Douglas L. Packer

BACKGROUND: Cardiac radioablation is emerging as a treatment modality for refractory ventricular tachycardia. This study aimed to evaluate the effects of radiation on the coronary arteries in a swine model of proton beam cardiac radioablation. METHODS: Eighteen swine underwent single-fraction 30 to 40 Gy pencil-beam scanning proton therapy targeting the left ventricle and were euthanized 12 to 40 weeks later. Treatment planning was performed without restricting the dose to the coronary arteries. The maximum point dose (D _max ) to the epicardial coronary arteries was calculated. In secondary analyses, the mean (D _mean ) and minimum dose received by the highest irradiated 0.01 cm ³ (D _0.01 ) of each coronary artery were also calculated. Coronary artery segments were harvested from the D _max sites for histological analysis, and the D _max was correlated with stenosis severity. RESULTS: Ninety-six coronary arteries were analyzed. No stenoses were observed by computed tomography imaging preirradiation. By histological analysis posteuthanasia, 25/96 (26%) coronaries sampled at their D _max sites had ≥75% stenosis. The median D _max was 4.7 Gy for the P max and stenosis ≥75% was 92.2%. A D _max value of 20.1 Gy best predicted stenosis ≥75%, with sensitivity 92.3% and specificity 87.1%. The AUC-ROCs for the associations of D _mean and D _0.01 with stenosis ≥75% were 84.8% and 91.6%, respectively. In histopathologic analysis, intimal hyperplasia was the most common coronary artery abnormality at the D _max sites, and it was present in 61.5% of all arteries and in 93.9% of arteries with D _max ≥20 Gy. CONCLUSIONS: In this preclinical model of proton beam cardiac radioablation, coronary stenoses occurred in a dose-dependent manner, with D _max showing the closest correlation with stenosis ≥75%. These data provide for the first time a framework for dose constraint considerations for the coronary arteries during treatment planning for cardiac radioablation and thoracic malignancy radiation.

BACKGROUND: Power-controlled radiofrequency ablation with irrigated-tip catheters has been the norm for ventricular ablation for almost 2 decades. New catheter technology has recently integrated more accurate tissue temperature sensing enabling temperature-controlled irrigated ablation. We aimed to investigate the in vivo ablation parameters and lesion formation characteristics in ventricular myocardium using a novel temperature-controlled radiofrequency catheter. METHODS: Twenty canines were divided into 3 groups: 4 noninfarcted, acute (phase I); 8 noninfarcted, chronic (phase II); and 8 infarcted, chronic (phase III). Lesions were delivered with a temperature-controlled radiofrequency system utilizing a chemical vapor deposit diamond for efficient thermal diffusivity. In phase I, 17 ablation settings were tested (temperature set points, 50/60/70 °C; ablation duration, 15/30/60/90/120 s; and power limit, 30/50 W). Four and one of these sets of parameters were further tested in phases II and III, respectively. Lesions were assessed by ex vivo contrast-enhanced magnetic resonance imaging and gross pathology 5 weeks after ablation in phases II/III. RESULTS: Across all phases, 111 ablation lesions were delivered. Ablation with the power limit of 50 W, the temperature set point of 60 °C, and the duration of 60 s produced significantly larger and deeper lesions (mean, 569.2 mm ³ ; mean maximal depth, 9.8 mm) compared with 50 W/60 °C/30 s (mean, 340.4 mm ³ ; mean maximal depth, 8.3 mm) and 50 W/50 °C/60 s (mean, 227 mm ³ ; mean maximal depth, 6.9 mm), with P <0.05 for all pairwise comparisons. Ablation of infarcted myocardium in phase III (50 W/60 °C/30 s) resulted in smaller impedance and bipolar electrogram amplitude changes and lesion size compared with ablation in normal myocardium with the same settings. No steam pop, myocardial perforation, or char formation was observed in any of the 111 ablations across all phases. CONCLUSIONS: In vivo radiofrequency ablation in a canine model with a diamond-tip temperature-controlled catheter using a temperature set point of 60 °C and a power limit of 50 W created large lesions without steam pop risk in both normal and infarcted ventricular myocardia.

Background: Particle therapy is a noninvasive, catheter-free modality for cardiac ablation. We previously demonstrated the efficacy for creating ablation lesions in the porcine heart. Despite several earlier studies, the exact mechanism of early biophysical effects of proton and photon beam delivery on the myocardium remain incompletely resolved. Methods: Ten normal and 9 infarcted in situ porcine hearts received proton beam irradiation (40 Gy) delivered to the left ventricular myocardium with follow-up for 8 weeks. High-resolution electroanatomical mapping of the left ventricular was performed at baseline and follow-up. Bipolar voltage amplitude, conduction velocity, and connexin-43 were determined within the irradiated and nonirradiated areas. Results: The irradiated area in normal hearts showed a significant reduction of bipolar voltage amplitude (10.1±4.9 mV versus 5.7±3.2, P P =0.03) beginning at 4 weeks after irradiation. In infarcted myocardium after irradiation, bipolar voltage amplitude of the infarct scar (2.0±2.9 versus 0.8±0.7 mV, P =0.008) was significantly reduced as well as the conduction velocity in the infarcted heart (43.7±15.7 versus 26.3±11.4 cm/s, P =0.02). There were no significant changes in bipolar voltage amplitude and conduction velocity in nonirradiated myocardium. Myocytolysis, capillary hyperplasia, and dilation were seen in the irradiated myocardium 8 weeks after irradiation. Active caspase-3 and reduction of connexin-43 expression began in irradiated myocardium 1 week after irradiation and decreased over 8 weeks. Conclusions: Irradiation of the myocardium with proton beams reduce connexin-43 expression, conduction velocity, and bipolar conducted electrogram amplitude in a large porcine model. The changes in biomarkers preceded electrophysiological changes after proton beam therapy.

Background: Pulsed field ablation uses electrical pulses to cause nonthermal irreversible electroporation and induce cardiac cell death. Pulsed field ablation may have effectiveness comparable to traditional catheter ablation while preventing thermally mediated complications. Methods: The PULSED AF pivotal study (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF) was a prospective, global, multicenter, nonrandomized, paired single-arm study in which patients with paroxysmal (n=150) or persistent (n=150) symptomatic atrial fibrillation (AF) refractory to class I or III antiarrhythmic drugs were treated with pulsed field ablation. All patients were monitored for 1 year using weekly and symptomatic transtelephonic monitoring; 3-, 6-, and 12-month ECGs; and 6- and 12-month 24-hour Holter monitoring. The primary effectiveness end point was freedom from a composite of acute procedural failure, arrhythmia recurrence, or antiarrhythmic escalation through 12 months, excluding a 3-month blanking period to allow recovery from the procedure. The primary safety end point was freedom from a composite of serious procedure- and device-related adverse events. Kaplan-Meier methods were used to evaluate the primary end points. Results: Pulsed field ablation was shown to be effective at 1 year in 66.2% (95% CI, 57.9 to 73.2) of patients with paroxysmal AF and 55.1% (95% CI, 46.7 to 62.7) of patients with persistent AF. The primary safety end point occurred in 1 patient (0.7%; 95% CI, 0.1 to 4.6) in both the paroxysmal and persistent AF cohorts. Conclusions: PULSED AF demonstrated a low rate of primary safety adverse events (0.7%) and provided effectiveness consistent with established ablation technologies using a novel irreversible electroporation energy to treat patients with AF. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04198701.