Endothelin Receptor Blocker Reverses Breast Cancer-Induced Cardiac Remodeling

Zaid H Maayah; Mourad Ferdaoussi; Aristeidis E Boukouris; Shingo Takahara; Subhash K Das; Mostafa Khairy; John R Mackey; Edith Pituskin; Gopinath Sutendra; D Ian Paterson; Jason R B Dyck

doi:10.1016/j.jaccao.2023.02.004

Endothelin Receptor Blocker Reverses Breast Cancer-Induced Cardiac Remodeling

JACC CardioOncol. 2023 May 2;5(5):686-700. doi: 10.1016/j.jaccao.2023.02.004. eCollection 2023 Oct.

Authors

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, Qatar University Health, Qatar University, Doha, Qatar.
² Faculty Saint-Jean, University of Alberta, Edmonton, Alberta, Canada.
³ Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
⁴ Division of Cardiovascular Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
⁵ Cardiovascular Research Centre, Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
⁶ Cross Cancer Institute, Edmonton, Alberta, Canada.
⁷ Division of Cardiology, University of Ottawa Heart Institute, University of Ottawa, Ottawa, Ontario, Canada.

Abstract

Background: Although some cancer therapies have overt and/or subclinical cardiotoxic effects that increase subsequent cardiovascular risk in breast cancer patients, we have recently shown that the breast tumor itself can also induce cardiac hypertrophy through the activation of the endothelin system to contribute to cardiovascular risk. However, the extent to which the suppression of the activation of the endothelin system could improve cardiac remodeling in breast cancer patients has yet to be investigated.

Objectives: We aimed to retrospectively assess the cardiac morphology/function in patients with breast cancer before receiving cancer chemotherapy and to investigate if the suppression of the activation of the endothelin system improves cardiac remodeling in a mouse model of breast cancer.

Methods: Our study involved 28 previously studied women with breast cancer (including 24 after tumor resection) before receiving adjuvant therapy and 17 control healthy women. In addition, we explored how the endothelin system contributed to breast cancer-induced cardiac remodeling using a mouse model of breast cancer.

Results: Our results indicate that before chemotherapy, breast cancer patients already exhibit relative cardiac remodeling and subclinical cardiac dysfunction, which was associated with the activation of the endothelin system. Importantly, our mouse data also show that the endothelin receptor blocker atrasentan significantly lessened cardiac remodeling and improved cardiac function in a preclinical model of breast cancer.

Conclusions: Although our findings should be further examined in other preclinical/clinical models, our data suggest that endothelin receptor blockers may play a role in cardiac health in individuals with breast cancer. (Understanding and Treating Heart Failure With Preserved Ejection Fraction: Novel Mechanisms, Diagnostics and Potential Therapeutics [Alberta HEART]; NCT02052804 and Multidisciplinary Team Intervention in Cardio-Oncology [TITAN]; NCT01621659).

Keywords: breast tumor; cardiac remodeling; endothelin system.

Associated data

ClinicalTrials.gov/NCT01621659