Stereotactic arrhythmia radioablation (STAR) is an innovative, noninvasive technique that delivers high-dose ionizing radiation in one fraction to ablate arrhythmogenic myocardial substrates, particularly in patients with drug- and ablation-refractory ventricular tachycardia (VT). Adapted from stereotactic body radiotherapy (SBRT), a technique employed in oncology, STAR uses advanced imaging and precision treatment planning to accurately target myocardial scar tissue and conduction pathways, while minimizing exposure to surrounding healthy cardiac and extracardiac structures.1

The clinically accepted dose for STAR in humans is 25 Gy, derived from preclinical animal studies demonstrating antiarrhythmic effects without excessive toxicity.2 Early preclinical studies that investigated cardiac RT used higher doses between 40 and 160 Gy to induce late-stage cardiac fibrosis and cause subacute atrioventricular block, whereas lower doses did not achieve these effects.3,4

These prior studies did not clarify how 25 Gy leads to acute reduction in VT burden. Notably, Zhang et al.5 found that this dose did not result in catheter ablation-like scar formation in explanted specimens from cardiac RT patients. Instead, in mice and patients, they observed that a dose of 25 Gy persistently increases levels of cardiac conduction proteins and enhances ventricular conduction, identifying cardiomyocyte Notch signaling as a potential mechanism through which radiation may reprogram conduction.

In support of this hypothesis, histopathological analyses have documented dose-dependent changes in fibroblast activation, extracellular matrix deposition, and microvascular integrity, providing a biological rationale for the clinical application of STAR.6,7 Furthermore, preclinical studies have demonstrated acute upregulation of Connexin-43 and voltage-gated sodium channels (Nav1.5) within hours of irradiation, suggesting a rapid electrophysiological modulation that may contribute to the early antiarrhythmic effects of STAR.5

Since its first human application in 2012,8 STAR has shown promising results in patients with therapy-resistant VT. Several case series and prospective cohort studies have confirmed its safety and efficacy, since the first published case in Europe9 reporting no episode of malignant arrhythmia detected by the implantable cardioverter-defibrillator (ICD) during a 120-day follow-up.

A recent systematic review and meta-analysis1 analyzed 10 prospective studies involving 82 STAR-treated patients. The reported 12-month survival rate was 73% (95% CI, 61-83) and the incidence of grade ≥3 treatment-related adverse events (AEs) was 11% (95% CI, 4-20) within 90 days of therapy. Among 61 patients with available data, 1-year freedom from recurrence was 30% (95% CI, 16-49), while 1-year recurrence-free survival was 21% in 60 patients (95% CI, 8-46). Data on reduction in treated VT episodes were retrieved from 61 patients across 8 trials, with most patients achieving a ≥ 95% reduction in VT burden. Specifically, the proportions of patients achieving a given VT burden reduction were 61% (95% CI, 45-74), 80% (95% CI, 62-91), and 90% (77-96) for 95%, 75%, and 50% thresholds, respectively.

As STAR remains an emerging therapy with limited large-scale validation, the European Union has launched STOPSTORM (Standardized Treatment and Outcome Platform for Stereotactic Therapy of Re-entrant Tachycardia by a Multidisciplinary consortium) under the Horizon 2020 framework to coordinate multicenter research and standardize protocols.10 A more detailed description of its objectives is provided in Section 7.2.

VT is defined as 3 or more consecutive ventricular beats occurring at a rate of at least 100 beats per minute, originating from the ventricular myocardium or the specialized conduction system distal to the atrioventricular node.11 While most cases of VT are associated with structural heart disease, such as ischemic cardiomyopathy or dilated cardiomyopathy, approximately 10% occurs in patients with structurally normal hearts, often arising from the right or left ventricular outflow tracts.12

In its incessant form, VT is characterized by continuous or frequently recurring episodes that persist despite optimal pharmacologic and interventional therapies. This condition poses a substantial clinical challenge, as it can cause heart failure, provoke frequent implantable cardioverter-defibrillator (ICD) shocks, and significantly increase the risk of sudden cardiac death. In the United States alone, VT and ventricular fibrillation are responsible for an estimated 300,000 sudden cardiac deaths annually.13 Survivors often experience repeated hospitalizations, psychological distress from ICD discharges, and diminished quality of life (QoL). These burdens highlight the urgent need for innovative and less invasive therapeutic approaches capable of providing effective arrhythmia suppression without exacerbating comorbidities or procedural risk.

The acute management of VT focuses on stabilizing the patient and correcting any associated hemodynamic instability. Amiodarone remains the most used antiarrhythmic agent due to its broad-spectrum efficacy and relatively favorable short-term safety profile.14 However, its long-term use is associated with several serious adverse effects, which include photosensitivity (25%-75%), blue-grey skin discoloration (4%-9%), hypothyroidism (6%), pulmonary toxicity (1%-17%), hyperthyroidism (0.9%-2%), corneal optic neuropathy (≤1%-2%), peripheral neuropathy (0.3% annually), and hepatotoxicity.15

For patients with recurrent or drug-refractory VT, catheter ablation -via endocardial and/or epicardial access- represents a cornerstone intervention. Acute procedural success rates range from 50% to 90%, depending on the underlying substrate. Nevertheless, recurrence rates remain high, with up to 50% of patients experiencing VT relapse within 1 year, especially in presence of structural VT.16 Additionally, the procedural risks include cardiac perforation, peripheral thromboembolism, vascular injury, and limited access to deep intramural arrhythmogenic substrates.

Long-term management strategies are guided by the risk of sudden cardiac death. For patients with sustained VT in structural heart disease not attributable to reversible causes, ICD implantation is typically recommended for secondary prevention.14 However, frequent ICD discharges can severely affect patients’ psychological well-being and quality of life.

