Arrhythmic risk biomarkers for the assessment of drug cardiotoxicity: From experiments to computer simulations

Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences

Volumn 368, Issue 1921, 2010, Pages 3001-3025

  Corrias, A ^a   Jie, X ^a   Romero, L ^b   Bishop, M J ^a   Bernabeu, M ^a   Pueyo, E ^a,c   Rodriguez, B ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITAT POLITÈCNICA DE VALÈNCIA   (Spain)

^c UNIVERSITY OF ZARAGOZA   (Spain)

Author keywords

Biomarkers; Cardiac electrophysiology; Electrocardiogram; Modelling

Indexed keywords

ANIMALS; ELECTROPHYSIOLOGY; HEART; NEUROLOGY;

ANIMAL SPECIES; CARDIAC ELECTROPHYSIOLOGY; CARDIOTOXICITY; COMPUTATIONAL MODELLING; DRUG SAFETY; EXPERIMENTAL TECHNIQUES; ION CHANNEL; LITERATURE REVIEWS; MULTISCALES; OPEN SOURCES;

COMPUTER SIMULATION;

BIOLOGICAL MARKER;

ANIMAL; BIOLOGICAL MODEL; CHEMICALLY INDUCED DISORDER; COMPUTER SIMULATION; DRUG TOXICITY; HEART ARRHYTHMIA; HUMAN; METABOLISM; REVIEW; RISK;

ANIMALS; ARRHYTHMIAS, CARDIAC; BIOLOGICAL MARKERS; COMPUTER SIMULATION; DRUG TOXICITY; HUMANS; MODELS, BIOLOGICAL; RISK;

EID: 77953806557     PISSN: 1364503X     EISSN: None     Source Type: Journal    
DOI: 10.1098/rsta.2010.0083     Document Type: Article

References (118)

