Skip to main content

Advertisement

Log in

Report and Recommendations of the Workshop of the European Centre for the Validation of Alternative Methods for Drug-Induced Cardiotoxicity

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Cardiotoxicity is among the leading reasons for drug attrition and is therefore a core subject in non-clinical and clinical safety testing of new drugs. European Centre for the Validation of Alternative Methods held in March 2008 a workshop on “Alternative Methods for Drug-induced Cardiotoxicity” in order to promote acceptance of alternative methods reducing, refining or replacing the use of laboratory animals in this field. This review reports the outcome of the workshop. The participants identified the major clinical manifestations, which are sensitive to conventional drugs, to be arrhythmias, contractility toxicity, ischaemia toxicity, secondary cardiotoxicity and valve toxicity. They gave an overview of the current use of alternative tests in cardiac safety assessments. Moreover, they elaborated on new cardiotoxicological endpoints for which alternative tests can have an impact and provided recommendations on how to cover them.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Kola, I., & Landis, J. (2004). Can the pharmaceutical industry reduce attrition rates? Nature Reviews Drug discovery, 3, 711–715.

    Article  PubMed  CAS  Google Scholar 

  2. Lasser, K. E., Allen, P. D., Woolhandler, S. J., Himmelstein, D. U., Wolfe, S. M., & Bor, D. H. (2002). Timing of new black box warnings and withdrawals for prescription medications. JAMA, 287, 2215–2220.

    Article  PubMed  Google Scholar 

  3. Kennedy, T. (1997). Managing the drug discovery/development interface. Drug Discovery Today, 2(9), 436–444.

    Article  Google Scholar 

  4. Redfern, W. S., Wakefield, I. D., Prior, H., Pollard, C. E., Hammond, T. G., & Valentin, J. P. (2002). Safety pharmacology—a progressive approach. Fundamental & Clinical Pharmacology, 16, 161–173.

    Article  CAS  Google Scholar 

  5. Stephens, M. D. B. (2004). Stephens’ detection of new adverse drug reactions. In J. Talbot & P. Waller (Eds.) (5th ed.). Malden, MA, USA: Wiley InterScience.

  6. Fung, M., Thornton, A., Mybeck, K., Wu, J. H., Hornbuckle, K., & Muniz, E. (2001). Evaluation of the characteristics of safety withdrawal of prescription drugs from worldwide pharmaceuticals markets—1960 to 1999. Drug Information Journal, 35, 293–317.

    Google Scholar 

  7. Car, B. (2006). Enabling technologies in reducing attrition due to safety failures. American Drug Discovery, 1, 31–34.

    Google Scholar 

  8. Krejsa, C. M., Horvath, D., Rogalski, S. L., et al. (2003). Predicting ADME properties and side effects: The bioprint approach. Current Opinion in Drug Discovery & Development, 6, 470–480.

    CAS  Google Scholar 

  9. Budnitz, D. S., Pollock, D. A., Weidenbach, K. N., Mendelsohn, A. B., Schroeder, T. J., & Annest, J. L. (2006). National surveillance of emergency department visits for outpatient adverse drug events. JAMA, 296, 1858–1866.

    Article  PubMed  CAS  Google Scholar 

  10. Lexchin, J. (2005). Drug withdrawals from the Canadian market for safety reasons, 1963–2004. CMAJ, 172, 765–767.

    PubMed  Google Scholar 

  11. Redfern, W. S., Carlsson, L., Davis, A. S., et al. (2003). Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development. Cardiovascular Research, 58, 32–45.

    Article  PubMed  CAS  Google Scholar 

  12. EMEA. (1999). ICH topic S4 duration of chronic toxicity testing in animals rodent and non rodent toxicity testing. London: EMEA. http://www.emea.europa.eu/pdfs/human/ich/030095en.pdf. Accessed 09 Jan 2008.

  13. EMEA. (2008). Guideline on repeated dose toxicity (draft). London: EMEA. http://www.emea.europa.eu/pdfs/human/swp/48831307en.pdf. Accessed 08 Aug 2008.

  14. EMEA. (2001). ICH topic S7A safety pharmacology studies for human pharmaceuticals. London: EMEA. http://www.emea.europa.eu/pdfs/human/ich/053900en.pdf. Accessed 08 Aug 2007.

