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

https://doi.org/10.1016/j.radonc.2011.10.011Get rights and content

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 16 Gy were delivered to the hearts of mice and damage was evaluated at 20, 40, and 60 weeks, 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 40 weeks after 2, 8, and 16 Gy. Cardiac blood volume was decreased at 20 and 60 weeks after irradiation. Histological examination revealed inflammatory changes at 20 and 40 weeks after 8 and 16 Gy. Microvascular density in the left ventricle was decreased at 40 and 60 weeks after 8 and 16 Gy, with functional damage to remaining microvasculature manifest as decreased alkaline phosphatase (2, 8, and 16 Gy), increased von Willebrand Factor and albumin leakage from vessels (8 and 16 Gy), and amyloidosis (16 Gy). 16 Gy lead to sudden death between 30 and 40 weeks in 38% of mice.

Conclusions

Irradiation with 2 and 8 Gy induced modest changes in murine cardiac function within 20 weeks 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.

Section snippets

Mice and irradiation procedure

Male C57BL/6J mice aged 8–12 weeks (from Charles River Laboratories, France) were randomly allocated to different treatment groups and housed in a temperature-controlled room with 12 h light–dark cycle. Standard mouse chow and water were provided ad libitum. During irradiation or sham treatment (0 Gy) unanaesthetized mice were held in a prone position, in restraining jigs with the thorax fixed using adjustable hinges. Single doses of 2, 8, or 16 Gy were given to the heart using 250 kV X-rays,

Mouse survival and weight

There were very few unscheduled deaths after 2 and 8 Gy cardiac irradiation, although heart/body weight ratios of irradiated mice were 12–13% lower than in age-matched controls at 40 weeks and body weights were reduced by 6–13% at 60 weeks (Table 1). After 16 Gy, 38% of mice died or had to be humanely killed between 30 and 40 weeks. Because of these unscheduled deaths, all remaining animals in the 16 Gy group were killed at 40 weeks.

Non-invasive cardiac imaging

SPECT/CT and ultrasound were used to examine whether irradiation

Discussion

This study demonstrated that irradiation affects cardiac structure and microvascular function in a dose and time-dependent manner, with substantial damage after intermediate and high dose irradiation (8 and 16 Gy) and minor alterations after lower doses (2 Gy). Moreover, high doses induced changes at earlier time points and these effects progressed in time.

The transient increase in MVD at 20 weeks after 2 and 8 Gy was presumably due to stimulated proliferation in response to damage, whereas

Conflict of interest statement

There were no conflicts of interest.

Acknowledgments

The authors thank Bert Pool, Department of Nuclear Medicine, The Netherlands Cancer Institute, for help with the NanoSPECT/CT and Dr. Jack Cleutjens, Department of Pathology, the University of Maastricht, for help with the Leica Qwin morphometry system.

This research was funded by the European Atomic Energy Community’s Seventh Framework Program, grant 211403 (Cardiorisk), and the Dutch Cancer Foundation, grant NKI 2008-3993.

References (22)

Cited by (0)

1

These authors contributed equally (performing experiments and analyses).

2

These authors contributed equally (designing and supervision of the study).

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