Stereotactic Ablative radiation therapy (SABR) for cardiac arrhythmia: A new therapeutic option?

AIM: Stereotactic ablative radiation therapy (SABR) is used in non-oncologic indications, recently even for cardiac arrhythmias. Thus, aim of this analysis is to review preclinical, early clinical evidences and future direction of the latter new treatment approach. METHOD: A collection of available data regarding SABR and cardiac arrhythmias was made, by Pubmed research and 2 independent researchers, including preclinical and clinical data. A review of ongoing trials was conducted on ClinicalTrials.gov. RESULTS: Preclinical research conducted in animal models showed that a safe and effective noninvasive treatment approach for cardiac arrhythmias could be represented by SABR with a median time of response around 2-3 months. The treatment dose plays a crucial role: the atrioventricular node would seem more radiosensitive than the other cardiac electric zones. Clinical data, such as published case series, case reports and early prospective studies, have already suggested the feasibility, efficacy and safety of SABR (25 Gy in one session) for refractory ventricular arrhythmias. CONCLUSION: Considering the ongoing trials of SABR and new technological improvements in radiotherapy (e.g. hybrid magnetic resonance) and in arrhythmias noninvasive mapping systems, the future analyses will improve the reliability of those preliminary results.

Ablative Radiotherapy as a Noninvasive Alternative to Catheter Ablation for Cardiac Arrhythmias.

PURPOSE OF REVIEW: Stereotactic radioablation is a commonly utilized technology to noninvasively treat solid tumors with precision and efficacy. Using a robotic arm mounted delivery system, multiple low-dose ionizing radiation beams are delivered from multiple angles, concentrating ablative energy at the target tissue. Recently, this technology has been evaluated for treatment of cardiac arrhythmias. This review will present the basic underlying principles, proof-of-principle studies, and clinical experience with stereotactic arrhythmia radioablation. RECENT FINDINGS: Most recently, stereotactic radioablation has been used to safely and effectively treat a limited number of patients with malignant arrhythmias, including ventricular tachycardia (VT) and atrial fibrillation (AF). Treatment protocols, outcomes, ongoing studies, and future directions will be discussed. Stereotactic radioablation is a well-established technology that has been shown to be a safe and effective therapy for patients with drug-refractory cardiac arrhythmias, including VT and AF. Further clinical evaluation to define safety and efficacy in larger populations of patients is needed.

Stereotactic Arrhythmia Radioablation (STAR): A Multidisciplinary Narrative Minireview of Preclinical Studies.

The aim of this narrative review of the literature was to collect and analyze the results of the published preclinical studies on stereotactic arrhythmia radioablation (STAR) in the treatment of refractory cardiac arrhythmias. A literature search was conducted on PubMed using the following terms: ("stereotactic" OR "SBRT" OR "SABR" OR "radioablation" OR "radiosurgery") AND ("arrhythmia" OR "tachycardia"). Preclinical and pathological reports published in English without time limit, comprising studies of STAR in animal models and histological analyzes of explanted animal and human hearts were included. The analyzed studies confirm that doses lower than 25 Gy seem to produce sub-optimal therapeutic results whereas doses >35 Gy are less safe in terms of radiation-induced toxicity. However, long-term results (>1 year) are still missing and reporting outcomes based on low dose irradiation (≤15 Gy). Finally, STAR proved to be an effective therapy in the analyzed studies despite the irradiation of rather different cardiac targets. Therefore, additional studies are needed to: 1) compare the outcomes of STAR at doses of 25 Gy versus 30 Gy; 2) evaluate the long-term results (>1 year) in animal models irradiated at doses similar to those used in the clinic; 3) define the optimal target.

Ablative radiosurgery for cardiac arrhythmias - A systematic review.

