Acute myocardial ischemia is an imbalance between myocardial blood supply and demand, which is caused by the cessation of blood flow within the heart resulting from an obstruction in one of the major coronary arteries. A severe blockage may result in a region of nonperfused tissue known as ischemic core (IC). As a result, a border zone (BZ) between perfused and nonperfused regions is created due to differences in blood and oxygen supplies. Recent experimental findings reveal a complex “finger-like” geometry in BZ; however, its effect on arrhythmogenicity is not clear. Ephaptic coupling, which relies on the intercalated disk between cell ends, has been suggested to play an active role in mediating intercellular electrical communication when gap junctions are impaired. In this paper, we explored the interplay between ephaptic coupling and the geometry of BZ on action potential propagation across the ischemic region. Our study shows that ephaptic coupling can greatly suppress the occurrence of a conduction block, which points to its beneficial effect. The beneficial effect of ephaptic coupling is more evident in BZ with the “finger-like” geometry. In addition, the complex geometry of BZ, i.e., more frequent, deeper, and wider “fingers,” promotes the conduction through the ischemic region. In contrast, the larger size of IC impedes the cardiac conduction across the ischemic region. Our results also show that ephaptic coupling promotes the impact of the complex geometry of BZ on signal propagation; however, it inhibits the impact of IC size.

1.
W.
Shim
and
P.
Wong
, “
Stem cell cardiomyoplasty: State-of-the-art
,”
Ann. Acad. Med. Singapore
33
,
451
460
(
2004
).
2.
R. M.
Smith
,
A. J.
Black
,
S. S.
Velamakanni
,
T.
Akkin
, and
E. G.
Tolkacheva
, “
Visualizing the complex 3D geometry of the perfusion border zone in isolated rabbit heart
,”
Appl. Opt.
51
,
2713
2721
(
2012
).
3.
J. P.
Kucera
,
S.
Rohr
, and
Y.
Rudy
, “
Localization of sodium channels in intercalated disks modulates cardiac conduction
,”
Circ. Res.
91
,
1176
1182
(
2002
).
4.
P. E.
Hand
and
C. S.
Peskin
, “
Homogenization of an electrophysiological model for a strand of cardiac myocytes with gap-junctional and electric-field coupling
,”
Bull. Math. Biol.
72
,
1408
1424
(
2010
).
5.
J.
Lin
and
J. P.
Keener
, “
Microdomain effects on transverse cardiac propagation
,”
Biophys. J.
106
,
925
931
(
2014
).
6.
Y.
Mori
,
G. I.
Fishman
, and
C. S.
Peskin
, “
Ephaptic conduction in a cardiac strand model with 3d electrodiffusion
,”
Proc. Natl. Acad. Sci. U.S.A.
105
,
6463
6468
(
2008
).
7.
R.
Veeraraghavan
,
S.
Poelzing
, and
R. G.
Gourdie
, “
Intercellular electrical communication in the heart: A new, active role for the intercalated disk
,”
Cell Commun. Adhes.
21
,
161
167
(
2014
).
8.
E. D.
Copene
and
J. P.
Keener
, “
Ephaptic coupling of cardiac cells through the junctional electric potential
,”
J. Math. Biol.
57
,
265
284
(
2008
).
9.
J. B.
Picone
,
N.
Sperelakis
, and
J. E.
Mann
, “
Expanded model of the electric field hypothesis for propagation in cardiac muscle
,”
Math. Comput. Model.
15
,
17
35
(
1991
).
10.
J.
Lin
and
J. P.
Keener
, “
Ephaptic coupling in cardiac myocytes
,”
IEEE Trans. Biomed. Eng.
60
,
576
582
(
2013
).
11.
M. J.
Janse
and
A. L.
Wit
, “
Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction
,”
Physiol. Rev.
69
,
1049
1169
(
1989
).
12.
R.
Coronel
,
F.
Wilms-Schopman
,
T.
Opthof
,
J.
Cinca
,
J.
Fiolet
, and
M. J.
Janse
, “
Reperfusion arrhythmias in isolated perfused pig hearts. Inhomogeneities in extracellular potassium, ST and TQ potentials, and transmembrane action potentials
,”
Circ. Res.
71
,
1131
1142
(
1992
).
13.
R. M.
Shaw
and
Y.
Rudy
, “
Electrophysiologic effects of acute myocardial ischemia. A mechanistic investigation of action potential conduction and conduction failure
,”
Circ. Res.
80
,
124
138
(
1997
).
14.
R. M.
Shaw
and
Y.
Rudy
, “
The vulnerable window for unidirectional block in cardiac tissue: Characterization and dependence on membrane excitability and intercellular coupling
,”
J. Cardiovasc. Electrophysiol.
6
,
115
131
(
1995
).
