Stanford Cardiovascular Institute, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., R.M.W., N.S., J.C.W.).
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA (T.K., C.K.L., J.-W.R., J.Z.Z., A.O., N.M., L.T., N.S., J.C.W.).
Circulation. 2019 May 21;139(21):2451-2465. doi: 10.1161/CIRCULATIONAHA.118.037357.
Molecular targeted chemotherapies have been shown to significantly improve the outcomes of patients who have cancer, but they often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype in comparison to the cardiotoxicity induced by conventional chemotherapies.
We used the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing to further examine the effect of trastuzumab on iPSC-CMs. We also generated human induced pluripotent stem cells from patients receiving trastuzumab and examined whether patients' phenotype could be recapitulated in vitro by using patient-specific iPSC-CMs.
We found that clinically relevant doses of trastuzumab significantly impaired the contractile and calcium-handling properties of iPSC-CMs without inducing cardiomyocyte death or sarcomeric disorganization. RNA-sequencing and subsequent functional analysis revealed mitochondrial dysfunction and altered the cardiac energy metabolism pathway as primary causes of trastuzumab-induced cardiotoxic phenotype. Human iPSC-CMs generated from patients who received trastuzumab and experienced severe cardiac dysfunction were more vulnerable to trastuzumab treatment than iPSC-CMs generated from patients who did not experience cardiac dysfunction following trastuzumab therapy. It is important to note that metabolic modulation with AMP-activated protein kinase activators could avert the adverse effects induced by trastuzumab.
Our results indicate that alterations in cellular metabolic pathways in cardiomyocytes could be a key mechanism underlying the development of cardiac dysfunction following trastuzumab therapy; therefore, targeting the altered metabolism may be a promising therapeutic approach for trastuzumab-induced cardiac dysfunction.
分子靶向化疗已被证明能显著改善癌症患者的预后，但它们常引起心血管副作用，限制了其应用并损害了患者的生活质量。与传统化疗引起的毒性相比，这些疗法引起的心脏功能障碍，尤其是曲妥珠单抗，表现出明显不同的心脏毒性临床表型。
我们使用人诱导多能干细胞衍生的心肌细胞（iPSC-CM）平台来确定曲妥珠单抗诱导的心脏功能障碍的潜在细胞机制。我们评估了曲妥珠单抗对来自健康个体的 iPSC-CMs 的结构和功能特性的影响，并进行了 RNA 测序，以进一步研究曲妥珠单抗对 iPSC-CMs 的影响。我们还从接受曲妥珠单抗治疗的患者中生成了人诱导多能干细胞，并通过使用患者特异性 iPSC-CMs 来检查患者表型是否可以在体外重现。
我们发现，临床相关剂量的曲妥珠单抗显著损害了 iPSC-CMs 的收缩和钙处理特性，而不会诱导心肌细胞死亡或肌节紊乱。RNA 测序和随后的功能分析显示，线粒体功能障碍和改变心脏能量代谢途径是曲妥珠单抗诱导心脏毒性表型的主要原因。与未经历曲妥珠单抗治疗后心脏功能障碍的患者相比，从接受曲妥珠单抗治疗并经历严重心脏功能障碍的患者中生成的 iPSC-CMs 对曲妥珠单抗治疗更为敏感。需要注意的是，使用 AMP 激活蛋白激酶激活剂进行代谢调节可以避免曲妥珠单抗引起的不良反应。
我们的结果表明，心肌细胞中细胞代谢途径的改变可能是曲妥珠单抗治疗后心脏功能障碍发展的关键机制；因此，靶向改变的代谢可能是治疗曲妥珠单抗诱导的心脏功能障碍的一种有前途的治疗方法。
