Inhibition of intercellular coupling stabilizes spiral-wave reentry, whereas enhancement of the coupling destabilizes the reentry in favor of early termination.
Spiral-wave (SW) reentry is a major organizing principle of ventricular tachycardia/fibrillation (VT/VF). We tested a hypothesis that pharmacological modification of gap junction (GJ) conductance affects the stability of SW reentry in a two-dimensional (2D) epicardial ventricular muscle layer prepared by endocardial cryoablation of Langendorff-perfused rabbit hearts. Action potential signals were recorded and analyzed by high-resolution optical mapping. Carbenoxolone (CBX; 30 μM) and rotigaptide (RG, 0.1 μM) were used to inhibit and enhance GJ coupling, respectively. CBX decreased the space constant (λ) by 36%, whereas RG increased it by 22-24% (n = 5; P < 0.01). During centrifugal propagation, there was a linear relationship between the wavefront curvature (κ) and local conduction velocity (LCV): LCV = LCV(0) - D·κ (D, diffusion coefficient; LCV(0), LCV at κ = 0). CBX decreased LCV(0) and D by 27 ± 3 and 57 ± 3%, respectively (n = 5; P < 0.01). RG increased LCV(0) and D by 18 ± 3 and 54 ± 5%, respectively (n = 5, P < 0.01). The regression lines with and without RG crossed, resulting in a paradoxical decrease of LCV with RG at κ > ~60 cm(-1). SW reentry induced after CBX was stable, and the incidence of sustained VTs (>30 s) increased from 38 ± 4 to 85 ± 4% after CBX (n = 18; P < 0.01). SW reentry induced after RG was characterized by decremental conduction near the rotation center, prominent drift and self-termination by collision with the anatomical boundaries, and the incidence of sustained VTs decreased from 40 ± 5 to 17 ± 6% after RG (n = 13; P < 0.05). These results suggest that decreased intercellular coupling stabilizes SW reentry in 2D cardiac muscle, whereas increased coupling facilitates its early self-termination.
Department of Cardiovascular Research, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
Yoshio
Y
Takemoto
Hiroki
H
Takanari
Haruo
H
Honjo
Norihiro
N
Ueda
Masahide
M
Harada
Sara
S
Kato
Masatoshi
M
Yamazaki
Ichiro
I
Sakuma
Tobias
T
Opthof
Itsuo
I
Kodama
Kaichiro
K
Kamiya
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002229:Carbenoxolone / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D004195:Disease Models, Animal; D022062:Electrophysiologic Techniques, Cardiac; D017629:Gap Junctions / Q000187:drug effects* / Q000378:metabolism; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009842:Oligopeptides / Q000494:pharmacology*; D010477:Perfusion; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors; D014693:Ventricular Fibrillation / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D056969:Voltage-Sensitive Dye Imaging
D000889:Anti-Arrhythmia Agents; D009842:Oligopeptides; C477643:rotigaptide; D002229:Carbenoxolone