1. Ajiro, Y., Hagiwara, N. & Kasanuki, H. 2005 Assessment of markers for identifying patients at risk for life-threatening arrhythmic events in Brugada syndrome. J. Cardiovasc. Electrophysiol. 16, 45-51. (doi:10.1046/j.1540-8167. 2005.04313.x (Pubitemid 40165450)
2. An, R. H., Bangalore, R., Rosero, S. Z. & Kass, R. S. 1996 Lidocaine block of LQT-3 mutant human NA+ channels. Circ. Res. 79, 103-108.
3. Andersen, M. P., Xue, J. Q., Graff, C., Hardahl, T., Toft, E., Kanters, J. K., Christiansen, M., Jensen, H. K. & Struijk, J. J. 2007 A robust method for quantification of IKr-related T-wave morphology abnormalities. Comput. Cardiol. 34, 341-344. (doi:10.1109/CIC.2007.47454910
4. Anderson, K. P., Walker, R., Lux, R. L., Ershler, P. R., Menlove, R., Williams, M. R., Krall, R. & Moddrelle, D. 1990 Conduction velocity depression and drug-induced ventricular tachyarrhythmias. Effects of lidocaine in the intact canine heart. Circulation 81, 1024-1038.
5. Antzelevitch, C., Sicouri, S., Di Diego, J. M., Burashnikov, A., Viskin, S., Shimizu, W., Yan, G. X., Kowey, P. & Zhang, L. 2007 Does Tpeak - Tend provide an index of transmural dispersion of repolarisation? Heart Rhythm 4, 1114-1116. (doi:10.1016/j.hrthm.2007.05.028) (Pubitemid 47163756)
6. Baher, A., Qu, Z., Hayatdavoudi, A., Lamp, S. T., Yang, M. J., Xie, F., Turner, S., Garfinkel, A. & Weiss, J. N. 2007 Short-term cardiac memory and mother rotor fibrillation. Am. J. Physiol. Heart Circ. Physiol. 292, H180-H189. (doi:10.1152/ajpheart.00944.2005) Bauer, A. et al. 1999 Rate- and site-dependent effects of propafenone, dofetilide, and the new I(Ks)-blocking agent chromanol 293b on individual muscle layers of the intact canine heart. Circulation 100, 2184-2190.
7. Bean, B. P., Cohen, C. J. & Tsien, R. W. 1983 Lidocaine block of cardiac sodium channels. J. Gen. Physiol. 81, 613-642. (doi:10.1085/jgp.81.5. 613)
8. Benatar, A., Cools, F., Decraene, T., Bougatef, A. & Vandenplas, Y. 2002 The T wave as a marker of dispersion of ventricular repolarisation in premature infants before and while on treatment with the I(KR) channel blocker cisapride. Cardiol. Young 12, 32-36. (doi:10.1017/S1047951102000069) (Pubitemid 41238745)
9. Berger, R. D., Kasper, E. K., Baughman, K. L., Marban, E., Calkins, H. & Tomaselli, G. F. 1997 Beat-to-beat QT interval variability: novel evidence for repolarisation lability in ischemic and nonischemic dilated cardiomyopathy. Circulation 96, 1557-1565.
10. Bernabeu, M. O. et al. 2009 Grid computing simulations of ion channel block effects on the ECG using 3D anatomically-based models. Comput. Cardiol. 36, 213-216.
11. Bishop, M. J., Plank, G., Burton, R. A., Scheider, J. E., Gavaghan, D. J., Grau, V. & Kohl, P. 2010 Development of an anatomically detailed MRI-derived rabbit ventricular model and assessment of its impact on simulations of electrophysiological function. Am. J. Physiol. Heart Circ. Physiol. 298, H699-H718.
12. Bloomfield, D. M., Hohnloser, S. H. & Cohen, R. J. 2002 Interpretation and classification of microvolt T wave alternans tests. J. Cardiovasc. Electrophysiol. 13, 502-512. (doi:10.1046/ j. 1540-8167.2002.00502.x
13. Bnsz, T. et al. 2009 Reverse rate dependency is an intrinsic property of canine cardiac preparations. Cardiovasc. Res. 84, 237-244.
14. Bodi, I., Mikala, G., Koch, S. E., Akhter, S. A. & Schwartz, A. 2005 The L-type calcium channel in the heart: the beat goes on. J. Clin. Invest. 115, 3306-3317. (doi:10.1172/JCI27167) (Pubitemid 43121813)
15. Bradley, C. P., Pullan, A. J. & Hunter, P. J. 2000 Effects of material properties and geometry on electrocardiographic forward simulations. Ann. Biomed. Eng. 28, 721-741. (doi:10.1114/1.1289467)
16. Busch, A. E., Busch, G. L., Ford, E., Suessbrich, H., Lang, H. J., Greger, R., Kunzelmann, K., Attali, B. & Stuhmer, W. 1997 The role of the IsK protein in the specific pharmacological properties of the IKs channel complex. Br. J. Pharmacol. 122, 187-189. (doi:10.1038/sj.bjp.0701434) (Pubitemid 27397187)
