Microvascular Damage as Initial Event of Scar Formation after Carbon Ion Irradiation of Cardiac Substructures

The irradiation of the heart during thoracic cancer radiotherapy can lead to changes in the cardiac electrophysiology. These findings were applied in a first in vivo feasibility study using scanned carbon ion irradiation to establish an alternative, non-invasive treatment method for cardiac arrhythmias. Damage to the small blood vessels (microvasculature) after cardiac irradiation is putatively an initial event for longterm effects like fibrosis and finally electrophysiological changes. However, the exact underlying mechanisms of those effects after high dosed carbon ion irradiation of small volumes are not fully understood. Therefore, irradiation–induced vascular damage was characterized in a porcine model for the ablation of potentially arrhythmogenic cardiac substructures in the presented thesis. The irradiation of target areas, the left ventricle (LV) and atrio–ventricular node (AVN), was performed with high doses. The LV target was exposed to 40 Gy. For the AVN target, a dose– escalation study was performed. Consequently, the AVN was irradiated with 25, 40 or 55 Gy. The irradiation of entrance channel regions resulted in the deposition of medium doses (7 – 17 Gy). All target groups exhibited electrophysiological changes in target areas. These changes were presumably caused by the formation of a fibrous scar. However, heterogeneous results for the scar formation were obtained among animals of the same dose group. Correspondingly, the vascular damage (haemorrhage and loss of microvessels) and subsequent tissue responses (inflammatory processes and cell death) were investigated in this thesis. Their repeated occurrence pointed to an uncompleted scar formation. Aside from target areas, nontargeted regions were also investigated to detect potential side effects. In entrance channel regions, hints for a delayed progression of tissue remodelling were found. However, the damage in irradiated tissue was not spreading to unirradiated cardiac regions during the investigated time frame (until six months after irradiation). Furthermore, no systemic inflammation was detected after the applied carbon ion irradiation