Noninvasive radioablation is the application of stereotactic radiosurgery (one fraction of very high-dose radiotherapy delivered to the target with submillimeter accuracy) in cardiac arrhythmias. Noninvasive radioablation is a promising technique because it eliminates risks of radiofrequency catheter ablation and its associated hospitalization. Early reported studies show promising results, with no procedural-related complications and a decreased arrhythmia burden at early to mid-term follow-up.^1-8 However, in our experience with noninvasive radioablation, even though we have similarly observed an initial decrease in ventricular arrhythmia burden, significant recurrence was ineluctable by the end of the 1-year follow-up.⁹ When trying to reconcile these results, it's important to consider the current biological and technical limitations of this novel technique.

With radiosurgery, the mechanism of injury is postulated to be a combination of vascular injury (leading to tissue hypoxia and necrosis) and apoptotic cell death (resulting in fibrosis and scar formation), which occur over days to months.¹⁰ Although 25 Gy is the dose used in current clinical studies, histologic and physiologic data from pre-clinical dose studies have shown that doses >30 Gy are required to achieve consistent scar formation at 6 months.^11,12 Underdosing might lead to an initial beneficial effect due to acute (vasogenic- and cytokine-release-related) edema, but recurrence occurs in the long term due to lack of uniform myocardial cell death.¹³ However, given the current technical limitations, delivering higher target doses might be not safe while trying to spare the surrounding organs, and longer-term safety outcomes are necessary before dose escalation. It is also possible that a dose of 25 Gy is adequate but that longer times (>12 months) are required for transmural scar formation in a tissue mostly comprising terminally differentiated cells, yielding to a higher arrhythmic risk in the mid- to long term, during which increased antiarrhythmic drug coverage might be necessary. Although early (<3 months) histology examination on human hearts after stereotactic arrhythmic radioablation using 25 Gy has shown no to mild acute inflammatory changes, longer-term data are missing.^3,8 Given these uncertainties, formal assessment of lesion formation (i.e., serial electroanatomic mapping, biopsy, magnetic resonance imaging, and computed tomography) on the irradiated myocardial tissue should be incorporated in future human studies to better understand the dynamics of the biological effects of radioablation and more precisely determine the appropriate dosing protocols to optimize safety and efficacy.

Radioablation-related injury is not a cell-specific effect; it is important to concentrate radiation exposure to the target, with a rapid dose falloff to minimize toxicity to surrounding tissue. The myocardial scar is a challenging target for stereotactic radioablation because 1) it is not accurately defined by current imaging techniques, 2) it is asymmetrical, and 3) it has complex motion, all while being surrounded by various radio-sensitive organs.

For noninvasive radioablation planning, the myocardial scar is defined by areas of myocardial thinning on contrast-enhanced computed tomography, and it is usually correlated with low-voltage areas found on electroanatomical mapping, the clinical ventricular tachycardia (VT) morphology on the 12-lead electrocardiogram, or other means of noninvasive VT mapping.³ Each technique has its limitations, such as the inability to detect the extent of the border zone, presence of multiple non-scar-related factors affecting local voltage, or localization of exit versus critical isthmus sites.^14,15 Although this approach of integration of anatomical and functional information is key, current adopted technologies might not accurately define the true anatomical extent of the clinically relevant arrhythmogenic substrate to be translated into the radioablation target. Secondly, given the asymmetrical nature of the scar, it is harder to provide uniform irradiation with minimal spillage of significant doses to the surrounding healthy organs at risk.¹⁶ Indeed, in patients who underwent repeat catheter ablation, there is evidence of incomplete ablation within the dense scar, with fragmented and delayed potentials noted in tissue well within the irradiated volume.9 Third, movement of the target results in either the target receiving less than the prescribed dose or the surrounding organs at risk receiving an additional, unnecessary dose. To avoid the latter, there are strict dose-limit guidelines, which can lead to inadequate radiation dosing to the target volume. As for the former, the myocardial scar lies in an organ that is constantly moving, itself and within the chest. Although there are several techniques to properly follow radiosurgical targets that move along the respiratory cycle and thus limit damage to the surrounding mediastinum and lung fields, little is known about how to properly manage cardiac motion.¹⁷ To date, we have no good real-time indicator to track myocardial movement (i.e., contractility), which was usually accounted for by adding a fixed margin to the clinical target volume, the static anatomical target that includes the transmural myocardium encompassing the scar. Indeed, previous four-dimensional imaging studies have shown that both the left atrial and ventricular myocardium display significant volumetric, positional, and morphological variations throughout the cardiac cycle.^18-20 Therefore, the lack of a direct, real-time, patient-specific target margin might lead to inadequate/non-uniform irradiation despite good planned dosimetry and target coverage parameters. This effect is expected to be more pronounced in the periphery of the irradiated volume (penumbra), with an incomplete, non-transmural ablation maturing over time, which indeed has been observed in patients undergoing repeat catheter ablation for VT recurrence.^9,21

