Human Heart Cardiomyocytes in Drug Discovery and Research: New Opportunities in Translational Sciences

Najah       Abi-Gerges; Paul    E.   Miller; Andre       Ghetti
doi:10.2174/1389201021666191210142023
Abstract

In preclinical drug development, accurate prediction of drug effects on the human heart is critically important, whether in the context of cardiovascular safety or for the purpose of modulating cardiac function to treat heart disease. Current strategies have significant limitations, whereby, cardiotoxic drugs can escape detection or potential life-saving therapies are abandoned due to false positive toxicity signals. Thus, new and more reliable translational approaches are urgently needed to help accelerate the rate of new therapy development. Renewed efforts in the recovery of human donor hearts for research and in cardiomyocyte isolation methods, are providing new opportunities for preclinical studies in adult primary cardiomyocytes. These cells exhibit the native physiological and pharmacological properties, overcoming the limitations presented by artificial cellular models, animal models and have great potential for providing an excellent tool for preclinical drug testing. Adult human primary cardiomyocytes have already shown utility in assessing drug-induced cardiotoxicity risk and helping in the identification of new treatments for cardiac diseases, such as heart failure and atrial fibrillation. Finally, strategies with actionable decision-making trees that rely on data derived from adult human primary cardiomyocytes will provide the holistic insights necessary to accurately predict human heart effects of drugs.
Keywords: Small molecule drug discovery, human heart, adult human primary cardiomyocytes, cardiotoxicity, atrial fibrillation, heart failure, translational sciences.
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Graphical Abstract

[1] 
Witchel, H.J.; Milnes, J.T.; Mitcheson, J.S.; Hancox, J.C.; Hancox, J.C. Troubleshooting problems with in vitro screening of drugs for QT interval prolongation using HERG K+ channels expressed in mammalian cell lines and Xenopus oocytes. J. Pharmacol. Toxicol. Methods,  2002, 48(2), 65-80.
[http://dx.doi.org/10.1016/S1056-8719(03)00041-8] [PMID:  14565563] 
[2] 
Thomas, P.; Smart, T.G. HEK293 cell line: A vehicle for the expression of recombinant proteins. J. Pharmacol. Toxicol. Methods,  2005, 51(3), 187-200.
[http://dx.doi.org/10.1016/j.vascn.2004.08.014] [PMID:  15862464] 
[3] 
Ford, J.; Milnes, J.; Wettwer, E.; Christ, T.; Rogers, M.; Sutton, K.; Madge, D.; Virag, L.; Jost, N.; Horvath, Z.; Matschke, K.; Varro, A.; Ravens, U. Human electrophysiological and pharmacological properties of XEN-D0101: A novel atrial-selective Kv1.5/IKur inhibitor. J. Cardiovasc. Pharmacol.,  2013, 61(5), 408-415.
[http://dx.doi.org/10.1097/FJC.0b013e31828780eb] [PMID:  23364608] 
[4] 
Crumb, W.J., Jr; Pigott, J.D.; Clarkson, C.W. Description of a nonselective cation current in human atrium. Circ. Res.,  1995, 77(5), 950-956.
[http://dx.doi.org/10.1161/01.RES.77.5.950] [PMID:  7554149] 
[5] 
Fermini, B.; Hancox, J.C.; Abi-Gerges, N.; Bridgland-Taylor, M.; Chaudhary, K.W.; Colatsky, T.; Correll, K.; Crumb, W.; Damiano, B.; Erdemli, G.; Gintant, G.; Imredy, J.; Koerner, J.; Kramer, J.; Levesque, P.; Li, Z.; Lindqvist, A.; Obejero-Paz, C.A.; Rampe, D.; Sawada, K.; Strauss, D.G.; Vandenberg, J.I. A new perspective in the field of cardiac safety testing through the comprehensive in vitro proarrhythmia assay paradigm. J. Biomol. Screen.,  2016, 21(1), 1-11.
[http://dx.doi.org/10.1177/1087057115594589] [PMID:  26170255] 
[6] 
Yu, H.B.; Li, M.; Wang, W.P.; Wang, X.L. High throughput screening technologies for ion channels. Acta Pharmacol. Sin.,  2016, 37(1), 34-43.
[http://dx.doi.org/10.1038/aps.2015.108] [PMID:  26657056] 
[7] 
Li, T.; Lu, G.; Chiang, E.Y.; Chernov-Rogan, T.; Grogan, J.L.; Chen, J. High-throughput electrophysiological assays for voltage gated ion channels using SyncroPatch 768PE. PLoS One,  2017, 12(7) e0180154
[http://dx.doi.org/10.1371/journal.pone.0180154] [PMID:  28683073] 
[8] 
Mirams, G.R.; Cui, Y.; Sher, A.; Fink, M.; Cooper, J.; Heath, B.M.; McMahon, N.C.; Gavaghan, D.J.; Noble, D. Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. Cardiovasc. Res.,  2011, 91(1), 53-61.
[http://dx.doi.org/10.1093/cvr/cvr044] [PMID:  21300721] 
[9] 
Elkins, R.C.; Davies, M.R.; Brough, S.J.; Gavaghan, D.J.; Cui, Y.; Abi-Gerges, N.; Mirams, G.R. Variability in high-throughput ion-channel screening data and consequences for cardiac safety assessment. J. Pharmacol. Toxicol. Methods,  2013, 68(1), 112-122.
[http://dx.doi.org/10.1016/j.vascn.2013.04.007] [PMID:  23651875] 
[10] 
Britton, O.J.; Abi-Gerges, N.; Page, G.; Ghetti, A.; Miller, P.E.; Rodriguez, B. Quantitative comparison of effects of dofetilide, sotalol, quinidine, and verapamil between human ex vivo trabeculae and in silico ventricular models incorporating inter-individual action potential variability. Front. Physiol.,  2017, 8, 597.
[http://dx.doi.org/10.3389/fphys.2017.00597] [PMID:  28868038] 
[11] 
Chang, K.C.; Dutta, S.; Mirams, G.R.; Beattie, K.A.; Sheng, J.; Tran, P.N.; Wu, M.; Wu, W.W.; Colatsky, T.; Strauss, D.G.; Li, Z. Uncertainty quantification reveals the importance of data variability and experimental design considerations for in silico proarrhythmia risk assessment. Front. Physiol.,  2017, 8, 917.
[http://dx.doi.org/10.3389/fphys.2017.00917] [PMID:  29209226] 
[12] 
Passini, E.; Britton, O.J.; Lu, H.R.; Rohrbacher, J.; Hermans, A.N.; Gallacher, D.J.; Greig, R.J.H.; Bueno-Orovio, A.; Rodriguez, B. Human in silico drug trials demonstrate higher accuracy than animal models in predicting clinical pro-arrhythmic cardiotoxicity. Front. Physiol.,  2017, 8, 668.
[http://dx.doi.org/10.3389/fphys.2017.00668] [PMID:  28955244] 
[13] 
Sager, P.T.; Gintant, G.; Turner, J.R.; Pettit, S.; Stockbridge, N. Rechanneling the cardiac proarrhythmia safety paradigm: A meeting report from the Cardiac Safety Research Consortium. Am. Heart J.,  2014, 167(3), 292-300.
[http://dx.doi.org/10.1016/j.ahj.2013.11.004] [PMID:  24576511] 
[14] 
Colatsky, T.; Fermini, B.; Gintant, G.; Pierson, J.B.; Sager, P.; Sekino, Y.; Strauss, D.G.; Stockbridge, N. The Comprehensive In Vitro proarrhythmia Assay (CiPA) initiative - update on progress. J. Pharmacol. Toxicol. Methods,  2016, 81, 15-20.
[http://dx.doi.org/10.1016/j.vascn.2016.06.002] [PMID:  27282641] 
[15] 
Gintant, G.; Sager, P.T.; Stockbridge, N. Evolution of strategies to improve preclinical cardiac safety testing. Nat. Rev. Drug Discov.,  2016, 15(7), 457-471.
[http://dx.doi.org/10.1038/nrd.2015.34] [PMID:  26893184] 
[16] 
Dutta, S.; Chang, K.C.; Beattie, K.A.; Sheng, J.; Tran, P.N.; Wu, W.W.; Wu, M.; Strauss, D.G.; Colatsky, T.; Li, Z. Optimization of an in silico cardiac cell model for proarrhythmia risk assessment. Front. Physiol.,  2017, 8, 616.
[http://dx.doi.org/10.3389/fphys.2017.00616] [PMID:  28878692] 
[17] 
Li, Z.; Ridder, B.J.; Han, X.; Wu, W.W.; Sheng, J.; Tran, P.N.; Wu, M.; Randolph, A.; Johnstone, R.H.; Mirams, G.R.; Kuryshev, Y.; Kramer, J.; Wu, C.; Crumb, W.J., Jr; Strauss, D.G. Assessment of an in silico model for proarrhythmia risk prediction under the CiPA initiative. Clin. Pharmacol. Ther.,  2019, 105(2), 466-475.
[http://dx.doi.org/10.1002/cpt.1184] [PMID:  30151907] 
[18] 
Potet, F.; Bouyssou, T.; Escande, D.; Baró, I. Gastrointestinal prokinetic drugs have different affinity for the human cardiac human ether-à-gogo K(+) channel. J. Pharmacol. Exp. Ther.,  2001, 299(3), 1007-1012.
[PMID:  11714889] 
[19] 
Kirsch, G.E.; Trepakova, E.S.; Brimecombe, J.C.; Sidach, S.S.; Erickson, H.D.; Kochan, M.C.; Shyjka, L.M.; Lacerda, A.E.; Brown, A.M. Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus pattern. J. Pharmacol. Toxicol. Methods,  2004, 50(2), 93-101.
[http://dx.doi.org/10.1016/j.vascn.2004.06.003] [PMID:  15385083] 
[20] 
Rezazadeh, S.; Hesketh, J.C.; Fedida, D. Rb+ flux through hERG channels affects the potency of channel blocking drugs: correlation with data obtained using a high-throughput Rb+ efflux assay. J. Biomol. Screen.,  2004, 9(7), 588-597.
[http://dx.doi.org/10.1177/1087057104264798] [PMID:  15475478] 
[21] 
Yao, J.A.; Du, X.; Lu, D.; Baker, R.L.; Daharsh, E.; Atterson, P. Estimation of potency of HERG channel blockers: Impact of voltage protocol and temperature. J. Pharmacol. Toxicol. Methods,  2005, 52(1), 146-153.
[http://dx.doi.org/10.1016/j.vascn.2005.04.008] [PMID:  15936218] 
[22] 
Milnes, J.T.; Witchel, H.J.; Leaney, J.L.; Leishman, D.J.; Hancox, J.C. Investigating dynamic protocol-dependence of hERG potassium channel inhibition at 37°C: Cisapride versus dofetilide. J. Pharmacol. Toxicol. Methods,  2010, 61(2), 178-191.
[http://dx.doi.org/10.1016/j.vascn.2010.02.007] [PMID:  20172036] 
[23] 
Windley, M.J.; Abi-Gerges, N.; Fermini, B.; Hancox, J.C.; Vandenberg, J.I.; Hill, A.P. Measuring kinetics and potency of hERG block for CiPA. J. Pharmacol. Toxicol. Methods,  2017, 87, 99-107.
[http://dx.doi.org/10.1016/j.vascn.2017.02.017] [PMID:  28192183] 
[24] 
Lee, W.; Windley, M.J.; Perry, M.D.; Vandenberg, J.I.; Hill, A.P. Protocol-dependent differences in IC50 values measured in hERG assays occur in apredictable way and can be used to quantify state preference of drug binding. Mol. Pharmacol.,  2019, 95(50), 537-550.
[http://dx.doi.org/10.1124/mol.118.115220] [PMID:  30770456] 
[25] 
Crumb, W.J., Jr; Vicente, J.; Johannesen, L.; Strauss, D.G. An evaluation of 30 clinical drugs against the comprehensive in vitro proarrhythmia assay (CiPA) proposed ion channel panel. J. Pharmacol. Toxicol. Methods,  2016, 81, 251-262.
[http://dx.doi.org/10.1016/j.vascn.2016.03.009] [PMID:  27060526] 
[26] 
Anon. ICH S7B note for guidance on the nonclinical evaluation of
the potential for delayed ventricular repolarization (QT interval
prolongation) by human pharmaceuticals, https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7B/Step4/S7B_Guideline.pdfCHMP/ICH/423/02Accessed May 25.  2005.
[27] 
Cavero, I.; Crumb, W. ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: a critical analysis. Expert Opin. Drug Saf.,  2005, 4(3), 509-530.
[http://dx.doi.org/10.1517/14740338.4.3.509] [PMID:  15934857] 
[28] 
Chiang, A.Y.; Bass, A.S.; Cooper, M.M.; Engwall, M.J.; Menton, R.G.; Thomas, K. ILSI-HESI cardiovascular safety subcommittee dataset: an analysis of the statistical properties of QT interval and rate-corrected QT interval (QTc). J. Pharmacol. Toxicol. Methods,  2007, 56(2), 95-102.
