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Identification and characterization of a ouabain-like compound from human plasma. <i>Proc Natl Acad Sci USA<\/i> 1991; 88: 6259\u20136263.","DOI":"10.1073\/pnas.88.14.6259"},{"key":"2","doi-asserted-by":"crossref","unstructured":"2. Altamirano J, Li Y, DeSantiago J, Piacentino V 3rd, Houser SR, Bers DM. The inotropic effect of cardioactive glycosides in ventricular myocytes requires Na+-Ca2+ exchanger function. <i>J Physiol<\/i> 2006; 575: 845\u2013854.","DOI":"10.1113\/jphysiol.2006.111252"},{"key":"3","doi-asserted-by":"crossref","unstructured":"3. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. <i>JAMA<\/i> 2003; 289: 871\u2013878.","DOI":"10.1001\/jama.289.7.871"},{"key":"4","doi-asserted-by":"crossref","unstructured":"4. Ferrier GR. Digitalis arrhythmias: Role of oscillatory afterpotentials. <i>Prog Cardiovasc Dis<\/i> 1977; 19: 459\u2013474.","DOI":"10.1016\/0033-0620(77)90010-X"},{"key":"5","doi-asserted-by":"crossref","unstructured":"5. Gonano LA, Sepulveda M, Rico Y, Kaetzel M, Valverde CA, Dedman J, et al. Calcium-calmodulin kinase II mediates digitalis-induced arrhythmias. <i>Circ Arrhythm Electrophysiol<\/i> 2011; 4: 947\u2013957.","DOI":"10.1161\/CIRCEP.111.964908"},{"key":"6","doi-asserted-by":"crossref","unstructured":"6. Sapia L, Palomeque J, Mattiazzi A, Petroff MV. Na+\/K+-ATPase inhibition by ouabain induces CaMKII-dependent apoptosis in adult rat cardiac myocytes. <i>J Mol Cell Cardiol<\/i> 2010; 49: 459\u2013468.","DOI":"10.1016\/j.yjmcc.2010.04.013"},{"key":"7","doi-asserted-by":"crossref","unstructured":"7. Ramirez-Ortega M, Zarco G, Maldonado V, Carrillo JF, Ramos P, Ceballos G, et al. Is digitalis compound-induced cardiotoxicity, mediated through guinea-pig cardiomyocytes apoptosis? <i>Eur J Pharmacol<\/i> 2007; 566: 34\u201342.","DOI":"10.1016\/j.ejphar.2007.03.033"},{"key":"8","doi-asserted-by":"crossref","unstructured":"8. Jiang D, Xiao B, Yang D, Wang R, Choi P, Zhang L, et al. RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR). <i>Proc Natl Acad Sci USA<\/i> 2004; 101: 13062\u201313067.","DOI":"10.1073\/pnas.0402388101"},{"key":"9","doi-asserted-by":"crossref","unstructured":"9. Sepulveda M, Gonano LA, Back TG, Chen SR, Vila Petroff M. Role of CaMKII and ROS in rapid pacing-induced apoptosis. <i>J Mol Cell Cardiol<\/i> 2013; 63: 135\u2013145.","DOI":"10.1016\/j.yjmcc.2013.07.013"},{"key":"10","doi-asserted-by":"crossref","unstructured":"10. Koval OM, Guan X, Wu Y, Joiner ML, Gao Z, Chen B, et al. CaV1.2 beta-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations. <i>Proc Natl Acad Sci USA<\/i> 2010; 107: 4996\u20135000.","DOI":"10.1073\/pnas.0913760107"},{"key":"11","doi-asserted-by":"crossref","unstructured":"11. Di Carlo MN, Said M, Ling H, Valverde CA, De Giusti VC, Sommese L, et al. CaMKII-dependent phosphorylation of cardiac ryanodine receptors regulates cell death in cardiac ischemia\/reperfusion injury. <i>J Mol Cell Cardiol<\/i> 2014; 74: 274\u2013283.","DOI":"10.1016\/j.yjmcc.2014.06.004"},{"key":"12","doi-asserted-by":"crossref","unstructured":"12. Ruiz-Meana M, Fernandez-Sanz C, Garcia-Dorado D. The SR-mitochondria interaction: A new player in cardiac pathophysiology. <i>Cardiovasc Res<\/i> 2010; 88: 30\u201339.","DOI":"10.1093\/cvr\/cvq225"},{"key":"13","doi-asserted-by":"crossref","unstructured":"13. Priori SG, Chen SR. Inherited dysfunction of sarcoplasmic reticulum Ca2+ handling and arrhythmogenesis. <i>Circ Res<\/i> 2011; 108: 