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      The effect of ionizing radiation through cardiac stereotactic body radiation therapy on myocardial tissue for refractory ventricular arrhythmias: A review

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          Abstract

          Cardiac stereotactic body radiation therapy (cSBRT) is a non-invasive treatment modality that has been recently reported as an effective treatment for ventricular arrhythmias refractory to medical therapy and catheter ablation. The approach leverages tools developed and refined in radiation oncology, where experience has been accumulated in the treatment of a wide variety of malignant conditions. However, important differences exist between rapidly dividing malignant tumor cells and fully differentiated myocytes in pathologically remodeled ventricular myocardium, which represent the respective radiation targets. Despite its initial success, little is known about the radiobiology of the anti-arrhythmic effect cSBRT. Pre-clinical data indicates a late fibrotic effect of that appears between 3 and 4 months following cSBRT, which may result in conduction slowing and block. However, there is clear clinical evidence of an anti-arrhythmic effect of cSBRT that precedes the appearance of radiation induced fibrosis for which the mechanism is unclear. In addition, the data to date suggests that even the late anti-arrhythmic effect of cSBRT is not fully attributable to radiation.-induced fibrosis. Pre-clinical data has identified upregulation of proteins expected to result in both increased cell-to-cell coupling and excitability in the early post cSBRT period and demonstrated an associated increase in myocardial conduction velocity. These observations indicate a complex response to radiotherapy and highlight the lack of clarity regarding the different stages of the anti-arrhythmic mechanism of cSBRT. It may be speculated that in the future cSBRT therapy could be planned to deliver both early and late radiation effects titrated to optimize the combined anti-arrhythmic efficacy of the treatment. In addition to these outstanding mechanistic questions, the optimal patient selection, radiation modality, radiation dose and treatment planning strategy are currently being investigated. In this review, we consider the structural and functional effect of radiation on myocardium and the possible anti-arrhythmic mechanisms of cSBRT. Review of the published data highlights the exciting prospects for the development of knowledge and understanding in this area in which so many outstanding questions exist.

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          Most cited references38

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          Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC): an introduction to the scientific issues.

          Advances in dose-volume/outcome (or normal tissue complication probability, NTCP) modeling since the seminal Emami paper from 1991 are reviewed. There has been some progress with an increasing number of studies on large patient samples with three-dimensional dosimetry. Nevertheless, NTCP models are not ideal. Issues related to the grading of side effects, selection of appropriate statistical methods, testing of internal and external model validity, and quantification of predictive power and statistical uncertainty, all limit the usefulness of much of the published literature. Synthesis (meta-analysis) of data from multiple studies is often impossible because of suboptimal primary analysis, insufficient reporting and variations in the models and predictors analyzed. Clinical limitations to the current knowledge base include the need for more data on the effect of patient-related cofactors, interactions between dose distribution and cytotoxic or molecular targeted agents, and the effect of dose fractions and overall treatment time in relation to nonuniform dose distributions. Research priorities for the next 5-10 years are proposed. Copyright 2010 Elsevier Inc. All rights reserved.
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            Radiation-induced vascular damage in tumors: implications of vascular damage in ablative hypofractionated radiotherapy (SBRT and SRS).

            We have reviewed the studies on radiation-induced vascular changes in human and experimental tumors reported in the last several decades. Although the reported results are inconsistent, they can be generalized as follows. In the human tumors treated with conventional fractionated radiotherapy, the morphological and functional status of the vasculature is preserved, if not improved, during the early part of a treatment course and then decreases toward the end of treatment. Irradiation of human tumor xenografts or rodent tumors with 5-10 Gy in a single dose causes relatively mild vascular damages, but increasing the radiation dose to higher than 10 Gy/fraction induces severe vascular damage resulting in reduced blood perfusion. Little is known about the vascular changes in human tumors treated with high-dose hypofractionated radiation such as stereotactic body radiotherapy (SBRT) or stereotactic radiosurgery (SRS). However, the results for experimental tumors strongly indicate that SBRT or SRS of human tumors with doses higher than about 10 Gy/fraction is likely to induce considerable vascular damages and thereby damages the intratumor microenvironment, leading to indirect tumor cell death. Vascular damage may play an important role in the response of human tumors to high-dose hypofractionated SBRT or SRS.
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              Noninvasive Cardiac Radiation for Ablation of Ventricular Tachycardia