[http://dx.doi.org/10.1016/j.vascn.2007.04.002] [PMID:  17588780] 
[29] 
Pugsley, M.K.; Guth, B.; Chiang, A.Y.; Doyle, J.M.; Engwall, M.; Guillon, J.M.; Hoffmann, P.K.; Koerner, J.E.; Mittelstadt, S.W.; Pierson, J.B.; Rossman, E.I.; Sarazan, D.R.; Parish, S.T. An evaluation of the utility of LVdP/dt40, QA interval, LVdP/dtmin and Tau as indicators of drug-induced changes in contractility and lusitropy in dogs. J. Pharmacol. Toxicol. Methods,  2017, 85, 1-21.
[http://dx.doi.org/10.1016/j.vascn.2017.01.002] [PMID:  28065821] 
[30] 
Anon.,  ICH S7A note for guidance on the safety pharmacology studies for human pharmaceuticals., https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7A/Step4/S7A_Guideline.pdf2000
[31] 
Guth, B.D. Preclinical cardiovascular risk assessment in modern drug development. Toxicol. Sci.,  2007, 97(1), 4-20.
[http://dx.doi.org/10.1093/toxsci/kfm026] [PMID:  17351262] 
[32] 
Wall, R.J.; Shani, M. Are animal models as good as we think? Theriogenology,  2008, 69(1), 2-9.
[http://dx.doi.org/10.1016/j.theriogenology.2007.09.030] [PMID:  17988725] 
[33] 
Perrin, S. Preclinical research: Make mouse studies work. Nature,  2014, 507(7493), 423-425.
[http://dx.doi.org/10.1038/507423a] [PMID:  24678540] 
[34] 
Waring, M.J.; Arrowsmith, J.; Leach, A.R.; Leeson, P.D.; Mandrell, S.; Owen, R.M.; Pairaudeau, G.; Pennie, W.D.; Pickett, S.D.; Wang, J.; Wallace, O.; Weir, A. An analysis of the attrition of drug candidates from four major pharmaceutical companies. Nat. Rev. Drug Discov.,  2015, 14(7), 475-486.
[http://dx.doi.org/10.1038/nrd4609] [PMID:  26091267] 
[35] 
Hwang, T.J.; Carpenter, D.; Lauffenburger, J.C.; Wang, B.; Franklin, J.M.; Kesselheim, A.S. Failure of investigational drugs in late stage clinical development and publication of trial results. JAMA Intern. Med.,  2016, 176(12), 1826-1833.
[http://dx.doi.org/10.1001/jamainternmed.2016.6008] [PMID:  27723879] 
[36] 
Pound, P.; Ritskes-Hoitinga, M. Is it possible to overcome issues of external validity in preclinical animal research? Why most animal models are bound to fail. J. Transl. Med.,  2018, 16(1), 304.
[http://dx.doi.org/10.1186/s12967-018-1678-1] [PMID:  30404629] 
[37] 
Noujaim, S.F.; Lucca, E.; Muñoz, V.; Persaud, D.; Berenfeld, O.; Meijler, F.L.; Jalife, J. From mouse to whale: A universal scaling relation for the PR Interval of the electrocardiogram of mammals. Circulation,  2004, 110(18), 2802-2808.
[http://dx.doi.org/10.1161/01.CIR.0000146785.15995.67] [PMID:  15505092] 
[38] 
Manzo, A.; Ootaki, Y.; Ootaki, C.; Kamohara, K.; Fukamachi, K. Comparative study of heart rate variability between healthy human subjects and healthy dogs, rabbits and calves. Lab. Anim.,  2009, 43(1), 41-45.
[http://dx.doi.org/10.1258/la.2007.007085] [PMID:  19001066] 
[39] 
Zhang, G.Q.; Zhang, W. Heart rate, lifespan, and mortality risk. Ageing Res. Rev.,  2009, 8(1), 52-60.
[http://dx.doi.org/10.1016/j.arr.2008.10.001] [PMID:  19022405] 
[40] 
Sham, J.S.; Hatem, S.N.; Morad, M. Species differences in the activity of the Na(+)-Ca2+ exchanger in mammalian cardiac myocytes. J. Physiol.,  1995, 488(Pt 3), 623-631.
[http://dx.doi.org/10.1113/jphysiol.1995.sp020995] [PMID:  8576853] 
[41] 
Meyer, R.; Linz, K.W.; Surges, R.; Meinardus, S.; Vees, J.; Hoffmann, A.; Windholz, O.; Grohé, C. Rapid modulation of L-type calcium current by acutely applied oestrogens in isolated cardiac myocytes from human, guinea-pig and rat. Exp. Physiol.,  1998, 83(3), 305-321.
[http://dx.doi.org/10.1113/expphysiol.1998.sp004115] [PMID:  9639341] 
[42] 
Akar, F.G.; Wu, R.C.; Deschenes, I.; Armoundas, A.A.; Piacentino, V., III; Houser, S.R.; Tomaselli, G.F. Phenotypic differences in transient outward K+ current of human and canine ventricular myocytes: insights into molecular composition of ventricular Ito. Am. J. Physiol. Heart Circ. Physiol.,  2004, 286(2), H602-H609.
[http://dx.doi.org/10.1152/ajpheart.00673.2003] [PMID:  14527940] 
[43] 
Rudy, Y.; Silva, J.R. Computational biology in the study of cardiac ion channels and cell electrophysiology. Q. Rev. Biophys.,  2006, 39(1), 57-116.
[http://dx.doi.org/10.1017/S0033583506004227] [PMID:  16848931] 
[44] 
O’Hara, T.; Rudy, Y. Arrhythmia formation in subclinical (“silent”) long QT syndrome requires multiple insults: Quantitative mechanistic study using the KCNQ1 mutation Q357R as example. Heart Rhythm,  2012, 9(2), 275-282.
[http://dx.doi.org/10.1016/j.hrthm.2011.09.066] [PMID:  21952006] 
[45] 
Jost, N.; Virág, L.; Comtois, P.; Ordög, B.; Szuts, V.; Seprényi, G.; Bitay, M.; Kohajda, Z.; Koncz, I.; Nagy, N.; Szél, T.; Magyar, J.; Kovács, M.; Puskás, L.G.; Lengyel, C.; Wettwer, E.; Ravens, U.; Nánási, P.P.; Papp, J.G.; Varró, A.; Nattel, S. Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs. J. Physiol.,  2013, 591(17), 4189-4206.
[http://dx.doi.org/10.1113/jphysiol.2013.261198] [PMID:  23878377] 
[46] 
Wang, Z.G.; Pelletier, L.C.; Talajic, M.; Nattel, S. Effects of flecainide and quinidine on human atrial action potentials. Role of rate-dependence and comparison with guinea pig, rabbit, and dog tissues. Circulation,  1990, 82(1), 274-283.
[http://dx.doi.org/10.1161/01.CIR.82.1.274] [PMID:  2114235] 
[47] 
Glukhov, A.V.; Flagg, T.P.; Fedorov, V.V.; Efimov, I.R.; Nichols, C.G.; Differential, K. (ATP) channel pharmacology in intact mouse heart. J. Mol. Cell. Cardiol.,  2010, 48(1), 152-160.
[http://dx.doi.org/10.1016/j.yjmcc.2009.08.026] [PMID:  19744493] 
[48] 
Fedorov, V.V.; Glukhov, A.V.; Ambrosi, C.M.; Kostecki, G.; Chang, R.; Janks, D.; Schuessler, R.B.; Moazami, N.; Nichols, C.G.; Efimov, I.R. Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts. J. Mol. Cell. Cardiol.,  2011, 51(2), 215-225.
[http://dx.doi.org/10.1016/j.yjmcc.2011.04.016] [PMID:  21586291] 
[49] 
Iafrate, A.J.; Feuk, L.; Rivera, M.N.; Listewnik, M.L.; Donahoe, P.K.; Qi, Y.; Scherer, S.W.; Lee, C. Detection of large-scale variation in the human genome. Nat. Genet.,  2004, 36(9), 949-951.
[http://dx.doi.org/10.1038/ng1416] [PMID:  15286789] 
[50] 
Weir, B.S.; Cardon, L.R.; Anderson, A.D.; Nielsen, D.M.; Hill, W.G. Measures of human population structure show heterogeneity among genomic regions. Genome Res.,  2005, 15(11), 1468-1476.
[http://dx.doi.org/10.1101/gr.4398405] [PMID:  16251456] 
[51] 
McClellan, J.; King, M.C. Genetic heterogeneity in human disease. Cell,  2010, 141(2), 210-217.
[http://dx.doi.org/10.1016/j.cell.2010.03.032] [PMID:  20403315] 
[52] 
Seok, J.; Warren, H.S.; Cuenca, A.G.; Mindrinos, M.N.; Baker, H.V.; Xu, W.; Richards, D.R.; McDonald-Smith, G.P.; Gao, H.; Hennessy, L.; Finnerty, C.C.; López, C.M.; Honari, S.; Moore, E.E.; Minei, J.P.; Cuschieri, J.; Bankey, P.E.; Johnson, J.L.; Sperry, J.; Nathens, A.B.; Billiar, T.R.; West, M.A.; Jeschke, M.G.; Klein, M.B.; Gamelli, R.L.; Gibran, N.S.; Brownstein, B.H.; Miller-Graziano, C.; Calvano, S.E.; Mason, P.H.; Cobb, J.P.; Rahme, L.G.; Lowry, S.F.; Maier, R.V.; Moldawer, L.L.; Herndon, D.N.; Davis, R.W.; Xiao, W.; Tompkins, R.G. Inflammation and host response to injury, large scale collaborative research program. genomic responses in mouse models poorly mimic human inflammatory diseases. Proc. Natl. Acad. Sci. USA,  2013, 110(9), 3507-3512.
[http://dx.doi.org/10.1073/pnas.1222878110] [PMID:  23401516] 
[53] 
Johansson, I.; Ingelman-Sundberg, M. Genetic polymorphism and toxicology-with emphasis on cytochrome p450. Toxicol. Sci.,  2011, 120(1), 1-13.
[http://dx.doi.org/10.1093/toxsci/kfq374] [PMID:  21149643] 
[54] 
Li, Q.; Hickman, M.R. Pharmacokinetics and Pharmacodynamics of antimalrrial drugs used in combination therapy; Bentham Science Publishers, 2015, pp. 395-440.
[http://dx.doi.org/10.2174/9781681080543115010013] 
[55] 
Sági, J.C.; Egyed, B.; Kelemen, A.; Kutszegi, N.; Hegyi, M.; Gézsi, A.; Herlitschke, M.A.; Rzepiel, A.; Fodor, L.E.; Ottóffy, G.; Kovács, G.T.; Erdélyi, D.J.; Szalai, C.; Semsei, A.F. Possible roles of genetic variations in chemotherapy related cardiotoxicity in pediatric acute lymphoblastic leukemia and osteosarcoma. BMC Cancer,  2018, 18(1), 704.
[http://dx.doi.org/10.1186/s12885-018-4629-6] [PMID:  29970035] 
[56] 
Hayden, E.C. Stem cells: The growing pains of pluripotency. Nature,  2011, 473(7347), 272-274.
[http://dx.doi.org/10.1038/473272a] [PMID:  21593837] 
[57] 
Snir, M.; Kehat, I.; Gepstein, A.; Coleman, R.; Itskovitz-Eldor, J.; Livne, E.; Gepstein, L. Assessment of the ultrastructural and proliferative properties of human embryonic stem cell-derived cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol.,  2003, 285(6), H2355-H2363.
[http://dx.doi.org/10.1152/ajpheart.00020.2003] [PMID:  14613910] 
[58] 
Gherghiceanu, M.; Barad, L.; Novak, A.; Reiter, I.; Itskovitz-Eldor, J.; Binah, O.; Popescu, L.M. Cardiomyocytes derived from human embryonic and induced pluripotent stem cells: Comparative ultrastructure. J. Cell. Mol. Med.,  2011, 15(11), 2539-2551.
[http://dx.doi.org/10.1111/j.1582-4934.2011.01417.x] [PMID:  21883888] 
[59] 
Rao, C.; Prodromakis, T.; Kolker, L.; Chaudhry, U.A.R.; Trantidou, T.; Sridhar, A.; Weekes, C.; Camelliti, P.; Harding, S.E.; Darzi, A.; Yacoub, M.H.; Athanasiou, T.; Terracciano, C.M. The effect of microgrooved culture substrates on calcium cycling of cardiac myocytes derived from human induced pluripotent stem cells. Biomaterials,  2013, 34(2399) e2411
[http://dx.doi.org/10.1016/j.biomaterials.2012.11.055] 
[60] 
Stoehr, A.; Neuber, C.; Baldauf, C.; Vollert, I.; Friedrich, F.W.; Flenner, F.; Carrier, L.; Eder, A.; Schaaf, S.; Hirt, M.N.; Aksehirlioglu, B.; Tong, C.W.; Moretti, A.; Eschenhagen, T.; Hansen, A. Automated analysis of contractile force and Ca2+ transients in engineered heart tissue. Am. J. Physiol. Heart Circ. Physiol.,  2014, 306(9), H1353-H1363.
[http://dx.doi.org/10.1152/ajpheart.00705.2013] [PMID:  24585781] 
[61] 
Lee, Y.K.; Ng, K.M.; Lai, W.H.; Chan, Y.C.; Lau, Y.M.; Lian, Q.; Tse, H.F.; Siu, C.W. Calcium homeostasis in human induced pluripotent stem cell-derived cardiomyocytes. Stem Cell Rev Rep,  2011, 7(4), 976-986.