871\u2013883.","DOI":"10.1161\/CIRCRESAHA.110.226845"},{"key":"14","doi-asserted-by":"crossref","unstructured":"14. Ho HT, Liu B, Snyder JS, Lou Q, Brundage EA, Velez-Cortes F, et al. Ryanodine receptor phosphorylation by oxidized CaMKII contributes to the cardiotoxic effects of cardiac glycosides. <i>Cardiovasc Res<\/i> 2014; 101: 165\u2013174.","DOI":"10.1093\/cvr\/cvt233"},{"key":"15","doi-asserted-by":"crossref","unstructured":"15. Hwang HS, Hasdemir C, Laver D, Mehra D, Turhan K, Faggioni M, et al. Inhibition of cardiac Ca2+ release channels (RyR2) determines efficacy of class I antiarrhythmic drugs in catecholaminergic polymorphic ventricular tachycardia. <i>Circ Arrhythm Electrophysiol<\/i> 2011; 4: 128\u2013135.","DOI":"10.1161\/CIRCEP.110.959916"},{"key":"16","doi-asserted-by":"crossref","unstructured":"16. Zhou Q, Xiao J, Jiang D, Wang R, Vembaiyan K, Wang A, et al. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. <i>Nat Med<\/i> 2011; 17: 1003\u20131009.","DOI":"10.1038\/nm.2406"},{"key":"17","doi-asserted-by":"crossref","unstructured":"17. Wehrens XH, Lehnart SE, Reiken SR, Deng SX, Vest JA, Cervantes D, et al. Protection from cardiac arrhythmia through ryanodine receptor-stabilizing protein calstabin2. <i>Science<\/i> 2004; 304: 292\u2013296.","DOI":"10.1126\/science.1094301"},{"key":"18","unstructured":"18. Greenberg B. Nonselective versus selective beta-blockers in the management of chronic heart failure: Clinical implications of the carvedilol or Metoprolol European Trial. <i>Rev Cardiovasc Med<\/i> 2004; 5(Suppl 1): S10\u2013S17."},{"key":"19","unstructured":"19. Stroe AF, Gheorghiade M. Carvedilol: Beta-blockade and beyond. <i>Rev Cardiovasc Med<\/i> 2004; 5(Suppl 1): S18\u2013S27."},{"key":"20","doi-asserted-by":"crossref","unstructured":"20. Remme WJ. Which beta-blocker is most effective in heart failure? <i>Cardiovasc Drugs Ther<\/i> 2010; 24: 351\u2013358.","DOI":"10.1007\/s10557-010-6247-7"},{"key":"21","doi-asserted-by":"crossref","unstructured":"21. Vila-Petroff M, Salas MA, Said M, Valverde CA, Sapia L, Portiansky E, et al. CaMKII inhibition protects against necrosis and apoptosis in irreversible ischemia-reperfusion injury. <i>Cardiovasc Res<\/i> 2007; 73: 689\u2013698.","DOI":"10.1016\/j.cardiores.2006.12.003"},{"key":"22","doi-asserted-by":"crossref","unstructured":"22. Picht E, Zima AV, Blatter LA, Bers DM. SparkMaster: Automated calcium spark analysis with ImageJ. <i>Am J Physiol Cell Physiol<\/i> 2007; 293: C1073\u2013C1081.","DOI":"10.1152\/ajpcell.00586.2006"},{"key":"23","doi-asserted-by":"crossref","unstructured":"23. Burridge PW, Matsa E, Shukla P, Lin ZC, Churko JM, Ebert AD, et al. Chemically defined generation of human cardiomyocytes. <i>Nat Methods<\/i> 2014; 11: 855\u2013860.","DOI":"10.1038\/nmeth.2999"},{"key":"24","doi-asserted-by":"crossref","unstructured":"24. Questa M, Romorini L, Bluguermann C, Solari CM, Neiman G, Luzzani C, et al. Generation of iPSC line iPSC-FH2.1 in hypoxic conditions from human foreskin fibroblasts. <i>Stem Cell Res<\/i> 2016; 16: 300\u2013303.","DOI":"10.1016\/j.scr.2015.12.026"},{"key":"25","doi-asserted-by":"crossref","unstructured":"25. ten Tusscher KH, Panfilov AV. Alternans and spiral breakup in a human ventricular tissue model. <i>Am J Physiol Heart Circ Physiol<\/i> 2006; 291: H1088\u2013H1100.","DOI":"10.1152\/ajpheart.00109.2006"},{"key":"26","doi-asserted-by":"crossref","unstructured":"26. Mazzocchi G, Sommese L, Palomeque J, Felice JI, Di Carlo MN, Fainstein D, et al. Phospholamban ablation rescues the enhanced propensity to arrhythmias