Dispersion of cardiac action potential duration and the initiation of re-entry: a computational study.
BACKGROUND
The initiation of re-entrant cardiac arrhythmias is associated with increased dispersion of repolarisation, but the details are difficult to investigate either experimentally or clinically. We used a computational model of cardiac tissue to study systematically the association between action potential duration (APD) dispersion and susceptibility to re-entry.


METHODS
We simulated a 60 x 60 mm2 D sheet of cardiac ventricular tissue using the Luo-Rudy phase 1 model, with maximal conductance of the K+ channel gKmax set to 0.004 mS mm(-2). Within the central 40 x 40 mm region we introduced square regions with prolonged APD by reducing gKmax to between 0.001 and 0.003 mS mm(-2). We varied (i) the spatial scale of these regions, (ii) the magnitude of gKmax in these regions, and (iii) cell-to-cell coupling.


RESULTS
Changing spatial scale from 5 to 20 mm increased APD dispersion from 49 to 102 ms, and the susceptible window from 31 to 86 ms. Decreasing gKmax in regions with prolonged APD from 0.003 to 0.001 mS mm-2 increased APD dispersion from 22 to 70 ms, and the susceptible window from <1 to 56 ms. Decreasing cell-to-cell coupling by changing the diffusion coefficient from 0.2 to 0.05 mm2 ms(-1) increased APD dispersion from 57 to 88 ms, and increased the susceptible window from 41 to 74 ms.


CONCLUSIONS
We found a close association between increased APD dispersion and susceptibility to re-entrant arrhythmias, when APD dispersion is increased by larger spatial scale of heterogeneity, greater electrophysiological heterogeneity, and weaker cell-to-cell coupling.
Clayton
Richard H
RH
Department of Computer Science, University of Sheffield, UK. r.h.clayton@sheffield.ac.uk
Holden
Arun V
AV
D000200:Action Potentials; D000818:Animals; D003198:Computer Simulation; D004198:Disease Susceptibility / Q000503:physiopathology; D004562:Electrocardiography / Q000379:methods; D006329:Heart Conduction System / Q000503:physiopathology*; D006352:Heart Ventricles / Q000503:physiopathology*; D006801:Humans; D008564:Membrane Potentials; D008955:Models, Cardiovascular; D017180:Tachycardia, Ventricular / Q000503:physiopathology*; D014693:Ventricular Fibrillation / Q000503:physiopathology*
Am J Physiol. 1999 Feb;276(2):H413-23
9950840
Circulation. 1992 Aug;86(2):467-74
1638716
Circ Res. 1991 Jun;68(6):1501-26
1709839
Prog Biophys Mol Biol. 2004 Jun-Jul;85(2-3):501-22
15142759
Circ Res. 1994 Jun;74(6):1071-96
7514509
Circulation. 1995 Aug 1;92(3):595-605
7634474
Cardiovasc Res. 1996 Jun;31(6):953-62
8759252
Cardiovasc Res. 2004 May 1;62(2):407-14
15094360
Am Heart J. 1964 Feb;67:200-20
14118488
Prog Biophys Mol Biol. 2004 Jun-Jul;85(2-3):473-99
15142758
Circulation. 1983 Jun;67(6):1356-67
6851031
Am J Physiol Heart Circ Physiol. 2001 Feb;280(2):H535-45
11158949
Biophys J. 2000 May;78(5):2392-404
10777735
Biophys J. 1998 Jul;75(1):1-14
9649363
J Am Coll Cardiol. 1997 Mar 15;29(4):817-24
9091529
Circ Res. 1976 Aug;39(2):168-77
939001
Am J Physiol Heart Circ Physiol. 2001 Dec;281(6):H2597-603
11709428
Circ Res. 1985 Sep;57(3):432-42
4028346
J Theor Biol. 1998 Feb 21;190(4):295-312
9533866
Circulation. 2002 Jun 25;105(25):3053-61
12082002
J Cardiovasc Electrophysiol. 2001 Feb;12(2):196-206
11232619
Cardiovasc Res. 2001 Apr;50(1):10-23
11282074
Circulation. 2003 Nov 11;108(19):2298-303
14609997
Heart Rhythm. 2004 Sep;1(3):334-44
15851180
IEEE Trans Biomed Eng. 1999 Sep;46(9):1166-8
10493080
Am J Physiol. 1999 Jan;276(1):H269-83
9887041
Annu Rev Physiol. 2000;62:25-50
10845083
Phys Med Biol. 2003 Jan 7;48(1):95-111
12564503
Circ Res. 1964 Jan;14:44-60
14104163
Circ Res. 2001 Dec 7;89(12):1216-23
11739288
Circ Res. 2002 May 17;90(9):E73-87
12016272
Physiol Meas. 2001 Aug;22(3):R15-34
11556683
J Cardiovasc Pharmacol. 1999 Feb;33(2):323-34
10028944
Circ Res. 1990 May;66(5):1310-27
2335029
J Cardiovasc Electrophysiol. 1995 Feb;6(2):115-31
7780627
Chaos. 2002 Sep;12(3):819-828
12779610
Cardiovasc Res. 1999 Jun;42(3):583-90
10533597
Circulation. 2000 Oct 3;102(14):1664-70
11015345
Circulation. 1987 Jul;76(1):226-36
3594771
Phys Rev Lett. 2002 Oct 14;89(16):168102
12398758
Cardiovasc Res. 2004 Sep 1;63(4):645-52
15306220
Circ Res. 1964 Jun;14:516-24
14169970
Circulation. 1999 May 11;99(18):2466-74
10318671
Circ Res. 1989 Nov;65(5):1426-40
2805251
Ann N Y Acad Sci. 2004 May;1015:133-43
15201155
Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1310-21
14630634