Stereotactic body radiotherapy (SBRT) is a high precision technique that is commonly used for malignant lesions in lung, liver, pancreas and spine. Recent reports suggest promise in use of SBRT as a tool in atrial and ventricular cardiac arrhythmias. The present systematic review deals with the use of SBRT technology for this novel indication. A PubMed search was done for articles published between 1990 and 2020. All original articles, case reports, case series of treated patients were included in the analyses. Out of the 55 articles in PubMed search, our search found 1 phase I/II clinical case series, 3 clinical case reports, 3 animal studies and 4 dosimetric studies related to cardiac SBRT for arrythmias. All studies used a uniform cardiac dose of 25Gy. The available preclinical, dosimetric and clinical studies have suggested that SBRT for cardiac arrhythmias could become a potential alternative in suitable patients. Cardiac and radiation oncology community await further data and experience in this modality, including safety and outcomes.

Early Changes in Rat Heart After High-Dose Irradiation: Implications for Antiarrhythmic Effects of Cardiac Radioablation.

Background Noninvasive cardiac radioablation is employed to treat ventricular arrhythmia. However, myocardial changes leading to early-period antiarrhythmic effects induced by high-dose irradiation are unknown. This study investigated dose-responsive histologic, ultrastructural, and functional changes within 1 month after irradiation in rat heart. Methods and Results Whole hearts of wild-type Lewis rats (N=95) were irradiated with single fraction 20, 25, 30, 40, or 50 Gy and explanted at 1 day or 1, 2, 3, or 4 weeks' postirradiation. Microscopic pathologic changes of cardiac structures by light microscope with immunohistopathologic staining, ultrastructure by electron microscopy, and functional evaluation by ECG and echocardiography were studied. Despite high-dose irradiation, no myocardial necrosis and apoptosis were observed. Intercalated discs were widened and disrupted, forming uneven and twisted junctions between adjacent myocytes. Diffuse vacuolization peaked at 3 weeks, suggesting irradiation dose-responsiveness, which was correlated with interstitial and intracellular edema. CD68 immunostaining accompanying vacuolization suggested mononuclear cell infiltration. These changes were prominent in working myocardium but not cardiac conduction tissue. Intracardiac conduction represented by PR and QTc intervals on ECG was delayed compared with baseline measurements. ST segment was initially depressed and gradually elevated. Ventricular chamber dimensions and function remained intact without pericardial effusion. Conclusions Mononuclear cell-related intracellular and extracellular edema with diffuse vacuolization and intercalated disc widening were observed within 1 month after high-dose irradiation. ECG indicated intracardiac conduction delay with prominent ST-segment changes. These observations suggest that early antiarrhythmic effects after cardiac radioablation result from conduction disturbances and membrane potential alterations without necrosis.

A Review of Cardiac Radioablation (CR) for Arrhythmias: Procedures, Technology, and Future Opportunities.

PURPOSE: Cardiac radioablation (CR), a new treatment for cardiac arrhythmias such as ventricular tachycardia and atrial fibrillation, has had promising clinical outcomes to date. There is consequent desire for rapid clinical adoption. However, CR presents unique challenges to radiation therapy, and it is paramount that clinical adoption be performed safely and effectively. Recent reviews comprehensively detail patient selection, clinical history, treatment outcomes, and treatment toxicities but only briefly mention the technical aspects of CR. To address this knowledge gap, this review collates currently available knowledge regarding CR technology choice and procedural details to help inform and guide clinics considering implementing their own CR program, to aid technique standardization, and to highlight areas that require further development or verification. METHODS AND MATERIALS: Original preclinical and clinical scientific articles that sufficiently detailed CR technical aspects, including pretreatment electrophysiology and imaging, motion analysis and management techniques, treatment planning, and/or treatment delivery, were identified within a comprehensive literature search. RESULTS: Nineteen preclinical and 18 clinical scientific articles sufficiently detailed the technical aspects of CR treatment deliveries on live subjects. The technical aspects of these scientific articles were diverse: Preclinical treatments have been performed with brachytherapy, photons, protons, and carbon ions, and clinical treatments have been performed with photons using conventional, robotic, and magnetic resonance imaging guided systems. Other technical aspects demonstrated similar variability. CONCLUSIONS: This review summarizes the technical aspects and procedural details of preclinical and clinical CR treatment deliveries and highlights the complexity and current variability of CR. There is need for standardized procedural reporting to aid multicenter and multiplatform evaluation and potential for significant technological improvements in imaging, planning, delivery, and monitoring to maximize the clinical outcomes for selected patients with arrhythmia.

