First-in-man case of non-invasive proton radiotherapy for the treatment of refractory ventricular tachycardia in advanced heart failure.

Abstract

Radiofrequency catheter ablation (RFCA) is the gold standard therapy for recurrent scar-related ventricular tachycardia (VT), but its efficacy is suboptimal. In patients with advanced heart failure with reduced ejection fraction (HFrEF), RFCA-related potential need for advanced haemodynamic support and periprocedural mortality represent major limiting factors.1 Stereotactic arrhythmia radioablation (STAR) is an emerging non-invasive approach potentially overcoming some of the limitations of RFCA. Previous studies2-4 used a single 25 Gy photon dose with good acute tolerance and reduced VT burden; yet, caution for potential cardiac and pulmonary long-term side effects was raised.3 Particle radiotherapy using protons or carbon ions has a dosimetric advantage over photons due to local high-dose delivery capability while minimizing the off-target dose.5 Yet, hitting an actively moving target such as the heart with particles is technically challenging and so far, the technique has been tested only in experimental models.4, 6 We describe the case of a 73-year-old man suffering from idiopathic cardiomyopathy and HFrEF (left ventricular ejection fraction 20%, left ventricular end-diastolic volume index 110 mL/m2, New York Heart Association class III) complicated by severe mitral regurgitation, carrier of a biventricular implantable cardioverter-defibrillator. He was referred to our Center for a life-threatening electrical storm with multiple shocks due to recurrent, not tolerated, monomorphic VTs (cycle length 410 ms). Two previous attempts of endo-epicardial VT ablation (Figure 1A), multiple oral anti-arrhythmic drugs and bilateral cardiac sympathetic denervation were ineffective. VT morphology was compatible with an intramyocardial origin from the postero-lateral basal left ventricle. Continuous lidocaine infusion (on top of oral amiodarone) was the only strategy able to control VTs. The dramatic clinical scenario prompted us to consider non-invasive VT ablation. A non-invasive mapping using electrocardiographic imaging during clinical VT was performed before the procedure (Figure 1B). Based on invasive (from the last VT ablation, Figure 1A) and non-invasive mapping data, a clinical target volume of 12.6 mL of cardiac tissue was identified in the left ventricular postero-lateral basal wall. Compensation for respiratory motion, estimated cardiac motion and set-up characteristics led to a final planning volume of 27.7 mL. The local Ethics Committee approved the intervention as compassionate treatment. A single dose of 25 Gy relative biological effectiveness was delivered by means of two orthogonal proton beams (Figure 1C) undergoing intensity modulation particle therapy technique and respiratory gating. The patient remained free from VT for almost 2 months after STAR and we did not observe side effects. Left ventricular global longitudinal peak systolic strain (LPSS) at 1 month after STAR was slightly improved (−4% vs. −2.7%). On the contrary, a local reduction of LPSS in the medio-basal postero-lateral left ventricle was observed, suggesting that the proton beams effectively hit the target zone. In a limited period spanning from day 54 to day 59 after the STAR procedure, 11 episodes of VT (same morphology as the clinical VT but with slower cycle, haemodynamically better tolerated and responsive to overdrive pacing) occurred, as compared to 242 events recorded in the 2 months before the procedure. Following dose up-titration of oral anti-arrhythmic drugs, no further episodes of VT were recorded. Unexpectedly, the patient died due to septic shock 77 days after the procedure. This is the first-in-man report of single-dose proton radiotherapy for refractory VT management. The procedure was well tolerated, safe and resulted in an almost immediate VT suppression followed by an overall dramatic reduction of VT episodes. Nevertheless, the temporary recurrence of the clinical VT between day 54 and day 59 after the procedure suggests caution regarding the long-lasting effects of this procedure. So far, some case reports and a few case-series, all using single high dose of photons, have been reported but the optimal dose and the time-to-effect still need to be defined.2-4 Pre-clinical studies demonstrated that doses of at least 25 Gy are required, with more homogeneous and transmural scar formation as the dose further increases, and that scar consolidation can take up to 4 months with photons and up to 6 months with protons.4 Yet, an almost immediate VT suppression was also observed in some patients, underlying a still limited understanding of the cardiac effects of radiations. Early up-regulation of connexin-43 expression in cardiomyocytes,6 leading to increased conduction velocity and decreased repolarization heterogeneity, combined with early endothelial cell vacuolization and oedema, have been proposed as transient mechanisms of acute VT suppression while the scar formation process is not yet completed. In conclusion, our case suggests that STAR with protons for refractory VT is feasible and safe in HFrEF. Compared with photons, protons have the potential to reduce cardiac and extra-cardiac toxicity. More research is needed to optimize compensation for cardiorespiratory movements, to define the most appropriate proton dose and to unveil the mechanisms and the time kinetics for STAR antiarrhythmic effects. Conflict of interest: None declared.