Lehmann, H. Immo

Introduction: Highly precise irradiation using carbon-12 (12C) ions is a new means for catheter-free ablation. Besides energy deposition leading to the dose distribution, nuclear interactions lead to by-product β+-activity that can be measured using positron-emission-tomography (PET). Hypothesis: In-beam PET scanning during focused myocardial irradiation using 12C can adequately depict 12C dose deposition. Methods: Pigs were irradiated with 25, 40, and 55 Gy for AV node (AVN), LA-PV junction, and local LV freewall ablations. PET measurement was performed by means of a double head camera system installed at irradiation site. Coincidences were captured in end-expiration during beam extraction pauses of the accelerator. Results: Evaluation of PET images was qualitatively performed using the coronal plane of the activity distribution superimposed on the contrast-CT in the center of the target contour. Strong β+-activities were measured in AVN and LV ablations. In AVN ablations, activity was localized to the target location, without target activity spreading to the level of the aortic root or coronary sinus (Figure A). Local LV irradiations revealed strong activity in the target location, slightly extending into left lung and chest wall (Figure B). In 55 Gy animals, the cardiac entry channel showed increased activity, decreasing in 40 Gy and more so in 25 Gy animals. Conclusion: This is the first study applying in-beam PET to track 12C dose-deposition into the target location for catheter-free ablation in intact animals. Correlation of β+-activity to electrophysiological outcome, lesion induction, and potential side-effects may be critically important in dosing therapy and predicting outcomes.

Introduction: The spatial thermodynamics of very high power-short duration (vHPSD) radiofrequency (RF) application during pulmonary vein isolation (PVI) in in-vivo model has not been well characterized. This study was conducted to investigate the distance-temperature relationship during vHPSD-RF ablation. Methods: PVI was performed using the vHPSD catheter with the settings of 90W, RF time of 4 sec and 15mL/min irrigation in a canine model. Catheter contact force (CF) of 10-20g was defined as ‘normal’ and CF >20g as ‘firm’ CF. Tissue temperature was monitored using thermocouples implanted at the surface of the left atrial-pulmonary vein junction, left phrenic nerve, and the luminal esophagus. PVI using a standard contact-force sensing catheter (SCF) (settings of 35W, 30sec and 30mL/min irrigation) was performed for comparison. Results: A total of 334 TC profiles in 4 animals was investigated. Time to maximum tissue temperature (MTT) (6.0sec [vHPSD/normal CF] vs. 30.5 sec [SCF/normal CF], p<0.001; 8.0sec [vHPSD/firm CF] vs. 24.0sec [SCF/firm CF], p=0.022) was shorter with vHPSD than in SCF groups. MTT within 10mm from catheter-tip was lower in vHPSD ablation with normal CF than using SCF ablation (median 41.9°C [interquartile-range; 40.2-46.1] vs. 49.5°C [45.9-56.2], p=0.013). The distance margin to keep the MTT below 39ºC, 42ºC, and 50ºC were 4.9mm, 4.2mm, and 3.4mm, respectively in the vHPDS group. This margin was larger (8.0mm, 6.6mm, and 4.6mm) in the SCF group. Conclusion: Our study underscores that vHPSD creates greater resistive heating than conventional catheter ablation.

Abstract Aims With the implementation of saline-enhanced radiofrequency (SERF) needle-tip ablation, real-time validation of lesion formation is needed for the controllable creation of transmural lesions. The aim of the study was to analyse the ability of two-dimensional intracardiac echocardiography (2D-ICE) to guide and validate SERF ablation in real-time. Methods and results Fifty-six SERF energy deliveries at left ventricular sites of 11 dogs guided by 2D-ICE were analysed (power: 15–50 W; time: 25–120 s; irrigation saline: 60°C with 10 mL/min flow rate). Catheter tip/tissue orientation and lesion formation could be well detected by 2D-ICE in 49 (87.5%) energy deliveries. Gross pathology analysis confirmed excellent 2D-ICE lesion localization, the ability to detect transmural lesions (70% sensitivity, 47% specificity) and positive correlation between 2D-ICE and the corresponding gross pathology measurements of ‘maximal lesion depth’; (repeated measures correlation: rrm = 0.43, P = 0.012) and ‘depth at maximal lesion width’ (D@MW; rrm = 0.51, P = 0.003). The median angle between SERF catheter tip and endocardium was 76° [interquartile range (IQR) 58–83°]. The more perpendicular the catheter tip/tissue orientation was the deeper D@MW (rrm = 0.32, P = 0.045). Grade 3 microbubbles on 2D-ICE during ablation, indicating inadequate catheter tip/tissue contact, was associated with smaller lesion volumes than with Grade 1 microbubbles (284.8 mm3 [IQR 151.3–343.1] vs. 2114.1 mm3 [IQR 1437.0–3026.3], P &lt; 0.001). Conclusion With excellent lesion localization and a 70% detection rate of transmural lesions, 2D-ICE is well suited to validate SERF ablation lesion formation in real-time. The catheter tip/tissue angle impacts the lesion formation and through perpendicular catheter positioning, deeper intramural areas of the myocardium can be reached.

