Detection of early radiation-induced heart disease


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Shahana Hussain1, Karen Bowman2, George Don Jones2, Rohan Machhar1, Ruth Barber1, Tim Gant3, George Tanteles2, Gerry McCann4, Chris Steadman4, Christopher Talbot1, Paul Symonds2, Nicola Royle1, Richard Camplejohn1, Julian Barwell1
1Department of Genetics, University of Leicester, Leicester, UK, 2Department of Cancer studies Molecular Medicine, University of Leicester, Leicester, UK, 3MRC Toxicology Unit, Leicester, UK, 4Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

Background

Breast cancer (BC) survivors are at increased risk of significant cardiovascular (CV) morbidity 10-years post-radiotherapy (RTH)(1,2). An underlying mechanism is thought to be premature CV ageing. We aimed to detect sub-clinical cardiac damage (with MRI and/or microRNA) and correlate these with in vitro markers of biological ageing. Plasma microRNA29c has shown to be a novel biomarker of an unfit heart(3) and is involved in the downstream processing of Mcl-1, an anti-apoptotic protein and the COL2A1 gene coding for type II collagen.

Method

10 BC patients receiving adjuvant left-sided RTH underwent cardiac MRI and in vitro assays (Sub-G1 peak assay (AR), comet assay, telomere length, oxidative stress measurement) before treatment, six-weeks and one-year post-treatment. These assays were replicated, along with microRNA profiling in 25 BC patients pre and 6-weeks post-RTH. MicroRNA profiling was also performed on cardiac tissue and plasma samples from 24 female BALB/c mice after direct and sham whole body X-ray irradiation.

Results

Cardiac MRI analysis showed no definitive changes post-RTH.
There was a reduction in the AR (P=0.002), increase in comet tail (P=0.033) and urinary 8-oxo-DG (P=0.031) at 6-weeks post-RTH, however telomere length showed no significant changes. These assays had returned to pre-treatment levels at one-year post-RTH.
Mouse models showed downregulation of MicroRNA29c levels post-RTH in both cardiac tissue (P=0.046) and plasma (P=0.02), and upregulation of Mcl-1 in cardiac tissue (P=0.001). There was a dose correlation response between radiation exposure to cardiac tissue and the reduction in miRNA29c. We have shown that this reduction in MiRNA29c can also be detected in left-sided BC patients six-weeks post-RTH (P=0.002).

Conclusion

MiRNA29c may be an early indicator of radiation-induced heart disease (RIHD), and shows high specificity to direct cardiac irradiation. Downstream microRNA expression changes on Mcl-1 and COL2A1 provide a potential mechanistic pathway for RIHD through a failure of apoptosis and increased cardiac tissue fibrosis.