              BACKGROUND Recent advances have enabled noninvasive mapping of cardiac arrhythmias with electrocardiographic imaging and noninvasive delivery of precise ablative radiation with stereotactic body radiation therapy (SBRT). We combined these techniques to perform catheter-free, electrophysiology-guided, noninvasive cardiac radioablation for ventricular tachycardia. METHODS We targeted arrhythmogenic scar regions by combining anatomical imaging with noninvasive electrocardiographic imaging during ventricular tachycardia that was induced by means of an implantable cardioverter–defibrillator (ICD). SBRT simulation, planning, and treatments were performed with the use of standard techniques. Patients were treated with a single fraction of 25 Gy while awake. Efficacy was assessed by counting episodes of ventricular tachycardia, as recorded by ICDs. Safety was assessed by means of serial cardiac and thoracic imaging. RESULTS From April through November 2015, five patients with high-risk, refractory ventricular tachycardia underwent treatment. The mean noninvasive ablation time was 14 minutes (range, 11 to 18). During the 3 months before treatment, the patients had a combined history of 6577 episodes of ventricular tachycardia. During a 6-week postablation “blanking period” (when arrhythmias may occur owing to postablation inflammation), there were 680 episodes of ventricular tachycardia. After the 6-week blanking period, there were 4 episodes of ventricular tachycardia over the next 46 patient-months, for a reduction from baseline of 99.9%. A reduction in episodes of ventricular tachycardia occurred in all five patients. The mean left ventricular ejection fraction did not decrease with treatment. At 3 months, adjacent lung showed opacities consistent with mild inflammatory changes, which had resolved by 1 year. CONCLUSIONS In five patients with refractory ventricular tachycardia, noninvasive treatment with electrophysiology-guided cardiac radioablation markedly reduced the burden of ventricular tachycardia. (Funded by Barnes–Jewish Hospital Foundation and others.)
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                Author and article information

                Contributors
                Journal
                Front Cardiovasc Med
                Front Cardiovasc Med
                Front. Cardiovasc. Med.
                Frontiers in Cardiovascular Medicine
                Frontiers Media S.A.
                2297-055X
                15 September 2022
                2022
                : 9
                : 989886
                Affiliations
                [1] 1Brigham and Women's Hospital , Boston, MA, United States
                [2] 2Harvard Medical Schools , Boston, MA, United States
                [3] 3School of Biomedical Engineering and Imaging Sciences, King's College , London, United Kingdom
                [4] 4Guy's and St. Thomas's NHS Foundation Trust , London, United Kingdom
                Author notes

                Edited by: Roberto Rordorf, San Matteo Hospital Foundation (IRCCS), Italy

                Reviewed by: Veronica Dusi, University of Turin, Italy; Josef Kautzner, Institute for Clinical and Experimental Medicine (IKEM), Czechia

                *Correspondence: John Whitaker john.whitaker@ 123456kcl.ac.uk

                This article was submitted to Cardiac Rhythmology, a section of the journal Frontiers in Cardiovascular Medicine

                Article
                10.3389/fcvm.2022.989886
                9520407
                36186961
                b3a69864-ebb8-413e-8551-729e8e9ee538
                Copyright © 2022 Whitaker, Zei, Ahmad, Niederer, O'Neill and Rinaldi.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 July 2022
                : 08 August 2022
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 39, Pages: 12, Words: 8687
                Categories
                Cardiovascular Medicine
                Review

                cardiac stereotactic body radiation therapy,ventricular tachycardia,cellular response,cardiomyopathy,ablation electrophysiology

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