Immune checkpoint inhibitors (ICIs) exhibit remarkable antitumor activity and immune-related cardiotoxicity of unknown pathomechanism. The aim of the study was to investigate the ICI class-dependent cardiotoxicity in vitro and pembrolizumab’s (Pem’s) cardiotoxicity in vivo, seeking for translational prevention means. Cytotoxicity was investigated in primary cardiomyocytes and splenocytes, incubated with ipilimumab, Pem and avelumab. Pem’s cross-reactivity was assessed by circular dichroism (CD) on biotechnologically produced human and murine PD-1 and in silico. C57BL6/J male mice received IgG4 or Pem for 2 and 5 weeks. Echocardiography, histology, and molecular analyses were performed. Coronary blood flow velocity mapping and cardiac magnetic resonance imaging were conducted at 2 weeks. Human EA.hy926 endothelial cells were incubated with Pem-conditioned media from human mononuclear cells, in presence and absence of statins and viability and molecular signaling were assessed. Atorvastatin (20 mg/kg, daily) was administered in vivo, as prophylaxis. Only Pem exerted immune-related cytotoxicity in vitro. Pem’s cross-reactivity with the murine PD-1 was confirmed by CD and docking. In vivo, Pem initiated coronary endothelial and diastolic dysfunction at 2 weeks and systolic dysfunction at 5 weeks. At 2 weeks, Pem induced ICAM-1 and iNOS expression and intracardiac leukocyte infiltration. At 5 weeks, Pem exacerbated endothelial activation and triggered cardiac inflammation. Pem led to immune-related cytotoxicity in EA.hy926 cells, which was prevented by atorvastatin. Atorvastatin mitigated functional deficits, by inhibiting endothelial dysfunction in vivo. We established for the first time an in vivo model of Pem-induced cardiotoxicity. Coronary endothelial dysfunction precedes Pem-induced cardiotoxicity, whereas atorvastatin emerges as a novel prophylactic therapy.

免疫检查点抑制剂（ICIs）表现出显着的抗肿瘤活性和未知病理机制的免疫相关心脏毒性。该研究的目的是研究ICI类别依赖性体外心脏毒性和pembrolizumab（Pem's）体内心脏毒性，寻求转化预防手段。在与 ipilimumab、Pem 和 avelumab 一起孵育的原代心肌细胞和脾细胞中研究了细胞毒性。 Pem 的交叉反应性通过生物技术生产的人和鼠 PD-1 的圆二色性 (CD) 和计算机进行评估。 C57BL6/J 雄性小鼠接受 IgG4 或 Pem 治疗 2 周和 5 周。进行了超声心动图、组织学和分子分析。两周时进行冠状动脉血流速度测绘和心脏磁共振成像。在存在和不存在他汀类药物的情况下，将人 EA.hy926 内皮细胞与来自人单核细胞的 Pem 条件培养基一起孵育，并评估活力和分子信号传导。体内施用阿托伐他汀（20 mg/kg，每日）作为预防。只有 Pem 在体外发挥免疫相关的细胞毒性。通过 CD 和对接证实了 Pem 与鼠 PD-1 的交叉反应性。在体内，Pem 在 2 周时引发冠状动脉内皮和舒张功能障碍，在 5 周时引发收缩功能障碍。 2 周时，Pem 诱导 ICAM-1 和 iNOS 表达以及心内白细胞浸润。第 5 周时，Pem 加剧了内皮激活并引发心脏炎症。 Pem 在 EA.hy926 细胞中导致免疫相关的细胞毒性，而阿托伐他汀可以阻止这种毒性。阿托伐他汀通过抑制体内内皮功能障碍来减轻功能缺陷。我们首次建立了Pem诱导的心脏毒性体内模型。冠状动脉内皮功能障碍先于 Pem 引起的心脏毒性，而阿托伐他汀作为一种新型预防性疗法出现。