Biological Cardiac Tissue Effects of High-Energy Heavy Ions - Investigation for Myocardial Ablation.

Noninvasive X-ray stereotactic treatment is considered a promising alternative to catheter ablation in patients affected by severe heart arrhythmia. High-energy heavy ions can deliver high radiation doses in small targets with reduced damage to the normal tissue compared to conventional X-rays. For this reason, charged particle therapy, widely used in oncology, can be a powerful tool for radiosurgery in cardiac diseases. We have recently performed a feasibility study in a swine model using high doses of high-energy C-ions to target specific cardiac structures. Interruption of cardiac conduction was observed in some animals. Here we report the biological effects measured in the pig heart tissue of the same animals six months after the treatment. Immunohistological analysis of the target tissue showed (1.) long-lasting vascular damage, i.e. persistent hemorrhage, loss of microvessels, and occurrence of siderophages, (2.) fibrosis and (3.) loss of polarity of targeted cardiomyocytes and wavy fibers with vacuolization. We conclude that the observed physiological changes in heart function are produced by radiation-induced fibrosis and cardiomyocyte functional inactivation. No effects were observed in the normal tissue traversed by the particle beam, suggesting that charged particles have the potential to produce ablation of specific heart targets with minimal side effects.

Extensive Use of 3D Nonfluoroscopic Mapping Systems for Reducing Radiation Exposure during Catheter Ablation Procedures: An Analysis of 10 Years of Activity.

PURPOSE: 3D nonfluoroscopic mapping systems (NMSs) are generally used in the catheter ablation (CA) of complex ventricular and atrial arrhythmias. The aim of this study was to evaluate the efficacy, safety, and long-term effect of the extended, routine use of NMSs for CA. METHODS: Our study involved 1028 patients who underwent CA procedures from 2007 to 2016. Initially, CA procedures were performed mainly with the aid of fluoroscopy. From October 2008, NMSs were used for all procedures. RESULTS: The median fluoroscopy time of the overall CA procedures fell by 71%: from 29.2 min in 2007 to 8.4 min in 2016. Over the same period, total X-ray exposure decreased by 65%: from 58.18 Gy⁎cm2 to 20.19 Gy⁎cm2. This reduction was achieved without prolonging the total procedure time. In AF CA procedures, the median fluoroscopy time fell by 85%, with an 86% reduction in total X-ray exposure. In SVT CA procedures, the median fluoroscopy time fell by 93%, with a 92% reduction in total X-ray exposure. At the end of the follow-up period, the estimated probability of disease-free survival was 67.7% at 12 months for AF CA procedures and 97.2% at 3 months for SVT CA, without any statistically significant difference between years. CONCLUSIONS: Our study shows the feasibility of using NMSs as the main imaging modality to guide CA. The extended, routine use of NMSs dramatically reduces radiation exposure, with only slight fluctuations due to the process of acquiring experience on the part of untrained operators, without affecting disease-free survival.

Noninvasive cardiac arrhythmia ablation with particle beams.

Cardiac arrhythmias are a major health burden, associated with reduced quality of life and substantial morbidity and mortality. Current therapy includes moderately effective medication and catheter-based ablation of arrhythmogenic substrates in the heart. Catheter interventions frequently have to be repeated due to recurrent arrhythmia, can have rare but severe side-effects and are less suited especially for potentially lethal left ventricular tachycardia. Noninvasive alternatives are therefore warranted. Photon and ion beam radiotherapy has been studied in animal models and first patient cases have been reported using photons. Ion beams might offer the possibility to greatly reduce dose to surrounding healthy tissue, including critical cardiac substructures. Based on a recently conducted animal study, we report advantages and disadvantages of 4D-ion beam therapy, and strategies necessary for a clinical transition. Motion management of both respiration and heartbeat are discussed, as well as range uncertainty resulting from both regular motion and interfractional anatomic changes. Image guidance both in 3D and 4D has to be employed for a safe irradiation, but also population-based data on motion variability and time behavior of interfractional changes are necessary. Range verification could play a crucial role at least during development of clinical protocols. For clinical realization, it appears necessary to suppress or conformally mitigate the large respiratory motion to avoid normal tissue complications. Cardiac motion has to be incorporated into treatment planning, either through adequate range-considering internal margins or through more conformal strategies such as ECG-based gating or even 4D-optimization. The latter strategies would necessitate online 4D image guidance.

