Cellular consequences of non-ablative radiotherapy, a novel approach to ventricular tachycardias

Background and aims: Radiotherapy (RT) with a single application of ionizing radiation (STAR) has been suggested as a non-invasive alternative to radiofrequency in ablating ventricular tachycardia (VT). Emerging data reveal that STAR may suppress VT without substrate destruction, by enhancing impulse conduction instead, through increased expression of NaV1.5 channels and connexin 43. The study aims to investigate electrophysiology and intracellular Ca2+ dynamics in cardiomyocytes (CMs) from mice subjected to in-vivo RT. The emerging data led us to evaluate biochemical changes potentially linking electrophysiological response to ionizing irradiation. Methods: CMs isolated 2 weeks after RT with low-dose (15 Gy) or high-dose (25 Gy) were compared to those of sham-treated mice (CTRL). We evaluated: i) the properties of the transient (INaT) and sustained (INasus) components of INa; ii) AP parameters, including the prevalence of Early After-Depolarizations (EADs); iii) intracellular Ca2+ dynamics; iv) CaMKII phosphorylation and v) ROS content. Results: 25 Gy RT i) increased INaT and, to a larger extent, INasus (increased INasus/INaT ratio); ii) increased AP amplitude, +dV/dtMAX and duration (APD) and facilitated EADs; iii) depressed intracellular Ca2+ dynamics. 15 Gy RT had similar but smaller effects (dose-dependency). 25 Gy RT reduced CaMKII phosphorylation but increased cell ROS content, thus providing a mechanism for the late component of INa (INaL) enhancement. Conclusions: The results support the view that STAR may supress VT by increasing conduction velocity, with APD prolongation providing an additional mechanism. On the other hand, INasus enhancement and Ca2+ handling depression may impair electrical stability and contractility in the irradiated region.