. A., Allen D. G. (2007). Intracellular calcium handling in ventricular myocytes from mdx mice. Am. J. Physiol. Heart Circ. Physiol. 292, H846–H855. 10.1152/ajpheart.00688.2006 PubMed DOI

Zhu R., Millrod M. A., Zambidis E. T., Tung L. (2016). Variability of action potentials within and among cardiac cell clusters derived from human embryonic stem cells. Sci. Rep. 6:18544. 10.1038/srep18544 PubMed DOI PMC

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