BACKGROUND:Clinical data supporting cardiac radioablation (CRA) for ventricular tachycardia (VT) are currently limited to photon-based irradiation. Proton irradiation may allow more precise targeting with reduced radiation exposure of non-target tissues. OBJECTIVE:This study aimed to evaluate the early-stage feasibility of catheter-free proton CRA for the management of refractory VT. METHODS:This first-in-human, non-randomized trial enrolled patients with left ventricular ejection fraction (LVEF) <50% and VT refractory to antiarrhythmic drugs and prior catheter ablation(s). A single fraction of 30 Gy intensity-modulated proton therapy was delivered. Patients were followed for up to 2 years post-treatment. RESULTS:7 patients underwent treatment (6 males, mean age 68 years). Median target volume was 17cm3 (range 8.3-64.9 cm3). A median of only 4% of non-target myocardium received ≥20 Gy. Patients were followed for a median of 514 days (range 66-730 days, cumulative 107 patient-months). The rate of VT events declined from 7.24 per patient-month in the 3 months before treatment to 1.52 per patient-month during follow-up (79% event rate reduction). No probable or definite treatment-related serious adverse events occurred. Median LVEF was 26% (IQR 23%-39%) at baseline and 25% (IQR 18%-32%) at last available follow-up. 2 patients underwent heart transplant 66 and 514 days after treatment because of end-stage heart failure and VT, and 3 patients died at 155 days (end-stage heart failure), 502 days (end-stage heart failure), and 529 days (sudden non-arrhythmic death, likely heart failure-related). CONCLUSION:Catheter-free proton CRA for refractory VT was feasible and without definite evidence of associated toxicity, supporting further investigation in larger prospective studies.

Background Cardiac radioablation (CRA) is an emerging treatment modality for refractory ventricular tachycardia. The mechanisms underlying the antiarrhythmic effect of CRA remain incompletely understood. Objectives The goal of this study was to investigate the nature and time course of key gene expression of apoptosis, conduction, and fibrosis after 40 Gy proton beam CRA. Methods In 18 swine, left ventricular (LV) targets were treated with a single-fraction 40 Gy proton beam. Myocardium was harvested from an irradiated LV target (IR-40Gy LV), the border area (IR-Border LV), and non-irradiated remote location (Remote LV) 1 to 32 weeks later. Apoptosis was assessed with the terminal deoxynucleotidyl transferase dUTP nick end labeling method that detects DNA breaks in the late phase of apoptosis. Markers of cellular survival, electrical conduction, and fibrosis were also assessed with real-time polymerase chain reaction. Results Terminal deoxynucleotidyl transferase dUTP nick end labeling staining suggested ongoing apoptosis in IR-40Gy LV through 20 to 32 weeks, with a peak at 4 to 8 weeks. Statistically significant expression reduction of TNNT2 (encoding cardiac troponin T) was noted in the IR-40Gy LV group compared with the Remote LV group at 1 to 2 weeks and through 20 to 32 weeks. IR-40Gy LV and IR-Border LV showed patterns of expression reduction of genes of myocardial conduction, including SCN5A, GJA1, and GJA5 (encoding NaV1.5, connexins 43 and 40, respectively) beginning at 4 to 8 weeks. Fibrosis genes COL1A1 and COL3A1 (encoding collagen types I and III) exhibited statistically significant expression up-regulation late after irradiation (20-32 weeks) in IR-40Gy LV relative to Remote LV. Conclusions Apoptosis peaked at 4 to 8 weeks and continued during several months of follow-up after proton beam irradiation. There was no evidence of up-regulation of conduction markers early after irradiation. Activation of fibrosis pathways occurred several weeks after irradiation.

Proton beam irradiation to the ventricular myocardium is emerging as a non-invasive treatment for ventricular tachycardia. Prior work has demonstrated that lesions can be visualized in myocardial tissue using delayed contrast enhanced magnetic resonance imaging (DCE-MRI) following proton beam therapy; however, an automated method for quantifying these lesions has not yet been described. Methods for quantitative assessment of DCE-MRI have been evaluated in other applications such as myocardial infarct scar and fibrosis in hypertropic cardiomyopathy. Enhanced regions in DCE-MRI can be defined by delineating a remote region (distant from scar or enhanced region) and then thresholding at 1-6 standard deviations (SD) above the mean voxel intensity in the remote myocardium. The current study aims to evaluate the appropriate threshold for automated measurement of lesions from DCE-MRI in ventricular myocardium following proton beam therapy. Eight swine were irradiated with 40 Gy proton beam in the anterior or lateral left ventricle and DCE-MRI was conducted prior to euthanasia (mean week: 18.0 +/- 5.2). A region of interest (ROI) in the non-target area receiving 05 Gy was contoured (remote ROI). The mean and SD of the signal intensity of the remote ROI were calculated. DCE-MRI was quantified with the use of different thresholds: 1-6SD above the mean signal intensity of the remote ROI. The gross pathology lesion volume was manually contoured and calculated using Image J software after administration of 2,3,5-triphenyltetrazolium chloride (TTC). We examined the agreement of the lesion size measured by DCE-MRI images and TTC pathology. Bland-Altman analysis demonstrated that the 3SD and 4SD threshold most closely aligned with the TTC gross pathology measurement.