  15. EMEA. (2005). ICH topic S7B the nonclinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by Human Pharmaceuticals. London: EMEA. http://www.emea.europa.eu/pdfs/human/ich/042302en.pdf. Accessed 08 Aug 2007.

  16. Konorev, E. A., Vanamala, S., & Kalyanaraman, B. (2008). Differences in doxorubicin-induced apoptotic signaling in adult and immature cardiomyocytes. Free Radical Biology and Medicine, 45, 1723–1728.

    Article  PubMed  CAS  Google Scholar 

  17. Barros, T. P., Alderton, W. K., Reynolds, H. M., Roach, A. G., & Berghmans, S. (2008). Zebrafish: An emerging technology for in vivo pharmacological assessment to identify potential safety liabilities in early drug discovery. British Journal of Pharmacology, 154, 1400–1413.

    Article  PubMed  CAS  Google Scholar 

  18. Robiolio, P. A., Rigolin, V. H., Wilson, J. S., et al. (1995). Carcinoid heart disease. Correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation, 92, 790–795.

    PubMed  CAS  Google Scholar 

  19. Redfield, M. M., Nicholson, W. J., Edwards, W. D., & Tajik, A. J. (1992). Valve disease associated with ergot alkaloid use: Echocardiographic and pathologic correlations. Annals of Internal Medicine, 117, 50–52.

    PubMed  CAS  Google Scholar 

  20. Roth, B. L. (2007). Drugs and valvular heart disease. New England Journal of Medicine, 356, 6–9.

    Article  PubMed  CAS  Google Scholar 

  21. Connolly, H. M., Crary, J. L., McGoon, M. D., et al. (1997). Valvular heart disease associated with fenfluramine-phentermine. New England Journal of Medicine, 337, 581–588.

    Article  PubMed  CAS  Google Scholar 

  22. Rothman, R. B., Baumann, M. H., Savage, J. E., et al. (2000). Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications. Circulation, 102, 2836–2841.

    PubMed  CAS  Google Scholar 

  23. Setola, V., Hufeisen, S. J., Grande-Allen, K. J., et al. (2003). 3, 4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Molecular Pharmacology, 63, 1223–1229.

    Article  PubMed  CAS  Google Scholar 

  24. Schade, R., Andersohn, F., Suissa, S., Haverkamp, W., & Garbe, E. (2007). Dopamine agonists and the risk of cardiac-valve regurgitation. New England Journal of Medicine, 356, 29–38.

    Article  PubMed  CAS  Google Scholar 

  25. Zanettini, R., Antonini, A., Gatto, G., Gentile, R., Tesei, S., & Pezzoli, G. (2007). Valvular heart disease and the use of dopamine agonists for Parkinson’s disease. New England Journal of Medicine, 356, 39–46.

    Article  PubMed  CAS  Google Scholar 

  26. Reiffel, J. A. (1996). Data-driven decisions: The importance of clinical trials in arrhythmia management. Journal of Cardiovascular Pharmacology and Therapeutics, 1, 79–88.

    Article  PubMed  Google Scholar 

  27. Hondeghem, L. M. (1994). Computer aided development of antiarrhythmic agents with class IIIa properties. Journal of Cardiovascular Electrophysiology, 5, 711–721.

    Article  PubMed  CAS  Google Scholar 

  28. Carmeliet, E., & Mubagwa, K. (1998). Antiarrhythmic drugs and cardiac ion channels: Mechanisms of action. Progress in Biophysics and Molecular Biology, 70, 1–72.

    Article  PubMed  CAS  Google Scholar 

  29. Whalley, D. W., Wendt, D. J., & Grant, A. O. (1995). Basic concepts in cellular cardiac electrophysiology: Part I: Ion channels, membrane currents, and the action potential. Pacing and Clinical Electrophysiology, 18, 1556–1574.

    Article  PubMed  CAS  Google Scholar 

  30. Lawrence, C. L., Pollard, C. E., Hammond, T. G., & Valentin, J. P. (2005). Nonclinical proarrhythmia models: Predicting Torsades de Pointes. Journal of Pharmacological and Toxicological Methods, 52, 46–59.

    Article  PubMed  CAS  Google Scholar 

  31. Carlsson, L., Abrahamsson, C., Andersson, B., Duker, G., & Schiller-Linhardt, G. (1993). Proarrhythmic effects of the class III agent almokalant: Importance of infusion rate, QT dispersion, and early afterdepolarisations. Cardiovascular Research, 27, 2186–2193.