17. Busse, D., Templin, S., Mikus, G., Schwab, M., Hofmann, U., Eichelbaum, M. & Kivist, K. T. 2006 Cardiovascular effects of (R)- and (S)-verapamil and racemic verapamil in humans: a placebo-controlled study. Eur. J. Clin. Pharmacol. 62, 613-619. (doi:10.1007/s00228-006-0154-7) (Pubitemid 44127989)
18. Campbell, T. J. 1983 Kinetics of onset of rate-dependent effects of class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc. Res. 17, 344-352. (doi:10.1093/ cvr/17.6.344)
19. Carlsson, L., Amos, G. J., Andersson, B., Drews, L., Duker, G. & Wadstedt, G. 1997 Electrophysiological characterization of the prokinetic agents cisapride and mosapride in vivo and in vitro: implications for proarrhythmic potential? J. Pharmacol. Exp. Ther. 282, 220-227.
20. Chen, S. et al. 2003 KCNQ1 mutations in patients with a family history of lethal cardiac arrhythmias and sudden death. Clin. Genet. 63, 273-282. (doi:10.1034/j. 1399-0004.2003.00048.x
21. Cheng, J. H. & Kodama, I. 2004 Two components of delayed rectifier K+ current in heart: molecular basis, functional diversity, and contribution to repolarisation. Acta Pharmacol. Sin. 25, 137-145.
22. Cordes, J. S., Sun, Z., Lloyd, D. B., Bradley, J. A., Opsahl, A. C., Tengowski, M. W., Chen, X. & Zhou, J. 2005 Pentamidine reduces hERG expression to prolong the QT interval. Br. J. Pharmacol. 145, 15-23. (doi:10.1038/sj.bjp.0706140) (Pubitemid 40675544)
23. Couderc, J. P., Zareba, W., Moss, A. J., Sarapa, N., Morganroth, J. & Darpo, B. 2003 Identification of sotalol-induced changes in repolarisation with T wave area-based repolarisation duration parameters. J. Electrocardiol. 36, 115-120. (doi:10.1016/j.jelectrocard.2003.09.034) (Pubitemid 38049771)
24. Couderc, J. P., Vaglio, M., Xia, X., McNitt, S. & Hyrien, O. 2006 Electrocardiographic method for identifying drug-induced repolarisation abnormalities associated with a reduction of the rapidly activating delayed rectifier potassium current. Conf. Proc. IEEE Eng. Med. Biol. Soc. 1, 4010-4015.
25. Couderc, J. P., Zhou, M., Sarapa, N. & Zareba, W. 2008 Investigating the effect of sotalol on the repolarisation intervals in healthy young individuals. J. Electrocardiol. 41, 595-602. (doi:10.1016/j.jelectrocard.2008. 06.013)
26. Della Paschoa, O. E., Luckow, V., Trenk, D., Jahnchen, E. & Santos, S. R. 1995 Prolongation of the PQ interval as a measure of therapeutic inequivalence between two formulations of diltiazem. Eur. J. Clin. Pharmacol. 48, 45-49. (doi:10.1007/BF00202171)
27. Duan, J. J., Ma, J. H., Zhang, J. H., Wang, J. H., Zou, J. H. & Tu, D. N. 2007 Verapamil blocks HERG channel by the helix residue Y652 and F656 in the S6 transmembrane domain. Acta Pharmacol. Sin. 28, 959-967. (doi:10.1111/j. 1745-7254.2007.00562.x
28. Faber, G. M. & Rudy, Y. 2000 Action potential and contractility changes in [Na(+)](i) overloaded cardiac myocytes: a simulation study. Biophys. J. 78, 2392-2404. (doi:10.1016/S0006-3495(00) 76783-X
29. Fossa, A. A. et al. 2007 Analyses of dynamic beat-to-beat QT-TQ interval (ECG restitution) changes in humans under normal sinus rhythm and prior to an event of torsades de pointes during QT prolongation caused by sotalol. Ann. Noninvasive Electrocardiol. 12, 338-348. (doi:10.1111/j.1542-474X.2007.00183.x (Pubitemid 350013256)
30. Gallacher, D. J., Van de Water, A., van der Linde, H., Hermans, A. N., Lu, H. R., Towart, R. & Volders, P. G. 2007 In vivo mechanisms precipitating torsades de pointes in a canine model of drug-induced long-QT1 syndrome. Cardiovasc. Res. 76, 247-256. (doi:10.1016/j.cardiores. 2007.06.019)
