Cardiac radiotherapy transiently alters left ventricular electrical properties and induces cardiomyocyte-specific ventricular substrate changes in heart failure

Abstract

Aims: Ongoing clinical trials investigate the therapeutic value of stereotactic cardiac radioablation (cRA) in heart failure patients with ventricular tachycardia. Animal data indicate an effect on local cardiac conduction properties. However, the exact mechanism of cRA in patients remains elusive. Aim of the current study was to investigate in vivo and in vitro myocardial properties in heart failure and ventricular tachycardia upon cRA.

Methods and results: High-density 3D electroanatomic mapping in sinus rhythm was performed in a patient with a left ventricular assist device and repeated ventricular tachycardia episodes upon several catheter-based endocardial radio-frequency ablation attempts. Subsequent to electroanatomic mapping and cRA of the left ventricular septum, two additional high-density electroanatomic maps were obtained at 2- and 4-month post-cRA. Myocardial tissue samples were collected from the left ventricular septum during 4-month post-cRA from the irradiated and borderzone regions. In addition, we performed molecular biology and mitochondrial density measurements of tissue and isolated cardiomyocytes. Local voltage was altered in the irradiated region of the left ventricular septum during follow-up. No change of local voltage was observed in the control (i.e. borderzone) region upon irradiation. Interestingly, local activation time was significantly shortened upon irradiation (2-month post-cRA), a process that was reversible (4-month post-cRA). Molecular biology unveiled an increased expression of voltage-dependent sodium channels in the irradiated region as compared with the borderzone, while Connexin43 and transforming growth factor beta were unchanged (4-month post-cRA). Moreover, mitochondrial density was decreased in the irradiated region as compared with the borderzone.

Conclusion: Our study supports the notion of transiently altered cardiac conduction potentially related to structural and functional cellular changes as an underlying mechanism of cRA in patients with ventricular tachycardia.

Keywords: Ablation; Cardiac radiotherapy; Left ventricular assist device; Translational research; Ventricular tachycardia.