Key result
In vivo doxorubicin administration caused T-tubule disarray and pronounced changes in electrical activity of cardiac myocytes, and subsequent trastuzumab administration exacerbated these abnormalities.
Why the study?
Combined anthracycline and trastuzumab therapy in HER2-positive cancer is limited by cardiotoxicity, but the respective roles of the two agents are incompletely understood.
Does sequential administration of doxorubicin and trastuzumab alter cardiac performance, T-tubule organization, and electrophysiology in an adult rat model?
Does sequential administration of doxorubicin and trastuzumab alter cardiac performance, T-tubule organization, and electrophysiology in an adult rat model?
Doxorubicin and trastuzumab have distinct but interactive effects on T-tubule organization and intracellular calcium handling, contributing to cardiotoxicity and arrhythmogenicity.
Answers are grounded in this paper and cite their sources.
Dox-induced T-tubule disarray and electrical instability may be worsened by subsequent trastuzumab; leaves open optimal sequencing and monitoring strategies in HER2-positive patients.
Background 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. Objective To assess cardiac performance, T-tubule organization, electrophysiological changes and intracellular Ca 2+ handling in cardiac myocytes (CMs) using an in vivo rat model of Dox/Trz-related cardiotoxicity. Methods and Results 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 2+ transient decay. Although APD, DADs, BVR and Ca 2+ transient decay recovered over time after the cessation of Dox treatment, subsequent Trz administration exacerbated these abnormalities. Trz, but not Dox, reduced Ca 2+ transient amplitude and SR Ca 2+ content, although only Dox treatment was associated with SERCA downregulation. Finally, Dox treatment increased Ca 2+ spark frequency, resting Ca 2+ waves, sarcoplasmic reticulum (SR) Ca 2+ leak, and long-lasting Ca 2+ release events (so-called Ca 2+ “embers”), partially reproduced by Trz treatment. Conclusion 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 2+ 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.
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Altomare et al. (2021) studied Chemotherapy-induced cardiotoxicity. Doxorubicin combined with Trastuzumab vs. Phosphate-buffered saline (PBS) was evaluated on Left ventricular function, T-tubule organization, and electrophysiological changes. In vivo doxorubicin administration caused T-tubule disarray and pronounced changes in electrical activity of cardiac myocytes, and subsequent trastuzumab administration exacerbated these abnormalities.
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