Irradiation induced modest changes in murine cardiac function despite progressive structural damage to the myocardium and microvasculature

Seemann, Ingar; Gabriels, Karen; Visser, Nils L.; Hoving, Saske; te Poele, Johannes A.; Pol, Jeffrey F.; Gijbels, Marion J.; Janssen, Ben J.; van Leeuwen, Fijs W.; Daemen, Mat J.; Heeneman, Sylvia; Stewart, Fiona A.

doi:10.1016/j.radonc.2011.10.011

« Previous Next »Radiotherapy & Oncology
Volume 103, Issue 2 , Pages 143-150, May 2012

Irradiation induced modest changes in murine cardiac function despite progressive structural damage to the myocardium and microvasculature

Ingar Seemann
- Division of Experimental Therapy, The Netherlands Cancer Institute, The Netherlands
- Corresponding author. Address: The Netherlands Cancer Institute, Department of Experimental Therapy (C2), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
- These authors contributed equally (performing experiments and analyses).
Karen Gabriels
- Division of Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht, The Netherlands
- These authors contributed equally (performing experiments and analyses).
Nils L. Visser
- Division of Experimental Therapy, The Netherlands Cancer Institute, The Netherlands
Saske Hoving
- Division of Experimental Therapy, The Netherlands Cancer Institute, The Netherlands
Johannes A. te Poele
- Division of Experimental Therapy, The Netherlands Cancer Institute, The Netherlands
Jeffrey F. Pol
- Division of Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht, The Netherlands
Marion J. Gijbels
- Department of Molecular Genetics, University of Maastricht, The Netherlands
Ben J. Janssen
- Department of Pharmacology, University of Maastricht, The Netherlands
Fijs W. van Leeuwen
- Division of Diagnostic Oncology, The Netherlands Cancer Institute, The Netherlands
Mat J. Daemen
- Division of Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht, The Netherlands
- Chair of the Netherlands Society of Pathology, Department of Pathology, The Academic Medical Center, The Netherlands
Sylvia Heeneman
- Division of Experimental Vascular Pathology, Cardiovascular Research Institute Maastricht, The Netherlands
- These authors contributed equally (designing and supervision of the study).
Fiona A. Stewart
- Division of Experimental Therapy, The Netherlands Cancer Institute, The Netherlands
- These authors contributed equally (designing and supervision of the study).

Received 17 June 2011; received in revised form 17 October 2011; accepted 19 October 2011. published online 23 November 2011.

Abstract

Background

Radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiotoxicity, but the underlying mechanisms are unclear.

Methods

Single doses of 2, 8, or 16Gy were delivered to the hearts of mice and damage was evaluated at 20, 40, and 60weeks, relative to age matched controls. Single photon emission computed tomography (SPECT/CT) and ultrasound were used to measure cardiac geometry and function, which was related to histo-morphology and microvascular damage.

Results

Gated SPECT/CT and ultrasound demonstrated decreases in end diastolic and systolic volumes, while the ejection fraction was increased at 20 and 40weeks after 2, 8, and 16Gy. Cardiac blood volume was decreased at 20 and 60weeks after irradiation. Histological examination revealed inflammatory changes at 20 and 40weeks after 8 and 16Gy. Microvascular density in the left ventricle was decreased at 40 and 60weeks after 8 and 16Gy, with functional damage to remaining microvasculature manifest as decreased alkaline phosphatase (2, 8, and 16Gy), increased von Willebrand Factor and albumin leakage from vessels (8 and 16Gy), and amyloidosis (16Gy). 16Gy lead to sudden death between 30 and 40weeks in 38% of mice.

Conclusions

Irradiation with 2 and 8Gy induced modest changes in murine cardiac function within 20weeks but this did not deteriorate further, despite progressive structural and microvascular damage. This indicates that heart function can compensate for significant structural damage, although higher doses, eventually lead to sudden death.

Keywords: Irradiation, Cardiac damage, Microvascular damage