Inflammation and vascular remodeling in COVID-19 hearts

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE Angiogenesis Pub Date : 2022-11-12 DOI:10.1007/s10456-022-09860-7
Christopher Werlein, Maximilian Ackermann, Helge Stark, Harshit R. Shah, Alexandar Tzankov, Jasmin Dinonne Haslbauer, Saskia von Stillfried, Roman David Bülow, Ali El-Armouche, Stephan Kuenzel, Jan Lukas Robertus, Marius Reichardt, Axel Haverich, Anne Höfer, Lavinia Neubert, Edith Plucinski, Peter Braubach, Stijn Verleden, Tim Salditt, Nikolaus Marx, Tobias Welte, Johann Bauersachs, Hans-Heinrich Kreipe, Steven J. Mentzer, Peter Boor, Stephen M. Black, Florian Länger, Mark Kuehnel, Danny Jonigk
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引用次数: 10

Abstract

A wide range of cardiac symptoms have been observed in COVID-19 patients, often significantly influencing the clinical outcome. While the pathophysiology of pulmonary COVID-19 manifestation has been substantially unraveled, the underlying pathomechanisms of cardiac involvement in COVID-19 are largely unknown. In this multicentre study, we performed a comprehensive analysis of heart samples from 24 autopsies with confirmed SARS-CoV-2 infection and compared them to samples of age-matched Influenza H1N1 A (n = 16), lymphocytic non-influenza myocarditis cases (n = 8), and non-inflamed heart tissue (n = 9). We employed conventional histopathology, multiplexed immunohistochemistry (MPX), microvascular corrosion casting, scanning electron microscopy, X-ray phase-contrast tomography using synchrotron radiation, and direct multiplexed measurements of gene expression, to assess morphological and molecular changes holistically. Based on histopathology, none of the COVID-19 samples fulfilled the established diagnostic criteria of viral myocarditis. However, quantification via MPX showed a significant increase in perivascular CD11b/TIE2 + —macrophages in COVID-19 over time, which was not observed in influenza or non-SARS-CoV-2 viral myocarditis patients. Ultrastructurally, a significant increase in intussusceptive angiogenesis as well as multifocal thrombi, inapparent in conventional morphological analysis, could be demonstrated. In line with this, on a molecular level, COVID-19 hearts displayed a distinct expression pattern of genes primarily coding for factors involved in angiogenesis and epithelial-mesenchymal transition (EMT), changes not seen in any of the other patient groups. We conclude that cardiac involvement in COVID-19 is an angiocentric macrophage-driven inflammatory process, distinct from classical anti-viral inflammatory responses, and substantially underappreciated by conventional histopathologic analysis. For the first time, we have observed intussusceptive angiogenesis in cardiac tissue, which we previously identified as the linchpin of vascular remodeling in COVID-19 pneumonia, as a pathognomic sign in affected hearts. Moreover, we identified CD11b + /TIE2 + macrophages as the drivers of intussusceptive angiogenesis and set forward a putative model for the molecular regulation of vascular alterations.

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新冠肺炎心脏的炎症和血管重塑。
在新冠肺炎患者中观察到广泛的心脏症状,通常会显著影响临床结果。虽然肺新冠肺炎表现的病理生理学已基本阐明,但新冠肺炎心脏受累的潜在病理机制在很大程度上尚不清楚。在这项多中心研究中,我们对24例确诊感染严重急性呼吸系统综合征冠状病毒2型的尸检心脏样本进行了全面分析,并将其与年龄匹配的甲型H1N1流感(n = 16) ,淋巴细胞性非流感性心肌炎病例(n = 8) 和未发炎的心脏组织(n = 9) 。我们采用了传统的组织病理学、多重免疫组织化学(MPX)、微血管腐蚀铸造、扫描电子显微镜、使用同步辐射的X射线相位对比断层扫描和基因表达的直接多重测量,来全面评估形态学和分子变化。根据组织病理学,新冠肺炎样本均未达到病毒性心肌炎的既定诊断标准。然而,通过MPX的定量显示血管周CD11b/TIE2显著增加 + -新冠肺炎随时间变化的巨噬细胞,这在流感或非SARS-CoV-2病毒性心肌炎患者中未观察到。在超微结构上,可以证明肠套叠感受性血管生成和多灶性血栓的显著增加,这在传统的形态学分析中是不明显的。与此相一致,在分子水平上,新冠肺炎心脏显示出主要编码参与血管生成和上皮-间质转化(EMT)的因子的基因的独特表达模式,这些变化在任何其他患者组中都没有看到。我们得出的结论是,新冠肺炎的心脏受累是一种血管中心巨噬细胞驱动的炎症过程,不同于经典的抗病毒炎症反应,传统的组织病理学分析基本上未得到重视。我们首次在心脏组织中观察到套叠血管生成,我们之前将其确定为新冠肺炎肺炎血管重塑的关键,并将其作为受影响心脏的病理标志。此外,我们鉴定了CD11b + /TIE2 + 巨噬细胞是肠套叠血管生成的驱动因素,并为血管改变的分子调控建立了一个假定的模型。
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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
期刊最新文献
Correction: Mitochondrial control of hypoxia-induced pathological retinal angiogenesis. Angiogenesis is limited by LIC1-mediated lysosomal trafficking. Similarities and differences between brain and skin GNAQ p.R183Q driven capillary malformations. Inflammasome activation aggravates choroidal neovascularization. Timed topical dexamethasone eye drops improve mitochondrial function to prevent severe retinopathy of prematurity
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