    Article  PubMed  CAS  Google Scholar 

  32. Detre, E., Thomsen, M. B., Beekman, J. D., Petersen, K. U., & Vos, M. A. (2005). Decreasing the infusion rate reduces the proarrhythmic risk of NS-7: Confirming the relevance of short-term variability of repolarisation in predicting drug-induced torsades de pointes. British Journal of Pharmacology, 145, 397–404.

    Article  PubMed  CAS  Google Scholar 

  33. Hondeghem, L. M. (2008). QT prolongation is an unreliable predictor of ventricular arrhythmia. Heart Rhythm, 5, 1210–1212.

    Article  PubMed  Google Scholar 

  34. Gintant, G. A., Su, Z., Martin, R. L., & Cox, B. F. (2006). Utility of hERG assays as surrogate markers of delayed cardiac repolarization and QT safety. Toxicologic Pathology, 34, 81–90.

    Article  PubMed  CAS  Google Scholar 

  35. Antzelevitch, C., Shimizu, W., Yan, G. X., et al. (1999). The M cell: Its contribution to the ECG and to normal and abnormal electrical function of the heart. Journal of Cardiovascular Electrophysiology, 10, 1124–1152.

    Article  PubMed  CAS  Google Scholar 

  36. Shimizu, W., & Antzelevitch, C. (1999). Cellular basis for long QT, transmural dispersion of repolarization, and torsade de pointes in the long QT syndrome. Journal of Electrocardiology, 32(Suppl), 177–184.

    Article  PubMed  Google Scholar 

  37. Gavillet, B., Rougier, J. S., Domenighetti, A. A., et al. (2006). Cardiac sodium channel Nav1.5 is regulated by a multiprotein complex composed of syntrophins and dystrophin. Circulation Research, 99, 407–414.

    Article  PubMed  CAS  Google Scholar 

  38. Brendel, J., & Peukert, S. (2003). Blockers of the Kv1.5 channel for the treatment of atrial arrhythmias. Current Medicinal Chemistry Cardiovascular & Hematological Agents, 1, 273–287.

    Article  CAS  Google Scholar 

  39. Akiyama, T., Pawitan, Y., Greenberg, H., Kuo, C. S., & Reynolds-Haertle, R. A. (1991). Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the cardiac arrhythmia suppression trial. CAST investigators. American Journal of Cardiology, 68, 1551–1555.

    Article  PubMed  CAS  Google Scholar 

  40. Campbell, T. J. (1992). Subclassification of class I antiarrhythmic drugs: Enhanced relevance after CAST. Cardiovascular Drugs and Therapy, 6, 519–528.

    Article  PubMed  CAS  Google Scholar 

  41. Nagasawa, Y., Chen, J., & Hashimoto, K. (2005). Antiarrhythmic properties of a prior oral loading of amiodarone in in vivo canine coronary ligation/reperfusion-induced arrhythmia model: Comparison with other class III antiarrhythmic drugs. Journal of Pharmacological Science, 97, 393–399.

    Article  CAS  Google Scholar 

  42. Vaughan Williams, E. M. (1959). A study of intracellular potentials and contractions in atria, including evidence for an after-potential. Journal of Physiology, 149, 78–92.

    PubMed  CAS  Google Scholar 

  43. Ortega-Carnicer, J., Bertos-Polo, J., & Gutierrez-Tirado, C. (2001). Aborted sudden death, transient Brugada pattern, and wide QRS dysrhythmias after massive cocaine ingestion. Journal of Electrocardiology, 34, 345–349.

    Article  PubMed  CAS  Google Scholar 

  44. Ried, T., Rudy, B., Vega-Saenz, D. M., Lau, D., Ward, D. C., & Sen, K. (1993). Localization of a highly conserved human potassium channel gene (NGK2-KV4; KCNC1) to chromosome 11p15. Genomics, 15, 405–411.

    Article  PubMed  CAS  Google Scholar 

  45. Katchman, A. N., Koerner, J., Tosaka, T., Woosley, R. L., & Ebert, S. N. (2006). Comparative evaluation of HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Journal of Pharmacology and Experimental Therapeutics, 316, 1098–1106.

