StereoTactic Arrhythmia Radiotherapy in the NetherLands no. 2

Overview

Ventricular tachycardia (VT) is a malignant cardiac arrhythmia subjecting our patients to a high risk of sudden death, increased morbidity and reduced quality of life. Unfortunately, failure of treatment is common and VT recurrences remain an important concern. In these patients, stereotactic arrhythmia radiotherapy appears to be an effective and safe treatment. The mechanism of action however remains unknown and should be elucidated. The objective of this phase 2, single arm, monocenter, pre-post intervention study is to evaluate the efficacy and safety of stereotactic arrhythmia radiotherapy and obtain insights in the mechanism of action by evaluating electro-anatomical alterations of stereotactic arrhythmia radiotherapy in patients with therapy refractory ventricular tachycardia.

Ventricular tachycardia (VT) is a malignant cardiac arrhythmia leading to a sudden abolition of cardiac function directly followed by a shortage of oxygen supply to essential organs such as the brain and heart. For this reason, VT is a cardiac emergency and should be treated within seconds to minutes before irreversible and potentially fatal organ damage follows. Current treatment options are limited to anti-arrhythmic drugs, an implantable cardioverter defibrillator (ICD), and invasive catheter ablation. Unfortunately, invasive cardiac VT ablation has the lowest success rate and the highest complication rates among all arrhythmia ablations. Since the first case series published by Cuculich et al. (2017) and the first prospective trial published by Robinson et al. (2019), stereotactic arrhythmia radiotherapy (STAR) has evolved as a new treatment modality for patients with ventricular tachycardia refractory to conventional therapies. Patients are treated with a single radiotherapy fraction of 25 Gy at the determined pro-arrhythmic cardiac region with the use of standard stereotactic radiotherapy techniques. Experience with STAR is steadily growing worldwide. In the systematic review by Van der Ree et al. (2020), a reduction of \>85% in VT episodes with a simultaneously promising safety profile was shown. The mechanism of action of STAR is not yet fully known and is yet to be elucidated. The pathophysiological mechanism of VT relies on re-entry due to zigzag conduction by the surviving myocardial fibers in previously damaged heart tissue. At first, it was hypothesized that inducing cell-death by ionizing radiation leads to dense transmural fibrosis. As mature myocardial fibrosis is not able to propagate electrical activation this may lead to the abolishment of the zigzag conduction herewith reducing the chance of re-entry and VT. Fibrosis maturation takes several weeks to months to complete. However, the anti-arrhythmic effects seem to occur earlier. In preclinical studies, early electrophysiological alterations were demonstrated (Zhang et al. 2021). The gap-junction protein connexion-43 (Cx43) and the voltage gated sodium channels were upregulated, leading to a supraphysiological state with increased conduction velocity. Since a slow conduction pathway is required for re-entry, this could explain the timing of the observed effect, although the exact mechanism of action remains to be elucidated. In the STARNL-2 study we aim to confirm our STARNL-1 pilot (6 patients) efficacy and safety data in a larger cohort and obtain insights in the electro-anatomical alterations of stereotactic arrhythmia radiotherapy in patients with therapy refractory ventricular tachycardia.