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Regional, age-dependent, and genotype-dependent differences in ventricular action potential duration and activation time in 410 Langendorff-perfused mouse hearts

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Abstract

Although numerous studies have reported the effects of genetic alterations on murine electrophysiology, the range of normal values for ventricular activation, repolarization, and arrhythmias in mouse hearts is not known. We analyzed right ventricular (RV), left ventricular (LV), and septal activation times, monophasic action potential durations (APD), and right ventricular effective refractory periods during spontaneous rhythm, induced AV nodal block, right ventricular pacing (100–300 ms paced cycle length), and programmed stimulation in 410 beating, Langendorff-perfused, wild-type mouse hearts of CD1, DBAC3H, FVBN, C57/Bl6, and hybrid backgrounds (age 203 ± 132 days). Action potential duration was longer at longer cycle lengths. LV-APD prolonged more than RV-APD, resulting in an increased heterogeneity of APD at longer pacing cycle lengths. Higher heart weight/body weight ratio and DBAC3H and FVB/N backgrounds were associated with long APD, C57Bl/6 background was associated with short APD. Activation times were longer in older hearts. There were no clear-cut sex-dependent APD differences. Sustained spontaneous arrhythmias occurred in 1% of hearts, non-sustained arrhythmias in 18%. Induction of AV block and C57Bl/6 genetic background were associated with spontaneous arrhythmias. Programmed stimulation induced arrhythmias in 51% of hearts. Inducible arrhythmias were associated with advanced age and shorter refractory periods. Ventricular APD in beating mouse hearts show rate- and site-dependent changes comparable to man and large animals. Bradycardia provokes spontaneous arrhythmias in mouse heart, while age-dependent conduction slowing and short refractory periods predispose to induced arrhythmias. Genetic background influences repolarization and arrhythmogenesis. These findings provide systematic data for the design and interpretation of arrhythmia studies in murine disease models.

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References

  1. Alhaddad IA, Khalil M, Brown EJ Jr (2000) Osborn waves of hypothermia. Circulation 101:E233–E244

    PubMed  CAS  Google Scholar 

  2. Bjornstad H, Tande PM, Lathrop DA, Refsum H (1993) Effects of temperature on cycle length dependent changes and restitution of action potential duration in guinea pig ventricular muscle. Cardiovasc Res 27:946–950

    Article  PubMed  CAS  Google Scholar 

  3. Boengler K, Heusch G, Schulz R (2006) Connexin 43 and ischemic preconditioning: effects of age and disease. Exp Gerontol 41:485–488

    Article  PubMed  CAS  Google Scholar 

  4. Boyett MR, Jewell BR (1978) A study of the factors responsible for rate-dependent shortening of the action potential in mammalian ventricular muscle. J Physiol 285:359–380

    PubMed  CAS  Google Scholar 

  5. Brouillette J, Rivard K, Lizotte E, Fiset C (2005) Sex and strain differences in adult mouse cardiac repolarization: importance of androgens. Cardiovasc Res 65:148–157

    Article  PubMed  CAS  Google Scholar 

  6. Brouillette J, Trepanier-Boulay V, Fiset C (2003) Effect of androgen deficiency on mouse ventricular repolarization. J Physiol 546:403–413

    Article  PubMed  CAS  Google Scholar 

  7. Brugada P, Waldecker B, Kersschot Y, Zehender M, Wellens HJ (1986) Ventricular arrhythmias initiated by programmed stimulation in four groups of patients with healed myocardial infarction. J Am Coll Cardiol 8:1035–1040

    PubMed  CAS  Google Scholar 

  8. Brunet S, Aimond F, Li H, Guo W, Eldstrom J, Fedida D, Yamada KA, Nerbonne JM (2004) Heterogeneous expression of repolarizing, voltage-gated K+ currents in adult mouse ventricles. J Physiol 559:103–120

    Article  PubMed  CAS  Google Scholar 

  9. Casimiro MC, Knollmann BC, Ebert SN, Vary JC Jr, Greene AE, Franz MR, Grinberg A, Huang SP, Pfeifer K (2001) Targeted disruption of the Kcnq1 gene produces a mouse model of Jervell and Lange–Nielsen Syndrome. Proc Natl Acad Sci USA 98:2526–2531

    Article  PubMed  CAS  Google Scholar 

  10. Danik S, Cabo C, Chiello C, Kang S, Wit AL, Coromilas J (2002) Correlation of repolarization of ventricular monophasic action potential with ECG in the murine heart. Am J Physiol Heart Circ Physiol 283:H372–H381