    Article  PubMed  CAS  Google Scholar 

  46. Sanguinetti, M. C., Curran, M. E., Spector, P. S., & Keating, M. T. (1996). Spectrum of HERG K+ -channel dysfunction in an inherited cardiac arrhythmia. Proceedings of the National Academy of Sciences of the USA, 93, 2208–2212.

    Article  PubMed  CAS  Google Scholar 

  47. Fossa, A. A., Wisialowski, T., Wolfgang, E., et al. (2004). Differential effect of HERG blocking agents on cardiac electrical alternans in the guinea pig. European Journal of Pharmacology, 486(2), 209–221.

    Article  PubMed  CAS  Google Scholar 

  48. Saint, D. A. (2008). The cardiac persistent sodium current: An appealing therapeutic target? British Journal of Pharmacology, 153, 1133–1142.

    Article  PubMed  CAS  Google Scholar 

  49. Sasaki, K., Makita, N., Sunami, A., et al. (2004). Unexpected mexiletine responses of a mutant cardiac Na+ channel implicate the selectivity filter as a structural determinant of antiarrhythmic drug access. Molecular Pharmacology, 66, 330–336.

    Article  PubMed  CAS  Google Scholar 

  50. Nuss, H. B., & Marban, E. (1994). Electrophysiological properties of neonatal mouse cardiac myocytes in primary culture. Journal of Physiology, 479, 265–279.

    PubMed  Google Scholar 

  51. Franco, D., Demolombe, S., Kupershmidt, S., et al. (2001). Divergent expression of delayed rectifier K(+) channel subunits during mouse heart development. Cardiovascular Research, 52, 65–75.

    Article  PubMed  CAS  Google Scholar 

  52. Babij, P., Askew, G. R., Nieuwenhuijsen, B., et al. (1998). Inhibition of cardiac delayed rectifier K+ current by overexpression of the long-QT syndrome HERG G628S mutation in transgenic mice. Circulation Research, 83, 668–678.

    PubMed  CAS  Google Scholar 

  53. Bassani, R. A. (2006). Transient outward potassium current and Ca2+ homeostasis in the heart: Beyond the action potential. Brazilian Journal of Medical and Biological Research, 39, 393–403.

    Article  PubMed  CAS  Google Scholar 

  54. Carmeliet, E. (1993). K+ channels and control of ventricular repolarization in the heart. Fundamental & Clinical Pharmacology, 7, 19–28.

    Article  CAS  Google Scholar 

  55. Ruppersberg, J. P., & Fakler, B. (1996). Complexity of the regulation of Kir2.1K+ channels. Neuropharmacology, 35, 887–893.

    Article  PubMed  CAS  Google Scholar 

  56. Heusch, G., Skyschally, A., Gres, P., van Caster, P., Schilawa, D., & Schulz, R. (2009). Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: Protection beyond heart rate reduction. European Heart Journal, 29(18), 2265–2275.

    Article  Google Scholar 

  57. Rosen, M. R., Brink, P. R., Cohen, I. S., & Robinson, R. B. (2007). Biological pacemakers based on I(f). Medical & Biological Engineering & Computing, 45, 157–166.

    Article  Google Scholar 

  58. Robinson, R. B., Brink, P. R., Cohen, I. S., & Rosen, M. R. (2006). I(f) and the biological pacemaker. Pharmacological Research, 53, 407–415.

    Article  PubMed  CAS  Google Scholar 

  59. Barbuti, A., Baruscotti, M., & DiFrancesco, D. (2007). The pacemaker current: From basics to the clinics. Journal of Cardiovascular Electrophysiology, 18, 342–347.

    Article  PubMed  Google Scholar 

  60. Jiang, M., Zhang, M., Tang, D. G., et al. (2004). KCNE2 protein is expressed in ventricles of different species, and changes in its expression contribute to electrical remodeling in diseased hearts. Circulation, 109, 1783–1788.

    Article  PubMed  CAS  Google Scholar 

  61. Cavero, I., & Crumb, W. (2005). ICH S7B draft guideline on the non-clinical strategy for testing delayed cardiac repolarisation risk of drugs: A critical analysis. Expert Opinion on Drug Safety, 4, 509–530.

    Article  PubMed  Google Scholar 

  62. Wehrens, X. H., Lehnart, S. E., Huang, F., et al. (2003). FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell, 113, 829–840.