31. Gbadebo, T. D., Trimble, R. W., Khoo, M. S., Temple, J., Roden, D. M. & Anderson, M. E. 2002 Calmodulin inhibitor W-7 unmasks a novel electrocardiographic parameter that predicts initiation of torsade de pointes. Circulation 105, 770-774. (doi:10.1161/hc0602.103724) (Pubitemid 34157384)
32. Gerlach, U. 2003 Blockers of the slowly delayed rectifier potassium IKs channel: potential antiarrhythmic agents. Curr. Med. Chem. Cardiovasc. Hematol. Agents 1, 243-252. (doi:10.2174/1568016033477469)
33. Gima, K. & Rudy, Y. 2002 Ionic current basis of electrocardiographic waveforms: a model study. Circ. Res. 90, 889-896. (doi:10.1161/01.RES. 0000016960.61087.86) (Pubitemid 34633881)
34. Gintant, G. A., Su, Z., Martin, R. L. & Cox, B. F. 2006 Utility of hERG assays as surrogate markers of delayed cardiac repolarisation and QT safety. Toxicol. Pathol. 34, 81-90. (doi:10.1080/01926230500431376) (Pubitemid 43323264)
35. Graff, C., Matz, J., Andersen, M. P., Kanters, J., Toft, E., Pehrson, S. & Struijk, J. J. 2008 Sensitivity of QTc and T-wave morphology to small drug-induced electrocardiographic changes. Comput. Cardiol. 35, 319-322.
36. Hanck, D. A., Makielski, J. C. & Sheets, M. F. 2000 Lidocaine alters activation gating of cardiac Na channels. Pflugers Arch. 439, 814-821. (doi:10.1007/s004240051009) (Pubitemid 30191157)
37. Heng, M. K., Singh, B. N., Roche, A. H., Norris, R. M. & Mercer, C. J. 1975 Effects of intravenous verapamil on cardiac arrhythmias and on the electrocardiogram. Am. Heart J. 90, 487-498. (doi:10.1016/0002-8703(75)90431-7)
38. Herzberg, I. M., Trudeau, M. C. & Robertson, G. A. 1998 Transfer of rapid inactivation and sensitivity to the class III antiarrhythmic drug E-4031 from HERG to M-eag channels. J. Physiol. 511(Pt 1), 3-14. (doi:10.1111/j. 1469-7793.1998.003bi.x
39. Hockerman, G. H., Peterson, B. Z., Johnson, B. D. & Catterall, W. A. 1997 Molecular determinants of drug binding and action on L-type calcium channels. Annu. Rev. Pharmacol. Toxicol. 37, 361-396. (doi:10.1146/annurev. pharmtox.37.1.361)
40. Hondeghem, L. M. 2006 Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T-wave, incriminates safe drugs, and misses profibrillatory drugs. J. Cardiovasc. Electrophysiol. 17, 337-340. (doi:10.1111/j.1540-8167.2006.00347.x (Pubitemid 43344952)
41. Hondeghem, L. M. & Snyders, D. J. 1990 Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 81, 686-690.
42. Houltz, B., Darpo, B., Swedberg, K., Blomstrom, P., Brachmann, J., Crijns, H. J., Jensen, S. M., Svernhage, E., Vallin, H. & Edvardsson, N. 1999 Effects of the IKr-blocker almokalant and predictors of conversion of chronic atrial tachyarrhythmias to sinus rhythm. A prospective study. Cardiovasc. Drugs Ther. 13, 329-338. (doi:10.1023/A:1007759500274) (Pubitemid 29427991)
43. Ikeda, T., Takami, M., Sugi, K., Mizusawa, Y., Sakurada, H. & Yoshino, H. 2005 Noninvasive risk stratification of subjects with a Brugada-type electrocardiogram and no history of cardiac arrest. Ann. Noninvasive Electrocardiol. 10, 396-403. (doi:10.1111/j.1542-474X.2005.00055.x (Pubitemid 43942697)
44. January, C. T. & Riddle, J. M. 1989 Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ. Res. 64, 977-990.
45. Jost, N. et al. 2005 Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle. Circulation 112, 1392-1399. (doi:10.1161/CIRCULATIONAHA.105.550111) (Pubitemid 41291763)
46. Junttila, M. J. et al. 2008 Induced Brugada-type electrocardiogram, a sign for imminent malignant arrhythmias. Circulation 117, 1890-1893. (doi:10.1161/CIRCULATIONAHA.107.746495) (Pubitemid 351507478)
47. Kohlhardt, M., Bauer, B., Krause, H. & Fleckenstein, A. 1972 Differentiation of the transmembrane Na and Ca channels in mammalian cardiac fibres by the use of specific inhibitors. Pflugers Arch. 335, 309-322. (doi:10.1007/BF00586221)
48. Kroll, C. R. & Gettes, L. S. 2002 T wave alternans and torsades de pointes after the use of intravenous pentamidine. J. Cardiovasc. Electrophysiol. 13, 936-938. (doi:10.1046/j.1540-8167.2002.00936.x