[http://dx.doi.org/10.1007/s12015-011-9273-3] [PMID:  21614516] 
[62] 
Li, S.; Cheng, H.; Tomaselli, G.F.; Li, R.A. Mechanistic basis of excitation-contraction coupling in human pluripotent stem cell derived ventricular cardiomyocytes revealed by Ca2+ spark characteristics: direct evidence of functional Ca2+-induced Ca2+ release. Heart Rhythm,  2014, 11(1), 133-140.
[http://dx.doi.org/10.1016/j.hrthm.2013.10.006] [PMID:  24096168] 
[63] 
Kane, C.; Couch, L.; Terracciano, C.M.N. Excitation-contraction coupling of human induced pluripotent stem cell-derived cardiomyocytes. Front. Cell Dev. Biol.,  2015, 3, 59.
[http://dx.doi.org/10.3389/fcell.2015.00059] [PMID:  26484342] 
[64] 
Karakikes, I.; Ameen, M.; Termglinchan, V.; Wu, J.C. Human induced pluripotent stem cell-derived cardiomyocytes: Insights into molecular, cellular, and functional phenotypes. Circ. Res.,  2015, 117(1), 80-88.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.305365] [PMID:  26089365] 
[65] 
Kane, C.; Terracciano, C.M.N. Criteria for chamber-specific categorization of human cardiac myocytes derived from pluripotent stem cells. Stem Cells,  2017, 35(8), 1881-1897.
[http://dx.doi.org/10.1002/stem.2649] [PMID:  28577296] 
[66] 
Itzhaki, I.; Rapoport, S.; Huber, I.; Mizrahi, I.; Zwi-Dantsis, L.; Arbel, G.; Schiller, J.; Gepstein, L. Calcium handling in human induced pluripotent stem cell derived cardiomyocytes. PLoS One,  2011, 6(4) e18037
[http://dx.doi.org/10.1371/journal.pone.0018037] [PMID:  21483779] 
[67] 
Hartman, M.E.; Dai, D.F.; Laflamme, M.A. Human pluripotent stem cells: Prospects and challenges as a source of cardiomyocytes for in vitro modeling and cell-based cardiac repair. Adv. Drug Deliv. Rev.,  2016, 96, 3-17.
[http://dx.doi.org/10.1016/j.addr.2015.05.004] [PMID:  25980938] 
[68] 
van Meer, B.J.; Tertoolen, L.G.J.; Mummery, C.L. Measuring physiological responses of human pluripotent stem cell derived cardiomyocytes to drugs and disease. Stem Cells,  2016, 34(8), 2008-2015.
[http://dx.doi.org/10.1002/stem.2403] [PMID:  27250776] 
[69] 
Sala, L.; Bellin, M.; Mummery, C.L. Integrating cardiomyocytes from human pluripotent stem cells in safety pharmacology: has the time come? Br. J. Pharmacol.,  2017, 174(21), 3749-3765.
[http://dx.doi.org/10.1111/bph.13577] [PMID:  27641943] 
[70] 
Mummery, C.L. Perspectives on the use of human induced pluripotent stem cell-derived cardiomyocytes in biomedical research. Stem Cell Reports,  2018, 11(6), 1306-1311.
[http://dx.doi.org/10.1016/j.stemcr.2018.11.011] [PMID:  30540958] 
[71] 
Jonsson, M.K.; Vos, M.A.; Mirams, G.R.; Duker, G.; Sartipy, P.; de Boer, T.P.; van Veen, T.A. Application of human stem cell derived cardiomyocytes in safety pharmacology requires caution beyond hERG. J. Mol. Cell. Cardiol.,  2012, 52(5), 998-1008.
[http://dx.doi.org/10.1016/j.yjmcc.2012.02.002] [PMID:  22353256] 
[72] 
Veerman, C.C.; Kosmidis, G.; Mummery, C.L.; Casini, S.; Verkerk, A.O.; Bellin, M. Immaturity of human stem-cell-derived cardiomyocytes in culture: Fatal flaw or soluble problem? Stem Cells Dev.,  2015, 24(9), 1035-1052.
[http://dx.doi.org/10.1089/scd.2014.0533] [PMID:  25583389] 
[73] 
Blinova, K.; Stohlman, J.; Vicente, J.; Chan, D.; Johannesen, L.; Hortigon-Vinagre, M.P.; Zamora, V.; Smith, G.; Crumb, W.J.; Pang, L.; Lyn-Cook, B.; Ross, J.; Brock, M.; Chvatal, S.; Millard, D.; Galeotti, L.; Stockbridge, N.; Strauss, D.G. Comprehensive translational assessment of human induced pluripotent stem cell derived cardiomyocytes for evaluating drug-induced arrhythmias. Toxicol. Sci.,  2017, 155(1), 234-247.
[http://dx.doi.org/10.1093/toxsci/kfw200] [PMID:  27701120] 
[74] 
Lemoine, M.D.; Mannhardt, I.; Breckwoldt, K.; Prondzynski, M.; Flenner, F.; Ulmer, B.; Hirt, M.N.; Neuber, C.; Horváth, A.; Kloth, B.; Reichenspurner, H.; Willems, S.; Hansen, A.; Eschenhagen, T.; Christ, T. Human iPSC-derived cardiomyocytes cultured in 3D engineered heart tissue show physiological upstroke velocity and sodium current density. Sci. Rep.,  2017, 7(1), 5464.
[http://dx.doi.org/10.1038/s41598-017-05600-w] [PMID:  28710467] 
[75] 
Zeng, H.; Balasubramanian, B.; Lagrutta, A.; Sannajust, F. Response of human induced pluripotent stem cell-derived cardiomyocytes to several pharmacological agents when intrinsic syncytial pacing is overcome by acute external stimulation. J. Pharmacol. Toxicol. Methods,  2018, 91, 18-26.
[http://dx.doi.org/10.1016/j.vascn.2017.12.004] [PMID:  29330131] 
[76] 
Lemoine, M.D.; Lemoine, M.D.; Krause, T.; Koivumäki, J.T.; Prondzynski, M.; Schulze, M.L.; Girdauskas, E.; Willems, S.; Hansen, A.; Eschenhagen, T.; Christ, T. Human induced pluripotent stem cell-derived engineered heart tissue as a sensitive test system for T prolongation and arrhythmic triggers. Circ Arrhythm Electrophysiol,  2019, 11, e006035
[PMID:  29925535] 
[77] 
Kodama, M.; Furutani, K.; Kimura, R.; Ando, T.; Sakamoto, K.; Nagamori, S.; Ashihara, T.; Kurachi, Y.; Sekino, Y.; Furukawa, T.; Kanda, Y.; Kurokawa, J. Systematic expression analysis of genes related to generation of action potentials in human iPS cell-derived cardiomyocytes. J. Pharmacol. Sci.,  2019, 140(4), 325-330.
[http://dx.doi.org/10.1016/j.jphs.2019.06.006] 
[78] 
Ando, H.; Yoshinaga, T.; Yamamoto, W.; Asakura, K.; Uda, T.; Taniguchi, T.; Ojima, A.; Shinkyo, R.; Kikuchi, K.; Osada, T.; Hayashi, S.; Kasai, C.; Miyamoto, N.; Tashibu, H.; Yamazaki, D.; Sugiyama, A.; Kanda, Y.; Sawada, K.; Sekino, Y. A new paradigm for drug-induced torsadogenic risk assessment using human iPS cell-derived cardiomyocytes. J. Pharmacol. Toxicol. Methods,  2017, 84, 111-127.
[http://dx.doi.org/10.1016/j.vascn.2016.12.003] [PMID:  27956204] 
[79] 
Abi-Gerges, N.; Pointon, A.; Oldman, K.L.; Brown, M.R.; Pilling, M.A.; Sefton, C.E.; Garside, H.; Pollard, C.E. Assessment of extracellular field potential and Ca2+ transient signals for early QT/pro-arrhythmia detection using human induced pluripotent stem cell derived cardiomyocytes. J. Pharmacol. Toxicol. Methods,  2017, 83, 1-15.
[http://dx.doi.org/10.1016/j.vascn.2016.09.001] [PMID:  27622857] 
[80] 
Blinova, K.; Dang, Q.; Millard, D.; Smith, G.; Pierson, J.; Guo, L.; Brock, M.; Lu, H.R.; Kraushaar, U.; Zeng, H.; Shi, H.; Zhang, X.; Sawada, K.; Osada, T.; Kanda, Y.; Sekino, Y.; Pang, L.; Feaster, T.K.; Kettenhofen, R.; Stockbridge, N.; Strauss, D.G.; Gintant, G. International multisite study of human-induced pluripotent stem cell-derived cardiomyocytes for drug proarrhythmic potential assessment. Cell Rep.,  2018, 24(13), 3582-3592.
[http://dx.doi.org/10.1016/j.celrep.2018.08.079] [PMID:  30257217] 
[81] 
Nguyen, N.; Nguyen, W.; Nguyenton, B.; Ratchada, P.; Page, G.; Miller, P.E.; Ghetti, A.; Abi-Gerges, N. Adult human primary cardiomyocyte-based model for the simultaneous prediction of drug induced inotropic and pro-arrhythmia risk. Front. Physiol.,  2017, 8, 1073.
[http://dx.doi.org/10.3389/fphys.2017.01073] [PMID:  29311989] 
[82] 
Qu, Y.; Page, G.; Abi-Gerges, N.; Miller, P.E.; Ghetti, A.; Vargas, H.M. Action potential recording and pro-arrhythmia risk analysis in human ventricular trabeculae. Front. Physiol.,  2018, 8, 1109.
[http://dx.doi.org/10.3389/fphys.2017.01109] [PMID:  29354071] 
[83] 
Yamamoto, W.; Asakura, K.; Ando, H.; Taniguchi, T.; Ojima, A.; Uda, T.; Osada, T.; Hayashi, S.; Kasai, C.; Miyamoto, N.; Tashibu, H.; Yoshinaga, T.; Yamazaki, D.; Sugiyama, A.; Kanda, Y.; Sawada, K.; Sekino, Y. Electrophysiological characteristics of human ipsc-derived cardiomyocytes for the assessment of drug-induced proarrhythmic potential. PLoS One,  2016, 11(12) e0167348
[http://dx.doi.org/10.1371/journal.pone.0167348] [PMID:  27923051] 
[84] 
Yamazaki, D.; Kitaguchi, T.; Ishimura, M.; Taniguchi, T.; Yamanishi, A.; Saji, D.; Takahashi, E.; Oguchi, M.; Moriyama, Y.; Maeda, S.; Miyamoto, K.; Morimura, K.; Ohnaka, H.; Tashibu, H.; Sekino, Y.; Miyamoto, N.; Kanda, Y. Proarrhythmia risk prediction using human induced pluripotent stem cell-derived cardiomyocytes. J. Pharmacol. Sci.,  2018, 136, 249-256.
[http://dx.doi.org/10.1016/j.jphs.2018.02.005] 
[85] 
Asakura, K.; Hayashi, S.; Ojima, A.; Taniguchi, T.; Miyamoto, N.; Nakamori, C.; Nagasawa, C.; Kitamura, T.; Osada, T.; Honda, Y.; Kasai, C.; Ando, H.; Kanda, Y.; Sekino, Y.; Sawada, K. Improvement of acquisition and analysis methods in multi-electrode array experiments with iPS cell-derived cardiomyocytes. J. Pharmacol. Toxicol. Methods,  2015, 75, 17-26.
[http://dx.doi.org/10.1016/j.vascn.2015.04.002] [PMID:  25910965] 
[86] 
Brown, L.; Näbauer, M.; Erdmann, E. Additive positive inotropic effects of milrinone, ouabain and calcium in diseased human ventricular myocardium. Klin. Wochenschr.,  1986, 64(15), 708-712.
[http://dx.doi.org/10.1007/BF01712056] [PMID:  3762018] 
[87] 
Raffaeli, S.; Ferroni, C.; Spurgeon, H.A.; Capogrossi, M.C. Milrinone enhances cytosolic calcium transient and contraction in rat cardiac myocytes during beta-adrenergic stimulation. Int. J. Cardiol.,  1989, 25(Suppl. 1), S63-S69.
[http://dx.doi.org/10.1016/0167-5273(89)90095-8] [PMID:  2576017] 
[88] 
Ajiro, Y.; Hagiwara, N.; Katsube, Y.; Sperelakis, N.; Kasanuki, H. Levosimendan increases L-type Ca(2+) current via phosphodiesterase-3 inhibition in human cardiac myocytes. Eur. J. Pharmacol.,  2002, 435(1), 27-33.
[http://dx.doi.org/10.1016/S0014-2999(01)01569-2] [PMID:  11790375] 
[89] 
McCloskey, D.T.; Rokosh, D.G.; O’Connell, T.D.; Keung, E.C.; Simpson, P.C.; Baker, A.J. Alpha(1)-adrenoceptor subtypes mediate negative inotropy in myocardium from alpha(1A/C)-knockout and wild type mice. J. Mol. Cell. Cardiol.,  2002, 34(8), 1007-1017.
