Inflammation and vascular remodeling in COVID-19 hearts

Angiogenesis - Tập 26 - Trang 233-248 - 2022
Christopher Werlein1, Maximilian Ackermann2,3, Helge Stark1,4, Harshit R. Shah4, Alexandar Tzankov5, Jasmin Dinonne Haslbauer5, Saskia von Stillfried6, Roman David Bülow6, Ali El-Armouche7, Stephan Kuenzel7,8, Jan Lukas Robertus9, Marius Reichardt10, Axel Haverich11, Anne Höfer1,4, Lavinia Neubert1,4, Edith Plucinski1,4, Peter Braubach4, Stijn Verleden12, Tim Salditt10,13, Nikolaus Marx14, Tobias Welte4,15, Johann Bauersachs16, Hans-Heinrich Kreipe1, Steven J. Mentzer17,18, Peter Boor6,19, Stephen M. Black20, Florian Länger4, Mark Kuehnel1,4, Danny Jonigk1,4
1Institute of Pathology, Hannover Medical School, Hannover, Germany
2Institute of Pathology and Department of Molecular Pathology, Helios University Clinic Wuppertal, University of Witten/Herdecke, Wuppertal, Germany
3Institute of Functional and Clinical Anatomy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
4Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover, Germany
5Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
6Institute of Pathology, RWTH University of Aachen, Aachen, Germany
7Institute of Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
8Department of Dermatology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
9Department of Histopathology, Royal Brompton and Harefield NHS Foundation Trust, London, UK
10Institute for X-ray Physics, University of Göttingen, Göttingen, Germany
11Department of Cardiothoracic Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
12Department of Thoracic Medicine, Antwerp University Hospital, Antwerp, Belgium
13Cluster of Excellence “Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen, Göttingen, Germany
14Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany
15Clinic of Pneumology, Hannover Medical School, Hannover, Germany
16Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
17Laboratory of Adaptive and Regenerative Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
18Division of Thoracic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
19Institute of Pathology and Department of Nephrology, RWTH University of Aachen, Aachen, Germany
20Department of Cellular Biology and Pharmacology Translational Medicine, Florida International University, Florida, USA

Tóm tắt

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.

