Copyright © 2006, European Society of Cardiology
Heavy ion radiation up-regulates Cx43 and ameliorates arrhythmogenic substrates in hearts after myocardial infarction
aDepartment of Cardiology, Tokai University School of Medicine, Isehara, Japan
bDepartment of Nutritional Sciences, Tokyo University of Agriculture, Tokyo, Japan
cDepartment of Cardiac Physiology, National Cardiovascular Center Research Institute, Osaka, Japan
dNational Institute of Radiological Sciences, Chiba, Japan
eCardiology Unit, University of Rochester, Rochester, USA
fResearch Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
* Corresponding author. Tel.: +81 52 789 3871; fax: +81 52 789 3890. Email address: ikodama{at}riem.nagoya-u.ac.jp
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 7x7 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.
KEYWORDS Gap junctions; Connexin43; Heavy ion radiaton; Myocardial infarction; Ventricular arrhythmias; Arrhythmia (mechanisms); Epicardial mapping
1 The first two authors contributed equally to this work.