Sarcoidosis is a systemic inflammatory disease of unknown etiology (1). The disease is characterized by non-caseous granulomas and subsequent scarring in various organs including the heart. Cardiac sarcoidosis is associated with heart failure, conduction abnormalities, and life-threatening arrhythmias including ventricular tachycardia (VT) (2, 3). Treatment of cardiac sarcoidosis consists of immunomodulators and management of cardiac complications (4). In patients at risk of ventricular arrhythmias, an implantable cardioverter-defibrillator (ICD) is advised to prevent sudden cardiac death (5). However, despite immunosuppression, arrhythmic events occur frequently requiring anti-arrhythmic drugs (AAD) prescription and/or catheter ablations (5). In patients with AAD and catheter ablation refractory VT, stereotactic arrhythmia radioablation (STAR) has shown promising results; albeit, the worldwide experience is still very limited (6–10). Interestingly, since the 1980s, there are reports on the immunomodulatory effects of low-dose radiotherapy (11, 12). It has been suggested as an immunomodulatory treatment for patients with therapy refractory extra-cardiac sarcoidosis (13–15). Potentially, patients with both therapy refractory cardiac sarcoidosis and VT may benefit from a combined radiotherapy treatment. We report here on the beneficial and lasting effects of immunomodulatory low-dose whole-heart radiotherapy and high-dose STAR in a patient with cardiac sarcoidosis and recurrent VT refractory to conventional therapies.

The CTV and PTV for the immunomodulatory radiotherapy were 688 and 1,162 cc, respectively. For the STAR treatment, the VT-CTV consisted of the basal anterior and basal anteroseptal segments resulting in a VT-CTV of 8 cc and a VT-PTV of 16 cc. The mean irradiation dose (Dmean) to the heart for the two treatments combined was 9.1 Gy, and the maximum dose (Dmax) received was 27.5 Gy.

Figure 2 shows an overview of the repeated [¹⁸F]FDG-PET/CT scans. On the [¹⁸F]FDG-PET/CT scans prior to and 2 years before treatment, hypermetabolic areas of the anteroseptal segment and the posterior papillary muscle were observed. Three months after treatment, the hypermetabolic cardiac activity was reduced. Only in the basal anterior segment, corresponding to VT-PTV, a mild increase in metabolic activity was observed. Another [¹⁸F]FDG-PET/CT scan was performed 11 months after treatment and showed regression of this local hypermetabolic activity and no new pathological activity. The [¹⁸F]FDG-PET/CT scan at 55 months did not show any signs of active cardiac sarcoidosis, and a state of remission was achieved.

Figure 1 shows an overview of the ventricular arrhythmia burden and different therapies. Comparing the 54 months before and after radiotherapy treatments, the number of sustained VT episodes was reduced by 95% (1,089 pre-treatment vs. 53 after treatment). The number of non-sustained VT episodes was also reduced from 3,051 pre-treatment to 1,289 after treatment (−58%). It is important to acknowledge that this reduction in VT episodes is not only attributable to the radiotherapy treatments as several catheter ablations have been performed (Figure 1, red cross). Seven months after treatment, a new electrical storm occurred in the context of an influenza infection which resolved spontaneously. Because of the multiple arrhythmia recurrences after STAR, eventually, a seventh successful catheter ablation was performed 16 months after radiotherapy treatment. The recurrence was located on the border of the VT-CTV at the basal anteroseptal and mid-anteroseptal segments. Afterward, only two sustained VT episodes treated by ATP occurred during the following 38 months. The mitral valve regurgitation significantly reduced in the months after treatment.

During the follow-up of 55 months, we observed that the development of moderate aortic valve regurgitation was likely irradiation-related. No other irradiation-related adverse events occurred, and the left ventricular ejection fraction remained stable.

We present a patient with therapy refractory cardiac sarcoidosis and VTs treated with low-dose whole-heart radiotherapy and high-dose STAR. To our knowledge, this is the first report on the use of low-dose whole-heart radiotherapy as an immunomodulatory treatment for cardiac sarcoidosis. We showed a reduction in both inflammatory disease activity and VT episodes.

Previously, radiotherapy in cardiology was mostly known for its late radiation-induced cardiovascular complications (17). A paradigm shift occurred when STAR was introduced as a therapeutic option for therapy refractory ventricular arrhythmias (6–10). This shift also occurred in our tertiary academic referral center as the previous experiences with STAR were favorable (9).

The low-dose whole-heart irradiation was performed as a compassionate and experimental immunomodulatory treatment of cardiac sarcoidosis. The decision to perform this treatment was based on previous reports on the immunomodulatory effects of radiotherapy and the concurrent risks of current and future treatments (e.g., VT storm, complications of heart transplantation) (11, 12, 18). Reports on the treatment of patients with extra-cardiac sarcoidosis, mainly neurosarcoidosis, showed that radiotherapy could indeed be beneficial in managing disease activity (13–15). Reported doses widely varied between 10 and 60 Gy divided over 1–15 fractions. For safety reasons, we deviated from those reports and prescribed a lower dose. The disease activity was monitored by repeated [¹⁸F]FDG-PET/CT scans and showed a durable regression of inflammatory disease activity from 3 months onwards. It is important to mention that the dose received by the heart due to the combined radiotherapy treatment was higher than the initially prescribed, i.e., 4 Gy (Dmean 9.1 Gy). During follow-up, the only irradiation-related adverse event we observed was the development of moderate aortic valve disease at 46 months that is being conservatively managed (Dmean 24.7 Gy, Dmax 26.8 Gy). We consider this a mild and manageable adverse event, especially in light of complications of advancing disease and ultimately heart transplantation (4, 18).

The STAR treatment was performed because of its contraindication to catheter ablation. The reported efficacy and safety of STAR are promising in both ischemic and non-ischemic cardiomyopathies (6–10). European efforts are being undertaken to clinically validate STAR (STOPSTORM.eu project). In this patient, we were able to achieve a remarkable reduction in VTs. Ventricular arrhythmias in cardiac sarcoidosis are most often caused by reentry around post-inflammatory myocardial scars but may also occur as a consequence of active inflammation (2). Whether the marked reduction in VTs complementary to the performed catheter ablations was induced by the immunomodulatory effects of low-dose whole-heart irradiation, the anti-arrhythmic effect of high-dose STAR, a combination, or is due to other factors (e.g., natural course of the disease, medication) remains to be elucidated. Targeting the arrhythmogenic substrate for STAR in a patient with cardiac sarcoidosis is challenging as the substrate is often extensive and complex and may alter over time as the disease progresses (2). For this patient, the extensive information from the electroanatomical maps guided the delineation. The use of this targeting method in combination with the use of the system, which can track respiratory motion in real time during treatment delivery, allowed for a small target volume. Treating small volumes is especially important in this non-ischemic patient category when considering redo-STAR and that the underlying disease may progress (19, 20).

Here, we report for the first time on the beneficial and lasting effects of combined experimental immunomodulatory low-dose whole-heart radiotherapy and high-dose STAR in a patient with therapy refractory cardiac sarcoidosis and recurrent VT. Based on these promising results, radiotherapy could be considered in a compassionate and experimental manner for selected therapy refractory patients. However, caution is advised regarding (extra-)cardiac complications.