Thesis title: Valutazione delle alterazioni cardiache radioindotte in vivo ed in vitro
Cardiovascular diseases (CVD) are among the leading causes of morbidity and mortality. Arrhythmias are among CVDs, with an incidence between 4 and 12%.
These diseases can be identified and studied using numerous diagnostic methods, from less invasive methods such as 12-lead ECG, to more advanced imaging techniques such as echocardiography, cardiac CT, and cardiac MRI, to more invasive techniques such as intracavitary electrophysiology studies.
Possible treatments for arrhythmias include non-invasive methods such as oral drug therapy, to more complex therapies such as implantation of devices such as PMK or ICD, cardiac ablations, and cardiac denervation.
The identification of less invasive techniques has led authors around the world to initiate studies involving the use of cardiac radioablation with photons or heavy particles such as protons or carbon ions to ablate cardiac arrhythmogenic areas, creating controlled cardiac fibrosis with a non-invasive approach for the patient.
The studies were conducted on models, and a total dose of 25 Gy in a single session was defined as the optimal treatment schedule for achieving complete ablation.
These preliminary studies were followed by other centers that began performing experimental treatments on human patients, achieving reduction or elimination of Arrhythmic Storm with minimal or no acute side effects, i.e., during treatment or in the first three months following the end of treatment.
These results led the AIAC (Italian Association of Arrhythmology and Cardiac Pacing) to consider radiotherapy a promising, non-invasive strategy for patients deemed unsuitable for conventional ablation treatments or refractory to standard treatments on January 14, 2020.
In addition to cardiac radioablation, many radiotherapy treatments for tumors adjacent to the heart can also lead to diffuse radiation to cardiac subunits, such as radiotherapy (RT) to the lung, mediastinum, esophagus, or surrounding bone structures, among others.
The PhD program included three phases:
1. In vivo evaluation of the late effects of radiation treatments
on cardiac subunits with a retrospective study
2. In vivo evaluation of the late effects of radiation treatments
on cardiac subunits with a prospective study
3. In vitro evaluation of radiation-induced effects in murine cardiac fibroblasts.
Study 1, a retrospective study, was conducted in the Radiotherapy Department of San Camillo de' Lellis Hospital in Rieti and included:
1. Search and selection of patients treated with radiation to areas adjacent to the heart (lung, esophagus, dorsal vertebrae, etc.) with pre-RT cardiac evaluation (ECG, echocardiogram/cardio-CT, or cardiac MRI);
2. Contouring of cardiac substructures according to international guidelines;
3. Replanning and recalculation of the dose received on the recontoured cardiac substructures, with evaluation performed via a Dose/Volume histogram (DVH) using dedicated software and a Planning Treatment System (PTS);
4. Radiotherapy and cardiac follow-up, approximately one year after radiation treatment, to identify any morphological and/or pathophysiological alterations in the irradiated cardiac areas by performing a new cardiac examination;
5. Correlation of alterations/absorbed dose
The cardiac subunits evaluated are:
• Left ventricle
• Right ventricle
• Left atrium
• Right atrium
• Aortic valve
• Pulmonary valve
• Mitral valve
• Tricuspid valve
For each patient, the delivered dose was first analyzed and then converted to a normofractionated dose normalized to 1.8-2 Gy/Fx (EQD2), to equate all treatments and subsequently assess the dose limits of the cardiac substructures (dose conversion calculation algorithm: radformation.com/tools/bed-calculator).
After individually evaluating the doses received by each cardiac subunit of each patient and examining the maximum doses to each cardiac structure in the 30 patients analyzed, cardiac follow-up was evaluated for each patient at least 6 months later.
Echocardiograms ranged from a minimum of 6 months to a maximum of 6 years.
The comparison was between the pre-RT echocardiogram and the echocardiogram most distant from cardiac irradiation.
The results obtained in this retrospective study showed that all late echocardiograms showed an EF comparable to the pre-RT EF and no echocardiographically visible morphological or functional damage was observed over time. Furthermore, no patient showed or manifested clinical cardiac alterations attributable to radiation-induced changes.
