Anna Constantinescu

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.

Multigating, a 4D optimized beam tracking in scanned ion beam therapy.

The treatment of moving tumors with a scanned ion beam is challenging due to interplay effects and changing beam range. We propose multigating, as a method for 4D-treatment optimization and delivery. In 3D beam tracking, tracking vectors are added during delivery to beam spot positions based on the detected motion phase. This has the disadvantage of dose errors in case of complex motion patterns and an uncertain out-of-target dose distribution. In multigating, the motion phase for each beam spot is predefined, which allows to add the tracking vector prior to beam weight optimization on all motion phases. The synchronization of delivery and target motion is assured by fast gating. The feasibility of the delivery was shown in a film experiment and required only minor software modification to the treatment planning system. In a treatment planning study in 4 lung cancer patients, target coverage could be restored to the level of a static reference plan by multigating (V95 > 99%) but not by standard beam tracking (V95 < 95%). The conformity of the multigating plans was only slightly lower than those of the static plan, with a conformity number of 72.0% (median, range 64.6–76.6%) compared to 75.8% (70.8–81.5%) in spite of target motion of up to 22 mm. In conclusion, we showed the technical feasibility of multigating, a 4D-optimization and delivery method using scanned beams that allows for conformal and homogeneous dose delivery to moving targets also in case of complex motion.

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.

Catheter-free arrhythmia ablation using scanned carbon ion beams in a porcine model

Cardiac arrhythmias are a wide-spread disease associated with reduced quality of life, increased risks of stroke and sudden cardiac death. Catheter ablation and isolation of arrhythmogenic structures in the heart is the current standard treatment, but is invasive, complex, and shows varying effectiveness especially for progressive disease. The most common form is atrial fibrillation (AF), a too fast and ineffective contraction of the atria. AF often originates from the pulmonary veins (PV) and can be cured by isolating the veins. For persistent AF, the ablation of the AV node can be a last resort to prevent the AF from affecting the ventricles. The irregular scars caused by an infarct can lead to ventricular tachycardia (VT), which can cause sudden cardiac death. Homogenizing the scars can cure VT, but is difficult in the left ventricle, where the thick muscle tissue cannot be penetrated completely with catheter ablation. In this study, scanned carbon ions were investigated as a non-invasive alternative to induce the required electrically isolating fibrosis in the myocardium.

Heavy Ion Beam Irradiation of a Langendorff Heart

Matthias Prall1, J. Bauer2, A. Constantinescu1, J. Debus2, M. Durante1, C. Graeff1, T. Haberer2, H. Hauswald2, H. I. Lehmann4, D. L. Packer4, H. Prokesch2, D. Richter2, K. Sonnenberg2, G. Szabo2, R. Kaderka1, S. Korkmaz2, A. Weymann2, and C. Bert3 1GSI, Darmstadt, Germany; 2Universitatsklinikum Heidelberg, Germany; 3Universitatsklinikum Erlangen, Germany; 4Mayo Clinic College of Medicine, Rochester, MN, USA

Influence of cardiac motion on porcine AV node for the non-invasive treatment of atrial fibrillation with a scanned carbon ion beam

Atrial fibrillation (AF) is the most common cardiac arrhythmia and occurs in ∼2 % of the western population older than eighty [1]. Since age is an important risk factor for this disease, the prevalence is estimated to double in the next fifty years. One treatment strategy for reducing the ventricular rate in AF patients is atrioventricular (AV) node ablation, requiring the implantation of a pacemaker. It has recently be shown in animal studies that a non-invasive ablation on this target site is feasible with photons [2]. Similar experiments with carbon ions are planned for 2014 at GSI, where the AV node of swines will be irradiated. In order to assess the target displacement due to heart beat motion volume histograms (MVHs) were analyzed.