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

Erbeldinger, Nadine (2017)
Microvascular Damage as Initial Event of Scar Formation after Carbon Ion Irradiation of Cardiac Substructures.
Technische Universität Darmstadt
Ph.D. Thesis, Primary publication

Abstract

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.

Item Type: Ph.D. Thesis
Erschienen: 2017
Creators: Erbeldinger, Nadine
Type of entry: Primary publication
Title: Microvascular Damage as Initial Event of Scar Formation after Carbon Ion Irradiation of Cardiac Substructures
Language: English
Referees: Thiel, Prof. Dr. Gerhard ; Durante, Prof. Dr. Marco
Date: 2017
Place of Publication: Darmstadt
Refereed: 6 June 2017
URL / URN: http://tuprints.ulb.tu-darmstadt.de/6904
Abstract:

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.

Alternative Abstract:
Alternative abstract Language

Aus der Strahlentherapie ist bekannt, dass die Bestrahlung von Herzgewebe, welche im Zuge der Krebsbehandlung im Thorax stattfindet, zu elektrophysiologischen Veränderungen führen kann. Diese Erkenntnisse wurden für eine erste in vivo-Machbarkeitsstudie genutzt, um mit Kohlenstoffionen-Bestrahlung eine alternative, nicht-invasive Behandlungsmethode von Herzrhythmusstörungen zu etablieren. Es ist davon auszugehen, dass durch die Bestrahlung u.a. Schäden der kleinen Blutgefäße (Mikrovaskulatur) im Herzgewebe erzeugt werden. Diese stellen vermutlich Ausgangsereignisse für Langzeiteffekte wie Fibrose und schließlich Störungen der Elektrophysiologie dar. Dennoch sind die zugrundeliegenden Wirkungsweisen dieser Effekte nach hoch dosierter Bestrahlung eines geringen Volumens mit Kohlenstoffionen bisher noch nicht vollständig bekannt. Daher wurden in dieser Arbeit strahleninduzierte mikrovaskuläre Schäden nach Ablation potentiell arrhythmogener Substrukturen in Schweineherzen charakterisiert. Im Zuge dieses Projekts wurde die Bestrahlung des linken Ventrikels (LV) und Atrioventrikularknotens (AVN) mit hohen Dosen durchgeführt. Während der LV mit 40 Gy bestrahlt wurde, wurde eine Dosiseskalationsstudie mit 25; 40 oder 55 Gy bei Bestrahlung des AVN durchgeführt. Die Bestrahlung der Eingangskanäle führte zu einer dortigen Deposition mittlerer Dosen (7 – 17 Gy). In allen Gruppen wurden elektrophysiologische Veränderungen im Zielgewebe detektiert. Diese Veränderungen waren vermutlich durch eine fibrotische Narbenbildung bedingt. Dennoch war die Entwicklung des Narbengewebes auch für gleiche Dosisgruppen heterogen ausgeprägt. Dementsprechend wurden mikrovaskuläre Schäden (Hämorrhagie und Verlust der Mikrovaskulatur) und Folgeprozesse (Entzündungsprozesse und Zelltod) in der vorgelegten Arbeit untersucht. Das wiederholte Auftreten dieser Prozesse bedeutete, dass die Narbenbildung noch nicht abgeschlossen war. Neben den Analysen im Zielgewebe wurden auch andere Bereiche des Herzens untersucht, um mögliche Nebeneffekte festzustellen. In den Eingangskanälen wurden Hinweise auf ein verzögertes Fortschreiten von Gewebsveränderungen gefunden. Indes wurde in unbestrahlten Herzbereichen keine Schadensausbreitung während der untersuchten sechs Monate festgestellt. Zusätzlich wurden keine systemischen Entzündungsprozesse nach der applizierten Bestrahlung mit Kohlenstoffionen detektiert.

German
URN: urn:nbn:de:tuda-tuprints-69049
Classification DDC: 500 Science and mathematics > 570 Life sciences, biology
Divisions: 10 Department of Biology > Systems Biology of the Stress Response
10 Department of Biology > Radiation Biology and DNA Repair
10 Department of Biology
Date Deposited: 19 Nov 2017 20:55
Last Modified: 19 Nov 2017 20:55
PPN:
Referees: Thiel, Prof. Dr. Gerhard ; Durante, Prof. Dr. Marco
Refereed / Verteidigung / mdl. Prüfung: 6 June 2017
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