Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab
BackgroundCombined treatment with anthracyclines (e.g., doxorubicin; Dox) and trastuzumab (Trz), a humanized anti-human epidermal growth factor receptor 2 (HER2; ErbB2) antibody, in patients with HER2-positive cancer is limited by cardiotoxicity, as manifested by contractile dysfunction and arrhythm...
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Frontiers Media S.A.
2021-04-01
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| Series: | Frontiers in Physiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphys.2021.658790/full |
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| author | Claudia Altomare Alessandra Maria Lodrini Alessandra Maria Lodrini Giuseppina Milano Giuseppina Milano Vanessa Biemmi Edoardo Lazzarini Sara Bolis Sara Bolis Nicolò Pernigoni Eleonora Torre Martina Arici Mara Ferrandi Lucio Barile Lucio Barile Lucio Barile Marcella Rocchetti Giuseppe Vassalli Giuseppe Vassalli Giuseppe Vassalli |
| author_facet | Claudia Altomare Alessandra Maria Lodrini Alessandra Maria Lodrini Giuseppina Milano Giuseppina Milano Vanessa Biemmi Edoardo Lazzarini Sara Bolis Sara Bolis Nicolò Pernigoni Eleonora Torre Martina Arici Mara Ferrandi Lucio Barile Lucio Barile Lucio Barile Marcella Rocchetti Giuseppe Vassalli Giuseppe Vassalli Giuseppe Vassalli |
| author_sort | Claudia Altomare |
| collection | DOAJ |
| description | BackgroundCombined treatment with anthracyclines (e.g., doxorubicin; Dox) and trastuzumab (Trz), a humanized anti-human epidermal growth factor receptor 2 (HER2; ErbB2) antibody, in patients with HER2-positive cancer is limited by cardiotoxicity, as manifested by contractile dysfunction and arrhythmia. The respective roles of the two agents in the cardiotoxicity of the combined therapy are incompletely understood.ObjectiveTo assess cardiac performance, T-tubule organization, electrophysiological changes and intracellular Ca2+ handling in cardiac myocytes (CMs) using an in vivo rat model of Dox/Trz-related cardiotoxicity.Methods and ResultsAdult rats received 6 doses of either Dox or Trz, or the two agents sequentially. Dox-mediated left ventricular (LV) dysfunction was aggravated by Trz administration. Dox treatment, but not Trz, induced T-tubule disarray. Moreover, Dox, but not Trz monotherapy, induced prolonged action potential duration (APD), increased incidence of delayed afterdepolarizations (DADs) and beat-to-beat variability of repolarization (BVR), and slower Ca2+ transient decay. Although APD, DADs, BVR and Ca2+ transient decay recovered over time after the cessation of Dox treatment, subsequent Trz administration exacerbated these abnormalities. Trz, but not Dox, reduced Ca2+ transient amplitude and SR Ca2+ content, although only Dox treatment was associated with SERCA downregulation. Finally, Dox treatment increased Ca2+ spark frequency, resting Ca2+ waves, sarcoplasmic reticulum (SR) Ca2+ leak, and long-lasting Ca2+ release events (so-called Ca2+ “embers”), partially reproduced by Trz treatment.ConclusionThese results suggest that in vivo Dox but not Trz administration causes T-tubule disarray and pronounced changes in electrical activity of CMs. While adaptive changes may account for normal AP shape and reduced DADs late after Dox administration, subsequent Trz administration interferes with such adaptive changes. Intracellular Ca2+ handling was differently affected by Dox and Trz treatment, leading to SR instability in both cases. These findings illustrate the specific roles of Dox and Trz, and their interactions in cardiotoxicity and arrhythmogenicity. |
| first_indexed | 2024-12-19T05:19:41Z |
| format | Article |
| id | doaj.art-4fd0e3964088441d8bba60a7cafdb300 |
| institution | Directory Open Access Journal |
| issn | 1664-042X |
| language | English |
| last_indexed | 2024-12-19T05:19:41Z |
| publishDate | 2021-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Physiology |
| spelling | doaj.art-4fd0e3964088441d8bba60a7cafdb3002022-12-21T20:34:33ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2021-04-011210.3389/fphys.2021.658790658790Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With TrastuzumabClaudia Altomare0Alessandra Maria Lodrini1Alessandra Maria Lodrini2Giuseppina Milano3Giuseppina Milano4Vanessa Biemmi5Edoardo Lazzarini6Sara Bolis7Sara Bolis8Nicolò Pernigoni9Eleonora Torre10Martina Arici11Mara Ferrandi12Lucio Barile13Lucio Barile14Lucio Barile15Marcella Rocchetti16Giuseppe Vassalli17Giuseppe Vassalli18Giuseppe Vassalli19Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Foundation, Lugano, SwitzerlandDepartment of Biotechnology and Biosciences, Università degli Studi di Milano – Bicocca, Milan, ItalyLaboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Lugano, SwitzerlandLaboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Foundation, Lugano, SwitzerlandLaboratory of Cardiovascular