Acute Modulation of Arrhythmogenic Ventricular Substrate Following Cardiac Stereotactic Body Radiation Therapy

BACKGROUND: Cardiac stereotactic body radiation therapy (cSBRT) is a noninvasive, investigational treatment for refractory ventricular tachycardia (VT). The antiarrhythmic effects and time course of action of cSBRT on abnormal ventricular substrate remain poorly understood. OBJECTIVES: This study aimed to investigate the electrophysiological, molecular, and structural changes following cSBRT in a porcine infarct model. METHODS: Anterior myocardial infarction was created in a porcine model of infarct-related re-entrant VT (n = 8). Swine were randomized to cSBRT (n = 4) or control infarct (n = 4) groups. Baseline electrophysiology study and high-resolution electroanatomic maps were performed 8 to 10 weeks postinfarction. The cSBRT group received 25 Gy single-fraction photon radiation guided by initial left ventricular substrate maps. Cardiac magnetic resonance imaging followed by repeat electrophysiology study and mapping studies were performed 6 weeks later. RESULTS: cSBRT resulted in significant prolongation of the effective refractory period in remote, nontargeted myocardium (cSBRT: 216 ± 21-252 ± 11 ms, Δ +17% vs control: 234 ± 7-249 ± 1 ms, Δ +6.5%) and targeted scar tissue (cSBRT: 258 ± 10-291 ± 18 ms, Δ +13% vs control: 274 ± 13-284 ± 8 ms, Δ +3.7%; group × timepoint interaction P = 0.048). Sustained VT was inducible in all 8 subjects at the terminal timepoint. There was a trend toward more prolonged VT cycle length (cSBRT: 195 ± 19-295 ± 55 ms, Δ +53% vs control: 212 ± 15-261 ± 14 ms, Δ +23%; P = 0.22). Connexin-43 immunoreactive area density in the infarct region was lower in the cSBRT group (1.4% vs 2.7%, respectively; P < 0.01). There was no difference detected in late gadolinium enhancement volume (cSBRT: 29.3% ± 7.8% vs control: 27.2% ± 11.3%; P = 0.8) or histologic fibrosis (cSBRT: 54.9% ± 13.4% vs control: 54.6% ± 20.6%; P = 0.95). CONCLUSIONS: Delivery of 25 Gy cSBRT produced early electrical remodeling with increased effective refractory period and decreased connexin-43 area density, without evidence of increased fibrosis.