Efficacy and safety of radiofrequency catheter ablation in the elderly.

INTRODUCTION: Radiofrequency (RF) catheter ablation has not been widely undertaken in elderly patients. The aim of our study was to compare the success rate of radiofrequency ablation and the incidence of severe procedural complications in young-adult and elderly patients. METHODS: We enrolled all patients undergoing radiofrequency catheter ablation procedures for supraventricular and ventricular arrhythmias at our Cardiology Department from January 2000 to December 2005. The patients were divided into two groups according to age: patients aged <70 years (group A) and those aged >or=70 years (group B). Group B was then divided into two subgroups: B1 (age 70-79 years) and B2 (age >or=80 years). We recorded the incidence of procedural complications and the long-term efficacy (mean follow-up 46 +/- 20 months). RESULTS: We studied 605 patients, 69% in group A and 31% in group B (24% in subgroup B1 and 7% in B2). The prevalence of structural heart disease was higher in elderly patients than in young adults (83 vs 37%, p < 0.01). The rate of procedural complications was 1.3%; no differences emerged between groups A and B (1.2 vs 1.5%, p = NS) or among groups A, B1 and B2 (1.2 vs 1.4 vs 2%, p = NS). The success rate of catheter ablation was 91%, with no differences between the age-groups (92 vs 88%, p = NS) or among groups A, B1 and B2 (92 vs 88 vs 88%, p = NS). CONCLUSION: Catheter ablation in elderly and very elderly patients is as effective and safe as in young-adult subjects, at least in cases which do not require left heart catheterization.

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.

Beta-radiation for the creation of linear lesions in the canine atrium.

BACKGROUND: Creating linear lesions is important for the treatment of arrhythmias such as atrial flutter and fibrillation. Making these lesions with standard radiofrequency catheters can be difficult and may result in charring and thrombosis. The purpose of this study was to evaluate beta-radiation as a novel energy source for creating linear myocardial lesions. METHODS AND RESULTS: Eight dogs with intact conduction across the cavotricuspid isthmus were studied. The isthmus was irradiated (25 to 50 Gy) with strontium/yttrium-90 delivered via a deflectable 7F catheter (Novoste Corporation). There were no immediate effects, but bidirectional conduction block developed during follow-up studies in 7 of 8 dogs. The dog without conduction block received 25 Gy. After the animals were euthanized, histology revealed transmural, linear areas of fibrosis without any thrombus. CONCLUSIONS: Beta-radiation can safely and effectively create linear lesions that are contiguous and nonthrombogenic. This energy source may become an interesting adjunct to radiofrequency for the treatment of atrial flutter and fibrillation.

[The use of helium-neon laser in drug-resistant cardiac arrhythmias]. / Primenenie gelii-neonovogo lazera pri ustoichivykh k lekarstvennoi terapii aritmiiakh serdtsa.

Out of 85 patients with cardiac arrhythmias in the presence of chronic coronary heart disease, 28 who were resistant to ethacisine and allapinine were included into the study. They had frequent and persistent arrhythmias. The patients were divided into 2 groups: (1) the patients receiving intravenous He-Ne laser therapy in combination with one of the above drugs; (n = 17) and (2) those taking He-Ne laser therapy alone (n = 11). The efficacy of the therapies were controlled by 24-hour monitoring. An antiarrhythmic effect was more frequently observed when He-Ne laser was combined with one of the above drugs than when it was given alone (67.4 and 36.3%, respectively).