[http://dx.doi.org/10.1006/jmcc.2002.2049] [PMID:  12234770] 
[90] 
Brückner, R.; Meyer, W.; Mügge, A.; Schmitz, W.; Scholz, H. α-adrenoceptor-mediated positive inotropic effect of phenylephrine in isolated human ventricular myocardium. Eur. J. Pharmacol.,  1984, 99(4), 345-347.
[http://dx.doi.org/10.1016/0014-2999(84)90144-4] [PMID:  6329788] 
[91] 
Johnson, W.B.; Katugampola, S.; Able, S.; Napier, C.; Harding, S.E. Profiling of cAMP and cGMP phosphodiesterases in isolated ventricular cardiomyocytes from human hearts: Comparison with rat and guinea pig. Life Sci.,  2012, 90(9-10), 328-336.
[http://dx.doi.org/10.1016/j.lfs.2011.11.016] [PMID:  22261303] 
[92] 
Scott, C.W.; Zhang, X.; Abi-Gerges, N.; Lamore, S.D.; Abassi, Y.A.; Peters, M.F. An impedance-based cellular assay using human iPSC-derived cardiomyocytes to quantify modulators of cardiac contractility. Toxicol. Sci.,  2014, 142(2), 331-338.
[http://dx.doi.org/10.1093/toxsci/kfu186] [PMID:  25237062] 
[93] 
Pointon, A.; Harmer, A.R.; Dale, I.L.; Abi-Gerges, N.; Bowes, J.; Pollard, C.; Garside, H. Assessment of cardiomyocyte contraction in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol. Sci.,  2015, 144(2), 227-237.
[http://dx.doi.org/10.1093/toxsci/kfu312] [PMID:  25538221] 
[94] 
Mannhardt, I.; Eder, A.; Dumotier, B.; Prondzynski, M.; Krämer, E.; Traebert, M.; Söhren, K.D.; Flenner, F.; Stathopoulou, K.; Lemoine, M.D.; Carrier, L.; Christ, T.; Eschenhagen, T.; Hansen, A. Mannhardt, I.; Eder, A.; Dumotier, B.; Prondzynski, M.; Krämer, E.; Traebert, M.; Söhren, K.D.; Flenner, F.; Stathopoulou, K.; Lemoine, M.D.; Carrier, L.; Christ, T.; Eschenhagen, T.; Hansen, A. Blinded contractility analysis in hiPSC-cardiomyocytes in engineered heart tissue format: Comparison with human atrial trabeculae. Toxicol. Sci.,  2017, 158(1), 164-175.
[http://dx.doi.org/10.1093/toxsci/kfx081] [PMID:  28453742] 
[95] 
Hernández-Cascales, J. Does glucagon have a positive inotropic effect in the human heart? Cardiovasc. Diabetol.,  2018, 17(1), 148.
[http://dx.doi.org/10.1186/s12933-018-0791-z] [PMID:  30482191] 
[96] 
Holmes, A.; Bonner, F.; Jones, D. Assessing drug safety in human tissues - what are the barriers? Nat. Rev. Drug Discov.,  2015, 14(8), 585-587.
[http://dx.doi.org/10.1038/nrd4662] [PMID:  26205467] 
[97] 
Jackson, S.J.; Prior, H.; Holmes, A. The use of human tissue in safety assessment. J. Pharmacol. Toxicol. Methods,  2018, 93, 29-34.
[http://dx.doi.org/10.1016/j.vascn.2018.05.003] [PMID:  29753134] 
[98] 
Krijnen, P.A.J.; Nijmeijer, R.; Meijer, C.J.L.M.; Visser, C.A.; Hack, C.E.; Niessen, H.W.M. Apoptosis in myocardial ischaemia and infarction. J. Clin. Pathol.,  2002, 55(11), 801-811.
[http://dx.doi.org/10.1136/jcp.55.11.801] [PMID:  12401816] 
[99] 
Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol.,  2007, 35(4), 495-516.
[http://dx.doi.org/10.1080/01926230701320337] [PMID:  17562483] 
[100] 
Kalogeris, T.; Baines, C.P.; Krenz, M.; Korthuis, R.J. Ischemia/Reperfusion. Compr. Physiol.,  2016, 7(1), 113-170.
[http://dx.doi.org/10.1002/cphy.c160006] [PMID:  28135002] 
[101] 
Volk, M.L.; Reichert, H.A.; Lok, A.S.F.; Hayward, R.A. Variation in organ quality between liver transplant centers. Am. J. Transplant.,  2011, 11(5), 958-964.
[http://dx.doi.org/10.1111/j.1600-6143.2011.03487.x] [PMID:  21466651] 
[102] 
Page, G.; Ratchada, P.; Miron, Y.; Steiner, G.; Ghetti, A.; Miller, P.E.; Reynolds, J.A.; Wang, K.; Greiter-Wilke, A.; Polonchuk, L.; Traebert, M.; Gintant, G.A.; Abi-Gerges, N. Human ex-vivo action potential model for pro-arrhythmia risk assessment. J. Pharmacol. Toxicol. Methods,  2016, 81, 183-195.
[http://dx.doi.org/10.1016/j.vascn.2016.05.016] [PMID:  27235787] 
[103] 
Staes, C.J.; Huff, S.M.; Evans, R.S.; Narus, S.P.; Tilley, C.; Sorensen, J.B. Development of an information model for storing organ donor data within an electronic medical record. J. Am. Med. Inform. Assoc.,  2005, 12(3), 357-363.
[http://dx.doi.org/10.1197/jamia.M1689] [PMID:  15684132] 
[104] 
Howard, R.J.; Cochran, L.D.; Cornell, D.L. Organ procurement organizations and the electronic health record. Am. J. Transplant.,  2015, 15(10), 2562-2564.
[http://dx.doi.org/10.1111/ajt.13385] [PMID:  26138032] 
[105] 
Powell, T.; Sturridge, M.F.; Suvarna, S.K.; Terrar, D.A.; Twist, V.W. Intact individual heart cells isolated from human ventricular tissue. Br. Med. J. (Clin. Res. Ed.),  1981, 283(6298), 1013-1015.
[http://dx.doi.org/10.1136/bmj.283.6298.1013] [PMID:  6794742] 
[106] 
Bustamante, J.O.; Watanabe, T.; Murphy, D.A.; McDonald, T.F. Isolation of single atrial and ventricular cells from the human heart. Can. Med. Assoc. J.,  1982, 126(7), 791-793.
[PMID:  6280828] 
[107] 
Nánási, P.P.; Varró, A.; Lathrop, D.A. Isolation of human ventricular and atrial cardiomyocytes: Technical note. Cardioscience,  1993, 4(2), 111-116.
[PMID:  7688582] 
[108] 
Wang, Z.; Fermini, B.; Nattel, S. Delayed rectifier outward current and repolarization in human atrial myocytes. Circ. Res.,  1993, 73(2), 276-285.
[http://dx.doi.org/10.1161/01.RES.73.2.276] [PMID:  8330373] 
[109] 
Li, G.R.; Feng, J.; Yue, L.; Carrier, M.; Nattel, S. Evidence for two components of delayed rectifier K+ current in human ventricular myocytes. Circ. Res.,  1996, 78(4), 689-696.
[http://dx.doi.org/10.1161/01.RES.78.4.689] [PMID:  8635226] 
[110] 
Bird, S.D.; Doevendans, P.A.; van Rooijen, M.A.; Brutel de la Riviere, A.; Hassink, R.J.; Passier, R.; Mummery, C.L. The human adult cardiomyocyte phenotype. Cardiovasc. Res.,  2003, 58(2), 423-434.
[http://dx.doi.org/10.1016/S0008-6363(03)00253-0] [PMID:  12757876] 
[111] 
Piquereau, J.; Caffin, F.; Novotova, M.; Lemaire, C.; Veksler, V.; Garnier, A.; Ventura-Clapier, R.; Joubert, F. Mitochondrial dynamics in the adult cardiomyocytes: Which roles for a highly specialized cell? Front. Physiol.,  2013, 4, 102.
[http://dx.doi.org/10.3389/fphys.2013.00102] [PMID:  23675354] 
[112] 
Hoppel, C.L.; Tandler, B.; Fujioka, H.; Riva, A. Dynamic organization of mitochondria in human heart and in myocardial disease. Int. J. Biochem. Cell Biol.,  2009, 41(10), 1949-1956.
[http://dx.doi.org/10.1016/j.biocel.2009.05.004] [PMID:  19446651] 
[113] 
Eisner, D.A.; Caldwell, J.L.; Kistamás, K.; Trafford, A.W. Calcium and excitation-contraction coupling in the heart. Circ. Res.,  2017, 121(2), 181-195.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.310230] [PMID:  28684623] 
[114] 
Bers, D.M. Calcium cycling and signaling in cardiac myocytes. Annu. Rev. Physiol.,  2008, 70, 23-49.
[http://dx.doi.org/10.1146/annurev.physiol.70.113006.100455] [PMID:  17988210] 
[115] 
Bers, D.M. Cardiac excitation-contraction coupling. Nature,  2002, 415(6868), 198-205.
[http://dx.doi.org/10.1038/415198a] [PMID:  11805843] 
[116] 
O’Hara, T.; Virág, L.; Varró, A.; Rudy, Y. Simulation of the undiseased human cardiac ventricular action potential: Model formulation and experimental validation. PLOS Comput. Biol.,  2011, 7(5) e1002061
[http://dx.doi.org/10.1371/journal.pcbi.1002061] [PMID:  21637795] 
[117] 
Huang, J.H.; Lin, Y.K.; Hsieh, M.H.; Chen, S.A.; Chiu, W.C.; Chen, Y.J. Modulation of autonomic nervous activity in the termination of paroxysmal atrial fibrillation. Pacing Clin. Electrophysiol.,  2017, 40(4), 401-408.
[http://dx.doi.org/10.1111/pace.13045] [PMID:  28181276] 
[118] 
Sheeran, F.L.; Pepe, S. Mitochondrial bioenergetics and dysfunction in failing heart. Adv. Exp. Med. Biol.,  2017, 982, 65-80.
[http://dx.doi.org/10.1007/978-3-319-55330-6_4] [PMID:  28551782] 
[119] 
Pfleger, J.; Gresham, K.; Koch, W.J. G protein-coupled receptor kinases as therapeutic targets in the heart. Nat. Rev. Cardiol.,  2019, 16(10), 612-622.
[http://dx.doi.org/10.1038/s41569-019-0220-3] [PMID:  31186538] 
[120] 
Brown, L.; Näbauer, M.; Erdmann, E. The positive inotropic response to milrinone in isolated human and guinea pig myocardium. Naunyn Schmiedebergs Arch. Pharmacol.,  1986, 334(2), 196-201.
[http://dx.doi.org/10.1007/BF00505822] [PMID:  3024033] 
[121] 
Bristow, M.R.; Ginsburg, R.; Strosberg, A.; Montgomery, W.; Minobe, W. Pharmacology and inotropic potential of forskolin in the human heart. J. Clin. Invest.,  1984, 74(1), 212-223.
[http://dx.doi.org/10.1172/JCI111404] [PMID:  6330174] 
[122] 
Nankervis, R.; Lues, I.; Brown, L. Calcium sensitization as a positive inotropic mechanism in diseased rat and human heart. J. Cardiovasc. Pharmacol.,  1994, 24(4), 612-617.
[http://dx.doi.org/10.1097/00005344-199410000-00012] [PMID:  7528844] 
[123] 
Davia, K.; Davies, C.H.; Harding, S.E. Effects of inhibition of sarcoplasmic reticulum calcium uptake on contraction in myocytes isolated from failing human ventricle. Cardiovasc. Res.,  1997, 33(1), 88-97.
[http://dx.doi.org/10.1016/S0008-6363(96)00187-3] [PMID:  9059532] 
[124] 
Wachter, S.B.; Gilbert, E.M. Beta-adrenergic receptors, from their discovery and characterization through their manipulation to beneficial clinical application. Cardiology,  2012, 122(2), 104-112.
[http://dx.doi.org/10.1159/000339271] [PMID:  22759389] 
[125] 
Capote, L.A.; Mendez, P.; Lymperopoulos, A. GPCR signaling and cardiac function.,  Eur. J. Pharmacol.,  2015, 763(PtB), 143-148.
[126] 
de Winter, J.M.; Joureau, B.; Sequeira, V.; Clarke, N.F.; van der Velden, J.; Stienen, G.J.; Granzier, H.; Beggs, A.H.; Ottenheijm, C.A. Effect of levosimendan on the contractility of muscle fibers from nemaline myopathy patients with mutations in the nebulin gene. Skelet. Muscle,  2015, 5, 12.
[http://dx.doi.org/10.1186/s13395-015-0037-7] [PMID:  25949787] 
[127] 
Magyar, J.; Iost, N.; Körtvély, A.; Bányász, T.; Virág, L.; Szigligeti, P.; Varró, A.; Opincariu, M.; Szécsi, J.; Papp, J.G.; Nánási, P.P. Effects of endothelin-1 on calcium and potassium currents in undiseased human ventricular myocytes. Pflugers Arch.,  2000, 441(1), 144-149.