15.
O.
Bernus
,
C. W.
Zemlin
,
R. M.
Zaritsky
,
S. F.
Mironov
, and
A. M.
Pertsov
, “
Alternating conduction in the ischaemic border zone as precursor of reentrant arrhythmias: A simulation study
,”
Europace
7
,
S93
S104
(
2005
).
16.
P.
Beauchamp
,
C.
Choby
,
T.
Desplantez
,
K.
de Peyer
,
K.
Green
,
K. A.
Yamada
,
R.
Weingart
,
J. E.
Saffitz
, and
A. G.
Kléber
, “
Electrical propagation in synthetic ventricular myocyte strands from germline connexin43 knockout mice
,”
Circ. Res.
95
,
170
178
(
2004
).
17.
P.
Beauchamp
,
T.
Desplantez
,
M. L.
McCain
,
W.
Li
,
A.
Asimaki
,
G.
Rigoli
,
K. K.
Parker
,
J. E.
Saffitz
, and
A. G.
Kleber
, “
Electrical coupling and propagation in engineered ventricular myocardium with heterogeneous expression of connexin43
,”
Circ. Res.
110
,
1445
1453
(
2012
).
18.
R. M.
Shaw
and
Y.
Rudy
, “
Ionic mechanisms of propagation in cardiac tissue roles of the sodium and l-type calcium currents during reduced excitability and decreased gap junction coupling
,”
Circ. Res.
81
,
727
741
(
1997
).
19.
D.
Vaidya
,
H. S.
Tamaddon
,
C. W.
Lo
,
S. M.
Taffet
,
M.
Delmar
,
G. E.
Morley
, and
J.
Jalife
, “
Null mutation of connexin43 causes slow propagation of ventricular activation in the late stages of mouse embryonic development
,”
Circ. Res.
88
,
1196
1202
(
2001
).
20.
J.-A.
Yao
,
D. E.
Gutstein
,
F.
Liu
,
G. I.
Fishman
, and
A. L.
Wit
, “
Cell coupling between ventricular myocyte pairs from connexin43-deficient murine hearts
,”
Circ. Res.
93
,
736
743
(
2003
).
21.
N.
Sperelakis
, “
An electric field mechanism for transmission of excitation between myocardial cells
,”
Circ. Res.
91
,
985
987
(
2002
).
22.
N.
Sperelakis
and
J. E.
Mann
, “
Evaluation of electric field changes in the cleft between excitable cells
,”
J. Theor. Biol.
64
,
71
96
(
1977
).
23.
N.
Wei
,
Y.
Mori
, and
E. G.
Tolkacheva
, “
The dual effect of ephaptic coupling on cardiac conduction with heterogeneous expression of connexin 43
,”
J. Theor. Biol.
397
,
103
114
(
2016
).
24.
N.
Peters
,
C.
Green
,
P.
Poole-Wilson
, and
N.
Severs
, “
Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts
,”
Circulation
88
,
864
875
(
1993
).
25.
L. M.
Livshitz
and
Y.
Rudy
, “
Regulation of Ca2+ and electrical alternans in cardiac myocytes: Role of CAMKII and repolarizing currents
,”
Am. J. Physiol. Heart Circ. Physiol.
292
,
H2854
H2866
(
2007
).
26.
R. M.
Shaw
and
Y.
Rudy
, “
Electrophysiologic effects of acute myocardial ischemia: A theoretical study of altered cell excitability and action potential duration
,”
Cardiovasc. Res.
35
,
256
272
(
1997
).
27.
J.
Smith
,
C.
Green
,
N.
Peters
,
S.
Rothery
, and
N.
Severs
, “
Altered patterns of gap junction distribution in ischemic heart disease. An immunohistochemical study of human myocardium using laser scanning confocal microscopy
,”
Am. J. Pathol.
139
,
801
(
1991
).
28.
X.
Wang
and
A. M.
Gerdes
, “
Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: III. Intercalated disc remodeling
,”
J. Mol. Cell. Cardiol.
31
,
333
343
(
1999
).
29.
A.
Waldo
and
A.
Wit
, “
Mechanisms of cardiac arrhythmias
,”
Lancet
341
,
1189
1193
(
1993
).
30.
R.
Veeraraghavan
,
M. E.
Salama
, and
S.
Poelzing
, “
Interstitial volume modulates the conduction velocity-gap junction relationship
,”
Am. J. Physiol. Heart Circ. Physiol.
302
,
H278
H286
(
2011
).
31.
Y.
Prudat
and
J. P.
Kucera
, “
Nonlinear behaviour of conduction and block in cardiac tissue with heterogeneous expression of connexin 43
,”
J. Mol. Cell. Cardiol.
76
,
46
54
(
2014
).

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