Effects of cryoablation and radiofrequency ablation on endothelial and blood clotting activation.

Cryoablation (CA) emerged as an alternative procedure to radiofrequency (RF). The aim of this study was to compare haemostatic system alterations in patients undergoing RF or CA for atrioventricular nodal reentrant tachycardia ablation. von Willebrand factor (vWF), spontaneous whole blood platelet aggregation, prothrombin fragment F1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), plasminogen activator inhibitor type-1 (PAI-1), and clot lysis time (CLT) were determined in 48 patients (27 CA; 21 RF; 19M/29F, mean age 49.6 ± 17.6 years). Blood samples were obtained before the procedure (T0), immediately after (T1), and 24 h later (T2). At T1 both procedures were associated with a significant increase in levels of the endothelial activation marker vWF. At T2 vWF levels were lower in CA than in RF group. No changes in whole blood platelet aggregation before and after ablation procedures were observed. At T1 both groups determined an increase in blood clotting activation markers, F1 + 2, TAT, and DD. At T2 F1 + 2, TAT and DD levels were similar to baseline values. The comparison between RF and CA showed no significant differences in F1 + 2 and TAT levels, whereas at T1 DD levels were higher in CA group than in RF group. Both procedures induced a significant decrease in CLT, whereas no changes in PAI-1 levels were found. There were no significant differences in CLT and PAI-1 levels. The fibrinolytic efficiency analysis showed that at T1 DD/TAT and DD/F1 + 2 ratios were lower in RF group and remained lower in RF than in CA group at T2. CA procedure may be associated with a lower degree of endothelial damage and with a higher fibrinolytic capacity respect to RF.

Orthogonal electrode catheter array for mapping of endocardial focal site of ventricular activation.

Precise location of the endocardial site of origin of ventricular tachycardia may facilitate surgical and catheter ablation of this arrhythmia. The endocardial catheter mapping technique can locate the site of ventricular tachycardia within 4-8 cm2 of the earliest site recorded by the catheter. This report describes an orthogonal electrode catheter array (OECA) for mapping and radiofrequency ablation (RFA) of endocardial focal site of origin of a plunge electrode paced model of ventricular activation in dogs. The OECA is an 8 F five pole catheter with four peripheral electrodes and one central electrode (total surface area 0.8 cm2. In eight mongrel dogs, mapping was performed by arbitrarily dividing the left ventricle (LV) into four segments. Each segment was mapped with OECA to find the earliest segment. Bipolar and unipolar electrograms were obtained. The plunge electrode (not visible on fluoroscopy) site was identified by the earliest wave front arrival times of -30 msec or earlier at two or more electrodes (unipolar electrograms) with reference to the earliest recorded surface ECG (I, AVF, and V1). Validation of the proximity of the five electrodes of the OECA to the plunge electrode was performed by digital radiography and RFA. Pathological examination was performed to document the proximity of the OECA to the plunge electrode and also for the width, depth, and microscopic changes of the ablation. To find the segment with the earliest LV activation a total of 10 +/- 3 (mean +/- SD) positions were mapped. Mean arrival times at the two earlier electrodes were -39 +/- 4 msec and -35 +/- 3 msec. Digital radiography showed the plunge electrode to be within the area covered by all five electrodes in all eight dogs. The plunge electrode was within 1 cm2 area of the region of RFA in all eight dogs. The width and depth of ablation were 5 +/- 3.5 and 7 +/- 3.5 mm, respectively. Microscopic changes revealed coagulative necrosis, hemorrhage, and inflammatory changes in all RFAs. In conclusion, the OECA can map the endocardial focal site of origin of paced ventricular activation within 1 cm2 area in a canine model. RFA from the OECA can cause discrete ablations representing all five electrodes or cross-shaped ablation connecting central electrode to all four peripheral electrodes. This catheter holds promise for extending surgical and clinical catheter ablation procedures.