Background: Inability to eliminate intramural arrhythmogenic substrate may lead to recurrent ventricular tachycardia after catheter ablation. The aim of the present study was to evaluate intramural and full thickness lesion formation using a heated saline-enhanced radiofrequency (SERF) needle-tip catheter, compared with a conventional ablation catheter in normal and infarcted myocardium. Methods: Twenty-two adult mongrel dogs (30–40 kg, 15 normal and 7 myocardial infarct group) were studied. Lesions were created using the SERF catheter (40 W/50 °C) or a standard contact force (CF) catheter in both groups. Results: Comparing SERF to CF ablation, the SERF catheter produced larger lesion volumes than the standard CF catheter—even with >20 g of CF—in both normal (983.1±905.8 versus 461.9±178.3 mm 3 ; P =0.023) and infarcted left ventricular myocardium (1052.3±543.0 versus 340.3±160.5 mm 3 ; P =0.001). SERF catheter lesions were more often transmural than standard CF lesions with >20 g of CF in both groups (59.1% versus 7.7%; P <0.001 and 60.0% versus 12.5%; P =0.017, respectively). Using the SERF catheter, mean depth of ablated lesions reached 90% of the left ventricular wall in both normal and infarcted myocardium. Conclusions: The SERF catheter created more transmural and larger ablative lesions in both normal and infarcted canine myocardium. SERF ablation is a promising new approach for endocardial intramural and full thickness ablation of ventricular tachycardia substrate that is not accessible with current techniques.

Background: Proton beam therapy offers radiophysical properties that are appealing for noninvasive arrhythmia elimination. This study was conducted to use scanned proton beams for ablation of cardiac tissue, investigate electrophysiological outcomes, and characterize the process of lesion formation in a porcine model using particle therapy. Methods: Twenty-five animals received scanned proton beam irradiation. ECG-gated computed tomography scans were acquired at end-expiration breath hold. Structures (atrioventricular junction or left ventricular myocardium) and organs at risk were contoured. Doses of 30, 40, and 55 Gy were delivered during expiration to the atrioventricular junction (n=5) and left ventricular myocardium (n=20) of intact animals. Results: In this study, procedural success was tracked by pacemaker interrogation in the atrioventricular junction group, time-course magnetic resonance imaging in the left ventricular group, and correlation of lesion outcomes displayed in gross and microscopic pathology. Protein extraction (active caspase-3) was performed to investigate tissue apoptosis. Doses of 40 and 55 Gy caused slowing and interruption of cardiac impulse propagation at the atrioventricular junction. In 40 left ventricular irradiated targets, all lesions were identified on magnetic resonance after 12 weeks, being consistent with outcomes from gross pathology. In the majority of cases, lesion size plateaued between 12 and 16 weeks. Active caspase-3 was seen in lesions 12 and 16 weeks after irradiation but not after 20 weeks. Conclusions: Scanned proton beams can be used as a tool for catheter-free ablation, and time-course of tissue apoptosis was consistent with lesion maturation.

Background The Purkinje network appears to play a pivotal role in the triggering as well as maintenance of ventricular fibrillation. Irreversible electroporation ( IRE ) using direct current has shown promise as a nonthermal ablation modality in the heart, but its ability to target and ablate the Purkinje tissue is undefined. Our aim was to investigate the potential for selective ablation of Purkinje/fascicular fibers using IRE . Methods and Results In an ex vivo Langendorff model of canine heart (n=8), direct current was delivered in a unipolar manner at various dosages from 750 to 2500 V, in 10 pulses with a 90‐μs duration at a frequency of 1 Hz. The window of ventricular fibrillation vulnerability was assessed before and after delivery of electroporation energy using a shock on T‐wave method. IRE consistently eradicated all Purkinje potentials at voltages between 750 and 2500 V (minimum field strength of 250–833 V/cm). The ventricular electrogram amplitude was only minimally reduced by ablation: 0.6±2.3 mV ( P =0.03). In 4 hearts after IRE delivery, ventricular fibrillation could not be reinduced. At baseline, the lower limit of vulnerability to ventricular fibrillation was 1.8±0.4 J, and the upper limit of vulnerability was 19.5±3.0 J. The window of vulnerability was 17.8±2.9 J. Delivery of electroporation energy significantly reduced the window of vulnerability to 5.7±2.9 J ( P =0.0003), with a postablation lower limit of vulnerability=7.3±2.63 J, and the upper limit of vulnerability=18.8±5.2 J. Conclusions Our study highlights that Purkinje tissue can be ablated with IRE without any evidence of underlying myocardial damage.