49. Lande, G., Maison-Blanche, P., Fayn, J., Ghadanfar, M., Coumel, P. & Funck-Brentano, C. 1998 Dynamic analysis of dofetilide-induced changes in ventricular repolarisation. Clin. Pharmacol. Ther. 64, 312-321. (doi:10.1016/S0009-9236(98)90180-1) (Pubitemid 28462292)
50. Lengyel, C., Iost, N., Virag, L., Varro, A., Lathrop, D. A. & Papp, J. G. 2001 Pharmacological block of the slow component of the outward delayed rectifier current (I(Ks)) fails to lengthen rabbit ventricular muscle QT(c) and action potential duration. Br. J. Pharmacol. 132, 101-110.(doi:10.1038/sj.bjp. 0703777)
51. Liu, H., Tateyama, M., Clancy, C. E., Abriel, H. & Kass, R. S. 2002 Channel openings are necessary but not sufficient for use-dependent block of cardiac Na(+) channels by flecainide: evidence from the analysis of disease-linked mutations. J. Gen. Physiol. 120, 39-51. (doi:10.1085/jgp. 20028558) (Pubitemid 34755775)
52. Liu, H., Atkins, J. & Kass, R. S. 2003 Common molecular determinants of flecainide and lidocaine block of heart NA+ channels: evidence from experiments with neutral and quaternary flecainide analogues. J. Gen. Physiol. 121, 199-214. (doi:10.1085/jgp.20028723) (Pubitemid 36292990)
53. Liu, T., Brown, B. S., Wu, Y., Antzelevitch, C., Kowey, P. R. & Yan, G. X. 2006 Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias. Heart Rhythm 3, 948-956. (doi:10.1016/j.hrthm.2006.04.021) (Pubitemid 44103507)
54. Lloyd, C. M., Halstead, M. D. & Nielsen, P. F. 2004 CellML: its future, present and past. Prog. Biophys. Mol. Biol. 85, 433-450. (doi:10.1016/j.pbiomolbio.2004.01.004) (Pubitemid 38629921)
55. Lynch Jr, J. J. et al. 1999 Antiarrhythmic efficacy of selective blockade of the cardiac slowly activating delayed rectifier current, I(Ks), in canine models of malignant ischemic ventricular arrhythmia. Circulation 100, 1917-1922.
56. MacNeil, D. J. 1997 The side effect profile of class III antiarrhythmic drugs: focus on d,l-sotalol. Am. J. Cardiol. 80, 90G-98G. (doi:10.1016/S0002- 9149(97)00718-2)
57. Mahajan, A. et al. 2008 A rabbit ventricular action potential model replicating cardiac dynamics at rapid heart rates. Biophys. J. 94, 392-410. (doi:10.1529/biophysj.106.98160)
58. McDonald, T. F., Pelzer, D. & Trautwein, W. 1984 Cat ventricular muscle treated with D 600: characteristics of calcium channel block and unblock. J. Physiol. 352, 217-241.
59. McIntosh, M. A., Cobbe, S. M. & Smith, G. L. 2000 Heterogeneous changes in action potential and intracellular Ca2+ in left ventricular myocyte sub-types from rabbits with heart failure. Cardiovasc. Res. 45, 397-409. (doi:10.1016/S0008-6363(99)00360-0 (Pubitemid 30069505)
60. Milberg, P., Reinsch, N., Wasmer, K., Monnig, G., Stypmann, J., Osada, N., Breithardt, G., Haverkamp, W. & Eckardt, L. 2005 Transmural dispersion of repolarisation as a key factor of arrhythmogenicity in a novel intact heart model of LQT3. Cardiovasc. Res. 65, 397-404. (doi:10.1016/j.cardiores.2004.10. 016) (Pubitemid 40082481)
61. Moller, M. 1996 DIAMOND antiarrhythmic trials. Danish Investigations of Arrhythmia and Mortality on Dofetilide. Lancet 348, 1597-1598.
62. Morita, H. et al. 2003 Ventricular arrhythmia induced by sodium channel blocker in patients with Brugada syndrome. J. Am. Coll. Cardiol. 42, 1624-1631. (doi:10.1016/j.jacc.2003.06.004) (Pubitemid 37378444)
63. Noble, D. 1960 Cardiac action and pacemaker potentials based on the Hodgkin-Huxley equations. Nature 188, 495-497. (doi:10.1038/188495b0)
64. Numaguchi, H., Mullins, F. M., Johnson Jr, J. P., Johns, D. C., Po, S. S., Yang, I. C., Tomaselli, G. F. & Balser, J. R. 2000 Probing the interaction between inactivation gating and D-sotalol block of HERG. Circ. Res. 87, 1012-1018.