    Article  PubMed  CAS  Google Scholar 

  63. Vest, J. A., Wehrens, X. H., Reiken, S. R., et al. (2005). Defective cardiac ryanodine receptor regulation during atrial fibrillation. Circulation, 111, 2025–2032.

    Article  PubMed  CAS  Google Scholar 

  64. Koumi, S., & Wasserstrom, J. A. (1994). Acetylcholine-sensitive muscarinic K+ channels in mammalian ventricular myocytes. American Journal of Physiology, 266, H1812–H1821.

    PubMed  CAS  Google Scholar 

  65. Liu, L., & Nattel, S. (1997). Differing sympathetic and vagal effects on atrial fibrillation in dogs: Role of refractoriness heterogeneity. American Journal of Physiology, 273, H805–H816.

    PubMed  CAS  Google Scholar 

  66. Tucker, S. J., Gribble, F. M., Zhao, C., Trapp, S., & Ashcroft, F. M. (1997). Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor. Nature, 387, 179–183.

    Article  PubMed  CAS  Google Scholar 

  67. Rodrigo, G. C., & Standen, N. B. (2005). ATP-sensitive potassium channels. Current Pharmaceutical Design, 11, 1915–1940.

    Article  PubMed  CAS  Google Scholar 

  68. Noma, A. (1983). ATP-regulated K+ channels in cardiac muscle. Nature, 305, 147–148.

    Article  PubMed  CAS  Google Scholar 

  69. Wilde, A. A., & Janse, M. J. (1994). Electrophysiological effects of ATP sensitive potassium channel modulation: Implications for arrhythmogenesis. Cardiovascular Research, 28, 16–24.

    Article  PubMed  CAS  Google Scholar 

  70. Murry, C. E., Jennings, R. B., & Reimer, K. A. (1986). Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation, 74, 1124–1136.

    PubMed  CAS  Google Scholar 

  71. Gross, G. J., & Peart, J. N. (2003). KATP channels and myocardial preconditioning: An update. American Journal of Physiology-Heart and Circulatory Physiology, 285, H921–H930.

    PubMed  CAS  Google Scholar 

  72. Le Brigand, L., Virsolvy, A., Manechez, D., et al. (1999). In vitro mechanism of action on insulin release of S-22068, a new putative antidiabetic compound. British Journal of Pharmacology, 128, 1021–1026.

    Article  PubMed  CAS  Google Scholar 

  73. Proks, P., Treinies, I., Mest, H. J., & Trapp, S. (2002). Inhibition of recombinant K(ATP) channels by the antidiabetic agents midaglizole, LY397364 and LY389382. European Journal of Pharmacology, 452, 11–19.

    Article  PubMed  CAS  Google Scholar 

  74. Mukai, E., Ishida, H., Horie, M., Noma, A., Seino, Y., & Takano, M. (1998). The antiarrhythmic agent cibenzoline inhibits KATP channels by binding to Kir6.2. Biochemical and Biophysical Research Communications, 251(2), 477–481.

    Article  PubMed  CAS  Google Scholar 

  75. Zunkler, B. J., Kuhne, S., Rustenbeck, I., Ott, T., & Hildebrandt, A. G. (2000). Disopyramide block of K(ATP) channels is mediated by the pore-forming subunit. Life Sciences, 66, L-52.

    Google Scholar 

  76. Gribble, F. M., Davis, T. M., Higham, C. E., Clark, A., & Ashcroft, F. M. (2000). The antimalarial agent mefloquine inhibits ATP-sensitive K-channels. British Journal of Pharmacology, 131, 756–760.

    Article  PubMed  CAS  Google Scholar 

  77. Zunkler, B. J., & Wos, M. (2003). Effects of lomefloxacin and norfloxacin on pancreatic beta-cell ATP-sensitive K(+) channels. Life Sciences, 73, 429–435.

    Article  PubMed  CAS  Google Scholar 

  78. Zunkler, B. J., Claassen, S., Wos-Maganga, M., Rustenbeck, I., & Holzgrabe, U. (2006). Effects of fluoroquinolones on HERG channels and on pancreatic beta-cell ATP-sensitive K+ channels. Toxicology, 228, 239–248.

    Article  PubMed  CAS  Google Scholar 

  79. Saraya, A., Yokokura, M., Gonoi, T., & Seino, S. (2004). Effects of fluoroquinolones on insulin secretion and beta-cell ATP-sensitive K+ channels. European Journal of Pharmacology, 497, 111–117.