    PubMed  CAS  Google Scholar 

  11. Darrow BJ, Fast VG, Kleber AG, Beyer EC, Saffitz JE (1996) Functional and structural assessment of intercellular communication. Increased conduction velocity and enhanced connexin expression in dibutyryl cAMP-treated cultured cardiac myocytes. Circ Res 79:174–183

    PubMed  CAS  Google Scholar 

  12. Desai KH, Sato R, Schauble E, Barsh GS, Kobilka BK, Bernstein D (1997) Cardiovascular indexes in the mouse at rest and with exercise: new tools to study models of cardiac disease. Am J Physiol 272:H1053–H1061

    PubMed  CAS  Google Scholar 

  13. Doevendans PA, Daemen MJ, de Muinck ED, Smits JF (1998) Cardiovascular phenotyping in mice. Cardiovasc Res 39:34–49

    Article  PubMed  CAS  Google Scholar 

  14. Fabritz L, Kirchhof P, Franz MR, Eckardt L, Monnig G, Milberg P, Breithardt G, Haverkamp W (2003) Prolonged action potential durations, increased dispersion of repolarization, and polymorphic ventricular tachycardia in a mouse model of proarrhythmia. Basic Res Cardiol 98:25–32

    Article  PubMed  Google Scholar 

  15. Fabritz L, Kirchhof P, Franz MR, Nuyens D, Rossenbacker T, Ottenhof A, Haverkamp W, Breithardt G, Carmeliet E, Carmeliet P (2003) Effect of pacing and mexiletine on dispersion of repolarisation and arrhythmias in DeltaKPQ SCN5A (long QT3) mice. Cardiovasc Res 57:1085–1093

    Article  PubMed  CAS  Google Scholar 

  16. Fast VG, Darrow BJ, Saffitz JE, Kleber AG (1996) Anisotropic activation spread in heart cell monolayers assessed by high-resolution optical mapping: role of tissue discontinuities. Circ Res 79:115–127

    PubMed  CAS  Google Scholar 

  17. Franz MR, Bargheer K, Costard-Jackle A, Miller DC, Lichtlen PR (1991) Human ventricular repolarization and T wave genesis. Prog Cardiovasc Dis 33:369–384

    Article  PubMed  CAS  Google Scholar 

  18. Franz MR, Costard A (1988) Frequency-dependent effects of quinidine on the relationship between action potential duration and refractoriness in the canine heart in situ. Circulation 77:1177–1184

    PubMed  CAS  Google Scholar 

  19. Franz MR, Kirchhof PF, Fabritz CL, Zabel M (1995) Computer analysis of monophasic action potentials: manual validation and clinically pertinent applications. Pacing Clin Electrophysiol 18:1666–1678

    Article  PubMed  CAS  Google Scholar 

  20. Franz MR, Swerdlow CD, Liem LB, Schaefer J (1988) Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies. J Clin Invest 82:972–979

    Article  PubMed  CAS  Google Scholar 

  21. Gehrmann J, Berul CI (2000) Cardiac electrophysiology in genetically engineered mice. J Cardiovasc Electrophysiol 11:354–368

    Article  PubMed  CAS  Google Scholar 

  22. Gehrmann J, Frantz S, Maguire CT, Vargas M, Ducharme A, Wakimoto H, Lee RT, Berul CI (2001) Electrophysiological characterization of murine myocardial ischemia and infarction. Basic Res Cardiol 96:237–250

    Article  PubMed  CAS  Google Scholar 

  23. Gussak I, Chaitman BR, Kopecky SL, Nerbonne JM (2000) Rapid ventricular repolarization in rodents: electrocardiographic manifestations, molecular mechanisms, and clinical insights. J Electrocardiol 33:159–170

    Article  PubMed  CAS  Google Scholar 

  24. Gutstein DE, Morley GE, Tamaddon H, Vaidya D, Schneider MD, Chen J, Chien KR, Stuhlmann H, Fishman GI (2001) Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43. Circ Res 88:333–339

    PubMed  CAS  Google Scholar 

  25. Hart G (1994) Cellular electrophysiology in cardiac hypertrophy and failure. Cardiovasc Res 28:933–946

    Article  PubMed  CAS  Google Scholar 

  26. Hart G (2003) Exercise-induced cardiac hypertrophy: a substrate for sudden death in athletes? Exp Physiol 88:639–644

    Article  PubMed  CAS  Google Scholar 

  27. Hocher B, Thone-Reineke C, Rohmeiss P, Schmager F, Slowinski T, Burst V, Siegmund F, Quertermous T, Bauer C, Neumayer HH, Schleuning WD, Theuring F (1997) Endothelin-1 transgenic mice develop glomerulosclerosis, interstitial fibrosis, and renal cysts but not hypertension. J Clin Invest 99:1380–1389