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: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 (Dmax) to the epicardial coronary arteries was calculated. In secondary analyses, the mean (Dmean) and minimum dose received by the highest irradiated 0.01 cm3 (D0.01) of each coronary artery were also calculated. Coronary artery segments were harvested from the Dmax sites for histological analysis, and the Dmax 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 Dmax sites had ≥75% stenosis. The median Dmax 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 Dmax and stenosis ≥75% was 92.2%. A Dmax value of 20.1 Gy best predicted stenosis ≥75%, with sensitivity 92.3% and specificity 87.1%. The AUC-ROCs for the associations of Dmean and D0.01 with stenosis ≥75% were 84.8% and 91.6%, respectively. In histopathologic analysis, intimal hyperplasia was the most common coronary artery abnormality at the Dmax sites, and it was present in 61.5% of all arteries and in 93.9% of arteries with Dmax ≥20 Gy. CONCLUSIONS:In this preclinical model of proton beam cardiac radioablation, coronary stenoses occurred in a dose-dependent manner, with Dmax 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: Proton beam irradiation to the ventricular myocardium may enable non-invasive targeting of ventricular tachycardia. Previous work has demonstrated the feasibility of imaging ablation lesion with late gadolinium enhanced (LGE) cardiac magnetic resonance imaging (MRI). Hypothesis: We hypothesize that proton beam irradiation will lead to progressively increasing density of LGE corresponding to lesion formation during follow-up after treatment delivery. Aim: The aim of the current study was to determine the time course of LGE intensity in ventricular myocardium following proton beam therapy. Methods: Eleven swine were irradiated with 40 Gy proton beam in the anterior or lateral left ventricular (LV) followed by LGE cardiac MRI every 4 weeks for up to 24 weeks. After manual contouring of the endocardial and epicardial myocardium, a region of interest (ROI) in the area irradiated with 0-5 Gy was contoured (remote ROI). The mean and standard deviation (SD) of the signal intensity (SI) of the remote ROI were calculated. Light LGE was defined as voxels with SI > mean+2SD but < mean+3SD of the remote ROI, while voxels with SI > mean+3SD of the remote ROI were classified as having dense LGE. Voxels identified as bright due to image artifacts or noise were manually removed. The analysis was conducted in a fashion blinded to swine ID and time point after irradiation. Results: A total of 33 time points were analyzed (3.1 ± 1.4 MRI studies per swine). Figure 1A shows a representative time course of LGE in the same swine, progressing from diffuse light LGE at 8 weeks to dense LGE at 16-24 weeks. Figure 1B demonstrates the proportion of light versus dense LGE across timepoints in irradiated myocardial regions. At 8 weeks, light and dense LGE areas were evenly distributed. At 12 to 24 weeks, dense LGE increased to approximately 75%. The proportion of dense versus light LGE was significantly higher at 12, 16, and 24 weeks, as compared to 8 weeks. Conclusion: In ventricular myocardium, diffuse light LGE evident at 8 weeks progresses to denser LGE at 12-24 weeks following proton beam irradiation corresponding with lesion formation.

Cardiac radioablation (CRA) has emerged as a promising treatment modality for refractory ventricular arrhythmias. However, the gene expression profile underlying CRA effects on the myocardium is not well understood.

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.

Cardiac radioablation has emerged as a novel approach for the treatment of refractory scar-related ventricular tachycardia (VT). Current clinical evidence for this approach is limited to photon treatments. Cardiac and extracardiac radiation dose distributions in humans treated for VT with proton beam therapy have not been previously reported.

With ablation using a saline flow catheter tips, occasionally microbubbles will be seen, either from excessive heating or steam pops. The occurrence and implications of microbubble formation with PFA/IRE ablation has not been determined.

Background: With large lesion formation, there is a possibility of perforation or other cardiac related tissue changes.These have not been well evaluated in a in situ model.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: Therefore, 32 domestic swine underwent proton beam ablation to the left ventricle anterior wall, posterior wall, and apex.Each swine was subjected to monthly contrast-enhanced cardiac MRI to evaluate the post-irradiation effects.Importantly, the typical dose delivered after contouring, simulations, and treatment planning was between 30 and 40 Gy.Results: With these deliveries, a pericardial effusion was seen in 18 swine.These were first seen 4 weeks after the radiation and showed resolution in 87% within 14 days.Actual pericarditis was seen in 2 pigs after the ablation.There was no evidence of dissection of myocardial tissue, nor steam pops or their equivalent with particle therapy.The animals appeared to show no distress or irritation.With the pathology at the time of study showed no presence of pericarditis and no other complications.Also, there was significant correlation between animals with mean dose to myocardium and the grade of PE.Conclusion: As such, pericardial effusions may occur in the setting of particle therapy.Of note, these are minor however and do not appear to be of clinical significance.Still, this suggests the need for careful monitoring of animals in the post-procedure setting.