    Article  PubMed  CAS  Google Scholar 

  80. Kikuta, J., Ishii, M., Kishimoto, K., & Kurachi, Y. (2006). Carvedilol blocks cardiac KATP and KG but not IK1 channels by acting at the bundle-crossing regions. European Journal of Pharmacology, 529, 47–54.

    Article  PubMed  CAS  Google Scholar 

  81. Rang, H. P., Dale, M. M., Ritter, J. M., Flower, R. J. (2007). Pharmacology. Churchill Livingstone Elsevier (6th ed.).

  82. Bernstein, D., Fajardo, G., Zhao, M., et al. (2005). Differential cardioprotective/cardiotoxic effects mediated by beta-adrenergic receptor subtypes. American Journal of Physiology-Heart and Circulatory Physiology, 289, H2441–H2449.

    Article  PubMed  CAS  Google Scholar 

  83. Nuttall, S. L., Langford, N. J., & Kendall, M. J. (2000). Beta-blockers in heart failure. 1. Clinical evidence. Journal of Clinical Pharmacy & Therapeutics, 25, 395–398.

    Article  CAS  Google Scholar 

  84. Zhu, W. Z., Zheng, M., Koch, W. J., Lefkowitz, R. J., Kobilka, B. K., & Xiao, R. P. (2001). Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proceedings of the National Academy of Sciences of the USA, 98, 1607–1612.

    Article  PubMed  CAS  Google Scholar 

  85. Rona, G. (1985). Catecholamine cardiotoxicity. Journal of Molecular and Cellular Cardiology, 17, 291–306.

    Article  PubMed  CAS  Google Scholar 

  86. Harvey, R. D., & Belevych, A. E. (2003). Muscarinic regulation of cardiac ion channels. British Journal of Pharmacology, 139, 1074–1084.

    Article  PubMed  CAS  Google Scholar 

  87. Kurachi, Y. (1995). G protein regulation of cardiac muscarinic potassium channel. American Journal of Physiology, 269, C821–C830.

    PubMed  CAS  Google Scholar 

  88. James, A. F., & Hancox, J. C. (2007). More types than one: Multiple muscarinic receptor coupled K+ currents undergo remodelling in an experimental model of atrial fibrillation. British Journal of Pharmacology, 152, 981–983.

    Article  PubMed  CAS  Google Scholar 

  89. Shields, J. A. (2008). Heart block and prolonged Q-Tc interval following muscle relaxant reversal: A case report. AANA Journal, 76, 41–45.

    PubMed  Google Scholar 

  90. Bunemann, M., Lee, K. B., Pals-Rylaarsdam, R., Roseberry, A. G., & Hosey, M. M. (1999). Desensitization of G-protein-coupled receptors in the cardiovascular system. Annual Review of Physiology, 61, 169–192.

    Article  PubMed  CAS  Google Scholar 

  91. Cingolani, H. E., & Ennis, I. L. (2007). Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation, 115, 1090–1100.

    Article  PubMed  Google Scholar 

  92. Fliegel, L. (2009). Regulation of the Na(+)/H(+) exchanger in the healthy and diseased myocardium. Expert Opinion on Therapeutic Targets, 13, 55–68.

    Article  PubMed  CAS  Google Scholar 

  93. Karmazyn, M., Sawyer, M., & Fliegel, L. (2005). The Na(+)/H(+) exchanger: A target for cardiac therapeutic intervention. Current Drug Targets Cardiovascular & Hematological Disorders, 5, 323–335.

    Article  CAS  Google Scholar 

  94. Nakamura, T. Y., Iwata, Y., Arai, Y., Komamura, K., & Wakabayashi, S. (2008). Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circulation Research, 103, 891–899.

    Article  PubMed  CAS  Google Scholar 

  95. Takemasa, H., Nagatomo, T., Abe, H., et al. (2008). Coexistence of hERG current block and disruption of protein trafficking in ketoconazole-induced long QT syndrome. British Journal of Pharmacology, 153, 439–447.

    Article  PubMed  CAS  Google Scholar 

  96. van der Heyden, M. A., Smits, M. E., & Vos, M. A. (2008). Drugs and trafficking of ion channels: A new pro-arrhythmic threat on the horizon? British Journal of Pharmacology, 153, 406–409.