The final aspect to consider is safety. Peri-procedural risks are typically extremely low due to the noninvasive nature of treatment; this is one of the biggest advantages of noninvasive radioablation over catheter ablation. To date, there are no significant acute or early radiation-related complications described in all reports using the same dosing protocol (i.e., 25 Gy in a single fraction) up to 1-year follow-up. However, because late radiation injury is dose dependent and reflects tissue-specific vulnerability, longer surveillance is necessary to confirm this favorable safety profile.

Given these limitations and current gaps in knowledge, additional research is necessary prior to widespread use of noninvasive radioablation, which at this time should be limited to the controlled setting of clinical trials with uniform dose and follow-up protocols and consistent outcomes and definitions. This is key to fully establish the long-term efficacy and safety of this novel application of radiosurgery.

References

1. Cvek J, Neuwirth R, Knybel L, et al. Cardiac Radiosurgery for Malignant Ventricular Tachycardia. Cureus 2014;6:e190.
2. Loo BW Jr, Soltys SG, Wang L, et al. Stereotactic ablative radiotherapy for the treatment of refractory cardiac ventricular arrhythmia. Circ Arrhythm Electrophysiol 2015;8:748-50.
3. Cuculich PS, Schill MR, Kashani R, et al. Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia. N Engl J Med 2017;377:2325-36.
4. Jumeau R, Ozsahin M, Schwitter J, et al. Rescue procedure for an electrical storm using robotic non-invasive cardiac radio-ablation. Radiother Oncol 2018;128:189-91.
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11. Blanck O, Bode F, Gebhard M, et al. Dose-escalation study for cardiac radiosurgery in a porcine model. Int J Radiat Oncol Biol Phys 2014;89:590-8.
12. Lehmann HI, Graeff C, Simoniello P, et al. Feasibility Study on Cardiac Arrhythmia Ablation Using High-Energy Heavy Ion Beams. Sci Rep 2016;6:38895.
13. Tapio S. Pathology and biology of radiation-induced cardiac disease. J Radiat Res 2016;57:439-48.
14. Komatsu Y, Cochet H, Jadidi A, et al. Regional myocardial wall thinning at multidetector computed tomography correlates to arrhythmogenic substrate in postinfarction ventricular tachycardia: assessment of structural and electrical substrate. Circ Arrhythm Electrophysiol 2013;6:342-50.
15. Josephson ME, Anter E. Substrate Mapping for Ventricular Tachycardia: Assumptions and Misconceptions. JACC Clin Electrophysiol 2015;1:341-52.
16. Torrens M, Chung C, Chung HT, et al. Standardization of terminology in stereotactic radiosurgery: Report from the Standardization Committee of the International Leksell Gamma Knife Society: special topic. J Neurosurg 2014;121:2-15.
17. Dieterich S, Green O, Booth J. SBRT targets that move with respiration. Phys Med 2018;56:19-24.
18. Ipsen S, Blanck O, Lowther NJ, et al. Towards real-time MRI-guided 3D localization of deforming targets for non-invasive cardiac radiosurgery. Phys Med Biol 2016;61:7848-63.
19. Tong Y, Yin Y, Lu J, et al. Quantification of heart, pericardium, and left ventricular myocardium movements during the cardiac cycle for thoracic tumor radiotherapy. Onco Targets Ther 2018;11:547-54.
20. Hasnain AC, Suzuki A, Wang S, et al. Quantitative assessment of cardiac motion using multiphase computed tomography imaging with application to cardiac ablation therapy. In: Fei B, Webster RJ III, eds. Medical Imaging 2018: Image-Guided Procedures, Robotic Interventions, and Modeling 2018;10576:105762F.
21. Qian PC, Quadros K, Aguilar M, Mak R, Zei P, Tedrow UB. Recurrent ventricular tachycardia arising at the treatment borderzone after stereotactic radioablation in a patient with ischemic cardiomyopathy. Europace 2020:22:1053.

Clinical Topics: Arrhythmias and Clinical EP, Noninvasive Imaging, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Novel Agents, Magnetic Resonance Imaging

Keywords: Arrhythmias, Cardiac, Radiosurgery, Cicatrix, Mediastinum, Organs at Risk, Vascular System Injuries, Atrial Fibrillation, Follow-Up Studies, Tachycardia, Ventricular, Anti-Arrhythmia Agents, Catheter Ablation, Myocardium, Electrocardiography, Magnetic Resonance Imaging, Apoptosis

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