[http://dx.doi.org/10.1007/s004240000400] [PMID:  11205054] 
[128] 
Virág, L.; Iost, N.; Opincariu, M.; Szolnoky, J.; Szécsi, J.; Bogáts, G.; Szenohradszky, P.; Varró, A.; Papp, J.G. The slow component of the delayed rectifier potassium current in undiseased human ventricular myocytes. Cardiovasc. Res.,  2001, 49(4), 790-797.
[http://dx.doi.org/10.1016/S0008-6363(00)00306-0] [PMID:  11230978] 
[129] 
Farid, T.A.; Nair, K.; Massé, S.; Azam, M.A.; Maguy, A.; Lai, P.F.H.; Umapathy, K.; Dorian, P.; Chauhan, V.; Varró, A.; Al-Hesayen, A.; Waxman, M.; Nattel, S.; Nanthakumar, K. Role of KATP channels in the maintenance of ventricular fibrillation in cardiomyopathic human hearts. Circ. Res.,  2011, 109(11), 1309-1318.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.232918] [PMID:  21980123] 
[130] 
Jost, N.; Acsai, K.; Horváth, B.; Bányász, T.; Baczkó, I.; Bitay, M.; Bogáts, G.; Nánási, P.P. Contribution of I Kr and I K1 to ventricular repolarization in canine and human myocytes: Is there any influence of action potential duration? Basic Res. Cardiol.,  2009, 104(1), 33-41.
[http://dx.doi.org/10.1007/s00395-008-0730-3] [PMID:  18604626] 
[131] 
Voigt, N.; Zhou, X.B.; Dobrev, D. Isolation of human atrial myocytes for simultaneous measurements of Ca2+ transients and membrane currents. J. Vis. Exp.,  2013, 77(77) e50235
[PMID:  23852392] 
[132] 
Jiang, C.; Mochizuki, S.; Poole-Wilson, P.A.; Harding, S.E.; Mac- Leod, K.T. Effect of lemakalim on action potentials, intracellular calcium, and contraction in guinea pig and human cardiac myocytes. Cardiovasc. Res.,  1994, 28(6), 851-857.
[http://dx.doi.org/10.1093/cvr/28.6.851] [PMID:  7923291] 
[133] 
Guo, D.; Liu, Q.; Liu, T.; Elliott, G.; Gingras, M.; Kowey, P.R.; Yan, G.X. Electrophysiological properties of HBI-3000: A new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes. J. Cardiovasc. Pharmacol.,  2011, 57(1), 79-85.
[http://dx.doi.org/10.1097/FJC.0b013e3181ffe8b3] [PMID:  20980921] 
[134] 
Limberg, S.H.; Netter, M.F.; Rolfes, C.; Rinné, S.; Schlichthörl, G.; Zuzarte, M.; Vassiliou, T.; Moosdorf, R.; Wulf, H.; Daut, J.; Sachse, F.B.; Decher, N. TASK-1 channels may modulate action potential duration of human atrial cardiomyocytes. Cell. Physiol. Biochem.,  2011, 28(4), 613-624.
[http://dx.doi.org/10.1159/000335757] [PMID:  22178873] 
[135] 
Schmidt, C.; Wiedmann, F.; Voigt, N.; Zhou, X.B.; Heijman, J.; Lang, S.; Albert, V.; Kallenberger, S.; Ruhparwar, A.; Szabó, G.; Kallenbach, K.; Karck, M.; Borggrefe, M.; Biliczki, P.; Ehrlich, J.R.; Baczkó, I.; Lugenbiel, P.; Schweizer, P.A.; Donner, B.C.; Katus, H.A.; Dobrev, D.; Thomas, D. Upregulation of K(2P)3.1 K+ current causes action potential shortening in patients with chronic atrial fibrillation. Circulation,  2015, 132(2), 82-92.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.114.012657] [PMID:  25951834] 
[136] 
Beuckelmann, D.J.; Näbauer, M.; Erdmann, E. Intracellular calcium handling in isolated ventricular myocytes from patients with terminal heart failure. Circulation,  1992, 85(3), 1046-1055.
[http://dx.doi.org/10.1161/01.CIR.85.3.1046] [PMID:  1311223] 
[137] 
Beuckelmann, D.J.; Näbauer, M.; Erdmann, E. Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ. Res.,  1993, 73(2), 379-385.
[http://dx.doi.org/10.1161/01.RES.73.2.379] [PMID:  8330380] 
[138] 
Voigt, N.; Li, N.; Wang, Q.; Wang, W.; Trafford, A.W.; Abu-Taha, I.; Sun, Q.; Wieland, T.; Ravens, U.; Nattel, S.; Wehrens, X.H.; Dobrev, D. Enhanced sarcoplasmic reticulum Ca2+ leak and increased Na+-Ca2+ exchanger function underlies delayed afterdepolarizations in patients with chronic atrial fibrillation. Circulation,  2012, 125(17), 2059-2070.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.111.067306] [PMID:  22456474] 
[139] 
Signore, S.; Sorrentino, A.; Ferreira-Martins, J.; Kannappan, R.; Shafaie, M.; Del Ben, F.; Isobe, K.; Arranto, C.; Wybieralska, E.; Webster, A.; Sanada, F.; Ogórek, B.; Zheng, H.; Liu, X.; Del Monte, F.; D’Alessandro, D.A.; Wunimenghe, O.; Michler, R.E.; Hosoda, T.; Goichberg, P.; Leri, A.; Kajstura, J.; Anversa, P.; Rota, M. Inositol 1, 4, 5-trisphosphate receptors and human left ventricular myocytes. Circulation,  2013, 128(12), 1286-1297.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002764] [PMID:  23983250] 
[140] 
Herraiz-Martínez, A.; Álvarez-García, J.; Llach, A.; Molina, C.E.; Fernandes, J.; Ferrero-Gregori, A.; Rodríguez, C.; Vallmitjana, A.; Benítez, R.; Padró, J.M.; Martínez-González, J.; Cinca, J.; Hove-Madsen, L. Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes. Cardiovasc. Res.,  2015, 106(1), 76-86.
[http://dx.doi.org/10.1093/cvr/cvv046] [PMID:  25712961] 
[141] 
Voigt, N.; Heijman, J.; Wang, Q.; Chiang, D.Y.; Li, N.; Karck, M.; Wehrens, X.H.T.; Nattel, S.; Dobrev, D. Cellular and molecular mechanisms of atrial arrhythmogenesis in patients with paroxysmal atrial fibrillation. Circulation,  2014, 129(2), 145-156.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.006641] [PMID:  24249718] 
[142] 
Hardy, M.E.; Pollard, C.E.; Small, B.G.; Bridgland-Taylor, M.; Woods, A.J.; Valentin, J.P.; Abi-Gerges, N. Validation of a voltage-sensitive dye (di-4-ANEPPS)-based method for assessing drug induced delayed repolarisation in beagle dog left ventricular midmyocardial myocytes. J. Pharmacol. Toxicol. Methods,  2009, 60(1), 94-106.
[http://dx.doi.org/10.1016/j.vascn.2009.03.005] [PMID:  19414070] 
[143] 
Bedut, S.; Seminatore-Nole, C.; Lamamy, V.; Caignard, S.; Boutin, J.A.; Nosjean, O.; Stephan, J.P.; Coge, F. High-throughput drug profiling with voltage- and calcium-sensitive fluorescent probes in human iPSC-derived cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol.,  2016, 311(1), H44-H53.
[http://dx.doi.org/10.1152/ajpheart.00793.2015] [PMID:  27199128] 
[144] 
Hortigon-Vinagre, M.P.; Zamora, V.; Burton, F.L.; Green, J.; Gintant, G.A.; Smith, G.L. The use of ratiometric fluorescence measurements of the voltage sensitive dye di-4-anepps to examine action potential characteristics and drug effects on human induced pluripotent stem cell-derived cardiomyocytes. Toxicol. Sci.,  2016, 154(2), 320-331.
[http://dx.doi.org/10.1093/toxsci/kfw171] [PMID:  27621282] 
[145] 
Readnower, R.D.; Brainard, R.E.; Hill, B.G.; Jones, S.P. Standardized bioenergetic profiling of adult mouse cardiomyocytes. Physiol. Genomics,  2012, 44(24), 1208-1213.
[http://dx.doi.org/10.1152/physiolgenomics.00129.2012] [PMID:  23092951] 
[146] 
Menon, B.; Singh, M.; Ross, R.S.; Johnson, J.N.; Singh, K. beta-Adrenergic receptor-stimulated apoptosis in adult cardiac myocytes involves MMP-2-mediated disruption of beta1 integrin signaling and mitochondrial pathway. Am. J. Physiol. Cell Physiol.,  2006, 290(1), C254-C261.
[http://dx.doi.org/10.1152/ajpcell.00235.2005] [PMID:  16148033] 
[147] 
Kettlewell, S.; Cabrero, P.; Nicklin, S.A.; Dow, J.A.T.; Davies, S.; Smith, G.L. Changes of intra-mitochondrial Ca2+ in adult ventricular cardiomyocytes examined using a novel fluorescent Ca2+ indicator targeted to mitochondria. J. Mol. Cell. Cardiol.,  2009, 46(6), 891-901.
[http://dx.doi.org/10.1016/j.yjmcc.2009.02.016] [PMID:  19249308] 
[148] 
Pfeiffer, E.R.; Vega, R.; McDonough, P.M.; Price, J.H.; Whittaker, R. Specific prediction of clinical QT prolongation by kinetic image cytometry in human stem cell derived cardiomyocytes. J. Pharmacol. Toxicol. Methods,  2016, 81, 263-273.
[http://dx.doi.org/10.1016/j.vascn.2016.04.007] [PMID:  27095424] 
[149] 
Ren, J.; Wold, L.E. Measurement of cardiac mechanical function in isolated ventricular myocytes from rats and mice by computerized video-based imaging. Biol. Proced. Online,  2001, 3, 43-53.
[http://dx.doi.org/10.1251/bpo22] [PMID:  12734580] 
[150] 
Hayakawa, T.; Kunihiro, T.; Ando, T.; Kobayashi, S.; Matsui, E.; Yada, H.; Kanda, Y.; Kurokawa, J.; Furukawa, T. Image-based evaluation of contraction-relaxation kinetics of human-induced pluripotent stem cell-derived cardiomyocytes: Correlation and complementarity with extracellular electrophysiology. J. Mol. Cell. Cardiol.,  2014, 77, 178-191.
[http://dx.doi.org/10.1016/j.yjmcc.2014.09.010] [PMID:  25257913] 
[151] 
Marston, S.; Papadaki, M.; Yang, S.; Sheehan, A. Small molecules can restore the lusitropic response in animal models of HCM and dcm that are uncoupled by mutation. J. Muscle Res. Cell Motil.,  2019, 40(2), 227-274.
[PMID:  31396771] 
[152] 
Cook, D.; Brown, D.; Alexander, R.; March, R.; Morgan, P.; Satterthwaite, G.; Pangalos, M.N. Lessons learned from the fate of AstraZeneca’s drug pipeline: A five-dimensional framework. Nat. Rev. Drug Discov.,  2014, 13(6), 419-431.
[http://dx.doi.org/10.1038/nrd4309] [PMID:  24833294] 
[153] 
Anon.,  2005.https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Guideline.pdf
[154] 
Vargas, H.M.; Bass, A.S.; Koerner, J.; Matis-Mitchell, S.; Pugsley, M.K.; Skinner, M.; Burnham, M.; Bridgland-Taylor, M.; Pettit, S.; Valentin, J.P. Evaluation of drug-induced QT interval prolongation in animal and human studies: A literature review of concordance. Br. J. Pharmacol.,  2015, 172(16), 4002-4011.
[http://dx.doi.org/10.1111/bph.13207] [PMID:  26031452] 
[155] 
Stockbridge, N.; Morganroth, J.; Shah, R.R.; Garnett, C. Dealing with global safety issues: was the response to QT-liability of non-cardiac drugs well-coordinated? Drug Saf.,  2013, 36(3), 167-182.
[http://dx.doi.org/10.1007/s40264-013-0016-z] [PMID:  23417505] 
[156] 
Kanda, Y.; Yamazaki, D.; Osada, T.; Yoshinaga, T.; Sawada, K. Development of torsadogenic risk assessment using human induced pluripotent stem cell-derived cardiomyocytes: Japan iPS Cardiac Safety Assessment (JiCSA) update J. Pharmacol. Sci.,  2018, 138, 233e239.
[157] 
Abi-Gerges, N.; Indersmitten, T.; Truong, K.; Nguyen, W.; Nguyen, N.; Page, G.; Miller, P.E.; Ghetti, A. A Human cardiomyocyte-based platform for the profiling of positive inotropes with potential to treat heart failure. Mol. Biol. Cell,  2018, 29(26)
[158] 
Abi-Gerges, N.; Indersmitten, T.; Truong, K.; Nguyen, W.; Nguyen, N.; Page, G.; Miller, P.E.; Ghetti, A. Prediction of tyrosine kinase inhibitor contractility risk with adult human primary cardiomyocytes. Toxicologist, Suppl. Toxicol. Sci.,  2019, 168,158, (Abstract #3306).
[159] 
Anon.,  2019.https://database.ich.org/sites/default/files/E14S7B_IWG_Concept_Paper.pdf
[160] 
Belardinelli, L.; Dhalla, A.; Shryock, J. Abnormal left ventricular relaxation in patients with long QT syndrome. Eur. Heart J.,  2009, 30(22), 2813-2814.
