32 Profiling the effect of doxorubicin in a workloop model to assess myocardial muscle mechanics

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Abstract

Introduction

Despite the importance of anthracycline antibiotics such as Doxorubicin in anticancer pharmacology, their clinical value is jeopardised by their irreversible dose dependent cardiotoxicity, which is manifested via a number of pathways including reactive oxygen species. The mitochondrial permeability transition pore (MPTP) opening has been shown to be involved in myocardial injury, and may be involved in the myocardial mitochondrial disruption that is observed during doxorubicin treatment.1 The workloop model assesses muscle performance that closely matches the mechanics of the muscles in vivo. The aim of this project was to investigate the effects of Doxorubicin on myocardial function and the involvement of the MPTP.

Method

Papillary muscles were dissected and mounted on the workloop apparatus, perfused with oxygenated Krebs Heinslet buffer (pH 7.4) for 150 min in presence or absence of Doxorubicin (1 μM) ± Cyclosporine A (0.2 μM). The force produced was recorded and power output (W/Kg) was calculated accordingly.

Results and Discussion

In presence of Doxorubicin, the power output was significantly reduced compared to the absence of Doxorubicin (49±5 % vs 65±6%, p<0.001). In addition, over time Doxorubicin also reduced the peak force and force during shortening as well as decreasing the rate of activation of the muscle during workloops. Cyclosporine A was observed to significantly abrogate the negative inotropic response induced by Doxorubicin.

Conclusion

This is the first study to show cardiotoxic effects of Doxorubicin in a functional workloop model to determine its effects on muscle mechanics.

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