Altomare Claudia, Lodrini Alessandra Maria, Milano Giuseppina, Biemmi Vanessa, Lazzarini Edoardo, Bolis Sara, Pernigoni Nicolò, Torre Eleonora, Arici Martina, Ferrandi Mara, Barile Lucio, Rocchetti Marcella, Vassalli Giuseppe
Laboratory of Cellular and Molecular Cardiology, Cardiocentro Ticino Foundation, Lugano, Switzerland.
Department of Biotechnology and Biosciences, Università degli Studi di Milano - Bicocca, Milan, Italy.
Front Physiol. 2021 Apr 7;12:658790. doi: 10.3389/fphys.2021.658790. eCollection 2021.
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 handling in cardiac myocytes (CMs) using an 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 transient decay. Although APD, DADs, BVR and Ca transient decay recovered over time after the cessation of Dox treatment, subsequent Trz administration exacerbated these abnormalities. Trz, but not Dox, reduced Ca transient amplitude and SR Ca content, although only Dox treatment was associated with SERCA downregulation. Finally, Dox treatment increased Ca spark frequency, resting Ca waves, sarcoplasmic reticulum (SR) Ca leak, and long-lasting Ca release events (so-called Ca "embers"), partially reproduced by Trz treatment.
These results suggest that 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 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.
在人表皮生长因子受体2（HER2；ErbB2）阳性癌症患者中，蒽环类药物（如多柔比星；Dox）与曲妥珠单抗（Trz，一种人源化抗HER2抗体）联合治疗受到心脏毒性的限制，表现为收缩功能障碍和心律失常。两种药物在联合治疗心脏毒性中的各自作用尚未完全明确。
使用多柔比星/曲妥珠单抗相关心脏毒性的大鼠模型，评估心肌细胞（CMs）的心脏功能、T小管组织、电生理变化及细胞内钙处理情况。
成年大鼠接受6剂多柔比星或曲妥珠单抗，或两种药物序贯给药。曲妥珠单抗给药加重了多柔比星介导的左心室（LV）功能障碍。多柔比星治疗可诱导T小管紊乱，但曲妥珠单抗不会。此外，多柔比星单药治疗可诱导动作电位时程（APD）延长、延迟后去极化（DADs）发生率增加、复极化逐搏变异性（BVR）增加以及钙瞬变衰减减慢。虽然在多柔比星治疗停止后，APD、DADs、BVR和钙瞬变衰减随时间恢复，但随后的曲妥珠单抗给药使这些异常情况加剧。曲妥珠单抗可降低钙瞬变幅度和肌浆网（SR）钙含量，但只有多柔比星治疗与肌浆网钙ATP酶（SERCA）下调有关。最后，多柔比星治疗增加了钙火花频率、静息钙波、肌浆网（SR）钙泄漏以及持久钙释放事件（所谓的钙“余烬”），曲妥珠单抗治疗部分再现了这些情况。
这些结果表明，多柔比星给药而非曲妥珠单抗给药会导致T小管紊乱和心肌细胞电活动的明显变化。虽然适应性变化可能解释多柔比星给药后期正常的动作电位形状和减少的DADs，但随后的曲妥珠单抗给药会干扰这种适应性变化。多柔比星和曲妥珠单抗治疗对细胞内钙处理的影响不同，导致两种情况下肌浆网不稳定。这些发现阐明了多柔比星和曲妥珠单抗的具体作用及其在心脏毒性和致心律失常性中的相互作用。
