Heart transplantation is often an unrealizable therapeutic option for end-stage heart failure, which is why mechanical left ventricular assist devices (LVADs) become an increasingly important therapeutic alternative. Currently, there is a lack of information about molecular mechanisms which are influenced by LVADs, particularly regarding the pathophysiologically critical renin angiotensin system (RAS). We, therefore, determined regulation patterns of key components of the RAS and the β-arrestin signaling pathways in left ventricular (LV) tissue specimens from 8 patients with end-stage ischemic cardiomyopathy (ICM) and 12 patients with terminal dilated cardiomyopathy (DCM) before and after LVAD implantation and compared them with non-failing (NF) left ventricular tissue samples: AT1R, AT2R, ACE, ACE2, MasR, and ADAM17 were analyzed by polymerase chain reaction. ERK, phosphorylated ERK, p38, phosphorylated p38, JNK, phosphorylated JNK, GRK2, β-arrestin 2, PI3K, Akt, and phosphorylated Akt were determined by Western blot analysis. Angiotensin I and Angiotensin II were quantified by mass spectrometry. Patients were predominantly middle-aged (53 ± 10 years) men with severely impaired LV function (LVEF 19 ± 8%), when receiving LVAD therapy for a mean duration of 331 ± 317 days. Baseline characteristics did not differ significantly between ICM and DCM patients. By comparing failing with non-failing left ventricles, i.e., before LVAD implantation, a downregulation of AT1R, AT2R, and MasR and an upregulation of ACE, ACE2, GRK, β-arrestin, ERK, PI3K, and Akt were seen. Following LVAD support, then angiotensin I, ACE2, GRK, and β-arrestin were downregulated and AT2R, JNK, and p38 were upregulated. ACE, angiotensin II, AT1R, ADAM17, MasR, ERK, PI3K, and Akt remained unchanged. Some regulation patterns were influenced by the underlying etiology of heart failure, the severity of LV dysfunction at baseline, and the duration of LVAD therapy. Key components of the RAS and β-arrestin signaling pathways were divergently altered in failing left ventricles both before and after LVAD implantation, whereas a remarkable fraction remained unchanged. This indicates a rather incomplete molecular reverse remodeling, whose functional relevance has to be further evaluated.

中文翻译：

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LVAD 支持机械心脏卸载前后肾素血管紧张素系统在人类终末期心力衰竭中的变化。

对于终末期心力衰竭，心脏移植通常是一种无法实现的治疗选择，这就是机械左心室辅助装置 (LVAD) 成为越来越重要的治疗选择的原因。目前，缺乏关于受 LVAD 影响的分子机制的信息，特别是关于病理生理学上至关重要的肾素血管紧张素系统 (RAS)。因此，我们确定了 8 名终末期缺血性心肌病 (ICM) 患者和 12 名终末期扩张型心肌病 (DCM) 患者的左心室 (LV) 组织标本中 RAS 和 β-arrestin 信号通路关键成分的调节模式LVAD 植入前后，并将它们与非失败 (NF) 左心室组织样本进行比较：AT1R、AT2R、ACE、ACE2、MasR、通过聚合酶链反应分析ADAM17。ERK、磷酸化 ERK、p38、磷酸化 p38、JNK、磷酸化 JNK、GRK2、β-arrestin 2、PI3K、Akt 和磷酸化 Akt 通过蛋白质印迹分析确定。通过质谱法对血管紧张素 I 和血管紧张素 II 进行量化。当接受 LVAD 治疗平均持续时间为 331 ± 317 天时，患者主要是左室功能严重受损 (LVEF 19 ± 8%) 的中年 (53 ± 10 岁) 男性。ICM 和 DCM 患者的基线特征没有显着差异。通过比较失败与非失败左心室，即在 LVAD 植入前，可以看到 AT1R、AT2R 和 MasR 的下调以及 ACE、ACE2、GRK、β-arrestin、ERK、PI3K 和 Akt 的上调。在 LVAD 支持之后，然后是血管紧张素 I、ACE2、GRK、和 β-arrestin 下调，AT2R、JNK 和 p38 上调。ACE、血管紧张素 II、AT1R、ADAM17、MasR、ERK、PI3K 和 Akt 保持不变。一些调节模式受到心力衰竭的潜在病因、基线时左室功能障碍的严重程度和 LVAD 治疗持续时间的影响。RAS 和 β-arrestin 信号通路的关键成分在左心室衰竭中在 LVAD 植入之前和之后发生了不同的改变，而显着部分保持不变。这表明分子反向重塑相当不完整，其功能相关性必须进一步评估。基线时 LV 功能障碍的严重程度，以及 LVAD 治疗的持续时间。RAS 和 β-arrestin 信号通路的关键成分在左心室衰竭中在 LVAD 植入之前和之后发生了不同的改变，而显着部分保持不变。这表明分子反向重塑相当不完整，其功能相关性必须进一步评估。基线时 LV 功能障碍的严重程度，以及 LVAD 治疗的持续时间。RAS 和 β-arrestin 信号通路的关键成分在左心室衰竭中在 LVAD 植入之前和之后发生了不同的改变，而显着部分保持不变。这表明分子反向重塑相当不完整，其功能相关性必须进一步评估。