    Article  PubMed  CAS  Google Scholar 

  97. Dennis, A., Wang, L., Wan, X., & Ficker, E. (2007). hERG channel trafficking: Novel targets in drug-induced long QT syndrome. Biochemical Society Transactions, 35, 1060–1063.

    Article  PubMed  CAS  Google Scholar 

  98. Guo, J., Massaeli, H., Li, W., et al. (2007). Identification of IKr and its trafficking disruption induced by probucol in cultured neonatal rat cardiomyocytes. Journal of Pharmacology and Experimental Therapeutics, 321, 911–920.

    Article  PubMed  CAS  Google Scholar 

  99. Rajamani, S., Eckhardt, L. L., Valdivia, C. R., et al. (2006). Drug-induced long QT syndrome: hERG K+ channel block and disruption of protein trafficking by fluoxetine and norfluoxetine. British Journal of Pharmacology, 149, 481–489.

    Article  PubMed  CAS  Google Scholar 

  100. Hoffmann, P., & Warner, B. (2006). Are hERG channel inhibition and QT interval prolongation all there is in drug-induced torsadogenesis? A review of emerging trends. Journal of Pharmacological and Toxicological Methods, 53, 87–105.

    Article  PubMed  CAS  Google Scholar 

  101. Friedrichs, G. S., Patmore, L., & Bass, A. (2005). Non-clinical evaluation of ventricular repolarization (ICH S7B): Results of an interim survey of international pharmaceutical companies. Journal of Pharmacological and Toxicological Methods, 52, 6–11.

    Article  PubMed  CAS  Google Scholar 

  102. Lindgren, S., Bass, A. S., Briscoe, R., et al. (2008). Benchmarking safety pharmacology regulatory packages and best practice. Journal of Pharmacological and Toxicological Methods, 58, 99–109.

    Article  PubMed  CAS  Google Scholar 

  103. Gavaghan, C. L., Arnby, C. H., Blomberg, N., Strandlund, G., & Boyer, S. (2007). Development, interpretation and temporal evaluation of a global QSAR of hERG electrophysiology screening data. Journal of Computer-Aided Molecular Design, 21, 189–206.

    Article  PubMed  CAS  Google Scholar 

  104. Thai, K. M., & Ecker, G. F. (2007). Predictive models for HERG channel blockers: Ligand-based and structure-based approaches. Current Medicinal Chemistry, 14, 3003–3026.

    Article  PubMed  CAS  Google Scholar 

  105. Courtemanche, M., Ramirez, R. J., & Nattel, S. (1999). Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: Insights from a mathematical model. Cardiovascular Research, 42, 477–489.

    Article  PubMed  CAS  Google Scholar 

  106. Diaz, G. J., Daniell, K., Leitza, S. T., et al. (2004). The [3H]dofetilide binding assay is a predictive screening tool for hERG blockade and proarrhythmia: Comparison of intact cell and membrane preparations and effects of altering [K+]o. Journal of Pharmacological and Toxicological Methods, 50, 187–199.

    Article  PubMed  CAS  Google Scholar 

  107. Rezazadeh, S., Hesketh, J. C., & Fedida, D. (2004). Rb+ flux through hERG channels affects the potency of channel blocking drugs: Correlation with data obtained using a high-throughput Rb+ efflux assay. Journal of Biomolecular Screening, 9, 588–597.

    Article  PubMed  CAS  Google Scholar 

  108. Liu, C. J., Priest, B. T., Bugianesi, R. M., et al. (2006). A high-capacity membrane potential FRET-based assay for NaV1.8 channels. Assay Drug Development Technologies, 4, 37–48.

    Article  CAS  Google Scholar 

  109. Bianchi, L., Wible, B., Arcangeli, A., et al. (1998). Herg encodes a K+ current highly conserved in tumors of different histogenesis: A selective advantage for cancer cells? Cancer Research, 58, 815–822.

    PubMed  CAS  Google Scholar 

  110. Finkel, A., Wittel, A., Yang, N., Handran, S., Hughes, J., & Costantin, J. (2006). Population patch clamp improves data consistency and success rates in the measurement of ionic currents. Journal of Biomolecular Screening, 11, 488–496.