[http://dx.doi.org/10.1093/eurheartj/ehp444] [PMID:  19843555] 
[161] 
De Ferrari, G.M.; Schwartz, P.J. Long QT syndrome, a purely electrical disease? Not anymore. Eur. Heart J.,  2009, 30(3), 253-255.
[http://dx.doi.org/10.1093/eurheartj/ehn587] [PMID:  19151080] 
[162] 
Lou, Q.; Fedorov, V.V.; Glukhov, A.V.; Moazami, N.; Fast, V.G.; Efimov, I.R. Transmural heterogeneity and remodeling of ventricular excitation-contraction coupling in human heart failure. Circulation,  2011, 123(17), 1881-1890.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.989707] [PMID:  21502574] 
[163] 
Kaumann, A.J.; Olson, C.B. Temporal relation between long-lasting aftercontractions and action potentials in cat papillary muscles. Science,  1968, 161(3838), 293-295.
[http://dx.doi.org/10.1126/science.161.3838.293] [PMID:  5657338] 
[164] 
Nador, F.; Beria, G.; De Ferrari, G.M.; Stramba-Badiale, M.; Locati, E.H.; Lotto, A.; Schwartz, P.J. Unsuspected echocardiographic abnormality in the long QT syndrome. Diagnostic, prognostic, and pathogenetic implications. Circulation,  1991, 84(4), 1530-1542.
[http://dx.doi.org/10.1161/01.CIR.84.4.1530] [PMID:  1914095] 
[165] 
De Ferrari, G.M.; Nador, F.; Beria, G.; Sala, S.; Lotto, A.; Schwartz, P.J. Effect of calcium channel block on the wall motion abnormality of the idiopathic long QT syndrome. Circulation,  1994, 89(5), 2126-2132.
[http://dx.doi.org/10.1161/01.CIR.89.5.2126] [PMID:  8181137] 
[166] 
Nakayama, K.; Yamanari, H.; Otsuka, F.; Fukushima, K.; Saito, H.; Fujimoto, Y.; Emori, T.; Matsubara, H.; Uchida, S.; Ohe, T. Dispersion of regional wall motion abnormality in patients with long QT syndrome. Heart,  1998, 80(3), 245-250.
[http://dx.doi.org/10.1136/hrt.80.3.245] [PMID:  9875083] 
[167] 
Haugaa, K.H.; Edvardsen, T.; Leren, T.P.; Gran, J.M.; Smiseth, O.A.; Amlie, J.P. Left ventricular mechanical dispersion by tissue Doppler imaging: A novel approach for identifying high-risk individuals with long QT syndrome. Eur. Heart J.,  2009, 30(3), 330-337.
[http://dx.doi.org/10.1093/eurheartj/ehn466] [PMID:  18940888] 
[168] 
Edwards, A.G.; Louch, W.E. Species-dependent mechanisms of cardiac arrhythmia: A cellular focus. Clin. Med. Insights Cardiol.,  2017, 11, 1179546816686061
[http://dx.doi.org/10.1177/1179546816686061] [PMID:  28469490] 
[169] 
Chugh, S.S.; Havmoeller, R.; Narayanan, K.; Singh, D.; Rienstra, M.; Benjamin, E.J.; Gillum, R.F.; Kim, Y.H.; McAnulty, J.H., Jr; Zheng, Z.J.; Forouzanfar, M.H.; Naghavi, M.; Mensah, G.A.; Ezzati, M.; Murray, C.J. Worldwide epidemiology of atrial fibrillation: A Global Burden of Disease 2010 Study. Circulation,  2014, 129(8), 837-847.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.005119] [PMID:  24345399] 
[170] 
Heijman, J.; Voigt, N.; Nattel, S.; Dobrev, D. Cellular and molecular electrophysiology of atrial fibrillation initiation, maintenance, and progression. Circ. Res.,  2014, 114(9), 1483-1499.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.302226] [PMID:  24763466] 
[171] 
Heijman, J.; Algalarrondo, V.; Voigt, N.; Melka, J.; Wehrens, X.H.; Dobrev, D.; Nattel, S. The value of basic research insights into atrial fibrillation mechanisms as a guide to therapeutic innovation: a critical analysis. Cardiovasc. Res.,  2016, 109(4), 467-479.
[http://dx.doi.org/10.1093/cvr/cvv275] [PMID:  26705366] 
[172] 
Nattel, S.; Burstein, B.; Dobrev, D. Atrial remodeling and atrial fibrillation: mechanisms and implications. Circ Arrhythm Electrophysiol,  2008, 1(1), 62-73.
[http://dx.doi.org/10.1161/CIRCEP.107.754564] [PMID:  19808395] 
[173] 
Staerk, L.; Sherer, J.A.; Ko, D.; Benjamin, E.J.; Helm, R.H. Atrial fibrillation: Epidemiology, pathophysiology, and clinical outcomes. Circ. Res.,  2017, 120(9), 1501-1517.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.309732] [PMID:  28450367] 
[174] 
Heijman, J.; Guichard, J.B.; Dobrev, D.; Nattel, S. Translational challenges in atrial fibrillation. Circ. Res.,  2018, 122(5), 752-773.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.311081] [PMID:  29496798] 
[175] 
Wettwer, E.; Hála, O.; Christ, T.; Heubach, J.F.; Dobrev, D.; Knaut, M.; Varró, A.; Ravens, U. Role of IKur in controlling action potential shape and contractility in the human atrium: Influence of chronic atrial fibrillation. Circulation,  2004, 110(16), 2299-2306.
[http://dx.doi.org/10.1161/01.CIR.0000145155.60288.71] [PMID:  15477405] 
[176] 
Lalevée, N.; Nargeot, J.; Barrére-Lemaire, S.; Gautier, P.; Richard, S. Effects of amiodarone and dronedarone on voltage-dependent sodium current in human cardiomyocytes. J. Cardiovasc. Electrophysiol.,  2003, 14(8), 885-890.
[http://dx.doi.org/10.1046/j.1540-8167.2003.03064.x] [PMID:  12890054] 
[177] 
Poulet, C.; Wettwer, E.; Grunnet, M.; Jespersen, T.; Fabritz, L.; Matschke, K.; Knaut, M.; Ravens, U. Late sodium current in human atrial cardiomyocytes from patients in sinus rhythm and atrial fibrillation. PLoS One,  2015, 10(6) e0131432
[http://dx.doi.org/10.1371/journal.pone.0131432] [PMID:  26121051] 
[178] 
Sossalla, S.; Kallmeyer, B.; Wagner, S.; Mazur, M.; Maurer, U.; Toischer, K.; Schmitto, J.D.; Seipelt, R.; Schöndube, F.A.; Hasenfuss, G.; Belardinelli, L.; Maier, L.S. Altered Na(+) currents in atrial fibrillation effects of ranolazine on arrhythmias and contractility in human atrial myocardium. J. Am. Coll. Cardiol.,  2010, 55(21), 2330-2342.
[http://dx.doi.org/10.1016/j.jacc.2009.12.055] [PMID:  20488304] 
[179] 
Fischer, T.H.; Herting, J.; Mason, F.E.; Hartmann, N.; Watanabe, S.; Nikolaev, V.O.; Sprenger, J.U.; Fan, P.; Yao, L.; Popov, A.F.; Danner, B.C.; Schöndube, F.; Belardinelli, L.; Hasenfuss, G.; Maier, L.S.; Sossalla, S. Late INa increases diastolic SR-Ca2+-leak in atrial myocardium by activating PKA and CaMKII. Cardiovasc. Res.,  2015, 107(1), 184-196.
[http://dx.doi.org/10.1093/cvr/cvv153] [PMID:  25990311] 
[180] 
Milnes, J.T.; El-Haou, S.; Loose, S.; Jackson, C.; Tang, R.; Muirhead, I. In the absence of muscarinic activation, inhibition of Kir3.1/3.4 and Kir3.4/3.4, but not Kir3.1/3.4- alone prolongs repolarisation of atrial tissue from patients with atrial fibrillation. Circulation,  2014, 130, A20199
[181] 
Dinanian, S.; Boixel, C.; Juin, C.; Hulot, J.S.; Coulombe, A.; Rücker-Martin, C.; Bonnet, N.; Le Grand, B.; Slama, M.; Mercadier, J.J.; Hatem, S.N. Downregulation of the calcium current in human right atrial myocytes from patients in sinus rhythm but with a high risk of atrial fibrillation. Eur. Heart J.,  2008, 29(9), 1190-1197.
[http://dx.doi.org/10.1093/eurheartj/ehn140] [PMID:  18397872] 
[182] 
Skibsbye, L.; Poulet, C.; Diness, J.G.; Bentzen, B.H.; Yuan, L.; Kappert, U.; Matschke, K.; Wettwer, E.; Ravens, U.; Grunnet, M.; Christ, T.; Jespersen, T. Small-conductance calcium-activated Potassium (SK) channels contribute to action potential repolarization in human atria. Cardiovasc. Res.,  2014, 103(1), 156-167.
[http://dx.doi.org/10.1093/cvr/cvu121] [PMID:  24817686] 
[183] 
Christ, T.; Wettwer, E.; Voigt, N.; Hála, O.; Radicke, S.; Matschke, K.; Várro, A.; Dobrev, D.; Ravens, U. Pathology-specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation. Br. J. Pharmacol.,  2008, 154(8), 1619-1630.
[http://dx.doi.org/10.1038/bjp.2008.209] [PMID:  18536759] 
[184] 
Loose, S.; Mueller, J.; Wettwer, E.; Knaut, M.; Ford, J.; Milnes, J.; Ravens, U. Effects of IKur blocker MK-0448 on human right atrial action potentials from patients in sinus rhythm and in permanent atrial fibrillation. Front. Pharmacol.,  2014, 5, 26.
[http://dx.doi.org/10.3389/fphar.2014.00026] [PMID:  24624083] 
[185] 
Ford, J.; Milnes, J.; El Haou, S.; Wettwer, E.; Loose, S.; Matschke, K.; Tyl, B.; Round, P.; Ravens, U. The positive frequency dependent electrophysiological effects of the IKur inhibitor XEN D0103 are desirable for the treatment of atrial fibrillation. Heart Rhythm,  2016, 13(2), 555-564.
[http://dx.doi.org/10.1016/j.hrthm.2015.10.003] [PMID:  26455450] 
[186] 
Wettwer, E.; Christ, T.; Endig, S.; Rozmaritsa, N.; Matschke, K.; Lynch, J.J.; Pourrier, M.; Gibson, J.K.; Fedida, D.; Knaut, M.; Ravens, U. The new antiarrhythmic drug vernakalant: Ex vivo study of human atrial tissue from sinus rhythm and chronic atrial fibrillation. Cardiovasc. Res.,  2013, 98(1), 145-154.
[http://dx.doi.org/10.1093/cvr/cvt006] [PMID:  23341576] 
[187] 
Lagrutta, A.; Wang, J.; Fermini, B.; Salata, J.J. Novel, potent inhibitors of human Kv1.5 K+ channels and ultrarapidly activating delayed rectifier potassium current. J. Pharmacol. Exp. Ther.,  2006, 317(3), 1054-1063.
[http://dx.doi.org/10.1124/jpet.106.101162] [PMID:  16522807] 
[188] 
Sartiani, L.; Sartiani, L.; Cameli, M.; Dini, L.; Modillo, S.; Maccherini, M.; Le Grand, B.; Mugelli, A.; Cerbai, E. Remodeling of atrial action potential duration and atrial chamber deformation: a potential link in the development of atrial fibrillation? Cardiovasc. Res.,  2018, 114(Suppl. 1), S120.
[http://dx.doi.org/10.1093/cvr/cvy060.353] 
[189] 
Milnes, J.; Loose, S.; Poulet, C.; Kuenzel, S.; El-Haou, S.; Jackson, C.; Tang, R.; Madge, D.; Ford, J.; Ravens, U. The potent, selective cardiac acetylcholine-activated potassium current inhibitor XENR0706 prolongs human atrial action potential duration. Circulation,  2013, 128, A18632.
[190] 
Hartmann, N.; Mason, F.E.; Braun, I.; Pabel, S.; Voigt, N.; Schotola, H.; Fischer, T.H.; Dobrev, D.; Danner, B.C.; Renner, A.; Gummert, J.; Belardinelli, L.; Frey, N.; Maier, L.S.; Hasenfuss, G.; Sossalla, S. The combined effects of ranolazine and dronedarone on human atrial and ventricular electrophysiology. J. Mol. Cell. Cardiol.,  2016, 94, 95-106.
[http://dx.doi.org/10.1016/j.yjmcc.2016.03.012] [PMID:  27056421] 
[191] 
Ravens, U.; Poulet, C.; Wettwer, E.; Knaut, M. Atrial selectivity of antiarrhythmic drugs. J. Physiol.,  2013, 591(17), 4087-4097.
[http://dx.doi.org/10.1113/jphysiol.2013.256115] [PMID:  23732646] 
[192] 
Piccini, J.P.; Pritchett, E.L.; Davison, B.A.; Cotter, G.; Wiener, L.E.; Koch, G.; Feld, G.; Waldo, A.; van Gelder, I.C.; Camm, A.J.; Kowey, P.R.; Iwashita, J.; Dittrich, H.C. Randomized, double blind, placebo-controlled study to evaluate the safety and efficacy of a single oral dose of vanoxerine for the conversion of subjects with recent onset atrial fibrillation or flutter to normal sinus rhythm: RESTORE SR. Heart Rhythm,  2016, 13(9), 1777-1783.
