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Arrhythmia phenotype in mouse models of human long QT

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Abstract

Enhanced dispersion of repolarization (DR) was proposed as a unifying mechanism, central to arrhythmia genesis in the long QT (LQT) syndrome. In mammalian hearts, K+ channels are heterogeneously expressed across the ventricles resulting in ‘intrinsic’ DR that may worsen in long QT. DR was shown to be central to the arrhythmia phenotype of transgenic mice with LQT caused by loss of function of the dominant mouse K+ currents. Here, we investigated the arrhythmia phenotype of mice with targeted deletions of KCNE1 and KCNH2 genes which encode for minK/IsK and Merg1 (mouse homolog of human ERG) proteins resulting in loss of function of IKs and IKr, respectively. Both currents are important human K+ currents associated with LQT5 and LQT2. Loss of minK, a protein subunit that interacts with KvLQT1, results in a marked reduction of IKs giving rise to the Jervell and Lange–Nielsen syndrome and the reduced KCNH2 gene reduces MERG and IKr.

Hearts were perfused, stained with di-4-ANEPPS and optically mapped to compare action potential durations (APDs) and arrhythmia phenotype in homozygous minK (minK−/−) and heterozygous Merg1 (Merg+/−) deletions and littermate control mice. MinK−/− mice has similar APDs and no arrhythmias (n = 4). Merg+/− mice had prolonged APDs (from 20 ± 6 to 32 ± 9 ms at the base, p < 0.01; from 18 ± 5 to 25 ± 9 ms at the apex, p < 0.01; n = 8), longer refractory periods (RP) (36 ± 14 to 63 ± 27 at the base, p < 0.01 and 34 ± 5 to 53 ± 21 ms at the apex, p < 0.03; n = 8), higher DR 10.4 ± 4.1 vs. 14 ± 2.3 ms, p < 0.02) and similar conduction velocities (n = 8). Programmed stimulation exposed a higher propensity to VT in Merg+/− mice (60% vs. 10%). A comparison of mouse models of LQT based on K+ channel mutations important to human and mouse repolarization emphasizes DR as a major determinant of arrhythmia vulnerability.

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References

  1. Schwartz, P., Locati, E., Napolitano, C., & Priore, S. (1995). The long QT syndrome. In D. Zipes, & J. Jalife (Eds.), Cardiac Electrophysiology: From cell to bedside (p. 788−811, 2ndnd ed.). Philadelphia, PA: WB Saunders.

    Google Scholar 

  2. Surawicz, B. (1989). Electrophysiologic substrate of torsade de pointes: dispersion of repolarization or early afterdepolarizations? Journal of the American College of Cardiology, 14(1), 172−184.

    Article  PubMed  Google Scholar 

  3. Ackerman, M. J. (1998). The long QT syndrome: ion channel diseases of the heart. Mayo Clinic Proceedings, 73(3), 250−269.

    Article  PubMed  Google Scholar 

  4. Dessertenne, F. (1966). Ventricular tachycardia with 2 variable opposing foci. Archives des Maladies du Coeur et des Vaisseaux, 59(2), 263−272.

    PubMed  Google Scholar 

  5. El-Sherif, N., Chinushi, M., Caref, E. B., & Restivo, M. (1997). Electrophysiological mechanism of the characteristic electrocardiographic morphology of torsade de pointes tachyarrhythmias in the long-QT syndrome: detailed analysis of ventricular tridimensional activation patterns. Circulation, 96(12), 4392–4399.

    PubMed  CAS  Google Scholar 

  6. El-Sherif, N., Gough, W. B., & Restivo, M. (1991). Reentrant ventricular arrhythmias in the late myocardial infarction period: mechanism by which a short-long-short cardiac sequence facilitates the induction of reentry. Circulation, 83(1), 268–278.

    PubMed  CAS  Google Scholar 

  7. Frazier, D. W., Wolf, P. D., Wharton, J. M., Tang, A. S., Smith, W. M., & Ideker, R. E. (1989). Stimulus-induced critical point. Mechanism for electrical initiation of reentry in normal canine myocardium. The Journal of Clinical Investigation, 83(3), 1039–1052.

    Article  PubMed  CAS  Google Scholar 

  8. Smith, J. M., Clancy, E. A., Valeri, C. R., Ruskin, J. N., & Cohen, R. J. (1988). Electrical alternans and cardiac electrical instability. Circulation, 77(1), 110–121.