A new catheter has been developed which uses diamonds embedded in the catheter tip to enable temperature-guided ablation. The degree to which subsequent Magnetic Resonance (MR) findings correlate with actual tissue pathology has never been assessed.

A significant amount of information regarding large lesion formation has emerged over the last 5 – 6 years. Extensive studies have been performed with needle electrode, PFA ablation and protons. The consequence of large lesions have not been analyzed in the intact heart in situ.

Cardiac motion remains a challenge in the treatment of ventricular tachycardia with external beam ablation therapy. Current techniques involve expansion of the treatment area which can lead to unwanted collateral damage. Surrounding healthy tissue could be spared by gating the delivery of the beam to the cardiac cycle. In prior work, we assessed cardiac motion using in vivo fiducial markers and demonstrated that motion would be reduced if treatment were gated to half of the cardiac cycle, approximately corresponding to diastole. In the current work, we extend our prior analysis by quantitatively assessing the optimal gating window for motion reduction in the left ventricle. Motion was assessed in five porcine models with two fiducial clips per animal for a total of ten clips. The minimal cardiac motion occurred when the gating window started at 70% of the cardiac cycle. Without gating, three-dimensional cardiac motion was 7.0 ± 3.9 in x (left/right), 5.3 ± 2.5 in y (anterior/posterior), and 5.6 ± 2.3 in z (superior/inferior) mm. Using an optimal gating window, cardiac motion was 3.1 ± 1.8 in x (left/right), 2.5 ± 1.2 in y (anterior/posterior), and 3.1 ± 1.7 in z (superior/inferior) mm. The percentage reduction in motion with optimal gating was 51 ± 23 in x (left/right), 49 ± 21 in y (anterior/posterior), and 45 ± 24 % in z (superior/inferior). This work demonstrates that gating shows significant promise for reducing the effects of left ventricular motion when treating ventricular tachycardia with external beam ablation therapy.

More than 20 years ago, temperature was used to guide ablative intervention. This was subsequently replaced by power to drive intervention. Recently, temperature-guided ablation has been reintroduced into the ablation armament. But the anatomic and electrical characteristics of currently available temperature-controlled ablation is unclear.

Proton beam ablation (PBA) is proving its efficacy as a non-invasive modality for ablation of ventricular arrhythmias (VA). Patients with VA often have concomitant ischemic heart disease secondary to coronary artery disease.

Proton beam therapy has emerged as a promising tool for catheter-free arrhythmia ablation. We previously reported that proton beam lesions become visible in late gadolinium MRI (LGE-MRI) approximately 8 weeks after irradiation. Ablation lesions are also visible in histology; however, the time course of the biochemical changes in these lesions is not yet fully understood.

External beam ablation therapy has the potential to treat cardiac arrhythmias non-invasively by targeting arrhythmogenic myocardial tissue; however, a challenge of treating cardiac tissue with beam ablation therapy is cardiac motion. Currently, cardiac motion is typically compensated by expansion of the target volume which can potentially lead to collateral damage of surrounding healthy tissue. This collateral damage could be minimized by gating the beam delivery to a portion of the cardiac cycle. In prior work, we evaluated cardiac motion using anatomic landmarks in multi-phase cardiac computed tomography volumes of swine hearts across the left atria and ventricles. Other work evaluated left atrial motion using implanted fiducial clips. In the current work, we extend this prior work by quantifying cardiac motion using gold standard implanted fiducial clips across all four chambers of the heart. Cardiac motion varied by chamber, ranging from 2.1 to 7.2 mm in the x direction, 7.2 to 8.1 mm in the y direction, and 3.1 to 9.7 mm in the z direction. In addition, we quantify the reduction in motion if delivery were gated to phases 40% to 90% of the cardiac cycle, which corresponds to treating across 50% of the cardiac cycle. Cardiac motion across 50% of the cardiac cycle ranged from 1.1 to 5.3 mm in the x direction, 4.5 to 5.2 mm in the y direction, and 1.2 to 7.8 mm in the z direction. Percentage reduction in motion for treating during 50% of the cardiac cycle ranged from 18% to 47% in the x direction, 31% to 43% in the y direction, and 11% to 61% in the z direction. These results demonstrate that a substantial improvement in target localization could be achieved by gating the beam to 50% of the cardiac cycle.