Restitution analysis of alternans and its relationship to arrhythmogenicity in hypokalaemic Langendorff-perfused murine hearts.
Alternans and arrhythmogenicity were studied in hypokalaemic (3.0 mM K(+)) Langendorff-perfused murine hearts paced at high rates. Epicardial and endocardial monophasic action potentials were recorded and durations quantified at 90% repolarization. Alternans and arrhythmia occurred in hypokalaemic, but not normokalaemic (5.2 mM K(+)) hearts (P<0.01): this was prevented by treatment with lidocaine (10 microM, P<0.01). Fourier analysis then confirmed transition from monomorphic to polymorphic waveforms for the first time in the murine heart. Alternans and arrhythmia were associated with increases in the slopes of restitution curves, obtained for the first time in the murine heart, while the anti-arrhythmic effect of lidocaine was associated with decreased slopes. Thus, hypokalaemia significantly increased (P<0.05) maximal gradients (from 0.55+/-0.14 to 2.35+/-0.67 in the epicardium and from 0.67+/-0.13 to 1.87 +/-0.28 in the endocardium) and critical diastolic intervals (DIs) at which gradients equalled unity (from -2.14+/-0.52 ms to 50.93+/-14.45 ms in the epicardium and from 8.14+/-1.49 ms to 44.64+/-5 ms in the endocardium). While treatment of normokalaemic hearts with lidocaine had no significant effect (P>0.05) on either maximal gradients (0.78+/-0.27 in the epicardium and 0.83+/-0.45 in the endocardium) or critical DIs (6.06+/-2.10 ms and 7.04+/-3.82 ms in the endocardium), treatment of hypokalaemic hearts with lidocaine reduced (P<0.05) both these parameters (1.05+/-0.30 in the epicardium and 0.89+/-0.36 in the endocardium and 30.38+/-8.88 ms in the epicardium and 31.65+/-4.78 ms in the endocardium, respectively). We thus demonstrate that alternans contributes a dynamic component to arrhythmic substrate during hypokalaemia, that restitution may furnish an underlying mechanism and that these phenomena are abolished by lidocaine, both recapitulating and clarifying clinical findings.
Sabir
Ian N
IN
Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK.
Li
Lucia M
LM
Grace
Andrew A
AA
Huang
Christopher L-H
CL
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D004562:Electrocardiography; D004699:Endocardium / Q000503:physiopathology; D005583:Fourier Analysis; D006339:Heart Rate / Q000187:drug effects; D007008:Hypokalemia / Q000150:complications* / Q000503:physiopathology; D008012:Lidocaine / Q000494:pharmacology; D051379:Mice; D008955:Models, Cardiovascular; D010477:Perfusion; D010496:Pericardium / Q000503:physiopathology; D015203:Reproducibility of Results; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D008012:Lidocaine
Circulation. 1989 Nov;80(5):1421-31
2553299
Circ Res. 2000 Mar 3;86(4):408-17
10700445
Pacing Clin Electrophysiol. 1991 Jul;14(7):1105-11
1715547
J Am Coll Cardiol. 1991 Nov 1;18(5):1363-6
1918714
Am J Physiol Heart Circ Physiol. 2007 Jan;292(1):H614-21
16963611
Acta Physiol (Oxf). 2007 Jan;189(1):33-46
17280555
Pflugers Arch. 2007 May;454(2):209-22
17295037
J Physiol. 2007 May 15;581(Pt 1):277-89
17331992
Acta Physiol (Oxf). 2007 Sep;191(1):43-58
17524066
Pflugers Arch. 2007 Sep;454(6):925-36
17437126
Pacing Clin Electrophysiol. 1992 Jun;15(6):916-31
1376904
J Am Coll Cardiol. 1992 Aug;20(2):483-99
1634690
Circulation. 1993 May;87(5):1661-72
8491022
N Engl J Med. 1994 Jan 27;330(4):235-41
8272084
J Am Coll Cardiol. 1994 Jun;23(7):1541-6
8195511
J Cardiovasc Electrophysiol. 1994 May;5(5):445-61
8055149
Science. 1994 Nov 11;266(5187):1003-6
7973648
Circulation. 1996 Feb 1;93(3):407-11
8565156
Circ Res. 1996 Apr;78(4):660-75
8635224
J Cardiovasc Electrophysiol. 1996 Feb;7(2):144-8
8853024
Am J Cardiol. 1998 Nov 1;82(9):1127-9, A9
9817496
Am J Physiol. 1998 Nov;275(5 Pt 2):H1635-42
9815071
J Am Coll Cardiol. 1999 Feb;33(2):327-32
9973011
Circulation. 1999 Mar 16;99(10):1385-94
10077525
Circulation. 1999 Mar 23;99(11):1499-507
10086976
Circ Res. 1999 Apr 30;84(8):955-63
10222343
Cardiovasc Res. 1999 Jun;42(3):583-90
10533597
J Physiol. 2007 Jan 1;578(Pt 1):99-114
17095567
Proc Natl Acad Sci U S A. 2000 May 23;97(11):6061-6
10811880
Am J Physiol Heart Circ Physiol. 2000 Sep;279(3):H1248-55
10993791
Am J Physiol Heart Circ Physiol. 2000 Dec;279(6):H2665-72
11087219
Circ Res. 2000 Dec 8;87(12):1103-7
11110766
J Am Coll Cardiol. 2000 Dec;36(7):2247-53
11127468
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2526-31
11226272
J Cardiovasc Electrophysiol. 2001 Sep;12(9):1089-91
11573703
J Cardiovasc Electrophysiol. 2001 Nov;12(11):1286-94
11761418
Am J Physiol Heart Circ Physiol. 2002 Mar;282(3):H1063-70
11834505
J Cardiovasc Electrophysiol. 2002 Sep;13(9):910-4
12380931
Cardiovasc Res. 2003 Mar;57(3):599-614
12618222
Ann Noninvasive Electrocardiol. 2003 Jul;8(3):252-61; discussion 251
14510663
J Physiol. 2003 Oct 15;552(Pt 2):535-46
14561835
Circulation. 2003 Nov 25;108(21):2704-9
14581412
Circ Res. 2004 Apr 30;94(8):1083-90
15016735
J Appl Physiol. 1968 Aug;25(2):191-6
5666097
Am Heart J. 1975 Jan;89(1):45-50
1109551
Cardiovasc Res. 1978 Sep;12(9):555-65
737668
Am J Cardiol. 1984 Jun 1;53(11):1577-82
6731302
Drugs. 1984 Oct;28 Suppl 1:54-65
6499703
Acta Med Scand. 1984;216(5):525-30
6395642
Am J Cardiol. 1985 Aug 30;56(6):20D-23D
4036815
Am J Med. 1986 Apr 25;80(4A):13-22
3706349
Circ Res. 1988 Aug;63(2):286-305
3396153
Circ Res. 1999 Jul 23;85(2):174-81
10417399
J Cardiovasc Electrophysiol. 2004 Dec;15(12):1357-63
15610278
J Am Coll Cardiol. 2005 Jan 18;45(2):300-7
15653031
J Clin Invest. 2005 Aug;115(8):2018-24
16075042
Circ Res. 2006 May 26;98(10):1244-53
16728670
Heart Rhythm. 2006 Jul;3(7):771-8
16818204
Circ Res. 2006 Sep 1;99(5):520-7
16902177
Science. 1991 Apr 19;252(5004):437-40
2017682