    Article  PubMed  CAS  Google Scholar 

  28. Jeron A, Mitchell GF, Zhou J, Murata M, London B, Buckett P, Wiviott SD, Koren G (2000) Inducible polymorphic ventricular tachyarrhythmias in a transgenic mouse model with a long Q-T phenotype. Am J Physiol Heart Circ Physiol 278:H1891–H1898

    PubMed  CAS  Google Scholar 

  29. Jiang C, Atkinson D, Towbin JA, Splawski I, Lehmann MH, Li H, Timothy K, Taggart RT, Schwartz PJ, Vincent GM et al (1994) Two long QT syndrome loci map to chromosomes 3 and 7 with evidence for further heterogeneity. Nat Genet 8:141–147

    Article  PubMed  CAS  Google Scholar 

  30. Kiyosue T, Arita M, Muramatsu H, Spindler AJ, Noble D (1993) Ionic mechanisms of action potential prolongation at low temperature in guinea-pig ventricular myocytes. J Physiol 468:85–106

    PubMed  CAS  Google Scholar 

  31. Klein GJ, Ideker RE, Smith WM, Harrison LA, Kasell J, Wallace AG, Gallagher JJ (1979) Epicardial mapping of the onset of ventricular tachycardia initiated by programmed stimulation in the canine heart with chronic infarction. Circulation 60:1375–1384

    PubMed  CAS  Google Scholar 

  32. Knollmann BC, Katchman AN, Franz MR (2001) Monophasic action potential recordings from intact mouse heart: validation, regional heterogeneity, and relation to refractoriness. J Cardiovasc Electrophysiol 12:1286–1294

    Article  PubMed  CAS  Google Scholar 

  33. Knollmann BC, Schober T, Petersen AO, Sirenko SG, Franz MR (2007) Action potential characterization in intact mouse heart: steady-state cycle length dependence and electrical restitution. Am J Physiol Heart Circ Physiol 292:H614–H621

    Article  PubMed  CAS  Google Scholar 

  34. Kramer K, van Acker SA, Voss HP, Grimbergen JA, van der Vijgh WJ, Bast A (1993) Use of telemetry to record electrocardiogram and heart rate in freely moving mice. J Pharmacol Toxicol Methods 30:209–215

    Article  PubMed  CAS  Google Scholar 

  35. Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K, Nagai R, Oda H, Kuwaki T, Cao WH, Kamada N et al (1994) Elevated blood pressure and craniofacial abnormalities in mice deficient in endothelin-1. Nature 368:703–710

    Article  PubMed  CAS  Google Scholar 

  36. Lee RJ, Liem LB, Cohen TJ, Franz MR (1992) Relation between repolarization and refractoriness in the human ventricle: cycle length dependence and effect of procainamide. J Am Coll Cardiol 19:614–618

    Article  PubMed  CAS  Google Scholar 

  37. London B, Jeron A, Zhou J, Buckett P, Han X, Mitchell GF, 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. Proc Natl Acad Sci USA 95:2926–2931

    Article  PubMed  CAS  Google Scholar 

  38. Merot J, Probst V, Debailleul M, Gerlach U, Moise NS, Le Marec H, Charpentier F (2000) Electropharmacological characterization of cardiac repolarization in German shepherd dogs with an inherited syndrome of sudden death: abnormal response to potassium channel blockers. J Am Coll Cardiol 36:939–947

    Article  PubMed  CAS  Google Scholar 

  39. Meszaros J, Ryder KO, Hart G (1996) Transient outward current in catecholamine-induced cardiac hypertrophy in the rat. Am J Physiol 271:H2360–H2367

    PubMed  CAS  Google Scholar 

  40. Migliaro ER, Michelini M, Duran HN (1997) Action potential duration and contraction after rest at room temperature in guinea pig papillary muscle. Acta Physiol Pharmacol Ther Latinoam 47:107–118

    PubMed  CAS  Google Scholar 

  41. Nuyens D, Stengl M, Dugarmaa S, Rossenbacker T, Compernolle V, Rudy Y, Smits JF, Flameng W, Clancy CE, Moons L, Vos MA, Dewerchin M, Benndorf K, Collen D, Carmeliet E, Carmeliet P (2001) Abrupt rate accelerations or premature beats cause life-threatening arrhythmias in mice with long-QT3 syndrome. Nat Med 7:1021–1027

