Cancer patients receiving anthracycline-based chemotherapy (Anth-bC) may experience early cardiac fibrosis, which could be an important contributing mechanism to the development of impaired left ventricular (LV) function. Substance P, a neuropeptide that predominantly acts via the neurokinin 1 receptor (NK-1R), contributes to adverse myocardial remodelling and fibrosis in other cardiomyopathies. We sought to determine if NK-1R blockade is effective against doxorubicin (Dox – a frequently used Anth-bC)-induced cardiac fibrosis and cardiomyocyte apoptosis. In addition, we explored the direct effects of Dox on cardiac fibroblasts.
Male Sprague-Dawley rats were randomised to receive saline, six cycles of Dox (1.5 mg Dox/kg/cycle) or Dox with an NK-1R antagonist (L732138, 5 mg/kg/daily through Dox treatment). At 8 weeks after the initial dose of Dox, LV function and histopathological myocardial fibrosis and cell apoptosis were assessed. Collagen secretion was measured in vitro to test direct Dox activation of cardiac fibroblasts.
Rats undergoing Dox treatment (9 mg/kg cumulative dose) developed cardiac fibrosis and cardiomyocyte apoptosis. NK-1R blockade partially mitigated cardiac fibrosis while completely preventing cardiomyocyte apoptosis. This resulted in improved diastolic function. Furthermore, we found that Dox had direct effects on cardiac fibroblasts to cause increased collagen production and enhanced cell survival.
This study demonstrates that cardiac fibrosis induced by Anth-bC can be reduced by NK-1R blockade. The residual fibrotic response is likely due to direct Dox effects on cardiac fibroblasts to produce collagen.
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Published online: August 30, 2018
Accepted: August 14, 2018
Received in revised form: August 2, 2018
Received: May 18, 2018
© 2018 Published by Elsevier B.V. on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).