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

Abstract

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.

Radiosurgery for ventricular tachycardia: preclinical and clinical evidence and study design for a German multi-center multi-platform feasibility trial (RAVENTA)

“…Still, the cell biological mechanisms and the temporal process of the effects of RA/CRS are poorly understood. For a single fraction dose of 25 Gy, the phenomenon of marked clinical effects in terms of reduction of VT burden or ICD interventions without the clear formation of a scar has been reported from preclinical data [34,36,38,39] and even from patients treatments [24,31].…”

“…Finally, we added initial technical, pre-clinical, and clinical manuscripts not covered by the search based on our own experience in cardiac radiosurgery in the past 12 years. Evidence was finally extracted from the remaining 42 manuscripts, which include reports on two clinical trials [22,23], two clinical case series [24,25], eight case reports [19,20,[26][27][28][29][30][31], eight preclinical studies [18,[32][33][34][35][36][37][38][39], fourteen technical studies [40][41][42][43][44][45][46][47][48][49][50][51][52][53], and eight reviews or opinions [7,[54][55][56][57][58][59][60].…”

“…On the other hand, a lethal bronchial fistula occurred at a dose of 40 Gy in one minipig. The other group pursued the use of heavy ions instead of photons for RA/CRS [35,38,39]. In principle, particles have the major advantage over photons that the maximum dose intensity delivered per beam can be varied in depth at the so-called Bragg Peak, while for photons, the maximum dose is always close to the body surface (approximately 1.5 cm for 6 MeV photons).…”

“…In principle, particles have the major advantage over photons that the maximum dose intensity delivered per beam can be varied in depth at the so-called Bragg Peak, while for photons, the maximum dose is always close to the body surface (approximately 1.5 cm for 6 MeV photons). The authors conducted various animal experiments and reported histopathological findings in great detail, yet they also found that much higher doses are needed (> 25 Gy) to generate therapeutic effects [38,39].…”

“…Both patients received a single fraction radiation dose of 25 Gy to the VT substrate, as defined by electroanatomical voltage mapping and showed only limited-to-no toxicity with a significant reduction in VT burden and ICD shock frequency after treatment. The clinical treatment effects with 25 Gy were remarkable, given the results from the animal models, in which 25 Gy showed only limited-to-no effects on electrical block and transmural fibrosis [32][33][34][35][36][37][38][39]. It might be hypothesized that modulation of cardiac conduction rather than induction of transmural fibrosis explains the treatment effect seen after RA/CRS with 25 Gy.…”