Heavy ion radiation up-regulates Cx43 and ameliorates arrhythmogenic substrates in hearts after myocardial infarction.
OBJECTIVE
Radiation has been shown to enhance intercellular communication in the skin and lungs through an increase of connexin43 (Cx43) expression. If analogous Cx43 up-regulation is induced in the diseased heart, it would provide a new perspective in radiation therapy for arrhythmias. The aim of the present study is to test this hypothesis.


METHODS
Non-transmural myocardial infarction (MI) was created in 24 rabbits by microsphere injection into the coronary arteries. Twenty-four rabbits without MI were used as controls. Targeted external heavy ion beam irradiation (THIR; 15 Gy) was applied 2 weeks after MI with an accelerator (HIMAC, Chiba, Japan).


RESULTS
The THIR was associated with an increase of Cx43 mRNA and protein levels in the left ventricle in control as well as in MI rabbits. THIR also increased lateralization of Cx43, which was no longer colocalized with cadherins. In MI hearts, immunoreactive Cx43 signals were reduced in the peri-infarct zone, and the reduction was reversed by THIR. In-vivo epicardial potential mapping on the free wall (64 unipolar electrodes to cover 7 x 7 mm) in MI hearts revealed reduced conduction velocity, whereas dispersion of the activation-recovery interval (ARI) was increased compared with controls, and these changes were reversed by THIR. The vulnerability for ventricular tachyarrhythmias (VT/VF), which was estimated by programmed stimulation, was increased in MI hearts, and this increased vulnerability to arrhythmias was reversed by THIR.


CONCLUSIONS
THIR increases Cx43 expression, improves the conductivity, decreases the spatial heterogeneity of repolarization, and reduces the vulnerability of rabbit hearts to ventricular arrhythmias after MI. THIR could have an antiarrhythmic potential through an improvement of electrical coupling.
Amino
Mari
M
Department of Cardiology, Tokai University School of Medicine, Isehara, Japan.
Yoshioka
Koichiro
K
Tanabe
Teruhisa
T
Tanaka
Etsuro
E
Mori
Hidezo
H
Furusawa
Yoshiya
Y
Zareba
Wojciech
W
Yamazaki
Masatoshi
M
Nakagawa
Harumichi
H
Honjo
Haruo
H
Yasui
Kenji
K
Kamiya
Kaichiro
K
Kodama
Itsuo
I
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000517:prevention & control*; D015153:Blotting, Western / Q000379:methods; D018031:Connexin 43 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D017629:Gap Junctions / Q000378:metabolism; D006352:Heart Ventricles; D007150:Immunohistochemistry; D023421:Models, Animal; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D011878:Radiotherapy; D011882:Radiotherapy, High-Energy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D018031:Connexin 43; D012333:RNA, Messenger