65. Olsson, S. B., Harper, R., Rydn, L. & Hilmy, W. A. 1975 The effect of therapeutic doses of lidocaine hydrochloride on the effective refractory period of the right ventricle in man. Cardiovasc Res. 9, 621-626.
66. Pitt-Francis, J. et al. 2008 Chaste: using agile programming techniques to develop computational biology software. Phil. Trans. R. Soc. A 366, 3111-3136. (doi:10.1098/rsta.2008.0096)
67. Pitt-Francis, J. et al. 2009 Chaste: a test-driven approach to software development for biological modelling. Comput. Phys. Commun. 180, 2452-2471. (doi:10.1016/j.cpc.2009.07.019)
68. Potse, M., Dubé, B., Richer, J., Vinet, A. & Gulrajani, R. M. 2006 A comparison of monodomain and bidomain reaction-diffusion models for action potential propagation in the human heart. IEEE Trans. Biomed. Eng. 53, 2425-2435.
69. Priori, S. G. & Corr, P. B. 1990 Mechanisms underlying early and delayed afterdepolarizations induced by catecholamines. Am. J. Physiol. 258, H1796-H1805.
70. Ragsdale, D. S., McPhee, J. C., Scheuer, T. & Catterall, W. A. 1996 Common molecular determinants of local anesthetic, antiarrhythmic, and anticonvulsant block of voltage-gated NA+ channels. Proc. Natl Acad. Sci. USA 93, 9270-9275. (doi:10.1073/pnas.93.17.9270) (Pubitemid 26282053)
71. Romero, L., Pueyo, E., Fink, M. & Rodriguez, B. 2009 Impact of ionic current variability on human ventricular cellular electrophysiology. Am. J. Physiol. Heart. Circ. Physiol. 297, H1436-H1445. (doi:10.1152/ajpheart.00263. 2009)
72. Romero, L., Carbonell, B., Trenor, B., Rodriguez, B., Saiz, J. & Ferrero, J. M. In press. Inter-species comparison of ionic mechanisms of arrhythmic risk in rabbit and human. Heart Rhythm.
73. Rosenheck, S., Sousa, J., Calkins, H., Kadish, A. H. & Morady, F. 1990 The effect of rate on prolongation of ventricular refractoriness by quinidine in humans. Pacing Clin. Electrophysiol. 13, 1379-1384. (doi:10.1111/j. 1540-8159.1990.tb04012.x (Pubitemid 20383404)
74. Roy, M., Dumaine, R. & Brown, A. M. 1996 HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine. Circulation 94, 817-823.
75. Saint, D. A. 2008 The cardiac persistent sodium current: an appealing therapeutic target? Br. J. Pharmacol. 153, 1133-1142.
76. Saint, D. A., Ju, Y. K. & Gage, P. W. 1992 A persistent sodium current in rat ventricular myocytes. J. Physiol. 453, 219-231.
77. Salata, J. J. & Wasserstrom, J. A. 1988 Effects of quinidine on action potentials and ionic currents in isolated canine ventricular myocytes. Circ. Res. 62, 324-337.
78. Sanchez, C, Pueyo, E, Laguna, P. & Rodriguez, B. 2009 Cardiac memory in human atria and relation to arrhythmogenesis. Comput. Cardiol., 2009.
79. Sanguinetti, M. C., Jiang, C., Curran, M. E. & Keating, M. T. 1995 A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel. Cell 81, 299-307. (doi:10.1016/0092-8674(95) 90340-2)
80. Saucerman, J. J., Healy, S. N., Belik, M. E., Puglisi, J. L. & McCulloch, A. D. 2004 Proarrhythmic consequences of a KCNQ1 AKAP-binding domain mutation: computational models of whole cells and heterogeneous tissue. Circ. Res. 95, 1216-1224. (doi:10.1161/01.RES.0000150055.06226.4e (Pubitemid 39648213)
81. Schauer, T. & Catterall, W. A. 2006 Control of neuronal excitability by phosphorylation and ephosphorylation of sodium channels. Biochem. Soc. Trans. 34, 1299-1302.
82. Seebohm, G., Chen, J., Strutz, N., Culberson, C., Lerche, C. & Sanguinetti, M. C. 2003 Molecular eterminants of KCNQ1 channel block by a benzodiazepine. Mol. Pharmacol. 64, 70-77.(doi:10.1124/mol.64.1.70) (Pubitemid 36759819)
83. Sesti, F. & Goldstein, S. A. 1998 Single-channel characteristics of wild-type IKs channels and hannels formed with two minK mutants that cause long QT syndrome. J. Gen. Physiol. 112, 51-663. (doi:10.1085/jgp.112.6.651 (Pubitemid 29001777)
84. Shah, R. R. & Hondeghem, L. M. 2005 Refining detection of drug-induced proarrhythmia: QT nterval and TRIaD. Heart Rhythm 2, 758-772. (doi:10.1016/j.hrthm.2005.03.023 (Pubitemid 40903686)