[http://dx.doi.org/10.1016/j.hrthm.2016.04.012] [PMID:  27108936] 
[193] 
Heijman, J.; Ghezelbash, S.; Wehrens, X.H.; Dobrev, D. Serine/Threonine Phosphatases in Atrial Fibrillation. J. Mol. Cell. Cardiol.,  2017, 103, 110-120.
[http://dx.doi.org/10.1016/j.yjmcc.2016.12.009] [PMID:  28077320] 
[194] 
Komal, S.; Yin, J.J.; Wang, S.H.; Huang, C.Z.; Tao, H.L.; Dong, J.Z.; Han, S.N.; Zhang, L.R. MicroRNAs: Emerging biomarkers for atrial fibrillation. J. Cardiol.,  2019, S0914-5087(19), 30204-7.
[195] 
Trivedi, A; Hoffman, J.; Arora, R. Gene therapy for atrial fibrillation - How close to clinical implementation? Int. J. Cardiol.,  2019, S0167-5273(18), 33152-8.
[196] 
Lau, D.H.; Nattel, S.; Kalman, J.M.; Sanders, P. Modifiable risk factors for atrial fibrillation. Circulation,  2017, 136(6), 583-596.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.023163] [PMID:  28784826] 
[197] 
Benjamin, E.J.; Muntner, P.; Alonso, A.; Bittencourt, M.S.; Callaway, C.W.; Carson, A.P.; Chamberlain, A.M.; Chang, A.R.; Cheng, S.; Das, S.R.; Delling, F.N.; Djousse, L.; Elkind, M.S.V.; Ferguson, J.F.; Fornage, M.; Jordan, L.C.; Khan, S.S.; Kissela, B.M.; Knutson, K.L.; Kwan, T.W.; Lackland, D.T.; Lewis, T.T.; Lichtman, J.H.; Longenecker, C.T.; Loop, M.S.; Lutsey, P.L.; Martin, S.S.; Matsushita, K.; Moran, A.E.; Mussolino, M.E.; O’Flaherty, M.; Pandey, A.; Perak, A.M.; Rosamond, W.D.; Roth, G.A.; Sampson, U.K.A.; Satou, G.M.; Schroeder, E.B.; Shah, S.H.; Spartano, N.L.; Stokes, A.; Tirschwell, D.L.; Tsao, C.W.; Turakhia, M.P.; Van- Wagner, L.B.; Wilkins, J.T.; Wong, S.S.; Virani, S.S. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2019 Update: A Report from the American Heart Association. Circulation,  2019, 139(10), e56-e528.
[http://dx.doi.org/10.1161/CIR.0000000000000659] [PMID:  30700139] 
[198] 
Savarese, G.; Lund, L.H. Global Public Health Burden of Heart Failure. Card. Fail. Rev.,  2017, 3(1), 7-11.
[http://dx.doi.org/10.15420/cfr.2016:25:2] [PMID:  28785469] 
[199] 
Alvarez, P.; Hannawi, B.; Guha, A. Exercise and heart failure: Advancing knowledge and improving care. Methodist DeBakey Cardiovasc. J.,  2016, 12(2), 110-115.
[http://dx.doi.org/10.14797/mdcj-12-2-110] [PMID:  27486494] 
[200] 
Breitenstein, A.; Steffel, J. Devices in heart failure patients-who benefits from ICD and CRT? Front. Cardiovasc. Med.,  2019, 13(6:111.)
[http://dx.doi.org/10.3389/fcvm.2019.00111] 
[201] 
Rossignol, P.; Hernandez, A.F.; Solomon, S.D.; Zannad, F. Heart failure drug treatment. Lancet,  2019, 393(10175), 1034-1044.
[http://dx.doi.org/10.1016/S0140-6736(18)31808-7] [PMID:  30860029] 
[202] 
Tschöpe, C.; Kherad, B.; Klein, O.; Lipp, A.; Blaschke, F.; Gutterman, D.; Burkhoff, D.; Hamdani, N.; Spillmann, F.; Van Linthout, S. Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond. Eur. J. Heart Fail.,  2019, 21(1), 14-22.
[http://dx.doi.org/10.1002/ejhf.1349] [PMID:  30485591] 
[203] 
Røe, A.T.; Frisk, M.; Louch, W.E. Targeting cardiomyocyte Ca2+ homeostasis in heart failure. Curr. Pharm. Des.,  2015, 21(4), 431-448.
[http://dx.doi.org/10.2174/138161282104141204124129] [PMID:  25483944] 
[204] 
Peana, D.; Domeier, T.L. Cardiomyocyte Ca2+ homeostasis as a therapeutic target in heart failure with reduced and preserved ejection fraction. Curr. Opin. Pharmacol.,  2017, 33, 17-26.
[http://dx.doi.org/10.1016/j.coph.2017.03.005] [PMID:  28437711] 
[205] 
Bers, D.M. Altered cardiac myocyte Ca regulation in heart failure. Physiology (Bethesda),  2006, 21, 380-387.
[http://dx.doi.org/10.1152/physiol.00019.2006] [PMID:  17119150] 
[206] 
Louch, W.E.; Stokke, M.K.; Sjaastad, I.; Christensen, G.; Sejersted, O.M. No rest for the weary: Diastolic calcium homeostasis in the normal and failing myocardium. Physiology (Bethesda),  2012, 27(5), 308-323.
[http://dx.doi.org/10.1152/physiol.00021.2012] [PMID:  23026754] 
[207] 
Shah, S.J.; Blair, J.E.; Filippatos, G.S.; Macarie, C.; Ruzyllo, W.; Korewicki, J.; Bubenek-Turconi, S.I.; Ceracchi, M.; Bianchetti, M.; Carminati, P.; Kremastinos, D.; Grzybowski, J.; Valentini, G.; Sabbah, H.N.; Gheorghiade, M. HORIZON-HF Investigators. Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: results from the hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent: A randomized controlled trial in patients hospitalized with heart failure (HORIZON-HF) trial. Am. Heart J.,  2009, 157(6), 1035-1041.
[http://dx.doi.org/10.1016/j.ahj.2009.03.007] [PMID:  19464414] 
[208] 
Sarma, S.; Hieda, M.; Howden, E.J.; Hearon, C.; Lawley, J.; Livingston, S.; Samels, M.; Everding, B.; Levine, B.D. Hemodynamic response to exercise in Heart Failure with Preserved Ejection Fraction (HFpEF) Patients After Upregulation of SERCA2a. Circulation,  2017, 136, A19365
[209] 
Katz, A.M. Potential deleterious effects of inotropic agents in the therapy of chronic heart failure. Circulation,  1986, 73(3 Pt 2), III184-90.
[210] 
Hasenfuss, G.; Holubarsch, C.; Blanchard, E.M.; Mulieri, L.A.; Alpert, N.R.; Just, H. Influence of isoproterenol on myocardial energetics. Experimental and clinical investigations. Basic Res. Cardiol.,  1989, 84(Suppl. 1), 147-155.
[http://dx.doi.org/10.1007/BF02650354] [PMID:  2818454] 
[211] 
Conraads, V.M.; Metra, M.; Kamp, O.; De Keulenaer, G.W.; Pieske, B.; Zamorano, J.; Vardas, P.E.; Böhm, M.; Dei Cas, L. Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: Results of the ELANDD study. Eur. J. Heart Fail.,  2012, 14(2), 219-225.
[http://dx.doi.org/10.1093/eurjhf/hfr161] [PMID:  22147202] 
[212] 
Yamamoto, K.; Origasa, H.; Hori, M. J-DHF. Investigators. Effects of carvedilol on heart failure with preserved ejection fraction: The Japanese Diastolic Heart Failure Study (J-DHF). Eur. J. Heart Fail.,  2013, 15(1), 110-118.
[http://dx.doi.org/10.1093/eurjhf/hfs141] [PMID:  22983988] 
[213] 
Pitt, B.; Anker, S.D.; Böhm, M.; Gheorghiade, M.; Køber, L.; Krum, H.; Maggioni, A.P.; Ponikowski, P.; Voors, A.A.; Zannad, F.; Nowack, C.; Kim, S.Y.; Pieper, A.; Kimmeskamp-Kirschbaum, N.; Filippatos, G. Rationale and design of Mineralocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF): A randomized study of finerenone vs. eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease. Eur. J. Heart Fail.,  2015, 17(2), 224-232.
[http://dx.doi.org/10.1002/ejhf.218] [PMID:  25678098] 
[214] 
Filippatos, G.; Anker, S.D.; Böhm, M.; Gheorghiade, M.; Køber, L.; Krum, H.; Maggioni, A.P.; Ponikowski, P.; Voors, A.A.; Zannad, F.; Kim, S.Y.; Nowack, C.; Palombo, G.; Kolkhof, P.; Kimmeskamp-Kirschbaum, N.; Pieper, A.; Pitt, B. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur. Heart J.,  2016, 37(27), 2105-2114.
[http://dx.doi.org/10.1093/eurheartj/ehw132] [PMID:  27130705] 
[215] 
Pieske, B.; Butler, J.; Filippatos, G.; Lam, C.; Maggioni, A.P.; Ponikowski, P.; Shah, S.; Solomon, S.; Kraigher-Krainer, E.; Samano, E.T.; Scalise, A.V.; Müller, K.; Roessig, L.; Gheorghiade, M. SOCRATES Investigators and Coordinators. Rationale and design of the soluble guanylate cyclase stimulator in heart failure Studies (SOCRATES). Eur. J. Heart Fail.,  2014, 16(9), 1026-1038.
[http://dx.doi.org/10.1002/ejhf.135] [PMID:  25056511] 
[216] 
Gheorghiade, M.; Greene, S.J.; Butler, J.; Filippatos, G.; Lam, C.S.; Maggioni, A.P.; Ponikowski, P.; Shah, S.J.; Solomon, S.D.; Kraigher-Krainer, E.; Samano, E.T.; Müller, K.; Roessig, L.; Pieske, B. SOCRATES-REDUCED investigators and coordinators. effect of vericiguat, a soluble guanylate cyclase stimulator, on natriuretic peptide levels in patients with worsening chronic heart failure and reduced ejection fraction: The SOCRATES-REDUCED Randomized Trial. JAMA,  2015, 314(21), 2251-2262.
[http://dx.doi.org/10.1001/jama.2015.15734] [PMID:  26547357] 
[217] 
Armstrong, P.W.; Roessig, L.; Patel, M.J.; Anstrom, K.J.; Butler, J.; Voors, A.A.; Lam, C.S.P.; Ponikowski, P.; Temple, T.; Pieske, B.; Ezekowitz, J.; Hernandez, A.F.; Koglin, J.; O’Connor, C.M.A. A multicenter, randomized, double-blind, placebo-controlled trial of the efficacy and safety of the oral soluble guanylate cyclase stimulator: The Victoria Trial. JACC Heart Fail.,  2018, 6(2), 96-104.
[http://dx.doi.org/10.1016/j.jchf.2017.08.013] [PMID:  29032136] 
[218] 
Upadhya, B.; Kitzman, D.W. Heart failure with preserved ejection fraction in older adults. Heart Fail. Clin.,  2017, 13(3), 485-502.
[http://dx.doi.org/10.1016/j.hfc.2017.02.005] [PMID:  28602367] 
[219] 
Maier, L.S.; Layug, B.; Karwatowska-Prokopczuk, E.; Belardinelli, L.; Lee, S.; Sander, J.; Lang, C.; Wachter, R.; Edelmann, F.; Hasenfuss, G.; Jacobshagen, C. RAnoLazIne for the treatment of diastolic heart failure in patients with preserved ejection fraction: the RALI-DHF proof-of-concept study. JACC Heart Fail.,  2013, 1(2), 115-122.
[http://dx.doi.org/10.1016/j.jchf.2012.12.002] [PMID:  24621836] 
[220] 
Murray, G.L.; Colombo, J. Ranolazine preserves and improves left ventricular ejection fraction and autonomic measures when added to guideline-driven therapy in chronic heart failure. Heart Int.,  2014, 9(2), 66-73.
[http://dx.doi.org/10.5301/heartint.5000219] [PMID:  27004101] 
[221] 
Swedberg, K.; Komajda, M.; Böhm, M.; Borer, J.S.; Ford, I.; Dubost-Brama, A.; Lerebours, G.; Tavazzi, L. SHIFT Investigators. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet,  2010, 376(9744), 875-885.
