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Basic Research in Cardiology
Published in: Basic Research in Cardiology 5/2009

01-09-2009 | Original Contribution

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

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

Published in: Basic Research in Cardiology | Issue 5/2009

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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.
Literature
1.
Alhaddad IA, Khalil M, Brown EJ Jr (2000) Osborn waves of hypothermia. Circulation 101:E233–E244PubMed
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 27:946–950PubMedCrossRef
3.
Boengler K, Heusch G, Schulz R (2006) Connexin 43 and ischemic preconditioning: effects of age and disease. Exp Gerontol 41:485–488PubMedCrossRef
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 285:359–380PubMed
5.
Brouillette J, Rivard K, Lizotte E, Fiset C (2005) Sex and strain differences in adult mouse cardiac repolarization: importance of androgens. Cardiovasc Res 65:148–157PubMedCrossRef
6.
Brouillette J, Trepanier-Boulay V, Fiset C (2003) Effect of androgen deficiency on mouse ventricular repolarization. J Physiol 546:403–413PubMedCrossRef
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 8:1035–1040PubMed
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 559:103–120PubMedCrossRef
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 98:2526–2531PubMedCrossRef
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–H381PubMed
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 79:174–183PubMed
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–H1061PubMed
13.
Doevendans PA, Daemen MJ, de Muinck ED, Smits JF (1998) Cardiovascular phenotyping in mice. Cardiovasc Res 39:34–49PubMedCrossRef
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 98:25–32PubMedCrossRef
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 57:1085–1093PubMedCrossRef
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 79:115–127PubMed
17.
Franz MR, Bargheer K, Costard-Jackle A, Miller DC, Lichtlen PR (1991) Human ventricular repolarization and T wave genesis. Prog Cardiovasc Dis 33:369–384PubMedCrossRef
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 77:1177–1184PubMed
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 18:1666–1678PubMedCrossRef
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 82:972–979PubMedCrossRef
21.
Gehrmann J, Berul CI (2000) Cardiac electrophysiology in genetically engineered mice. J Cardiovasc Electrophysiol 11:354–368PubMedCrossRef
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 96:237–250PubMedCrossRef
23.
Gussak I, Chaitman BR, Kopecky SL, Nerbonne JM (2000) Rapid ventricular repolarization in rodents: electrocardiographic manifestations, molecular mechanisms, and clinical insights. J Electrocardiol 33:159–170PubMedCrossRef
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 88:333–339PubMed
25.
Hart G (1994) Cellular electrophysiology in cardiac hypertrophy and failure. Cardiovasc Res 28:933–946PubMedCrossRef
26.
Hart G (2003) Exercise-induced cardiac hypertrophy: a substrate for sudden death in athletes? Exp Physiol 88:639–644PubMedCrossRef
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 99:1380–1389PubMedCrossRef
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–H1898PubMed
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 8:141–147PubMedCrossRef
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 468:85–106PubMed
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 60:1375–1384PubMed
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 12:1286–1294PubMedCrossRef
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–H621PubMedCrossRef
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 30:209–215PubMedCrossRef
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 368:703–710PubMedCrossRef
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 19:614–618PubMedCrossRef
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 95:2926–2931PubMedCrossRef
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 36:939–947PubMedCrossRef
39.
Meszaros J, Ryder KO, Hart G (1996) Transient outward current in catecholamine-induced cardiac hypertrophy in the rat. Am J Physiol 271:H2360–H2367PubMed
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 47:107–118PubMed
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 7:1021–1027PubMedCrossRef
42.
Olgers TJ, Ubels FL (2006) The ECG in hypothermia: Osborn waves. Neth J Med 64:350, 353
43.
Opthof T, Coronel R (2000) Electrocardiogram of the normal mouse, Mus musculus: general considerations and genetic aspects. Cardiovasc Res 45:227–230PubMed
44.
Piao L, Li J, McLerie M, Lopatin AN (2007) Transgenic upregulation of I-K1 in the mouse heart is proarrhythmic. Basic Res Cardiol 102:416–428PubMedCrossRef
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 93:8630–8635PubMedCrossRef
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 45:421–426PubMedCrossRef
47.
Sager PT, Uppal P, Follmer C, Antimisiaris M, Pruitt C, Singh BN (1993) Frequency-dependent electrophysiologic effects of amiodarone in humans. Circulation 88:1063–1071PubMed
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 104:133–142PubMedCrossRef
49.
Tomaselli GF, Marban E (1999) Electrophysiological remodeling in hypertrophy and heart failure. Cardiovasc Res 42:270–283PubMedCrossRef
50.
Trepanier-Boulay V, St-Michel C, Tremblay A, Fiset C (2001) Gender-based differences in cardiac repolarization in mouse ventricle. Circ Res 89:437–444PubMedCrossRef
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 154:1474–1481PubMedCrossRef
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 80:805–811PubMedCrossRef
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 48:1377–1389PubMed
Metadata
Title
Regional, age-dependent, and genotype-dependent differences in ventricular action potential duration and activation time in 410 Langendorff-perfused mouse hearts
Authors
Christoph Waldeyer
Larissa Fabritz
Lisa Fortmueller
Joachim Gerss
Dierk Damke
Andreas Blana
Sandra Laakmann
Nina Kreienkamp
Daniela Volkery
Günter Breithardt
Paulus Kirchhof
Publication date
01-09-2009
Publisher
D. Steinkopff-Verlag
Published in
Basic Research in Cardiology / Issue 5/2009
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI
https://doi.org/10.1007/s00395-009-0019-1

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