    Article  PubMed  CAS  Google Scholar 

  42. Olgers TJ, Ubels FL (2006) The ECG in hypothermia: Osborn waves. Neth J Med 64:350, 353

    Google Scholar 

  43. Opthof T, Coronel R (2000) Electrocardiogram of the normal mouse, Mus musculus: general considerations and genetic aspects. Cardiovasc Res 45:227–230

    PubMed  CAS  Google Scholar 

  44. Piao L, Li J, McLerie M, Lopatin AN (2007) Transgenic upregulation of I-K1 in the mouse heart is proarrhythmic. Basic Res Cardiol 102:416–428

    Article  PubMed  Google Scholar 

  45. Reiss K, Cheng W, Ferber A, Kajstura J, Li P, Li B, Olivetti G, Homcy CJ, Baserga R, Anversa P (1996) Overexpression of insulin-like growth factor-1 in the heart is coupled with myocyte proliferation in transgenic mice. Proc Natl Acad Sci USA 93:8630–8635

    Article  PubMed  CAS  Google Scholar 

  46. Roscher R, Arlock P, Sjoberg T, Steen S (2001) Effects of dopamine on porcine myocardial action potentials and contractions at 37 degrees C and 32 degrees C. Acta Anaesthesiol Scand 45:421–426

    Article  PubMed  CAS  Google Scholar 

  47. Sager PT, Uppal P, Follmer C, Antimisiaris M, Pruitt C, Singh BN (1993) Frequency-dependent electrophysiologic effects of amiodarone in humans. Circulation 88:1063–1071

    PubMed  CAS  Google Scholar 

  48. Song Y, Yao Q, Zhu J, Luo B, Liang S (1999) Age-related variation in the interstitial tissues of the cardiac conduction system; and autopsy study of 230 Han Chinese. Forensic Sci Int 104:133–142

    Article  PubMed  CAS  Google Scholar 

  49. Tomaselli GF, Marban E (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 42:270–283

    Article  PubMed  CAS  Google Scholar 

  50. Trepanier-Boulay V, St-Michel C, Tremblay A, Fiset C (2001) Gender-based differences in cardiac repolarization in mouse ventricle. Circ Res 89:437–444

    Article  PubMed  CAS  Google Scholar 

  51. van der Linde HJ, Van Deuren B, Teisman A, Towart R, Gallacher DJ (2008) The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction. Br J Pharmacol 154:1474–1481

    Article  PubMed  CAS  Google Scholar 

  52. Wang Q, Shen J, Splawski I, Atkinson D, Li Z, Robinson JL, Moss AJ, Towbin JA, Keating MT (1995) SCN5A mutations associated with an inherited cardiac arrhythmia, long QT syndrome. Cell 80:805–811

    Article  PubMed  CAS  Google Scholar 

  53. Yeh HI, Chang HM, Lu WW, Lee YN, Ko YS, Severs NJ, Tsai CH (2000) Age-related alteration of gap junction distribution and connexin expression in rat aortic endothelium. J Histochem Cytochem 48:1377–1389

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Funded by DFG (Ki 731/1-1, Fa 413/3-1, SFB 656-A5), IZKF Münster (Core Unit CarTel and Kih 1/020/07), and Fondation LeDucq.

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Authors and Affiliations

  1. Department of Cardiology and Angiology, University Hospital Muenster, Münster, Germany

    Christoph Waldeyer, Larissa Fabritz, Lisa Fortmueller, Dierk Damke, Andreas Blana, Sandra Laakmann, Nina Kreienkamp, Daniela Volkery, Günter Breithardt & Paulus Kirchhof

  2. Interdisciplinary Center for Clinical Research, Münster, Germany

    Christoph Waldeyer, Larissa Fabritz, Lisa Fortmueller, Sandra Laakmann, Nina Kreienkamp & Paulus Kirchhof

  3. Department of Medical Informatics and Biomathematics, University Hospital Muenster, Münster, Germany

    Joachim Gerss

  4. Medizinische Klinik und Poliklinik C, Kardiologie und Angiologie, Universitätsklinikum Münster, 48129, Münster, Germany

    Paulus Kirchhof

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  1. Christoph Waldeyer
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  2. Larissa Fabritz
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  3. Lisa Fortmueller
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Waldeyer, C., Fabritz, L., Fortmueller, L. et al. Regional, age-dependent, and genotype-dependent differences in ventricular action potential duration and activation time in 410 Langendorff-perfused mouse hearts. Basic Res Cardiol 104, 523–533 (2009). https://doi.org/10.1007/s00395-009-0019-1

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