85. Sheets, M. F. & Hanck, D. A. 2003 Molecular action of lidocaine on the voltage sensors of sodium hannels. J. Gen. Physiol. 121, 163-175. (doi:10.1085/jgp.20028651) (Pubitemid 36255344)
86. Singh, S. N. & Patrick, J. 2007 Antiarrhythmic drugs. Curr. Treat. Options Cardiol. Med. 6, 57-364. (doi:10.1007/s11936-004-0019-2)
87. Smetana, P., Pueyo, E., Hnatkova, K., Batchvarov, V., Laguna, P. & Malik, M. 2004 (Individual atterns of dynamic QT/RR relationship in survivors of acute myocardial infarction and their elationship to antiarrhythmic efficacy of amiodarone. J. Cardiovasc. Electrophysiol. 15, 1147-1154. (doi:10.1046/j. 1540-8167.2004.04076.x
88. So, P. P., Backx, P. H. & Dorian, P. 2008 Slow delayed rectifier K+ current block by HMR 1556 ncreases dispersion of repolarisation and promotes torsades de pointes in rabbit ventricles. Br. . Pharmacol. 155, 1185-1194. (doi:10.1038/bjp.2008.354)
89. Song, Y., Shryock, J. C. & Belardinelli, L. 1998 Potentiating effect of acetylcholine on timulation by isoproterenol of L-type Ca2+ current and arrhythmogenic triggered activity in guinea pig ventricular myocytes. J. Cardiovasc. Electrophysiol. 9, 718-726. (doi:10.1111/j.1540-8167.1998.tb00959.x
90. Spector, P. S., Curran, M. E., Keating, M. T. & Sanguinetti, M. C. 1996 Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides. Circ. Res. 78, 499-503.
91. Splawski, I. et al. 2004 Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 119, 19-31. (doi:10.1016/j.cell.2004.09.011) (Pubitemid 39349317)
92. Suessbrich, H. & Busch, A. E. 1999 The IKs channel: coassembly of IsK (minK) and KvLQT1 proteins. Rev. Physiol. Biochem. Pharmacol. 137, 191-226.
93. Tada, T. et al. 2008 Clinical significance of macroscopic T-wave alternans after sodium channel blocker administration in patients with Brugada syndrome. J. Cardiovasc. Electrophysiol. 19, 56-61.
94. Tamargo, J., Caballero, R., Gomez, R., Valenzuela, C. & Delpon, E. 2004 Pharmacology of cardiac potassium channels. Cardiovasc. Res. 62, 9-33. (doi:10.1016/j.cardiores.2003.12.026) (Pubitemid 38326808)
95. ten Tusscher, K. H., Noble, D., Noble, P. J. & Panfilov, A. V. 2004 Am. J. Physiol. Heart Circ. Physiol. 286, H1573-H1589. (doi:10.1152/ajpheart. 00794.2003 (Pubitemid 38381170)
96. Thomsen, M. B., Verduyn, S. C., Stengl, M., Beekman, J. D., de Pater, G., van Opstal, J., Volders, P. G. & Vos, M. A. 2004 Increased short-term variability of repolarisation predicts d-sotalol-induced torsades de pointes in dogs. Circulation 110, 2453-2459. (doi:10.1161/01.CIR.0000145162.64183.C8) (Pubitemid 39407353)
97. Thomsen, M. B., Matz, J., Volders, P. G. & Vos, M. A. 2006a Assessing the proarrhythmic potential of drugs: current status of models and surrogate parameters of torsades de pointes arrhythmias. Pharmacol. Ther. 112, 150-170. (doi:10.1016/j.pharmthera.2005.04.009) (Pubitemid 44301487)
98. Thomsen, M. B., Volders, P. G., Beekman, J. D., Matz, J. & Vos, M. A. 2006b Beat-to-beat variability of repolarisation determines proarrhythmic outcome in dogs susceptible to drug-induced torsades de pointes. J. Am. Coll. Cardiol. 48, 1268-1276. (doi:10.1016/j.jacc.2006.05.048) (Pubitemid 44345129)
99. Trevor, A. & Katzung, B. 2003 Pharamcology. New York, NY: McGraw-Hill.
100. Tsuji, Y. et al. 2002 Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block. Circulation 106, 2012-2018. (doi:10.1161/01.CIR.0000031160.86313.24) (Pubitemid 35176310)
101. Vandenberg, J. I., Walker, B. D. & Campbell, T. J. 2001 HERG K+ channels: friend and foe. Trends Pharmacol. Sci. 22, 240-246. (doi:10.1016/S0165-6147(00)01662-X (Pubitemid 32411525)
102. van der Linde, H., Van de Water, A., Loots, W., Van Deuren, B., Lu, H. R., Van Ammel, K., Peeters, M. & Gallacher, D. J. 2005 A new method to calculate the beat-to-beat instability of QT duration in drug-induced long QT in anesthetized dogs. J. Pharmacol. Toxicol. Methods 52, 168-177. (doi:10.1016/j.vascn.2005.03.005) (Pubitemid 41008641)
