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

Abstract

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.

Stereotactic arrhythmia radioablation (STAR) has been suggested as a promising therapeutic alternative in cases of failed catheter ablation for recurrent ventricular tachycardia (VTs) and other cardiac arrhythmias in patients with structural heart disease (1-4). In fact, some clinical studies demonstrated the efficacy and safety of STAR in this setting, at least in the short term, particularly in reducing VT episodes (5-9).

Furthermore, some preclinical studies have been conducted in order to study the mechanisms of action and the biological-pathological effects of STAR (10-30). However, while some literature revisions of clinical studies are available (31-36), reviews specifically addressed to preclinical studies only are currently lacking.

For these reasons we considered as potentially useful a summary of available evidence in this field (10-30), in order to provide knowledge and awareness on the effects of STAR in experimental models. Therefore, the aim of this narrative literature review was to collect and analyze the results of the published preclinical studies on STAR in the treatment of refractory cardiac arrhythmias.

The review was written by a multidisciplinary team consisting of radiation oncologists, cardiologists, health physicists, radiologists, and translational research experts. The rationale and concept for this manuscript were proposed and discussed by the authors during a videoconference in January 2022.

Materials and Methods

A literature search was conducted on PubMed on 25 January 2022. The search strategy was as follows: (“stereotactic” OR “SBRT” OR “SABR” OR “radioablation” OR “radiosurgery”) AND (“arrhythmia” OR “tachycardia” OR “fibrillation”). We included in this review preclinical and pathological reports published in English, without time limits, comprising studies of STAR in animal models and histological analyses of explanted animal and human hearts. We excluded planning studies, clinical trials, literature reviews, guidelines, ongoing studies, and paper reporting duplicate data. The main results are presented in Table I.

Table I. Characteristics and main findings of the preclinical studies on stereotactic arrhythmia radioablation (STAR).

AF: Atrial fibrillation; AR: arrhythmia; AV: atrioventricular; CT: computed tomography; CCT: cardiac computed tomography; EAM: electroanatomical mapping; ICD: implantable cardioverter defibrillator; MRI: magnetic resonance imaging; RT: radiotherapy; STAR: stereotactic arrhythmia radioablation; VT: ventricular tachycardia.

Results

The results of the studies on STAR accuracy were as follows: i) the conformality of STAR dose distribution is lower using photons compared to carbon ions beams (20), ii) based on thermoluminescence and Mosfet dosimeters evaluation of the planning accuracy of CyberKnife-based STAR, the radiation dose was 5% less than expected on epicardium, 6% less than expected in coronary sinus, and 25% less in the esophagus (13), iii) in pigs models it is possible to deliver 35-40 Gy respecting the dose volume constraints to the chest wall, the esophagus, and great vessels (25).

In terms of therapeutic efficacy, the analyzed studies showed, after STAR, enhanced intracardiac conductivity (10), absence of spontaneous arrhythmias (12) and reduced arrhythmia inducibility compared to controls (19), decreased pulmonary vein electric waves after 6 months (22.5-40 Gy) (15), and complete atrioventricular block after irradiation with 25-55 Gy (20) or 35-50 Gy (21). Moreover, STAR’s short-term safety analyses showed no acute effects after 80-160 Gy in 16 fractions and after 90 Gy in 18 fractions (17) or after 25-55 Gy in a single fraction (20), absence of arrhythmic radiation-induced events (16), no myocardial damage after 70-160 Gy fractionated STAR (16,17) or after 35-50 Gy STAR delivered in a single fraction (21). Furthermore, the medium-term safety analyses on STAR showed no radiation damage 25-196 days after STAR (25-50 Gy) (12) or six months after STAR (22), and unimpaired myocardial function six months after STAR (up to 35 Gy) (14). Finally, in terms of long-term safety, two studies reported unchanged left ventricular ejection (after 15 Gy STAR) (19) and absence of side effects (after 5-15 Gy STAR) (11) one year after the treatment.

Studies on the biological effect of STAR showed: i) cell apoptosis (by detecting cleaved caspase-3 as a marker) in the irradiated volumes three months after treatment but not after six months (18,24), ii) increased expression of connexin 43 (10,11,19,27) and a variety of other proteins (28) and iii) increased gap junctions (11). Moreover, other studies reported: i) clear histological evidence of STAR effect on the target area, found by the loss of myocyte architecture and increased fibrin, vacuoles and calcification (12), and ii) fibrosis in the same area, detected by loss of the smooth cellular organization usually seen in normal AV nodes, extensive fibrin deposition and marked elastosis, but not in the surrounding tissues (21,24,26,30). Finally, a study on human explanted hearts showed subendocardial necrosis characterized by degenerative changes in myocytes with irregular and convoluted intercalated disc regions, loss of contractile elements and edematous mitochondria with loss of cisternae, and the myocardium surrounded by a border of fibrosis (23,30) (Figure 1).

Figure 1. Main effects of stereotactic arrhythmia radioablation (STAR).

Dose effect. Several studies evaluated any dose effect on biological consequences, radiation-induced toxicity, and therapeutic efficacy (11,14,15,17,18,20,22,29). In terms of biological effects, the following results were reported: i) increased expression of connexin 43 is evident only after STAR with dose ≥10 Gy (11), ii) transmural scarring of the heart is recorded only with STAR doses ≥32.5 Gy (14), while iii) transmural scarring of the target can be observed only after STAR doses >30 Gy (15). Additionally, regarding the dose effect on potential toxicity, the analyzed studies reported that fibrosis of healthy tissues is dose-dependent (14) and that, evaluating the effects after STAR delivered with carbon ions at doses of 25-55 Gy, deceleration and interruption of cardiac conduction are recorded only with doses ≥40 Gy (18). Generally, it has been observed that STAR is safe up to doses of 35 Gy in animal models (22).