    Article  PubMed  CAS  Google Scholar 

  111. Halbach, M., Egert, U., Hescheler, J., & Banach, K. (2003). Estimation of action potential changes from field potential recordings in multicellular mouse cardiac myocyte cultures 2. Cellular Physiology and Biochemistry, 13, 271–284.

    Article  PubMed  CAS  Google Scholar 

  112. Meyer, T., Sartipy, P., Blind, F., Leisgen, C., & Guenther, E. (2007). New cell models and assays in cardiac safety profiling. Expert Opinion on Drug Metabolism & Toxicology, 3, 507–517.

    Article  CAS  Google Scholar 

  113. Pillekamp, F., Halbach, M., Reppel, M., et al. (2007). Neonatal murine heart slices. A robust model to study ventricular isometric contractions. Cellular Physiology and Biochemistry, 20, 837–846.

    Article  PubMed  CAS  Google Scholar 

  114. Halbach, M., Pillekamp, F., Brockmeier, K., Hescheler, J., Muller-Ehmsen, J., & Reppel, M. (2006). Ventricular slices of adult mouse hearts—a new multicellular in vitro model for electrophysiological studies. Cellular Physiology and Biochemistry, 18, 1–8.

    Article  PubMed  CAS  Google Scholar 

  115. Yan, G. X., & Antzelevitch, C. (1998). Cellular basis for the normal T wave and the electrocardiographic manifestations of the long-QT syndrome. Circulation, 98, 1928–1936.

    PubMed  CAS  Google Scholar 

  116. Hondeghem, L. M., Carlsson, L., & Duker, G. (2001). Instability and triangulation of the action potential predict serious proarrhythmia, but action potential duration prolongation is antiarrhythmic. Circulation, 103, 2004–2013.

    PubMed  CAS  Google Scholar 

  117. Carlsson, L., Almgren, O., & Duker, G. (1990). QTU-prolongation and torsades de pointes induced by putative class III antiarrhythmic agents in the rabbit: Etiology and interventions. Journal of Cardiovascular Pharmacology, 16, 276–285.

    Article  PubMed  CAS  Google Scholar 

  118. Vos, M. A., Verduyn, S. C., Gorgels, A. P., Lipcsei, G. C., & Wellens, H. J. (1995). Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block. Circulation, 91, 864–872.

    PubMed  CAS  Google Scholar 

  119. Carlsson, L. (2006). In vitro and in vivo models for testing arrhythmogenesis in drugs. Journal of Internal Medicine, 259, 70–80.

    Article  PubMed  CAS  Google Scholar 

  120. Wu, L., Shryock, J. C., Song, Y., & Belardinelli, L. (2006). An increase in late sodium current potentiates the proarrhythmic activities of low-risk QT-prolonging drugs in female rabbit hearts. Journal of Pharmacology and Experimental Therapeutics, 316, 718–726.

    Article  PubMed  CAS  Google Scholar 

  121. Fossa, A. A., Depasquale, M. J., Raunig, D. L., Avery, M. J., & Leishman, D. J. (2002). The relationship of clinical QT prolongation to outcome in the conscious dog using a beat-to-beat QT-RR interval assessment. Journal of Pharmacology and Experimental Therapeutics, 302, 828–833.

    Article  PubMed  CAS  Google Scholar 

  122. Svernhage, E., Houltz, B., Blomström, P., et al. (1998). Early electrocardiographic signs of drug-induced torsades de pointes. Annals of Noninvasive Electrocardiology, 3, 252–260.

    Article  Google Scholar 

  123. Atiga, W. L., Calkins, H., Lawrence, J. H., Tomaselli, G. F., Smith, J. M., & Berger, R. D. (1998). Beat-to-beat repolarization lability identifies patients at risk for sudden cardiac death. Journal of Cardiovascular Electrophysiology, 9, 899–908.

    Article  PubMed  CAS  Google Scholar 

  124. 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 repolarization lability in ischemic and nonischemic dilated cardiomyopathy. Circulation, 96, 1557–1565.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Susanne Bremer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stummann, T.C., Beilmann, M., Duker, G. et al. Report and Recommendations of the Workshop of the European Centre for the Validation of Alternative Methods for Drug-Induced Cardiotoxicity. Cardiovasc Toxicol 9, 107–125 (2009). https://doi.org/10.1007/s12012-009-9045-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-009-9045-3

Keywords

Navigation