Prevention and Treatment of Functional and Structural Radiation Injury in the Rat Heart by Pentoxifylline and Alpha-Tocopherol

doi:10.1016/j.ijrobp.2008.04.042

International Journal of Radiation OncologyBiologyPhysics

Volume 72, Issue 1, 1 September 2008, Pages 170-177

https://doi.org/10.1016/j.ijrobp.2008.04.042 Get rights and content

Purpose

Radiation-induced heart disease (RIHD) is a severe side effect of thoracic radiotherapy. This study examined the effects of pentoxifylline (PTX) and α-tocopherol on cardiac injury in a rat model of RIHD.

Methods and Materials

Male Sprague-Dawley rats received fractionated local heart irradiation with a daily dose of 9 Gy for 5 days and were observed for 6 months after irradiation. Rats were treated with a combination of PTX, 100 mg/kg/day, and α-tocopherol (20 IU/kg/day) and received these compounds either from 1 week before until 6 months after irradiation or starting 3 months after irradiation, a time point at which histopathologic changes become apparent in our model of RIHD.

Results

Radiation-induced increases in left ventricular diastolic pressure (in mm Hg: 35 ± 6 after sham-irradiation, 82 ± 11 after irradiation) were significantly reduced by PTX and α-tocopherol (early treatment: 48 ± 7; late treatment: 53 ± 6). PTX and α-tocopherol significantly reduced deposition of collagen types I (radiation only: 3.5 ± 0.2 μm² per 100 μm²; early treatment: 2.7 ± 0.8; late treatment: 2.2 ± 0.2) and III (radiation only: 13.9 ± 0.8; early treatment: 11.0 ± 1.2; late treatment: 10.6 ± 0.8). On the other hand, radiation-induced alterations in heart/body weight ratios, myocardial degeneration, left ventricular mast cell densities, and most echocardiographic parameters were not significantly altered by PTX and α-tocopherol.

Conclusions

Treatment with PTX and α-tocopherol may have beneficial effects on radiation-induced myocardial fibrosis and left ventricular function, both when started before irradiation and when started later during the process of RIHD.

Introduction

Radiation-induced heart disease (RIHD) is a potentially life-threatening side effect of radiotherapy of thoracic and chest wall tumors when all or part of the heart is included in the radiation field. RIHD presents clinically several years after irradiation, and the disease process is progressive. Randomized studies show a significant increase in cardiac events in patients at least 10 years after treatment with radiotherapy for thoracic and chest wall tumors. Specifically, in patients treated before the 1980s, a twofold increase in cardiovascular mortality is seen after radiotherapy for Hodgkin's disease (1) and breast cancer (2). In patients treated in the 1980s and 1990s, a significant increase is found in cardiovascular mortality in patients treated with radiotherapy for left-sided breast cancer when compared to patients treated for right-sided breast cancer (3). Moreover, reduced mortality from breast cancer is often offset by an increase in mortality from heart disease in irradiated patients 4, 5. The heart continues to be a major organ at risk in thoracic radiotherapy despite recent advances in radiation delivery and treatment planning techniques. Nonetheless, there is currently no method or approach for preventing or reversing RIHD.

A prominent clinical manifestation of RIHD is myocardial fibrosis 3, 6. Pentoxifylline (PTX), a phosphodiesterase inhibitor first developed as a rheologic agent, has been shown to reduce radiation fibrosis in clinical studies when administered alone (7) or in combination with α-tocopherol (vitamin E) 8, 9. In many of these studies, treatment with PTX and α-tocopherol is started after radiation-induced fibrosis has become clinically manifest. On the other hand, not all studies show a beneficial effect of PTX and vitamin E on radiation fibrosis (10). Moreover, it is suggested that PTX may enhance radiation sensitivity when administered during radiation 11, 12.

In this study, we examined the effects of PTX in combination with α-tocopherol on cardiac structure and function after localized fractionated heart irradiation in rats. The efficacy of PTX and α-tocopherol was tested both when treatment was started 1 week before irradiation, and when treatment was started 3 months after irradiation, a time point at which histopathologic changes including myocardial fibrosis are apparent in our animal model (13).

Section snippets

Rat heart irradiation

All procedures in this study were approved by the Institutional Animal Care and Use Committee of the University of Arkansas for Medical Sciences. A total of 72 male Sprague-Dawley rats (180–200 g) were obtained from Harlan (Indianapolis, IN). All animals were maintained in our Division of Laboratory Medicine on a 12:12 light-to-dark cycle with free access to food and water.

After 2 weeks of acclimatization, rats were anesthetized with 2.5% isoflurane and irradiated with a Seifert Isovolt 320

In vivo and ex vivo cardiac function

Radiation induced significant reductions both in heart weight (F = 39.76, p < 0.001) and in heart/body weight ratio (F = 36.14, p < 0.001) as measured at 6 months (Table 1). Treatment with PTX and α-tocopherol did not alter body weight or heart/body weight ratio in any of the treatment groups.

Table 2 lists echocardiographic parameters obtained at 6 months after (sham-) irradiation. Radiation induced a significant increase in left ventricular anterior wall thickness, both in systole (F = 6.64, p

Discussion

This study used a rat model of fractionated local heart irradiation to assess the effects of PTX and α-tocopherol on cardiac radiation injury. At 6 months after irradiation, hearts showed increased ex vivo left ventricular diastolic pressures, indicative of left ventricular dysfunction. Radiation-induced diastolic dysfunction, which has been shown to occur in this animal model of RIHD, is possibly caused by reduced left ventricular size and increased deposition of myocardial collagen. A

Acknowledgments

The authors acknowledge Ashwini Kulkarni for excellent technical support and Dr. Sue A. Theus and Kimberly Henning of the Central Arkansas Veterans Healthcare System for excellent support in animal care and small animal echocardiography.

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159 relevant full-text original articles were reviewed. The heart only was the target volume in 67% of the studies and simulation details were unavailable for 44% studies. Dosimetry methods were reported in 31% studies. The pulmonary effects of whole and partial heart irradiation were reported in 13% studies. Seventy-eight unique dose-fractionation schedules were evaluated. Large heterogeneity was observed in the endpoints measured, and the reporting standards were highly variable.
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: Supported by grants from the Lance Armstrong Foundation (LAF06SY4 to MB) and the National Institutes of Health (CA83719 to MH-J).

: Conflict of interest: none.

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Biology ContributionPrevention and Treatment of Functional and Structural Radiation Injury in the Rat Heart by Pentoxifylline and Alpha-Tocopherol

Purpose

Methods and Materials

Results

Conclusions

Introduction

Section snippets

Rat heart irradiation

In vivo and ex vivo cardiac function

Discussion

Acknowledgments

Int J Radiat Oncol Biol Phys

Lancet Oncol

Am Heart J

Radiother Oncol

Radiother Oncol

J Hepatol

Kidney Int

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Ann Thorac Surg

Curr Opin Biotechnol

Long-term cause-specific mortality of patients treated for Hodgkin's disease

J Clin Oncol

Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy

J Clin Oncol

Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group

Lancet

Biology Contribution
Prevention and Treatment of Functional and Structural Radiation Injury in the Rat Heart by Pentoxifylline and Alpha-Tocopherol