Abstract Noninvasive ablation of cardiac arrhythmia by scanned particle radiotherapy is highly promising, but especially challenging due to cardiac and respiratory motion. Irradiations for catheter-free ablation in intact pigs were carried out at the GSI Helmholtz Center in Darmstadt using scanned carbon ions. Here, we present real-time electrocardiogram (ECG) data to estimate time-resolved (4D) delivered dose. For 11 animals, surface ECGs and temporal structure of beam delivery were acquired during irradiation. R waves were automatically detected from surface ECGs. Pre-treatment ECG-triggered 4D-CT phases were synchronized to the R – R interval. 4D-dose calculation was performed using GSI’s in-house 4D treatment planning system. Resulting dose distributions were assessed with respect to coverage ( D 95 and V 95), heterogeneity (HI = D 5– D 95) and normal tissue exposure. Final results shown here were performed offline, but first calculations were started shortly after irradiation The D 95 for TV and PTV was above 95% for 10 and 8 out of 11 animals, respectively. HI was reduced for PTV versus TV volumes, especially for some of the animals targeted at the atrioventricular junction, indicating residual interplay effects due to cardiac motion. Risk structure exposure was comparable to static and 4D treatment planning simulations. ECG-based 4D-dose reconstruction is technically feasible in a patient treatment-like setting. Further development of the presented approach, such as real-time dose calculation, may contribute to safe, successful treatments using scanned ion beams for cardiac arrhythmia ablation.

Background— This study sought to investigate external photon beam radiation for catheter-free ablation of the atrioventricular junction in intact pigs. Methods and Results— Ten pigs were randomized to either sham irradiation or irradiation of the atrioventricular junction (55, 50, 40, and 25 Gy). Animals underwent baseline electrophysiological evaluation, cardiac gated multi-row computed tomographic imaging for beam delivery planning, and intensity-modulated radiation therapy. Doses to the coronary arteries were optimized. Invasive follow-up was conducted ≤4 months after the irradiation. A mean volume of 2.5±0.5 mL was irradiated with target dose. The mean follow-up length after irradiation was 124.8±30.8 days. Out of 7 irradiated animals, complete atrioventricular block was achieved in 6 animals of all 4 dose groups (86%). Using the same targeting margins, ablation lesion size notably increased with the delivered dose because of volumetric effects of isodose lines around the target volume. The mean macroscopically calculated atrial lesion volume for all 4 dose groups was 3.8±1.1 mL, lesions extended anteriorly into the interventricular septum. No short-term side effects were observed. No damage was observed in the tissues of the esophagus, phrenic nerves, or trachea. However, histology revealed in-field beam effects outside of the target volume. Conclusions— Single-fraction doses as low as 25 Gy caused a lesion with interruption of cardiac impulse propagation using this respective target volume. With doses of ≤55 Gy, maximal point-doses to coronary arteries could be kept <7Gy, but target conformity of lesions was not fully achieved using this approach.

Background— Formation of microemboli during catheter ablation has been suggested as a cause for asymptomatic cerebral emboli. However, it is unknown which part of the process and ablation setting/strategy is most strongly related to this occurrence. Methods and Results— A total of 27 pigs were used. Catheter/sheath manipulations in left atrium were performed in 25 of 27 pigs outfitted with microemboli monitoring systems. Ablations using open-irrigated radiofrequency catheters were performed in 18 of 25 pigs. Two of 27 pigs did not undergo left atrial procedures and were injected with microembolic materials in the carotid artery to serve as positive controls. In total, 334 sheath/catheter manipulations (transseptal puncture, sheath flushing, catheter insertion, pulmonary vein venography, and sheath exchange) and 333 radiofrequency applications (power setting, 30/50 W; point-by-point/drag ablations) were analyzed. High microbubble volume in the extracorporeal circulation loop and a high number of microembolic signals in carotid artery were observed during sheath/catheter manipulations especially in saline/contrast injections at fast speed and ablations with steam pop. Fast sheath flushing produced significantly higher microbubble volume than slow sheath flushing (median, 12 200 versus 121 nL; P <0.0001). A total of 44 of 126 (35%) blood filters in the circulation loop showed microparticles (thrombus/coagulum and tissue). Most of them were seen after radiofrequency application especially in 50-W ablations, drag ablations, and steam pop. Brain magnetic resonance imaging showed positive-embolic lesions in control pigs. Conclusions— Formation of microbubbles was the greatest during fast saline/contrast injections and steam pops, whereas high-power radiofrequency applications, drag ablations, and steam pops produced most of the microparticles.