Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab.

Details

Serval ID
serval:BIB_2AD422170213
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Structural and Electrophysiological Changes in a Model of Cardiotoxicity Induced by Anthracycline Combined With Trastuzumab.
Journal
Frontiers in physiology
Author(s)
Altomare C., Lodrini A.M., Milano G., Biemmi V., Lazzarini E., Bolis S., Pernigoni N., Torre E., Arici M., Ferrandi M., Barile L., Rocchetti M., Vassalli G.
ISSN
1664-042X (Print)
ISSN-L
1664-042X
Publication state
Published
Issued date
2021
Peer-reviewed
Oui
Volume
12
Pages
658790
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Combined 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.
To assess cardiac performance, T-tubule organization, electrophysiological changes and intracellular Ca <sup>2+</sup> handling in cardiac myocytes (CMs) using an in vivo rat model of Dox/Trz-related cardiotoxicity.
Adult 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 Ca <sup>2+</sup> transient decay. Although APD, DADs, BVR and Ca <sup>2+</sup> transient decay recovered over time after the cessation of Dox treatment, subsequent Trz administration exacerbated these abnormalities. Trz, but not Dox, reduced Ca <sup>2+</sup> transient amplitude and SR Ca <sup>2+</sup> content, although only Dox treatment was associated with SERCA downregulation. Finally, Dox treatment increased Ca <sup>2+</sup> spark frequency, resting Ca <sup>2+</sup> waves, sarcoplasmic reticulum (SR) Ca <sup>2+</sup> leak, and long-lasting Ca <sup>2+</sup> release events (so-called Ca <sup>2+</sup> "embers"), partially reproduced by Trz treatment.
These 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 Ca <sup>2+</sup> 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.
Keywords
T-tubules, calcium handling, cardiotoxicity, doxorubicin, electrophysiology, trastuzumab
Pubmed
Web of science
Open Access
Yes
Create date
30/04/2021 17:46
Last modification date
07/05/2021 6:36
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