Mariann Gyöngyösi1, Dominika Lukovic1, Katrin Zlabinger1, Andreas Spannbauer1, Alfred Gugerell1, Noemi Pavo1, Denise Traxler1, Dietmar Pils2, Gerald Maurer1, Andras Jakab3,4, Martin Riesenhuber1, Andreas Pircher5, Johannes Winkler1, Jutta Bergler-Klein1. 1. Department of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. 2. Center for Medical Statistics, Informatics, and Intelligent Systems (CeMSIIS), and Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. 3. Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. 4. Center for MR-Research, University Children's Hospital Zurich, Steinwiesstraße 75, 8032 Zurich, Switzerland. 5. Division of Hematology and Oncology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria.
Abstract
AIMS: The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies. METHODS AND RESULTS: We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups. CONCLUSIONS: All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.
AIMS: The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies. METHODS AND RESULTS: We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups. CONCLUSIONS: All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.
Authors: Jutta Bergler-Klein; Peter P Rainer; Markus Wallner; Marc-Michael Zaruba; Jakob Dörler; Armin Böhmer; Tamara Buchacher; Maria Frey; Christopher Adlbrecht; Rupert Bartsch; Mariann Gyöngyösi; Ursula-Maria Fürst Journal: Wien Klin Wochenschr Date: 2022-05-04 Impact factor: 2.275
Authors: Jan M Leerink; Mabel van de Ruit; Elizabeth A M Feijen; Leontien C M Kremer; Annelies M C Mavinkurve-Groothuis; Yigal M Pinto; Esther E Creemers; Wouter E M Kok Journal: J Mol Med (Berl) Date: 2021-05-29 Impact factor: 4.599