Basic mechanism of atrial and ventricular arrhythmia suppression by heavy ion irradiation in hypercholesterolemic elderly rabbits

Abstract

Abstract Background Recent development of electrophysiology-guided noninvasive cardiac radioablation therapy for ventricular tachycardia attracts a great deal of attention as a novel antiarrhythmic strategy (Robinson CG, Circulation 2019). As to underlying mechanisms, however, much remains to be clarified. We reported before that a single targeted heavy ion irradiation (THIR 15Gy) to rabbit hearts increased connexin43 (Cx43) expression, and a reduction of vulnerability to ventricular arrhythmias after myocardial infarction. Purpose We investigated the effects of THIR on in-vivo cardiac electrophysiology and vulnerability to atrial and ventricular tachyarrhythmias in aged rabbits with hypercholesterolemia. Methods Sixteen three-year old rabbits were fed with high fat/cholesterol chow (0.5% cholesterol and 10% coconut oil) for 14 weeks. A single THIR 15Gy was applied to 8 rabbits (HC+THIR) with a heavy ion medical accelerator. Eight rabbits without THIR were used as control (HC). Results Serum cholesterol levels in the HC and HC+THIR were 1545+386 and 1569+328 mg/dl (n=8, NS). Atrial (P-wave) late potential in signal-averaged ECG in HC+THIR showed a significantly larger root mean square voltage (RMS) than those in HC (12+0.5 vs. 2+0.5μV, n=4, p<0.01). Ventricular late potentials in HC+THIR showed significantly less fQRS-D than HC (81+5 vs. 89+7 ms); less LAS40 (21+7 vs. 30+4 ms), and larger RMS (99+27 vs. 44+13μV) (n=4, p<0.04). Atrial tachycardia or fibrillation (AT/AF) was induced spontaneously or by programmed/burst pacing of the left atria (LA) in 4 out of 4 HC, whereas in only 1 out of 4 HC+THIR. Ventricular tachycardia or fibrillation (VT/VF) was induced spontaneously or by programmed pacing or left stellate stimulation in 4 out of 4 HC rabbits, whereas in only 1 out of 4 HC+THIR. Immunolabeled Cx40 densities in LA and RA tissue from HC+THIR rabbits were significantly higher than those from HC rabbits by 44% and 60%, respectively (n=4, p<0.01). Comparable upregulation of immunoreactive Cx43 was observed in LV and RV tissue from HC+THIR rabbits. Sympathetic nerve densities in LA, RA, LV and RV tissues, which was labeled with anti-neuronal growth-associated protein 43 (GAP43) antibody and tyrosine hydroxylase (TH) antibody were both significantly less in HC+THIR than those in HC. Conclusion These results suggest that THIR may improve cardiac conductivity of HC rabbits in favor of reduction of vulnerability to atrial and ventricular tachycardia/fibrillation, and that this antiarrhythmic effect is attributed to upregulation of gap junction protein (Cx40 and Cx43) and in part to prevention of sympathetic nerve sprouting. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): KAKENHI KIBAN (C) 53020