H. Immo Lehmann

Impact of Freezing Time and Balloon Size on the Thermodynamics and Isolation Efficacy During Pulmonary Vein Isolation Using the Second Generation Cryoballoon

Background—The differences in ablation characteristics of freezing time and balloon size using second generation cryoballoon are still unknown. Methods and Results—Twenty-six dogs underwent pulmonary vein (PV) isolation. Balloon and tissue temperatures (left atrial–PV junction, phrenic nerve, and internal esophagus) were monitored. The ablation duration was randomized to either 3 or 4 minutes, which did not show significant differences in temperature profiles, PV isolation success rate, complications, or histological changes. Twenty dogs underwent cryoablation using 28-mm cryoballoon, 6 dogs were done using the 23-mm cryoballoon. Positioning of the 23-mm cryoballoon was more distal in the PV, which resulted in better PV occlusion. Temperature profiles showed lower temperatures in the 23-mm cryoballoon than in the 28-mm cryoballoon (inner balloon, median [range]: −51.5 [−66.0 to −31.0] versus −43.0 [−64.0 to −26.0]°C, P<0.001; balloon surface: −43.0 [−60.0 to −15.8] versus −6.5 [−46.2 to 28.9]°C, P<0.001; left atrial–PV junction: −6.7 [−20.0 to 21.4] versus 15.8 [−14.4 to 35.1]°C, P<0.001), and trended toward a higher PV isolation success rate in the 23-mm cryoballoon. Histologically, deeper extensions of ablative lesions into the PV were seen with 23-mm cryoballoon, and larger ablative lesions were seen in the left atrial antrum using 28-mm cryoballoon. Conclusions—The efficacy of 3-minute ablation was not significantly different from 4-minute ablation in dogs. The 23-mm cryoballoon had a greater cooling effect than the 28-mm cryoballoon for small PVs, but showed narrower ablative lesions in the left atrial antrum.

Spatial and Time-Course Thermodynamics During Pulmonary Vein Isolation Using the Second-Generation Cryoballoon in a Canine In Vivo Model

Background—Thermodynamics in the left atrium–pulmonary vein (PV) junction, phrenic nerve, and esophagus during PV isolation (PVI) using the second-generation cryoballoon are not known. Methods and Results—Twenty dogs underwent PVI using second-generation cryoballoon. Ablations were performed for ⩽2 deliveries based on PVI without a bonus freeze. Inner balloon, balloon surface, and tissue temperatures were monitored during cryoablation. The tissue thermocouples were placed on the epicardial surface of the left atrium–PV junction, as well as on the phrenic nerve and within the esophagus. A total of 259 cryoballoon and 229 tissue tissue thermocouples profiles during 53 cryoablations of 40 PVs were analyzed. Acutely, PVI was achieved in 36 of 40 PVs (90%). Conductive tissue cooling spread radially from the balloon–left atrium–PV contact point. The lowest tissue temperatures were dependent on the distance of the tissue thermocouples to the balloon surface (r=0.85; P<0.001). In addition, blood flow leaks around the balloon had a warming effect on the balloon and tissue temperature profiles. Chronic isolation (mean, 48±16 days) was achieved in 27 of 36 PVs (75%). In 8 of 9 acutely isolated but with chronic reconnection PVs, the blood flow leak location was concordant with chronic reconnection gap. Although only 1 esophageal ulcerated lesion was observed, neither phrenic nerve palsy nor severe PV stenosis was seen in any dogs. Conclusions—Variance in tissue thermodynamics during cryothermal ablation depends on the distance from balloon and peri-balloon blood flow leaks. This information may be useful for successful PVI without severe complications.

Effect of Left Atrial Ablation Process and Strategy on Microemboli Formation During Irrigated Radiofrequency Catheter Ablation in an In Vivo Model

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.

Atrioventricular Node Ablation in Langendorff-Perfused Porcine Hearts Using Carbon Ion Particle Therapy

Background—Particle therapy, with heavy ions such as carbon-12 (12C), delivered to arrhythmogenic locations of the heart could be a promising new means for catheter-free ablation. As a first investigation, we tested the feasibility of in vivo atrioventricular node ablation, in Langendorff-perfused porcine hearts, using a scanned 12C beam. Methods and Results—Intact hearts were explanted from 4 (30–40 kg) pigs and were perfused in a Langendorff organ bath. Computed tomgraphic scans (1 mm voxel and slice spacing) were acquired and 12C ion beam treatment planning (optimal accelerator energies, beam positions, and particle numbers) for atrioventricular node ablation was conducted. Orthogonal x-rays with matching of 4 implanted clips were used for positioning. Ten Gray treatment plans were repeatedly administered, using pencil beam scanning. After delivery, positron emission tomography-computed tomgraphic scans for detection of &bgr;+ (11C) activity were obtained. A 12C beam with a full width at half maximum of 10 mm was delivered to the atrioventricular node. Delivery of 130 Gy caused disturbance of atrioventricular conduction with transition into complete heart block after 160 Gy. Positron emission computed tomgraphy demonstrated dose delivery into the intended area. Application did not induce arrhythmias. Macroscopic inspection did not reveal damage to myocardium. Immunostaining revealed strong &ggr;H2AX signals in the target region, whereas no &ggr;H2AX signals were detected in the unirradiated control heart. Conclusions—This is the first report of the application of a 12C beam for ablation of cardiac tissue to treat arrhythmias. Catheter-free ablation using 12C beams is feasible and merits exploration in intact animal studies as an energy source for arrhythmia elimination.