of mice with CaMKII-constitutive phosphorylation of RyR2 at site S2814. <i>J Physiol<\/i> 2016; 594: 3005\u20133030.","DOI":"10.1113\/JP271622"},{"key":"27","doi-asserted-by":"crossref","unstructured":"27. Davis J, Davis LC, Correll RN, Makarewich CA, Schwanekamp JA, Moussavi-Harami F, et al. A tension-based model distinguishes hypertrophic versus dilated cardiomyopathy. <i>Cell<\/i> 2016; 165: 1147\u20131159.","DOI":"10.1016\/j.cell.2016.04.002"},{"key":"28","doi-asserted-by":"crossref","unstructured":"28. Lotan CS, Miller SK, Pohost GM, Elgavish GA. Amiloride in ouabain-induced acidification, inotropy and arrhythmia: 23Na &amp; 31P NMR in perfused hearts. <i>J Mol Cell Cardiol<\/i> 1992; 24: 243\u2013257.","DOI":"10.1016\/0022-2828(92)93162-D"},{"key":"29","doi-asserted-by":"crossref","unstructured":"29. Satoh H, Ginsburg KS, Qing K, Terada H, Hayashi H, Bers DM. KB-R7943 block of Ca(2+) influx via Na(+)\/Ca(2+) exchange does not alter twitches or glycoside inotropy but prevents Ca(2+) overload in rat ventricular myocytes. <i>Circulation<\/i> 2000; 101: 1441\u20131446.","DOI":"10.1161\/01.CIR.101.12.1441"},{"key":"30","doi-asserted-by":"crossref","unstructured":"30. Chen X, Zhang X, Kubo H, Harris DM, Mills GD, Moyer J, et al. Ca2+ influx-induced sarcoplasmic reticulum Ca2+ overload causes mitochondrial-dependent apoptosis in ventricular myocytes. <i>Circ Res<\/i> 2005; 97: 1009\u20131017.","DOI":"10.1161\/01.RES.0000189270.72915.D1"},{"key":"31","doi-asserted-by":"crossref","unstructured":"31. Pogwizd SM, Bers DM. Cellular basis of triggered arrhythmias in heart failure. <i>Trends Cardiovasc Med<\/i> 2004; 14: 61\u201366.","DOI":"10.1016\/j.tcm.2003.12.002"},{"key":"32","doi-asserted-by":"crossref","unstructured":"32. Sacherer M, Sedej S, Wakula P, Wallner M, Vos MA, Kockskamper J, et al. JTV519 (K201) reduces sarcoplasmic reticulum Ca(2)(+) leak and improves diastolic function in vitro in murine and human non-failing myocardium. <i>Br J Pharmacol<\/i> 2012; 167: 493\u2013504.","DOI":"10.1111\/j.1476-5381.2012.01995.x"},{"key":"33","doi-asserted-by":"crossref","unstructured":"33. Gonano LA, Petroff MV. Subcellular mechanisms underlying digitalis-induced arrhythmias: Role of calcium\/calmodulin-dependent kinase II (CaMKII) in the transition from an inotropic to an arrhythmogenic effect. <i>Heart Lung Circ<\/i> 2014; 23: 1118\u20131124.","DOI":"10.1016\/j.hlc.2014.07.074"},{"key":"34","doi-asserted-by":"crossref","unstructured":"34. Mochizuki M, Yano M, Oda T, Tateishi H, Kobayashi S, Yamamoto T, et al. Scavenging free radicals by low-dose carvedilol prevents redox-dependent Ca2+ leak via stabilization of ryanodine receptor in heart failure. <i>J Am Coll Cardiol<\/i> 2007; 49: 1722\u20131732.","DOI":"10.1016\/j.jacc.2007.01.064"},{"key":"35","doi-asserted-by":"crossref","unstructured":"35. Swietach P, Spitzer KW, Vaughan-Jones RD. Modeling calcium waves in cardiac myocytes: Importance of calcium diffusion. <i>Front Biosci (Landmark Ed)<\/i> 2010; 15: 661\u2013680.","DOI":"10.2741\/3639"},{"key":"36","doi-asserted-by":"crossref","unstructured":"36. Braam SR, Tertoolen L, van de Stolpe A, Meyer T, Passier R, Mummery CL. Prediction of drug-induced cardiotoxicity using human embryonic stem cell-derived cardiomyocytes. <i>Stem Cell Res<\/i> 2010; 4: 107\u2013116.","DOI":"10.1016\/j.scr.2009.11.004"},{"key":"37","doi-asserted-by":"crossref","unstructured":"37. Kattman SJ, Witty AD, Gagliardi M, Dubois NC, Niapour M, Hotta A, et al. 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