Research, Lausanne University Hospital, Lausanne, SwitzerlandLaboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Lugano, SwitzerlandLaboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Lugano, SwitzerlandLaboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Foundation, Lugano, SwitzerlandLaboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Lugano, SwitzerlandLaboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Foundation, Lugano, SwitzerlandDepartment of Biotechnology and Biosciences, Università degli Studi di Milano – Bicocca, Milan, ItalyDepartment of Biotechnology and Biosciences, Università degli Studi di Milano – Bicocca, Milan, ItalyWindtree Therapeutics Inc., Warrington, PA, United StatesLaboratory for Cardiovascular Theranostics, Cardiocentro Ticino Foundation, Lugano, SwitzerlandFaculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, SwitzerlandInstitute of Life Science, Scuola Superiore Sant’Anna, Pisa, ItalyDepartment of Biotechnology and Biosciences, Università degli Studi di Milano – Bicocca, Milan, ItalyLaboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Foundation, Lugano, SwitzerlandFaculty of Biomedical Sciences, Università della Svizzera italiana, Lugano, SwitzerlandCenter for Molecular Cardiology, University of Zurich, Zurich, SwitzerlandBackgroundCombined treatment with anthracyclines (e.g., doxorubicin; Dox) and trastuzumab (Trz), a humanized anti-human epidermal growth factor receptor 2 (HER2; ErbB2) antibody, in patients with HER2-positive cancer is limited by cardiotoxicity, as manifested by contractile dysfunction and arrhythmia. The respective roles of the two agents in the cardiotoxicity of the combined therapy are incompletely understood.ObjectiveTo assess cardiac performance, T-tubule organization, electrophysiological changes and intracellular Ca2+ handling in cardiac myocytes (CMs) using an in vivo rat model of Dox/Trz-related cardiotoxicity.Methods and ResultsAdult rats received 6 doses of either Dox or Trz, or the two agents sequentially. Dox-mediated left ventricular (LV) dysfunction was aggravated by Trz administration. Dox treatment, but not Trz, induced T-tubule disarray. Moreover, Dox, but not Trz monotherapy, induced prolonged action potential duration (APD), increased incidence of delayed afterdepolarizations (DADs) and beat-to-beat variability of repolarization (BVR), and slower Ca2+ transient decay. Although APD, DADs, BVR and Ca2+ transient decay recovered over time after the cessation of Dox treatment, subsequent Trz administration exacerbated these abnormalities. Trz, but not Dox, reduced Ca2+ transient amplitude and SR Ca2+ content, although only Dox treatment was associated with SERCA downregulation. Finally, Dox treatment increased Ca2+ spark frequency, resting Ca2+ waves, sarcoplasmic reticulum (SR) Ca2+ leak, and long-lasting Ca2+ release events (so-called Ca2+ “embers”), partially reproduced by Trz treatment.ConclusionThese results suggest that in vivo Dox but not Trz administration causes T-tubule disarray and pronounced changes in electrical activity of CMs. While adaptive changes may account for normal AP shape and reduced DADs late after Dox administration, subsequent Trz administration interferes with such adaptive changes. Intracellular Ca2+ handling was differently affected by Dox and Trz treatment, leading to SR instability in both cases. These findings illustrate the specific roles of Dox and Trz, and their interactions in cardiotoxicity and arrhythmogenicity.https://www.frontiersin.org/articles/10.3389/fphys.2021.658790/fulldoxorubicintrastuzumabcardiotoxicityT-tubuleselectrophysiologycalcium handling |
| spellingShingle | Claudia Altomare Alessandra Maria Lodrini Alessandra Maria Lodrini Giuseppina Milano Giuseppina Milano Vanessa Biemmi Edoardo Lazzarini Sara Bolis Sara Bolis Nicolò Pernigoni Eleonora Torre Martina Arici Mara Ferrandi Lucio Barile Lucio Barile Lucio Barile Marcella Rocchetti Giuseppe Vassalli Giuseppe Vassalli Giuseppe Vassalli Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab Frontiers in Physiology doxorubicin trastuzumab cardiotoxicity T-tubules electrophysiology calcium handling |
| title | Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab |
| title_full | Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab |
| title_fullStr | Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab |
| title_full_unstemmed | Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab |
| title_short | Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab |
| title_sort | structural and electrophysiological changes in a model of cardiotoxicity induced by anthracycline combined with trastuzumab |
| topic | doxorubicin trastuzumab cardiotoxicity T-tubules electrophysiology calcium handling |
| url | https://www.frontiersin.org/articles/10.3389/fphys.2021.658790/full |
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