Basic Research in Cardiology ( IF 9.5 ) Pub Date : 2022-03-08 , DOI: 10.1007/s00395-022-00918-7 Luis Peter Haupt 1, 2 , Sabine Rebs 1, 2, 3 , Wiebke Maurer 1, 2 , Daniela Hübscher 1, 2 , Malte Tiburcy 2, 4 , Steffen Pabel 5 , Andreas Maus 1, 2, 6 , Steffen Köhne 1, 2 , Rewati Tappu 7, 8 , Jan Haas 7, 8 , Yun Li 9 , Andre Sasse 10 , Celio C X Santos 6 , Ralf Dressel 1, 2, 10 , Leszek Wojnowski 11 , Gertrude Bunt 12 , Wiebke Möbius 13, 14 , Ajay M Shah 6 , Benjamin Meder 7, 8 , Bernd Wollnik 2, 9 , Samuel Sossalla 1, 2, 5 , Gerd Hasenfuss 1, 2 , Katrin Streckfuss-Bömeke 1, 2, 3
Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20+ B-cell lymphoma who had received high doses of DOX and suffered cardiac dysfunction were studied and compared to control-iPSC CM from cancer survivors without cardiac symptoms. In cellular studies, ACT-iPSC CM were persistently more susceptible to DOX toxicity including augmented disorganized myofilament structure, changed mitochondrial shape, and increased apoptotic events. Consistently, ACT-iPSC CM and cardiac fibroblasts isolated from fibrotic human ACT myocardium exhibited higher DOX-dependent reactive oxygen species. In functional studies, Ca2+ transient amplitude of ACT-iPSC CM was reduced compared to control cells, and diastolic sarcoplasmic reticulum Ca2+ leak was DOX-dependently increased. This could be explained by overactive CaMKIIδ in ACT CM. Together with DOX-dependent augmented proarrhythmic cellular triggers and prolonged action potentials in ACT CM, this suggests a cellular link to arrhythmogenic events and contractile dysfunction especially found in ACT engineered human myocardium. CamKIIδ inhibition prevented proarrhythmic triggers in ACT. In contrast, control CM upregulated SERCA2a expression in a DOX-dependent manner, possibly to avoid heart failure conditions. In conclusion, we developed the first human patient-specific stem cell model of DOX-induced cardiac dysfunction from patients with B-cell lymphoma. Our results suggest that DOX-induced stress resulted in arrhythmogenic events associated with contractile dysfunction and finally in heart failure after persistent stress activation in ACT patients.
中文翻译:
阿霉素在侵袭性 B 细胞淋巴瘤癌症患者的多能干细胞模型中诱导心脏毒性
蒽环类药物的癌症治疗已被证明会诱发心血管并发症。本研究的目的是建立一种体外诱导的多能干细胞模型 (iPSC),该模型来自侵袭性 B 细胞淋巴瘤患者的蒽环类药物诱导的心脏毒性 (ACT),并检查多柔比星 (DOX) 治疗的 ACT- iPSC 心肌细胞 (CM) 可以重现患者表现出的临床特征,从而有助于揭示 DOX 依赖性病理机制。从具有 CD20 +的个体生成的 ACT-iPSC CM研究了接受高剂量 DOX 并患有心脏功能障碍的 B 细胞淋巴瘤,并与来自没有心脏症状的癌症幸存者的对照 iPSC CM 进行了比较。在细胞研究中,ACT-iPSC CM 持续更容易受到 DOX 毒性的影响,包括增强的无组织肌丝结构、改变的线粒体形状和增加的细胞凋亡事件。一致地,ACT-iPSC CM 和从纤维化人 ACT 心肌中分离的心脏成纤维细胞表现出更高的 DOX 依赖性活性氧。在功能研究中,与对照细胞和舒张肌质网 Ca 2+相比,ACT-iPSC CM 的 Ca 2+瞬时振幅降低泄漏依赖于 DOX 增加。这可以用 ACT CM 中过度活跃的 CaMKIIδ 来解释。连同 DOX 依赖性增强的促心律失常细胞触发因素和 ACT CM 中延长的动作电位,这表明细胞与致心律失常事件和收缩功能障碍之间存在联系,尤其是在 ACT 改造的人类心肌中。CamKIIδ 抑制阻止了 ACT 中的促心律失常触发。相反,对照 CM 以依赖于 DOX 的方式上调 SERCA2a 表达,可能是为了避免出现心力衰竭情况。总之,我们开发了第一个来自 B 细胞淋巴瘤患者的 DOX 诱导的心脏功能障碍的人类患者特异性干细胞模型。