[http://dx.doi.org/10.1016/S0140-6736(10)61198-1] [PMID:  20801500] 
[222] 
Sattar, Y.; Neisani Samani, E.; Zafrullah, F.; Latchana, S.; Patel, N.B. Ivabradine in congestive heart failure: Patient selection and perspectives. Cureus,  2019, 11(4) e4448
[http://dx.doi.org/10.7759/cureus.4448] [PMID:  31205834] 
[223] 
Pal, N.; Sivaswamy, N.; Mahmod, M.; Yavari, A.; Rudd, A.; Singh, S.; Dawson, D.K.; Francis, J.M.; Dwight, J.S.; Watkins, H.; Neubauer, S.; Frenneaux, M.; Ashrafian, H. Effect of selective heart rate slowing in heart failure with preserved ejection fraction. Circulation,  2015, 132(18), 1719-1725.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.115.017119] [PMID:  26338956] 
[224] 
Komajda, M.; Isnard, R.; Cohen-Solal, A.; Metra, M.; Pieske, B.; Ponikowski, P.; Voors, A.A.; Dominjon, F.; Henon-Goburdhun, C.; Pannaux, M.; Böhm, M. Preserved left ventricular Ejection Fraction Chronic Heart Failure with Ivabradine Study (EDIFY) Investigators. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur. J. Heart Fail.,  2017, 19(11), 1495-1503.
[http://dx.doi.org/10.1002/ejhf.876] [PMID:  28462519] 
[225] 
Teerlink, J.R.; Felker, G.M.; McMurray, J.J.; Solomon, S.D.; Adams, K.F., Jr; Cleland, J.G.; Ezekowitz, J.A.; Goudev, A.; Macdonald, P.; Metra, M.; Mitrovic, V.; Ponikowski, P.; Serpytis, P.; Spinar, J.; Tomcsányi, J.; Vandekerckhove, H.J.; Voors, A.A.; Monsalvo, M.L.; Johnston, J.; Malik, F.I.; Honarpour, N. COSMIC-HF Investigators. Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): A phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet,  2016, 388(10062), 2895-2903.
[http://dx.doi.org/10.1016/S0140-6736(16)32049-9] [PMID:  27914656] 
[226] 
Zsebo, K.; Yaroshinsky, A.; Rudy, J.J.; Wagner, K.; Greenberg, B.; Jessup, M.; Hajjar, R.J. Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: Analysis of recurrent cardiovascular events and mortality. Circ. Res.,  2014, 114(1), 101-108.
[http://dx.doi.org/10.1161/CIRCRESAHA.113.302421] [PMID:  24065463] 
[227] 
Jessup, M.; Greenberg, B.; Mancini, D.; Cappola, T.; Pauly, D.F.; Jaski, B.; Yaroshinsky, A.; Zsebo, K.M.; Dittrich, H.; Hajjar, R.J. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) Investigators. Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID): A phase 2 trial of intracoronary gene therapy of sarcoplasmic reticulum Ca2+-ATPase in patients with advanced heart failure. Circulation,  2011, 124(3), 304-313.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.111.022889] [PMID:  21709064] 
[228] 
Gao, R.; Zhang, J.; Cheng, L.; Wu, X.; Dong, W.; Yang, X.; Li, T.; Liu, X.; Xu, Y.; Li, X.; Zhou, M. A Phase II, randomized, double blind, multicenter, based on standard therapy, placebo-controlled study of the efficacy and safety of recombinant human neuregulin-1 in patients with chronic heart failure. J. Am. Coll. Cardiol.,  2010, 55(18), 1907-1914.
[http://dx.doi.org/10.1016/j.jacc.2009.12.044] [PMID:  20430261] 
[229] 
Gao, R.; Zhang, J.; Liu, H.; Wang, L.; Pang, X.; Fu, L.; Meng, F.; Zhou, M. A Phase III, randomized, double-blind, multicenter, placebo-controlled study of the efficacy and safety of Neucardin™ in patients with chronic heart failure. J. Am. Coll. Cardiol.,  2018, 71(11), 668.
[http://dx.doi.org/10.1016/S0735-1097(18)31209-9] 
[230] 
Sabbah, H.N.; Tocchetti, C.G.; Wang, M.; Daya, S.; Gupta, R.C.; Tunin, R.S.; Mazhari, R.; Takimoto, E.; Paolocci, N.; Cowart, D.; Colucci, W.S.; Kass, D.A. Nitroxyl (HNO): A novel approach for the acute treatment of heart failure. Circ Heart Fail,  2013, 6(6), 1250-1258.
[http://dx.doi.org/10.1161/CIRCHEARTFAILURE.113.000632] [PMID:  24107588] 
[231] 
Psotka, M.A.; Gottlieb, S.S.; Francis, G.S.; Allen, L.A.; Teerlink, J.R.; Adams, K.F., Jr; Rosano, G.M.C.; Lancellotti, P. Cardiac calcitropes, myotropes and mitotropes. J. Am. Coll. Cardiol.,  2019, 73(18), 2345-2353.
[http://dx.doi.org/10.1016/j.jacc.2019.02.051] [PMID:  31072579] 
[232] 
Vinge, L.E.; Raake, P.W.; Koch, W.J. Gene therapy in heart failure. Circ. Res.,  2008, 102(12), 1458-1470.
[http://dx.doi.org/10.1161/CIRCRESAHA.108.173195] [PMID:  18566312] 
[233] 
Doppler, S.A.; Deutsch, M.A.; Serpooshan, V.; Li, G.; Dzilic, E.; Lange, R.; Krane, M.; Wu, S.M. Mammalian heart regeneration: The race to the finish line. Circ. Res.,  2017, 120(4), 630-632.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.310051] [PMID:  28209796] 
[234] 
Kieserman, J.M.; Myers, V.D.; Dubey, P.; Cheung, J.Y.; Feldman, A.M. Current landscape of heart failure gene therapy. J. Am. Heart Assoc.,  2019, 8(10) e012239
[http://dx.doi.org/10.1161/JAHA.119.012239] [PMID:  31070089] 
[235] 
Segers, V.F.M.; Lee, R.T. Stem-cell therapy for cardiac disease. Nature,  2008, 451(7181), 937-942.
[http://dx.doi.org/10.1038/nature06800] [PMID:  18288183] 
[236] 
Sanganalmath, S.K.; Bolli, R. Cell therapy for heart failure: A comprehensive overview of experimental and clinical studies, current challenges, and future directions. Circ. Res.,  2013, 113(6), 810-834.
[http://dx.doi.org/10.1161/CIRCRESAHA.113.300219] [PMID:  23989721] 
[237] 
Chung, E.S.; Miller, L.; Patel, A.N.; Anderson, R.D.; Mendelsohn, F.O.; Traverse, J.; Silver, K.H.; Shin, J.; Ewald, G.; Farr, M.J.; Anwaruddin, S.; Plat, F.; Fisher, S.J.; AuWerter, A.T.; Pastore, J.M.; Aras, R.; Penn, M.S. Changes in ventricular remodelling and clinical status during the year following a single administration of stromal cell-derived factor-1 non-viral gene therapy in chronic ischaemic heart failure patients: The STOP-HF randomized Phase II trial. Eur. Heart J.,  2015, 36(33), 2228-2238.
[http://dx.doi.org/10.1093/eurheartj/ehv254] [PMID:  26056125] 
[238] 
Durrani, S.; Konoplyannikov, M.; Ashraf, M.; Haider, K.H. Skeletal myoblasts for cardiac repair. Regen. Med.,  2010, 5(6), 919-932.
[http://dx.doi.org/10.2217/rme.10.65] [PMID:  21082891] 
[239] 
Gan, L.M.; Lagerström-Fermér, M.; Carlsson, L.G.; Arfvidsson, C.; Egnell, A.C.; Rudvik, A.; Kjaer, M.; Collén, A.; Thompson, J.D.; Joyal, J.; Chialda, L.; Koernicke, T.; Fuhr, R.; Chien, K.R.; Fritsche-Danielson, R. Intradermal delivery of modified mRNA encoding VEGF-A in patients with type 2 diabetes. Nat. Commun.,  2019, 10(1), 871.
[http://dx.doi.org/10.1038/s41467-019-08852-4] [PMID:  30787295] 
[240] 
Patel, A.N.; Henry, T.D.; Quyyumi, A.A.; Schaer, G.L.; Anderson, R.D.; Toma, C.; East, C.; Remmers, A.E.; Goodrich, J.; Desai, A.S.; Recker, D.; DeMaria, A. ixCELL-DCM Investigators. Ixmyelocel-T for patients with ischaemic heart failure: A prospective randomised double-blind trial. Lancet,  2016, 387(10036), 2412-2421.
[http://dx.doi.org/10.1016/S0140-6736(16)30137-4] [PMID:  27059887] 
[241] 
Perin, E.C.; Borow, K.M.; Silva, G.V.; DeMaria, A.N.; Marroquin, O.C.; Huang, P.P.; Traverse, J.H.; Krum, H.; Skerrett, D.; Zheng, Y.; Willerson, J.T.; Itescu, S.; Henry, T.D.A.; Phase, II. Dose escalation study of allogeneic mesenchymal precursor cells in patients with ischemic or nonischemic heart failure. Circ. Res.,  2015, 117(6), 576-584.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.306332] [PMID:  26148930] 
[242] 
Borow, K.M.; Yaroshinsky, A.; Greenberg, B.; Perin, E.C. Phase 3 DREAM-HF trial of mesenchymal precursor cells in chronic heart failure. Circ. Res.,  2019, 125(3), 265-281.
[http://dx.doi.org/10.1161/CIRCRESAHA.119.314951] [PMID:  31318648] 
[243] 
Bolli, R.; Chugh, A.R.; D’Amario, D.; Loughran, J.H.; Stoddard, M.F.; Ikram, S.; Beache, G.M.; Wagner, S.G.; Leri, A.; Hosoda, T.; Sanada, F.; Elmore, J.B.; Goichberg, P.; Cappetta, D.; Solankhi, N.K.; Fahsah, I.; Rokosh, D.G.; Slaughter, M.S.; Kajstura, J.; Anversa, P. Cardiac Stem Cells in Patients with Ischaemic Cardiomyopathy (SCIPIO): Initial results of a randomised phase 1 trial. Lancet,  2011, 378(9806), 1847-1857.
[http://dx.doi.org/10.1016/S0140-6736(11)61590-0] [PMID:  22088800] 
[244] 
Ishigami, S.; Ohtsuki, S.; Eitoku, T.; Ousaka, D.; Kondo, M.; Kurita, Y.; Hirai, K.; Fukushima, Y.; Baba, K.; Goto, T.; Horio, N.; Kobayashi, J.; Kuroko, Y.; Kotani, Y.; Arai, S.; Iwasaki, T.; Sato, S.; Kasahara, S.; Sano, S.; Oh, H. Intracoronary cardiac progenitor cells in single ventricle physiology: The PERSEUS (Cardiac Progenitor Cell Infusion to Treat Univentricular Heart Disease) Randomized Phase 2 Trial. Circ. Res.,  2017, 120(7), 1162-1173.
[http://dx.doi.org/10.1161/CIRCRESAHA.116.310253] [PMID:  28052915] 
[245] 
Louch, W.E.; Sheehan, K.A.; Wolska, B.M. Methods in cardiomyocyte isolation, culture, and gene transfer. J. Mol. Cell. Cardiol.,  2011, 51(3), 288-298.
[http://dx.doi.org/10.1016/j.yjmcc.2011.06.012] [PMID:  21723873] 
[246] 
Ambrosi, C.M.; Sadananda, G.; Han, J.L.; Entcheva, E. Adeno associated virus mediated gene delivery: Implications for scalable in vitro and in vivo cardiac optogenetic models. Front. Physiol.,  2019, 10, 168.
[http://dx.doi.org/10.3389/fphys.2019.00168] [PMID:  30890951] 
[247] 
Kang, C.; Qiao, Y.; Li, G.; Baechle, K.; Camelliti, P.; Rentschler, S.; Efimov, I.R. Human organotypic cultured cardiac slices: New platform for high throughput preclinical human trials. Sci. Rep.,  2016, 6, 28798.
[http://dx.doi.org/10.1038/srep28798] [PMID:  27356882] 
[248] 
Aratyn-Schaus, Y.; Pasqualini, F.S.; Yuan, H.; McCain, M.L.; Ye, G.J.; Sheehy, S.P.; Campbell, P.H.; Parker, K.K. Coupling primary and stem cell-derived cardiomyocytes in an in vitro model of cardiac cell therapy. J. Cell Biol.,  2016, 212(4), 389-397.
[http://dx.doi.org/10.1083/jcb.201508026] [PMID:  26858266] 
[249] 
Ravenscroft, S.M.; Pointon, A.; Williams, A.W.; Cross, M.J.; Sidaway, J.E. Cardiac non-myocyte cells show enhanced pharmacological function suggestive of contractile maturity in stem cell Derived cardiomyocyte microtissues. Toxicol. Sci.,  2016, 152(1), 99-112.
[http://dx.doi.org/10.1093/toxsci/kfw069] [PMID:  27125969] 
[250] 
Archer, C.R.; Sargeant, R.; Basak, J.; Pilling, J.; Barnes, J.R.; Pointon, A. Characterization and validation of a human 3D cardiac microtissue for the assessment of changes in cardiac pathology. Sci. Rep.,  2018, 8(1), 10160.
[http://dx.doi.org/10.1038/s41598-018-28393-y] [PMID:  29976997] 
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DOI https://dx.doi.org/10.2174/1389201021666191210142023	Print ISSN 1389-2010
Publisher Name Bentham Science Publisher	Online ISSN 1873-4316
Current Pharmaceutical Biotechnology

Human Heart Cardiomyocytes in Drug Discovery and Research: New Opportunities in Translational Sciences

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