Packer, Douglas L.

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 <75% stenosis group and 29.7 Gy for the ≥75% stenosis group ( P <0.001). The AUC-ROC for the association between D 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.

AbstractIntroductionCatheter ablation of atrial fibrillation (AF) is frequently studied in randomized trials, observational and registry studies. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of future clinical studies on catheter ablation of AF, implement lessons learned from previous studies, and promote a higher degree of consistency across studies.BackgroundStudies on catheter ablation of AF may benefit from well‐described definitions of endpoints and consistent methodology and documentation of outcomes related to efficacy, safety and cost‐effectiveness. The availably of new, innovative technologies warrants further consideration about their application and impact on study design and the choice of endpoints. Moreover, recent insights gained from AF ablation studies suggest a reconsideration of some methodological aspects.MethodsA panel of clinical experts on catheter ablation of AF and designing and conducting clinical studies developed an expert opinion on the design and endpoints for studies on catheter ablation of AF. Discussions within the expert panel with the aim to reach consensus on predefined topics were based on outcomes reported in the literature and experiences from recent clinical trials.ResultsA comprehensive set of recommendations is presented. Key elements include the documentation of clinical AF, medication during the study, repeated ablations and their effect on endpoint assessments, postablation blanking and the choice of rhythm‐related and other endpoints.ConclusionThis expert opinion provides guidance and promotes consistency regarding design of AF catheter ablation studies and identified aspects requiring further research to optimize study design and methodology.CONDENSED ABSTRACTRecent insights from studies on catheter ablation of atrial fibrillation (AF) and the availability of new innovative technologies warrant reconsideration of methodological aspects related to study design and the choice and assessment of endpoints. This expert opinion, developed by clinical experts on catheter ablation of AF provides a comprehensive set of recommendations related to these methodological aspects. The aim of this expert opinion is to provide guidance for clinicians and industry regarding the development of clinical studies, implement lessons learned from previous studies, and promote a higher degree of consistency across studies.

Introduction: Point source ablation may be effective in eliminating stable ventricular tachycardia (VT), where actual mapping and ablation are possible. Ablating patients with unstable VT is more complicated and may require aggressive intervention. While small linear lesions have been utilized, the actual utility of longer linear homogenization for eliminating ventricular arrhythmias has not been examined. Methods: Therefore, the results of 86 patients undergoing VT ablation at Mayo Clinic were examined. 42 had underlying ischemic heart disease with an EF of 33.5 ± 16.8 had VT with a cycle length of 326 ± 165 ms, and had 2.5± 1.6 episodes of VT in the preceding three months. 32 required shocks for that tachycardia. Results: Of these, 21 patients (16 male, 5 female Age 67±18) underwent detailed linear ablation at the scar margin in an effort to homogenize that region. This was drawn into the infarct scar by decreasing the upper voltage boundary to 2.0. In these patients, 18 showed elimination of clinical VT. In addition, 12 showed a decrease in VT from 10 ± 8.7 episodes down to 2.5 ± 1.2 episodes of actual ventricular arrhythmias. The shock requirement decreased from 8.6 ±4.7 to 1.5 ±2.7. These patients had 7 ± 3.5 different VTs at the time of ablation. These data suggest not only a decrease the occurrence of VT, but an improved control of the arrhythmia as manifested by decreased frequency of episodes and a decrease in shock. This suggests a straightforward alternative to point source ablation or to the requirement of detailed LAVA intervention. Conclusion: Linear infarct edge homogenization is a straightforward means of ablating ventricular tachycardia’s, even when unstable. This approach may be simpler than seen with LAVA interventions.