Finally, in terms of therapeutic efficacy, the following evidence on the dose effect has been reported: i) the minimum dose to obtain a 100% electrocardiographic effect is 25 Gy, while after STAR at doses of 15-20 Gy only a partial effect is recorded (22), ii) in case of STAR delivered in multiple fractions, no changes in atrioventricular conduction are observed with 80 Gy in 16 fractions but only with 90 Gy in 18 fractions or 160 Gy in 16 fractions (17), and iii) an atrioventricular block occurs with any dose between 25 and 55 Gy (20).

Discussion

Methodology of the analyzed studies. Different experimental models were used in the analyzed studies, and in particular: living rabbits (10,11), mini-pigs (12,14,15), pigs (18,20,21,25), dogs (19) or dogs and pigs (13,22), explanted and reperfused pig hearts (16,17), explanted human hearts of non-ischemic cardiomyopathy patients after STAR in the context of transplantation (2,29), and human hearts evaluated postmortem (24,29). The experimental methods were also heterogeneous between studies including myocardial infarction induced by microsphere injection in coronary arteries (10,18) and STAR on healthy hearts (11,14,16,17,18,20,22). Some authors reported on planning accuracy using CyberKnife-based STAR (13), and on radiation dose on healthy tissues during STAR (25). Other authors reported on histological analysis of explanted human hearts (23,24).

STAR was based mainly on photons (12-15,20-25) but also on carbon-ions beams (10,11,16-19) and delivery using linear accelerators (14,15,20,21,22,23,25), synchrotrons (10,11,16-19), or CyberKnife (13,24). Furthermore, among the analyzed studies the irradiation was delivered to different targets: anterolateral left ventricular free wall (10,11), left ventricle (23), right ventricle (23), interventricular septum (23), lateral left ventricular wall (19,24), inferolateral left ventricular wall (24), inferior ventricular scar (24), cavotricuspid isthmus or atrial-ventricular node or pulmonary vein-left atrial junction or left atrial appendage (12,26), pulmonary vein ostia (13), pulmonary vein antrum (14,15), atrial-ventricular nodes (16,17,21,25), atrial-ventricular junction (20), and right upper pulmonary vein (22,26).

In some cases, the main endpoint of the studies was the STAR accuracy in terms of: i) planning accuracy, using thermoluminescence dosimeters and Mosfet dosimeters (13), ii) dose conformity, comparing photons-based intensity modulated radiotherapy versus carbon-ion radiotherapy (20), and iii) dose to the organs at risk when using a STAR dose of 35 or 40 Gy (25). Notably, most studies evaluated the STAR electrophysiological efficacy (10,12,14-22) or issues concerning treatment safety (26). Regarding the latter topic, some studies analyzed acute (early) events after STAR (17,20), late (1 year) radiation-induced effects after STAR (5-15 Gy) (11), ventricular ejection one year after STAR (19), and more generally radiation damage adjacent to the target after STAR delivered with different doses: 25-50 Gy (12,26), 25-55 Gy (20), 35-50 Gy (21), and 15-35 Gy (22). Furthermore, other studies focused on the impact of STAR on biological parameters such as: i) the levels of connexin 43 in heart tissue, a gap junction protein regulating the cell-to-cell communication (10,11,19,27), ii) the histopathological damage outside the target (12,14-17,20-22) and within the target (12,14,15,21-24), or iii) the apoptosis in cells within the target (18).

Conclusion

This review has some limitations. In fact, our analysis is a narrative review of the literature and therefore lacks quantitative analyses and is based on very heterogeneous studies in terms of experimental models, irradiation modalities, and evaluated endpoints. Actually, the heterogeneity of the included studies is the reason precluding any attempt to conduct a pooled analysis of the results.

However, even within these limits, our review leads to some possible conclusions that can be drawn. First, the analyzed studies confirm the existence of a therapeutic window, at least considering the short-medium term results, corresponding to STAR doses of 25-30 Gy. In fact, doses lower than 25 Gy seem to produce sub-optimal therapeutic results (20,22) while doses >35 Gy are less safe in terms of toxic effects (18,22). Second, long-term results (>1 year) are still missing and even those recorded one year after STAR are based on relatively low dose irradiation (≤15 Gy) (11,19). Finally, STAR proved to be an effective therapy in the analyzed studies, despite the irradiation of rather different cardiac targets (10-17,19-25).

Therefore, on the basis of these conclusions, further studies are warranted to: i) compare the efficacy and safety of STAR at doses of 25 Gy versus 30 Gy, ii) evaluate the long-term (>1 year) results in animal models irradiated at doses similar to those used in the clinic, iii) define the optimal target, in terms of anatomical structures and margins to be added to the latter, in order to obtain lasting therapeutic results without significant side effects.

Conflicts of Interest

The Authors declare no conflicts of interest in relation to this study.

Authors’ Contributions

Conceptualization: E.G., F.C., C.M., L.S., A.A., and A.G.M.; literature search and data collection and analysis: E.G., S.S., L.L., A.S., and S.C.; writing-original draft preparation: E.G., A.G.M., and A.A.; all Authors critically revised the work; all Authors have read and agreed to the published version of the manuscript.