Cardiovascular Research Advance Access published February 17, 2015 1

Letter regarding article by Han et al, “Study familial hypertrophic cardiomyopathy using patient specific induced pluripotent stem cells”

Torsten Christ1,2, Jussi T. Koivumäki3, Thomas Eschenhagen1,2 1

Department of Experimental Pharmacology and Toxicology, University Medical

Center Hamburg-Eppendorf, Germany 2

DZHK (German Centre for Cardiovascular Research), partner site

Hamburg/Kiel/Lübeck 3

Simula Research Laboratory, Center for Biomedical Computing and Center for

Cardiological Innovation Oslo, Norway

Address for Correspondence: PD Dr. med. Torsten Christ, Institut für experimentelle

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Martinistrasse 52, 20246 Hamburg, Germany, Tel: +4940741052180, Fax: +4940741054876, e-mail: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: [email protected].

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Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf,

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With great interest we read the article by Han et al. “Study Familial Hypertrophic Cardiomyopathy Using Patient Specific Induced Pluripotent Stem Cells” recently published in “Cardiovascular Research”.1 Life threatening ventricular arrhythmias in hypertrophic cardiomyopathy (HCM) remain a challenge not only for clinical management of individual patients, but also from the viewpoint of cellular cardiac electrophysiology. It remains an enigma how mutations of sarcomeric proteins can increase the propensity for arrhythmias. A recent concept suggests that the often increased Ca2+-binding affinity of mutated sarcomeres in HCM increases Ca2+ buffering and, by diastolic release of Ca2+, the propensity for arrhythmias.2 The advantage of patient-specific induced pluripotent stem cells (iPSC) should be that effects of patient-relevant mutations can be studied in the correct genetic and cellular

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derived cardiac myocytes can be evaluated without restriction in time and numbers. The critical and unanswered question is whether (immature) iPSC-derived cardiac myocytes really reflect the phenotype of the patient or predict it. Data answering this question is lacking also in the recent study. Han et al. report six-fold higher sodium current density and almost two-times higher APD90 in HCM-derived iPSC cardiac myocytes compared to those from healthy controls. Both numbers appear somewhat surprising. There are few data recording Na currents in human ventricular myocytes. Data indicates that different disease processes (congenital heart disease vs. cardiomyopathy, terminal heart failure vs. non-failing) do not affect sodium currents.3 However it should be noted that this work not specifically addressed HCM. Nevertheless calculations with a well-established computer model for human ventricular AP4 predict a 6-fold higher peak sodium current to cause 3-fold higher maximum upstroke velocity, but unchanged APD90 (own unpublished data). Unfortunately, data on upstroke velocity are lacking in the

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background. With the rich toolbox of experimental electrophysiology at hand, iPSC-

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current paper by Han et al.1 Transient outward potassium currents depicted in Fig. 5J likely indicate peak currents of Ito (no methodological details are given) and show a 25% increase in HCM-derived iPSC cardiac myocytes. Recent work in dog ventricular myocardium suggest that 90% block of Ito can evoke marked APD prolongation when other potassium channels are blocked.5 Therefore we would rather expect a shortening instead prolongation of APD because of increased Ito. However the mentioned above computer model suggest that such small increase in Ito should not affect APD90. Only the slight increase in L-type Ca2+-current density by about 50% would substantially prolong APD90 (+9% in our computer simulation). Thus, the measurements of ion currents and APD90 do not correspond to each other when applying an established computer model, indicating

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resemblance with that of mature undiseased ventricular myocytes (as reflected by experimental obtained from dog or computer models),or 2. that this particular patient shows more, not yet identified abnormalities in the delicate balance between depolarizing and repolarizing forces. Increases in APD90 at a magnitude described herein are expected to correlate with markedly prolonged QT-interval in the ECG of the respective patient. No such information is provided in the paper by Han et al. With regard to clinical implications of this study, it is important to note that marked QT prolongation is not a regular phenotype in patients with HCM. In the largest study into this question, QTc was only mildly associated with the extent of hypertrophy.6 In summary, the available clinical data argue against an LQT mechanism of HCM-related arrhythmias, and we believe that it is premature to conclude from the iPSC data obtained from just one patient that

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1. either that repolarization in HCM-derived iPSC cardiac myocytes has little

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the conduction delay and repolarization abnormalities in HCM result from changes of ionic currents and action potential duration.

Conflict of interest The authors declare no conflict of interest.

Reference List 1. Han L, Li Y, Tchao J, Kaplan AD, Lin B, Li Y, Mich-Basso J, Lis A, Hassan N, London B, Bett GC, Tobita K, Rasmusson RL, Yang L. Study familial

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cells. Cardiovasc Res. 2014 Sep 10. [Epub ahead of print] 2. Schober T, Huke S, Venkataraman R, Gryshchenko O, Kryshtal D, Hwang HS, Baudenbacher FJ, Knollmann BC. Myofilament Ca sensitization increases cytosolic Ca binding affinity, alters intracellular Ca homeostasis, and causes pause-dependent Ca-triggered arrhythmia. Circ Res. 2012;111:170-179. 3. Sakakibara Y, Furukawa T, Singer DH, Jia H, Backer CL, Arentzen CE, Wasserstrom JA. Sodium current in isolated human ventricular myocytes. Am J Physiol. 1993;265:H1301-1309. 4. ten Tusscher KH, Panfilov AV. Alternans and spiral breakup in a human ventricular tissue model. Am J Physiol Heart Circ Physiol 2006;291:H10881100. 5. Virág L, Jost N, Papp R, Koncz I, Kristóf A, Kohajda Z, Harmati G, CarbonellPascual B, Ferrero JM Jr, Papp JG, Nánási PP, Varró A. Analysis of the

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hypertrophic cardiomyopathy using patient-specific induced pluripotent stem

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contribution of I(to) to repolarization in canine ventricular myocardium. Br J Pharmacol. 2011;164:93-105. 6. Johnson JN, Grifoni C, Bos JM, Saber-Ayad M, Ommen SR, Nistri S, Cecchi F, Olivotto I, Ackerman MJ. Prevalence and clinical correlates of QT prolongation in patients with hypertrophic cardiomyopathy. Eur Heart J.

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2011;32:1114-1120.