    PubMed  CAS  Google Scholar 

  9. Shimizu, W., & Antzelevitch, C. (1998). Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation, 98(21), 2314–2322.

    PubMed  CAS  Google Scholar 

  10. Wit, A. L., Allessie, M. A., Bonke, F. I., Lammers, W., Smeets, J., & Fenoglio Jr., J. J. (1982). Electrophysiologic mapping to determine the mechanism of experimental ventricular tachycardia initiated by premature impulses. Experimental approach and initial results demonstrating reentrant excitation. The American Journal of Cardiology, 49(1), 166–185.

    Article  PubMed  CAS  Google Scholar 

  11. Antzelevitch, C., Sicouri, S., Litovsky, S. H., Lukas, A., Krishnan, S. C., Di Diego, J. M., Gintant, G. A., & Liu, D. W. (1991). Heterogeneity within the ventricular wall. Electrophysiology and pharmacology of epicardial, endocardial, and M cells. Circulation Research, 69(6), 1427–1449.

    PubMed  CAS  Google Scholar 

  12. Antzelevitch, C., Sicouri, S., Lukas, A., Nesterenko, V., Liu, D.-W., & Di Diego, J. M. (1994). Regional differences in the ventricular cells: physical implications. In D. P. Zipes, & J. Jalife (Eds.), Cardiac Electrophysiology: From cell to bedside (pp. 228–245). Philadelphia: WB Saunders.

    Google Scholar 

  13. Barry, D. M., & Nerbonne, J. M. (1996). Myocardial potassium channels: electrophysiological and molecular diversity. Annual Review of Physiology, 58, 363–394.

    Article  PubMed  CAS  Google Scholar 

  14. Salama, G., Lombardi, R., & Elson, J. (1987). Maps of optical action potentials and NADH fluorescence in intact working hearts. The American Journal of Physiology, 252(2 Pt 2), H384–H394.

    PubMed  CAS  Google Scholar 

  15. Efimov, I. R., Ermentrout, B., Huang, D. T., & Salama, G. (1996). Activation and repolarization patterns are governed by different structural characteristics of ventricular myocardium: experimental study with voltage-sensitive dyes and numerical simulations. Journal of Cardiovascular Electrophysiology, 7(6), 512–530.

    Article  PubMed  CAS  Google Scholar 

  16. Choi, B. R., Nho, W., Liu, T., & Salama, G. (2002). Life span of ventricular fibrillation frequencies. Circulation Research, 91(4), 339–345.

    Article  PubMed  CAS  Google Scholar 

  17. Baker, L. C., London, B., Choi, B. R., Koren, G., & Salama, G. (2000). Enhanced dispersion of repolarization and refractoriness in transgenic mouse hearts promotes reentrant ventricular tachycardia. Circulation Research, 86(4), 396–407.

    PubMed  CAS  Google Scholar 

  18. Szentadrassy, N., Banyasz, T., Biro, T., Szabo, G., Toth, B. I., Magyar, J., et al. (2005). Apico-basal inhomogeneity in distribution of ion channels in canine and human ventricular myocardium. Cardiovascular Research, 65(4), 851–860.

    Article  PubMed  CAS  Google Scholar 

  19. Mantravadi, R., Gabris, B., Liu, T., Choi, B. R., de Groat, W. C., Ng, G. A., et al. (2007). Autonomic nerve stimulation reverses ventricular repolarization sequence in rabbit hearts. Circulation Research, 100(7), e72–e80.

    Article  PubMed  CAS  Google Scholar 

  20. Niwa, N., Wang, W., Sha, Q., Marionneau, C., & Nerbonne, J. M. (2008). Kv4.3 is not required for the generation of functional Ito,f channels in adult mouse ventricles. Journal of Molecular and Cellular Cardiology, 44(1), 95–104.

    Article  PubMed  CAS  Google Scholar 

  21. Nerbonne, J. M. (2000). Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. The Journal of Physiology, 525(Pt 2), 285–298. In Process Citation.

    Article  PubMed  CAS  Google Scholar 

  22. Xu, H., Guo, W., & Nerbonne, J. M. (1999). Four kinetically distinct depolarization-activated K+ currents in adult mouse ventricular myocytes. The Journal of General Physiology, 113(5), 661–678.

    Article  PubMed  CAS  Google Scholar 

  23. London, B., Wang, D. W., Hill, J. A., & Bennett, P. B. (1998). The transient outward current in mice lacking the potassium channel gene Kv1.4. The Journal of Physiology, 509(Pt 1), 171–182.