Shared decision-making is therefore essential, balancing arrhythmia control with procedural risk and patient-reported outcomes. Additional treatment options may include optimization of underlying cardiac conditions, correction of structural abnormalities (e.g., valvular or coronary disease), escalation of antiarrhythmic therapy, repeat catheter ablation, autonomic modulation (such as sympathetic denervation),17 and, more recently, noninvasive options like STAR, particularly in patients who are poor candidates for further invasive procedures.18

The concept of using ionizing radiation to modulate cardiac electrophysiology dates to the 1980s, when early animal studies demonstrated that myocardial irradiation could cause transient conduction abnormalities and structural damage.19 However, limitations in imaging resolution, motion control, and dose delivery accuracy restricted these investigations to the preclinical domain.

Interest in cardiac radioablation was revitalized in the 2010s with the advent of advanced imaging modalities such as high-resolution computed tomography (CT) and magnetic resonance imaging (MRI), as well as respiratory and cardiac gating techniques, and stereotactic radiotherapy planning systems capable of submillimeter precision.

In 2012, the first human case of STAR was reported, demonstrating a dramatic reduction in VT episodes from an average of 562 per month to 52 over 9 months without acute or delayed complications.8 This landmark case established the feasibility of STAR as a noninvasive treatment for refractory VT and catalyzed further clinical research. These encouraging results were replicated in a small case series involving 5 patients, which confirmed substantial VT burden reduction with minimal adverse effects.20

Subsequent prospective data continued to support the clinical utility of STAR. In 2019, the first prospective report on 19 patients from the ENCORE-VT trial21 demonstrated that cardiac SBRT led to a VT burden reduction of over 75% in 89% of the 19 patients treated. Comparable findings were recently confirmed in the final analyses of the German multicenter feasibility trial RAVENTA,22 which reported a 73.7% 1-year freedom from index VT. Notably, only 1 grade ≥ 3 toxicity was reported as possibly related to STAR, involving progression of heart disease in the second month post treatment, ultimately requiring heart transplantation.

Additional encouraging evidence has emerged from the STARNL-1 and SMART-VT trials. The STARNL-123 reported a ≥ 50% reduction in treated VT -episodes in 4 out of 6 patients (67%) at the end of follow-up. Meanwhile, the SMART-VT24 showed a total VT burden reduction of 84.3% among 10 evaluable patients. These encouraging results have led to growing interest in STAR therapy.

To better understand the rationale behind these clinical outcomes, it is important to explore the underlying mechanisms of STAR. Stereotactic arrhythmia radioablation is based on stereotactic ablative radiotherapy (SBRT), a high-precision radiation technique developed in oncology to treat early-stage tumors such as lung and prostate cancer- as well as oligometastatic disease. Each year, thousands of patients with inoperable stage I lung cancer are successfully treated with SBRT, which delivers ablative radiation doses with submillimeter accuracy and minimal exposure to surrounding tissues.25

Among the pioneering studies, the RTOG 0236 phase II trial by Timmerman et al.,26 reported a 97.6% primary tumor control rate and a 3-year overall survival of 55.8% in medically inoperable patients with stage I non-small cell lung cancer (NSCLC) treated with 54 Gy in 3 fractions. Similarly, a large retrospective series from VU Medical Center27 investigated centrally and ultra-centrally located early-stage NSCLC, concluding that SABR is not significantly affected by tumor location, provided that appropriate fractionation and dose constraints are applied.

The characteristic of SBRT-and, by extension, STAR- is its ability to deliver a high, focal radiation dose to a well-defined target while sparing adjacent healthy tissue through rapid dose fall-off, reducing the risk of AEs. What distinguishes STAR from oncologic SBRT, however, is its mechanistic rationale. While cancer radiotherapy relies on fractionated doses to kill proliferating tumor cells, STAR delivers a single high dose (25 Gy) not to destroy cells, but to functionally modulate the arrhythmogenic substrate. Thus, despite employing similar delivery platforms -such as linear accelerators (LINACs), robotic systems like CyberKnife, or MRI-guided devices- STAR operates via distinct radiobiological mechanisms.

Initially, it was hypothesized that STAR functioned similarly to catheter ablation, inducing transmural myocardial fibrosis and thereby interrupting arrhythmic circuits through structural modification.2 However, growing evidence indicates that the currently prescribed dose of 25 Gy may primarily induce functional rather than structural changes.

Overall, available data support a biphasic response to STAR. In the early phase (hours to days post-irradiation), no overt necrosis or fibrosis is present. Instead, radiation induces subcellular stress, including edematous mitochondria and intercalated disc alterations, which impair conduction across myocardial tissue and contribute to early arrhythmia suppression.28 In the late phase (weeks to months), some degree of fibrosis or remodeling may occur, though not consistently or uniformly.

In animal studies, following 25 Gy exposure, radiation has been shown to upregulate key conduction proteins, including Nav1.5 and connexin-43, via activation of the Notch signaling pathway. These molecular changes have been associated with improved conduction velocity and narrowing of the QRS complex -markers of functional improvement in the absence of structural damage-, suggesting a form of “electrical reprogramming.”5

A unique clinical case report29 further supports this hypothesis, describing the explanted heart of a patient who exhibited a sustained antiarrhythmic response for nearly 1 year, before undergoing heart transplantation due to progressive heart failure. Histological examination of the explanted heart revealed no homogenous transmural fibrosis within the irradiated region. The myocardial structure was indistinguishable from that of patients with end-stage heart failure unrelated to radiotherapy, suggesting that the therapeutic effect had been achieved without scar formation.

Taken together, these findings reinforce the notion that functional changes -rather than fibrotic remodeling- may serve as the principal mechanism of action for STAR at clinical doses.