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Open Access 12-11-2022 | Myocarditis | Original Paper

Inflammation and vascular remodeling in COVID-19 hearts

Authors: 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

Published in: Angiogenesis | Issue 2/2023

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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Title: Inflammation and vascular remodeling in COVID-19 hearts
Authors: 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
Publication date: 12-11-2022
Publisher: Springer Netherlands
Keywords: Myocarditis
SARS-CoV-2
Influenza
COVID-19
Published in: Angiogenesis / Issue 2/2023
Print ISSN: 0969-6970
Electronic ISSN: 1573-7209
DOI: https://doi.org/10.1007/s10456-022-09860-7

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