    Article  PubMed  CAS  Google Scholar 

  24. Guo, W., Li, H., London, B., & Nerbonne, J. M. (2000). Functional consequences of elimination of i(to,f) and i(to,s): early afterdepolarizations, atrioventricular block, and ventricular arrhythmias in mice lacking Kv1.4 and expressing a dominant-negative Kv4 alpha subunit. Circulation Research, 87(1), 73–79.

    PubMed  CAS  Google Scholar 

  25. Brunet, S., Aimond, F., Li, H., Guo, W., Eldstrom, J., Fedida, D., Yamada, K. A., & Nerbonne, J. M. (2004). Heterogeneous expression of repolarizing, voltage-gated K+ currents in adult mouse ventricles. The Journal of Physiology, 559(Pt 1), 103–120.

    Article  PubMed  CAS  Google Scholar 

  26. Barry, D. M., Xu, H., Schuessler, R. B., & Nerbonne, J. M. (1998). Functional knockout of the transient outward current, long-QT syndrome, and cardiac remodeling in mice expressing a dominant-negative Kv4 alpha subunit. Circulation Research, 83(5), 560–567.

    PubMed  CAS  Google Scholar 

  27. London, B., Baker, L. C., Petkova-Kirova, P., Nerbonne, J. M., Choi, B. R., & Salama, G. (2007). Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT. The Journal of Physiology, 578(Pt 1), 115–129.

    PubMed  CAS  Google Scholar 

  28. Salama, G., & London, B. (2007). Mouse models of long QT syndrome. The Journal of Physiology, 578(Pt 1), 43–53.

    PubMed  CAS  Google Scholar 

  29. Choi, B. R., Burton, F., & Salama, G. (2002). Cytosolic Ca2+ triggers early afterdepolarizations and Torsade de Pointes in rabbit hearts with type 2 long QT syndrome. The Journal of Physiology, 543(Pt 2), 615–631.

    Article  PubMed  CAS  Google Scholar 

  30. Killeen, M. J., & Sabir, I. N. (2007). Repolarization gradients and arrhythmogenicity in the murine heart. The Journal of Physiology, 583(Pt 2), 419–420.

    Article  PubMed  CAS  Google Scholar 

  31. Pond, A. L., Scheve, B. K., Benedict, A. T., Petrecca, K., Van Wagoner, D. R., Shrier, A., et al. (2000). Expression of distinct ERG proteins in rat, mouse, and human heart. Relation to functional I(Kr) channels. The Journal of Biological Chemistry, 275(8), 5997−6006.

    Article  PubMed  Google Scholar 

  32. Babij, P., Askew, G. R., Nieuwenhuijsen, B., Su, C. M., Bridal, T. R., Jow, 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(6), 668–678.

    PubMed  CAS  Google Scholar 

  33. Lees-Miller, J. P., Guo, J., Somers, J. R., Roach, D. E., Sheldon, R. S., Rancourt, D. E., et al. (2003). Selective knockout of mouse ERG1 B potassium channel eliminates I(Kr) in adult ventricular myocytes and elicits episodes of abrupt sinus bradycardia. Molecular and Cellular Biology, 23(6), 1856–1862.

    Article  PubMed  CAS  Google Scholar 

  34. Kupershmidt, S., Yang, T., Anderson, M. E., Wessels, A., Niswender, K. D., Magnuson, M. A., et al. (1999). Replacement by homologous recombination of the minK gene with lacZ reveals restriction of minK expression to the mouse cardiac conduction system. Circulation Research, 84(2), 146–152.

    PubMed  CAS  Google Scholar 

  35. Drici, M. D., Arrighi, I., Chouabe, C., Mann, J. R., Lazdunski, M., Romey, G., et al. (1998). Involvement of IsK-associated K+ channel in heart rate control of repolarization in a murine engineered model of Jervell and Lange-Nielsen syndrome. Circulation Research, 83(1), 95–102.

    PubMed  CAS  Google Scholar 

  36. Casimiro, M. C., Knollmann, B. C., Ebert, S. N., Vary Jr, J. C., Greene, A. E., Franz, M. R., et al. (2001). Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange-Nielsen syndrome. Proceedings of the National Academy of Sciences of the United States of America, 98(5), 2526–2531.

    Article  PubMed  CAS  Google Scholar 

  37. Lee, M. P., Ravenel, J. D., Hu, R. J., Lustig, L. R., Tomaselli, G., Berger, R. D., et al. (2000). Targeted disruption of the Kvlqt1 gene causes deafness and gastric hyperplasia in mice. The Journal of Clinical Investigation, 106(12), 1447–1455.