All this leads us to consider that radiotherapy doses with normofractionated treatment plans of up to 60 Gy, not directed at the heart, would not appear to cause evident damage. However, clearly, considering the small number of cases and the type of patients with minimal follow-up opportunities due to the highly disabling disease they suffer from, they did not allow for more accurate investigations that could have led to better assessments.
The prospective, experimental in vivo study involved the radiotherapy center at Rieti Hospital participating in the VT ART Consortium: Radioablation for Ventricular Tachycardia (VT-ART-P); ClinicalTrials.gov ID NCT06922214;
Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
Study Title: VT-ART-P: Ablation and Radiotherapy of Ventricular Tachycardia, a Prospective Study
The objective of the study was to evaluate the efficacy and safety of stereotactic radiotherapy in the noninvasive ablation of ventricular tachycardia refractory to any other treatment.
In September 2024, a 75-year-old patient diagnosed with sustained ventricular tachycardia with ICD discharges (implanted in 2017 without coronary sinus retrieval) in a patient with ischemic heart disease (previous CABG in 2012) with dilated progression, severe reduction in left ventricular function, EF 20-25%, hypokinetic CMD, and apical thrombotic stratification, was identified and enrolled in the study.
On remote monitoring, he reported numerous episodes of VT interrupted by ATP and, in one episode, by an appropriate shock from the device.
The patient had reached maximal pharmacological therapy and was no longer indicated for endocavitary ablations.
On October 31, 2024, in collaboration with the radiotherapy department at the A. Gemelli Polyclinic, the patient underwent Radioablation.
Cardiac radioablation with a single 25 Gy dose.
The patient was evaluated up to 9 months after radiation treatment without evidence of a recurrence of arrhythmic discharges, which were found to be zero, or ICD intervention.
Eight months after cardiac radioablation, the follow-up echocardiogram was comparable with the previous ones, reporting an EF of 25%.
Considering the F-UP time of 8 months, it can be noted that no radiation-induced late effects on the heart were observed, nor did the patient experience clinical symptoms attributable to cardiac alterations due to the procedure.
The third study, with an in vitro evaluation of radiation-induced effects in murine cardiac fibroblasts, involved:
1. Definition of a dedicated radiotherapy treatment plan with a dose equivalent to that used in human cardiac radioablation (25 Gy in a single fraction), a plan with a dose of 12.5 Gy, and a test at 0 Gy;
2. Delivery via a linear accelerator (Linac) at the Radiotherapy Department of the San Camillo De Lellis Hospital in Rieti;
3. Analysis of the effects of radiotherapy treatment on murine cardiac fibroblasts at the Department of Experimental Medicine, Sapienza University of Rome, Prof. M. Sorice
The effects on cells were assessed using:
• Viability assay: Trypan Blue Assay
• Apoptosis assays: caspase activation (Western blot)
The results obtained demonstrate that:
• The CTRL vs. 12.5 Gy comparison is not statistically significant (p ≈ 0.086), but there is a tendency toward reduced viability.
• The CTRL vs. 25 Gy comparison shows a statistically significant difference (p < 0.05), suggesting that the 25 Gy dose significantly reduces cell viability.
Cells treated at different time points were analyzed for cleaved Parp1 expression using Western blot. This analysis showed a significant increase in cleaved Parp1 expression in samples stimulated with 12.5 Gy compared to the unstimulated control; furthermore, in samples stimulated with a double dose of 25 Gy, cleaved Parp1 expression was slightly increased.
These data indicate that radiation treatment induces damage, resulting in activation of the DNA repair process.
In conclusion, in radiotherapy, STAR treatments, along with other types of cardiac radiotherapy, are currently experimental therapies.
These approaches, which are often included in national and international trials, have benefited many patients who no longer had other therapeutic options and would have faced inevitable death.
In the acute setting, it is now well established that ablation of the arrhythmogenic focus with a total dose of 25 Gy in a single fraction yields excellent results in terminating arrhythmias.
Much more research remains to be done to precisely define the long-term effects of cardiac irradiation for the treatment of arrhythmias. Both in vivo and in vitro studies will increasingly investigate any possible alterations that may arise over time. However, there is hope that this treatment may be a potential aid in the treatment of serious cardiac diseases that cause suffering and death.