103. van Opstal, J. M., Verduyn, S. C., Winckels, S. K., Leerssen, H. M., Leunissen, J. D., Wellens, H. J. & Vos, M. A. 2002 The JT-area indicates dispersion of repolarisation in dogs with atrioventricular block. J. Interv. Card. Electrophysiol. 6, 113-120.
104. Varro, A., Balati, B., Iost, N., Takacs, J., Virag, L., Lathrop, D. A., Csaba, L., Talosi, L. & Papp, J. G. 2000 The role of the delayed rectifier component IKs in dog ventricular muscle and Purkinje fibre repolarisation. J. Physiol. 523, Pt 1, 67-81. (doi:10.1111/j.1469-7793.2000.00067.x
105. Varro, A., Biliczki, P., Iost, N., Virag, L., Hala, O., Kovacs, P., Matyus, P. & Papp, J. G. 2004 Theoretical possibilities for the development of novel antiarrhythmic drugs. Curr. Med. Chem. 11, 1-11. (doi:10.2174/ 0929867043456296)
106. Veeraraghavan, R. & Poelzing, S. 2008 Mechanisms underlying increased right ventricular conduction sensitivity to flecainide challenge. Cardiovasc. Res. 77, 749-756. (doi:10.1093/cvr/cvm090) (Pubitemid 351301867)
107. Verrier, R. L., Nearing, B. D. & Kwaku, K. F. 2005 Noninvasive sudden death risk stratification by ambulatory ECG-based T-wave alternans analysis: evidence and methodological guidelines. Ann. Noninvasive Electrocardiol. 10, 110-120. (doi:10.1111/j.1542-474X.2005.10103.x (Pubitemid 40476674)
108. Viswanathan, P. C. & Rudy, Y. 1999 Pause induced early afterdepolarizations in the long QT syndrome: a simulation study. Cardiovasc. Res. 42, 530-542. (doi:10.1016/S0008-6363(99)00035-8) (Pubitemid 29243178)
109. Waldo, A. L. et al. 1996 Effect of D-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction. The SWORD Investigators. Survival With Oral D-sotalol. Lancet 348, 7-12. (doi:10.1016/S0140-6736(96)02149-6) (Pubitemid 26237238)
110. Wang, Q. et al. 1996 Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias. Nat. Genet. 12, 17-23. (doi:10.1038/ng0196-17) (Pubitemid 26011314)
111. Weinberg, S., Iravanian, S. & Tung, L. 2008 Representation of collective electrical behavior of cardiac cell sheets. Biophys. J. 95, 1138-1150. (doi:10.1529/biophysj.107.128207)
112. Wellens, H. J., Brugada, P. & Farre, J. 1984 Ventricular arrhythmias: mechanisms and actions of antiarrhythmic drugs. Am. Heart J. 107, 1053-1057. (doi:10.1016/0002-8703(84)90174-1)
113. Wu, L., Guo, D., Li, H., Hackett, J., Yan, G. X., Jiao, Z., Antzelevitch, C., Shryock, J. C. & Belardinelli, L. 2008 Role of late sodium current in modulating the proarrhythmic and antiarrhythmic effects of quinidine. Heart Rhythm 5, 1726-1734. (doi:10.1016/j.hrthm.2008.09.008)
114. Yamabe, M., Sanyal, S. N., Miyamoto, S., Hadama, T., Isomoto, S. & Ono, K. 2007 Source. Three different bradycardic agents, zatebradine, diltiazem and propranolol, distinctly modify heart rate variability and QT-interval variability. Pharmacology 80, 293-303. (doi:10.1159/000107103) (Pubitemid 47557264)
115. Yamaguchi, M. et al. 2003 Twave peak-to-end interval and QT dispersion in acquired long QT syndrome: a new index for arrhythmogenicity. Clin. Sci. 105, 671-676. (doi:10.1042/CS20030010) (Pubitemid 38002357)
116. Yang, T. & Roden, D. M. 1996 Extracellular potassium modulation of drug block of IKr. Implications for torsade de pointes and reverse use-dependence. Circulation 93, 407-411.
117. Zeng, J. & Rudy, Y. 1995 Early afterdepolarizations in cardiac myocytes: mechanism and rate dependence. Biophys. J. 68, 949-964. (doi:10.1016/S0006-3495(95)80271-7)
118. Zhou, Z., Gong, Q., Ye, B., Fan, Z., Makielski, J. C., Robertson, G. A. & January, C. T. 1998 Properties of HERG channels stably expressed in HEK 293 cells studied at physiological temperature. Biophys. J. 74, 230-241. (doi:10.1016/S0006-3495(98)77782-3