    Article  PubMed  CAS  Google Scholar 

  38. London, B., Trudeau, M. C., Newton, K. P., Beyer, A. K., Copeland, N. G., Gilbert, D. J., et al. (1997). Two isoforms of the mouse ether-a-go-go-related gene coassemble to form channels with properties similar to the rapidly activating component of the cardiac delayed rectifier K+ current. Circulation Research, 81(5), 870–878.

    PubMed  CAS  Google Scholar 

  39. Marx, S. O., Kurokawa, J., Reiken, S., Motoike, H., D'Armiento, J., Marks, A. R., et al. (2002). Requirement of a macromolecular signaling complex for beta adrenergic receptor modulation of the KCNQ1-KCNE1 potassium channel. Science, 295(5554), 496–499.

    Article  PubMed  CAS  Google Scholar 

  40. Sanguinetti, M. C. (2000). Long QT syndrome: ionic basis and arrhythmia mechanism in long QT syndrome type 1. Journal of Cardiovascular Electrophysiology, 11(6), 710–712. In Process Citation.

    Article  PubMed  CAS  Google Scholar 

  41. London, B., Newton, K. P., Vesely, M., Wong, J., Ginsberg, G., & Slater, C. (1995). Cloning the mouse homolog of the long QT syndrome gene HERG. Circulation, 92, I–223.

    Google Scholar 

  42. Barhanin, J., Lesage, F., Guillemare, E., Fink, M., Lazdunski, M., & Romey, G. K. (1996). (V)LQT1 and lsK (minK) proteins associate to form the I(Ks) cardiac potassium current. Nature, 384(6604), 78–80.

    Article  PubMed  CAS  Google Scholar 

  43. Vetter, D. E., Mann, J. R., Wangemann, P., Liu, J., McLaughlin, K. J., Lesage, F., et al. (1996). Inner ear defects induced by null mutation of the isk gene. Neuron, 17(6), 1251–1264.

    Article  PubMed  CAS  Google Scholar 

  44. Baker, L. C., Wolk, R., Choi, B. R., Watkins, S., Plan, P., Shah, A., et al. (2004). Effects of mechanical uncouplers, diacetyl monoxime, and cytochalasin-D on the electrophysiology of perfused mouse hearts. American Journal of Physiology. Heart and Circulatory Physiology, 287(4), H1771–H1779.

    Article  PubMed  CAS  Google Scholar 

  45. London, B., Baker, L. C., Lee, J. S., Shusterman, V., Choi, B. R., Kubota, T., et al. (2003). Calcium-dependent arrhythmias in transgenic mice with heart failure. American Journal of Physiology. Heart and Circulatory Physiology, 284(2), H431–H441.

    PubMed  CAS  Google Scholar 

  46. Trepanier-Boulay, V., St-Michel, C., Tremblay, A., & Fiset, C. (2001). Gender-based differences in cardiac repolarization in mouse ventricle. Circulation Research, 89(5), 437–444.

    Article  PubMed  CAS  Google Scholar 

  47. Drici, M. D., Baker, L., Plan, P., Barhanin, J., Romey, G., & Salama, G. (2002). Mice display sex differences in halothane-induced polymorphic ventricular tachycardia. Circulation, 106(4), 497–503.

    Article  PubMed  Google Scholar 

  48. Brouillette, J., Rivard, K., Lizotte, E., & Fiset, C. (2005). Sex and strain differences in adult mouse cardiac repolarization: importance of androgens. Cardiovascular Research, 65(1), 148–157.

    Article  PubMed  CAS  Google Scholar 

  49. Choi, B. R., & Salama, G. (2000). Simultaneous maps of optical action potentials and calcium transients in guinea-pig hearts: mechanisms underlying concordant alternans. The Journal of Physiology, 529(Pt 1), 171–188. In Process Citation.

    Article  PubMed  CAS  Google Scholar 

  50. Kanai, A., & Salama, G. (1995). Optical mapping reveals that repolarization spreads anisotropically and is guided by fiber orientation in guinea pig hearts. Circulation Research, 77(4), 784–802.

    PubMed  CAS  Google Scholar 

  51. London, B., Jeron, A., Zhou, J., Buckett, P., Han, X., Mitchell, G. F., & Koren, G. (1998). Long QT and ventricular arrhythmias in transgenic mice expressing the N terminus and first transmembrane segment of a voltage-gated potassium channel. Proceedings of the National Academy of Sciences of the United States of America, 95(6), 2926–2931.

    Article  PubMed  CAS  Google Scholar 

  52. Zhou, J., Jeron, A., London, B., Han, X., & Koren, G. (1998). Characterization of a slowly inactivating outward current in adult mouse ventricular myocytes. Circulation Research, 83(8), 806–814.