Introduction: Electro-anatomic mapping (EAM) has been studied as a modality to improve the sensitivity and reduce false negative rates with endomyocardial biopsy (EMB). We systematically reviewed the literature describing EAM guided EMB. Methods: An experienced librarian developed search strategies for Ovid MEDLINE, Ovid Embase, Ovid CDR, Cochrane Central, Scopus and Web of Science. There were no restrictions on language or publication date. Animal studies were excluded. Search strategy included MESH headings and keywords including endomyocardial biopsy and electroanatomic mapping. Results: Out of 139 studies initially identified, 16 (9 case series, 7 case reports) were included in this systematic review. EAM guided EMB was performed in 152 patients and results of 241 biopsies were available for analysis. The most common indications for EAM guided EMB were suspected arrhythmogenic right ventricular cardiomyopathy (ARVC), myocarditis and cardiac sarcoidosis (CS). While fluoroscopic visualization of the bioptome close to mapping catheter was the most commonly utilized biopsy technique (n=7 studies), direct visualization of bioptome on CARTO (n=4) and on NavX (n=2) were used as well. Low voltage areas had abnormal myocardial histology more commonly (range 60-100%) than normal voltage areas (range 11-52%). Sensitivity of low voltage areas for abnormal myocardium ranged from 60% to 82%. EAM guided EMB appears safe and adverse events were noted in only one study (remote hemopericardium). Conclusions: EAM guided EMB is a safe and efficacious method to improve the sensitivity and reduce the false negative rate of conventional fluoroscopy guided biopsy.

Introduction: Cardiac veins serve as substrate for arrhythmogenesis, and are especially involved as foci in atrial fibrillation. Understanding cardiac vein anatomy along with myocardial extension into these structures can improve electrophysiological mapping and electrical isolation of arrhythmogenic substrate. Accurately defining cardiac vein anatomy is critical in improving success of ablation therapy for atrial fibrillation. Methods: We performed measurements on 620 formalin-fixed autopsy hearts explanted from October 1998 to July 2003. The integrity of the thoracic veins and their cardiac connections were examined and systematic measurements of the superior and inferior vena cavae, azygous vein, vein of Marshall, coronary sinus, and pulmonary veins were performed and data were analyzed using univariate statistics. Results: We found that muscular extensions into the pulmonary veins were visible in 99% of the examined hearts, and were circumferential around the vein ostia (99.6%). Muscle extension into the SVC was found in 78% of examined hearts. These extensions were largely circumferential around the ostium (39%), but were also found to be asymmetric in a majority of hearts. Asymmetry was found in hearts with longer muscle extensions; no symmetry was observed in extensions greater than 0.8cm. Muscle extensions into the IVC were not seen. Occasionally, macroscopic muscle extensions into the azygous vein were visible (6%). The vein of Marshall was found to be patent to probing in the majority of hearts examined (72%) and was almost always overlying the lateral left atrial endocardial ridge. Conclusions: Our data suggest that all pulmonary veins need to be electrically isolated during atrial fibrillation ablation because of the almost universal presence of myocardial tissue extending into the veins. Mapping of the SVC should be done circumferentially and if potentials are noted isolation should also be performed. The IVC did not have muscle extensions and is unlikely to be a site of arrhythmogenesis. The azygous vein occasionally had muscle extensions and thus requires mapping and possible isolation. The vein of Marshall can be a substrate for arrhythmogenesis and is accessible for ablation by targeting the lateral left atrial endocardial ridge.

Background: Cardiac proton beam ablation therapy has emerged as a promising tool for catheter-free arrhythmia ablation. The time course of the lesion change was demonstrated in MRI 8 weeks following the ablation; however, the pericardial effusion after the ablation has not been fully analyzed. Objective: The purpose of this study was to evaluate the pericardial effusion after pencil-beam scanned proton therapy on normal myocardium in swine in MRI. Methods: 32 domestic swine were irradiated with pencil-beam scanned proton therapy using irradiation doses of 30/40Gy to the left ventricle (LV) anterior wall, posterior wall, and apex. Each swine was subjected to monthly contrast-enhanced cardiac MRI to evaluate the post-irradiation effects. Results: Moderate to significant pericardial effusion (PE) was observed in 10 swine (31%), starting at 4 weeks, and increasing from 8-16 weeks until 24 weeks. With the exception of one case,, improvement was observed in all animals within a month from when the PE first became moderate or significant. . In the case where the significant PE did not improve, the PE was non-septic and transudate. Clinically, the PE did not cause cardiac tamponade and did not correlate to sudden death. Also, there was no correlation between animals with larger tissue volumes receiving higher dose (more than 20Gy) and the grade of PE . Conclusion: Proton beam radiation caused various grades of pericardial effusion, but in 90% of the animals, it resolved without intervention within a month with no major adverse events.

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 <0.0001) and conduction velocity (85±26 versus 55±13 cm/s, 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.