Feasibility Study on Cardiac Arrhythmia Ablation Using High-Energy Heavy Ion Beams

High-energy ion beams are successfully used in cancer therapy and precisely deliver high doses of ionizing radiation to small deep-seated target volumes. A similar noninvasive treatment modality for cardiac arrhythmias was tested here. This study used high-energy carbon ions for ablation of cardiac tissue in pigs. Doses of 25, 40, and 55 Gy were applied in forced-breath-hold to the atrioventricular junction, left atrial pulmonary vein junction, and freewall left ventricle of intact animals. Procedural success was tracked by (1.) in-beam positron-emission tomography (PET) imaging; (2.) intracardiac voltage mapping with visible lesion on ultrasound; (3.) lesion outcomes in pathohistolgy. High doses (40–55 Gy) caused slowing and interruption of cardiac impulse propagation. Target fibrosis was the main mediator of the ablation effect. In irradiated tissue, apoptosis was present after 3, but not 6 months. Our study shows feasibility to use high-energy ion beams for creation of cardiac lesions that chronically interrupt cardiac conduction.

Treatment Planning Studies in Patient Data With Scanned Carbon Ion Beams for Catheter-Free Ablation of Atrial Fibrillation.

Catheter ablation with isolation of the pulmonary veins is a common treatment option for atrial fibrillation but still has insufficient success rates and carries several interventional risks. These treatment planning studies assessed if high‐dose single fraction treatment with scanned carbon ions (12C) can be reliably delivered for AF ablation, while sparing risk structures and considering respiratory and contractile target motion.

External Arrhythmia Ablation Using Photon Beams

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.

Treatment of arrhythmias by external charged particle beams: a Langendorff feasibility study.

Abstract Hadron therapy has already proven to be successful in cancer therapy, and might be a noninvasive alternative for the ablation of cardiac arrhythmias in humans. We present a pilot experiment investigating acute effects of a 12C irradiation on the AV nodes of porcine hearts in a Langendorff setup. This setup was adapted to the requirements of charged particle therapy. Treatment plans were computed on calibrated CTs of the hearts. Irradiation was applied in units of 5 and 10 Gy over a period of about 3 h until a total dose of up to 160 Gy was reached. Repeated application of the same irradiation field helped to mitigate motion artifacts in the resulting dose distribution. After irradiation, PET scans were performed to verify accurate dose application. Acute AV blocks were identified. No other acute effects were observed. Hearts were kept in sinus rhythm for up to 6 h in the Langendorff setup. We demonstrated that 12C ions can be used to select a small target in the heart and, thereby, influence the electrical conduction system. Second, our pilot study seems to suggest that no adverse effects have to be expected immediately during heavy ion irradiation in performing subsequent experiments with doses of 30–60 Gy and intact pigs.

ECG-based 4D-dose reconstruction of cardiac arrhythmia ablation with carbon ion beams: application in a porcine model

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 GSIs in-house 4D treatment planning system. Resulting dose distributions were assessed with respect to coverage (D95 and V95), heterogeneity (HI  =  D5-D95) and normal tissue exposure. Final results shown here were performed offline, but first calculations were started shortly after irradiation The D95 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.

Immobilization for carbon ion beam ablation of cardiac structures in a porcine model

INTRODUCTION Whereas hadron therapy of static targets is clinically established, treatment of moving organs remains a challenge. One strategy is to minimize motion of surrounding tissue mechanically and to mitigate residual motion with an appropriate irradiation technique. In this technical note, we present and characterize such an immobilization technique for a novel noncancerous application: the irradiation of small targets in hearts with scanned carbon ion beams in a porcine model for elimination of arrhythmias. MATERIAL AND METHODS A device for immobilization was custom-built. Both for the treatment planning 4D-CT scan and for irradiation, breath-hold at end-exhale was enforced using a remotely-controlled respirator. Target motion was thus reduced to heartbeat only. Positioning was verified by orthogonal X-rays followed by couch shift if necessary. Reproducibility of bony anatomy, diaphragm, and heart position after repositioning and between repeated breath-hold maneuvers was evaluated on X-rays and cardiac-gated 4D-CTs. Treatment was post hoc simulated on sequential 4D-CTs for a subset of animals, after immediate repositioning and after a delay of one week, similar to the delay between imaging and irradiation. RESULTS Breath-hold without repositioning was highly reproducible with an RMS deviation of at most one millimeter. 4D-CTs showed larger deformations in soft tissue, but treatment simulation on sequential images resulted in full target coverage (V95 >95%). CONCLUSION The method of immobilization permitted reproducible positioning of mobile, thoracic targets for range-sensitive particle therapy. The presented immobilization strategy could be a reasonable approach for future animal investigations with the ultimate goal of translation to therapy in men.