    PubMed  CAS  Google Scholar 

  53. Shimizu, W., & Antzelevitch, C. (1998). Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of beta-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation, 98(21), 2314–2322.

    PubMed  CAS  Google Scholar 

  54. Han, W., Wang, Z., & Nattel, S. (2001). Slow delayed rectifier current and repolarization in canine cardiac Purkinje cells. American Journal of Physiology. Heart and Circulatory Physiology, 280(3), H1075–H1080.

    PubMed  CAS  Google Scholar 

  55. Balasubramaniam, R., Grace, A. A., Saumarez, R. C., Vandenberg, J. I., & Huang, C. L. (2003). Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1. The Journal of Physiology, 552(Pt 2), 535–546.

    Article  PubMed  CAS  Google Scholar 

  56. Thomas, G., Gurung, I. S., Killeen, M. J., Hakim, P., Goddard, C. A., Mahaut-Smith, M. P., et al. (2007). Effects of L-type Ca2+ channel antagonism on ventricular arrhythmogenesis in murine hearts containing a modification in the Scn5a gene modelling human long QT syndrome 3. The Journal of Physiology, 578(Pt 1), 85–97.

    PubMed  CAS  Google Scholar 

  57. Thomas, G., Killeen, M. J., Gurung, I. S., Hakim, P., Balasubramaniam, R., Goddard, C. A., et al. (2007). Mechanisms of ventricular arrhythmogenesis in mice following targeted disruption of KCNE1 modelling long QT syndrome 5. The Journal of Physiology, 578(Pt 1), 99–114.

    PubMed  CAS  Google Scholar 

  58. Jost, N., Virag, L., Bitay, M., Takacs, J., Lengyel, C., Biliczki, P., et al. (2005). Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle. Circulation, 112(10), 1392–1399.

    Article  PubMed  Google Scholar 

  59. Royer, A., Demolombe, S., El Harchi, A., Le Quang, K., Piron, J., Toumaniantz, G., et al. (2005). Expression of human ERG K+ channels in the mouse heart exerts anti-arrhythmic activity. Cardiovascular Research, 65(1), 128–137.

    Article  PubMed  CAS  Google Scholar 

  60. Liu, G. X., Zhou, J., Nattel, S., & Koren, G. (2004). Single-channel recordings of a rapid delayed rectifier current in adult mouse ventricular myocytes: basic properties and effects of divalent cations. The Journal of Physiology, 556(Pt 2), 401–413.

    Article  PubMed  CAS  Google Scholar 

  61. Kuo, H. C., Cheng, C. F., Clark, R. B., Lin, J. J., Lin, J. L., Hoshijima, M., et al. (2001). A defect in the Kv channel-interacting protein 2 (KChIP2) gene leads to a complete loss of I(to) and confers susceptibility to ventricular tachycardia. Cell, 107(6), 801–813.

    Article  PubMed  CAS  Google Scholar 

  62. Hondeghem, L. M. (1992). Development of class III antiarrhythmic agents. J Cardiovasc Pharmacol, 20(Suppl 2(2), S17–22.

    Article  PubMed  CAS  Google Scholar 

  63. Roden, D. M. (1993). Torsade de pointes. Clinical Cardiology, 16(9), 683–686.

    Article  PubMed  CAS  Google Scholar 

  64. Surawicz, B. (1987). Contributions of cellular electrophysiology to the understanding of the electrocardiogram. Experientia, 43(10), 1061–1068.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

This study was supported by National Institutes of Health (NIH) with RO1 grants HL 59614, HL 57929 and HL 70722 to Dr. Guy Salama; and HL-66096 and an American Heart Association Established Investigator Award to Dr. Barry London.

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Authors and Affiliations

  1. Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh, S312 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA, 15261, USA

    Guy Salama, Linda Baker , Robert Wolk & Barry London

  2. Medtronic, Inc., Minneapolis, MN, 55432, USA

    Linda Baker

  3. Pfizer Inc., Eastern Point Road, Groton, CT, 06340, USA

    Robert Wolk

  4. L’ Institut de Pharmacologie Moléculaire et Cellulaire, CNRS-UPR 411 Sophia Antipolis, 06560, Valbonne, France

    Jacques Barhanin

  5. Cardiovascular Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Barry London

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  1. Guy Salama
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Salama, G., Baker , L., Wolk, R. et al. Arrhythmia phenotype in mouse models of human long QT. J Interv Card Electrophysiol 24, 77–87 (2009). https://doi.org/10.1007/s10840-008-9339-6

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