Background
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.
Methods
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.
Results
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.
Conclusions
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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Heart, Lung and CirculationAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Long-term survival rates of cancer patients achieved by the end of the 20th century: a period analysis.Lancet. 2002; 360: 1131-1135
- Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: a retrospective cohort study.Breast Cancer Res. 2011; 13 (R64)
- Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.Circulation. 2015; 131: 1981-1988
- Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial.Lancet Oncol. 2013; 14: 72-80
- Mechanisms of cardiotoxicity of cancer chemotherapeutic agents: cardiomyopathy and beyond.Can J Cardiol. 2016; 32 (e5): 863-870
- Topoisomerase 2beta: a promising molecular target for primary prevention of anthracycline-induced cardiotoxicity.Clin Pharmacol Ther. 2014; 95: 45-52
- Progressive 3-month increase in LV myocardial ECV after anthracycline-based chemotherapy.JACC Cardiovasc Imaging. 2016;
- Anthracycline-associated t1 mapping characteristics are elevated independent of the presence of cardiovascular comorbidities in cancer survivors.Circ Cardiovasc Imaging. 2016; 9
- Cardiac MRI: a Translational imaging tool for characterizing anthracycline-induced myocardial remodeling.Curr Oncol Rep. 2016; 18: 48
- Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension.Int J Cardiol. 2013; 168: 4643-4651
- Distribution of specific substance P binding sites in the heart and adjacent great vessels of the Wistar white rat.Cell Tissue Res. 1996; 284: 495-500
- Substance P in heart failure: the good and the bad.Int J Cardiol. 2014; 170: 270-277
- Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells.Cardiovasc Res. 2011; 92: 420-429
- Substance P Receptor signaling mediates doxorubicin-induced cardiomyocyte apoptosis and triple-negative breast cancer chemoresistance.Biomed Res Int. 2016; 2016: 1959270
- Cardiac MRI: a central prognostic tool in myocardial fibrosis.Nat Rev Cardiol. 2015; 12: 18-29
- Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy.Am J Cardiol. 2013; 111: 717-722
- Characterization of the changes in cardiac structure and function in mice treated with anthracyclines using serial cardiac magnetic resonance imaging.Circ Cardiovas Imaging. 2016; : 2016
- Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment.Eur Heart J. 2011; 32: 670-679
- Cardiovascular magnetic resonance, fibrosis, and prognosis in dilated cardiomyopathy.J Am Coll Cardiol. 2006; 48: 1977-1985
- Substance P is associated with heart enlargement and apoptosis in murine dilated cardiomyopathy induced by Taenia crassiceps infection.J Parasitol. 2007; 93: 1121-1127
- Substance P is required for the pathogenesis of EMCV infection in mice.Int J Clin Exp Med. 2009; 2: 76-86
- Magnesium-deficiency-enhanced post-ischemic myocardial injury is reduced by substance P receptor blockade.J Mol Cell Cardiol. 1997; 29: 97-110
- EGFR-TKI, erlotinib, causes hypomagnesemia, oxidative stress, and cardiac dysfunction: attenuation by NK-1 receptor blockade.J Cardiovasc Pharmacol. 2015; 65: 54-61
- Aprepitant: a substance P antagonist for chemotherapy induced nausea and vomiting.Indian J Cancer. 2007; 44: 25-30
- Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur Heart J Cardiovasc Imaging. 2014; 15: 1063-1093
- Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines.Am J Cardiol. 2012; 110: 1679-1686
- Cardiac Atrophy and heart failure in cancer.Cardiac Fail Rev. 2017; 3: 62-65
- Prevention of liver cancer cachexia-induced cardiac wasting and heart failure.Eur Heart J. 2014; 35: 932-941
- An integrated characterization of serological, pathological, and functional events in doxorubicin-induced cardiotoxicity.Toxicol Sci. 2014; 140: 3-15
- Sexual dimorphism of doxorubicin-mediated cardiotoxicity: potential role of energy metabolism remodeling.Circ Heart Fail. 2015; 8: 98-108
- Antiemetics: American Society of Clinical Oncology clinical practice guideline update.J Clin Oncol. 2011; 29: 4189-4198
- Guideline for the prevention of acute nausea and vomiting due to antineoplastic medication in pediatric cancer patients.Pediatr Blood Cancer. 2013; 60: 1073-1082
Article info
Publication history
Published online: August 30, 2018
Accepted:
August 14,
2018
Received in revised form:
August 2,
2018
Received:
May 18,
2018
Identification
Copyright
© 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).