Tài liệu tham khảo

Gupta A, Madhavan MV, Sehgal K et al (2020) Extrapulmonary manifestations of COVID-19. Nat Med 26:1017–1032. https://doi.org/10.1038/s41591-020-0968-3 Smadja DM, Mentzer SJ, Fontenay M et al (2021) COVID-19 is a systemic vascular hemopathy: insight for mechanistic and clinical aspects. Springer, Netherlands Rovas A, Osiaevi I, Buscher K et al (2021) Microvascular dysfunction in COVID-19: the MYSTIC study. Angiogenesis 24:145–157. https://doi.org/10.1007/s10456-020-09753-7 Ackermann M, Verleden SE, Kuehnel M et al (2020) Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. N Engl J Med 383:120–128. https://doi.org/10.1056/NEJMoa2015432 Libby P, Lüscher T (2020) COVID-19 is, in the end, an endothelial disease. Eur Heart J 41:3038–3044. https://doi.org/10.1093/eurheartj/ehaa623 Philippe A, Gendron N, Bory O et al (2021) Von willebrand factor collagen-binding capacity predicts in-hospital mortality in COVID-19 patients: insight from VWF/ADAMTS13 ratio imbalance. Angiogenesis 24:407–411. https://doi.org/10.1007/s10456-021-09789-3 Philippe A, Chocron R, Gendron N et al (2021) Circulating von willebrand factor and high molecular weight multimers as markers of endothelial injury predict COVID-19 in-hospital mortality. Angiogenesis 24:505–517. https://doi.org/10.1007/s10456-020-09762-6 Smadja DM, Guerin CL, Chocron R et al (2020) Angiopoietin-2 as a marker of endothelial activation is a good predictor factor for intensive care unit admission of COVID-19 patients. Angiogenesis 23:611–620. https://doi.org/10.1007/s10456-020-09730-0 Basso C, Leone O, Rizzo S et al (2020) Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study. Eur Heart J 41:3827–3835. https://doi.org/10.1093/eurheartj/ehaa664 Weckbach LT, Curta A, Bieber S et al (2021) Myocardial inflammation and dysfunction in COVID-19-associated myocardial injury. Circ Cardiovasc Imaging. https://doi.org/10.1161/CIRCIMAGING.120.011713 Ghidini S, Gasperetti A, Winterton D et al (2021) Echocardiographic assessment of the right ventricle in COVID-19: a systematic review. Int J Cardiovasc Imaging 37:3499–3512. https://doi.org/10.1007/s10554-021-02353-6 Goudot G, Chocron R, Augy JL et al (2020) Predictive factor for COVID-19 worsening: insights for high-sensitivity troponin and D-dimer and correlation with right ventricular afterload. Front Med 7:1–11. https://doi.org/10.3389/fmed.2020.586307 Moody WE, Mahmoud-Elsayed HM, Senior J et al (2021) Impact of right ventricular dysfunction on mortality in patients hospitalized with COVID-19, according to race. CJC Open 3:91–100. https://doi.org/10.1016/j.cjco.2020.09.016 Yu C-M, Wong RS-M, Wu EB et al (2006) Cardiovascular complications of severe acute respiratory syndrome. Postgrad Med J 82:140–144. https://doi.org/10.1136/pgmj.2005.037515 Basu-Ray I, Almaddah NK, Adeboye A, Soos MP (2021) Cardiac manifestations of coronavirus (COVID-19). StatPearls, Treasure Island Edouard AR, Felten ML, Hebert JL et al (2004) Incidence and significance of cardiac troponin I release in severe trauma patients. Anesthesiology 101:1262–1268. https://doi.org/10.1097/00000542-200412000-00004 Halushka MK, Vander Heide RS (2021) Myocarditis is rare in COVID-19 autopsies: cardiovascular findings across 277 postmortem examinations. Cardiovasc Pathol. https://doi.org/10.1016/j.carpath.2020.107300 Tavazzi G, Pellegrini C, Maurelli M et al (2020) Myocardial localization of coronavirus in COVID-19 cardiogenic shock. Eur J Heart Fail 22:911–915. https://doi.org/10.1002/ejhf.1828 Albert CL, Carmona-Rubio AE, Weiss AJ et al (2020) The enemy within: sudden-onset reversible cardiogenic shock with biopsy-proven cardiac myocyte infection by severe acute respiratory syndrome coronavirus 2. Circulation 142:1865–1870. https://doi.org/10.1161/CIRCULATIONAHA.120.050097 Zeng JH, Liu YX, Yuan J et al (2020) First case of COVID-19 complicated with fulminant myocarditis: a case report and insights. Infection 48:773–777. https://doi.org/10.1007/s15010-020-01424-5 Thomas Aretz H (1987) Myocarditis: the dallas criteria. Hum Pathol 18:619–624. https://doi.org/10.1016/S0046-8177(87)80363-5 Halushka MK, Vander RS (2020) Myocarditis is rare in COVID-19 autopsies: cardiovascular findings across 277 postmortem examinations. Cardiovasc Pathol. https://doi.org/10.1016/j.carpath.2020.107300 Walsh C, Tafforeau P, Wagner W et al (2021) Hierarchical phase-contrast tomography bridges the gap between intact human organ and cellular scale imaging. bioRxiv. https://doi.org/10.1101/2022.07.02.498430 Liu F, Han K, Blair R et al (2021) SARS-CoV-2 infects endothelial cells In vivo and in vitro. Front Cell Infect Microbiol 11:1–13. https://doi.org/10.3389/fcimb.2021.701278 Chen P, Simons M (2016) When endothelial cells go rogue. EMBO Mol Med 8:1–2. https://doi.org/10.15252/emmm.201505943 Potenta S, Zeisberg E, Kalluri R (2008) The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer 99:1375–1379. https://doi.org/10.1038/sj.bjc.6604662 Yakupova EI, Maleev GV, Krivtsov AV, Plotnikov EY (2022) Macrophage polarization in hypoxia and ischemia/reperfusion: insights into the role of energetic metabolism. Exp Biol Med. https://doi.org/10.1177/15353702221080130 Shahid F, Lip GYH, Shantsila E (2018) Role of monocytes in heart failure and atrial fibrillation. J Am Heart Assoc 7:1–17. https://doi.org/10.1161/JAHA.117.007849 Fraccarollo D, Neuser J, Möller J et al (2021) Expansion of cd10neg neutrophils and cd14+ hla-drneg/low monocytes driving proinflammatory responses in patients with acute myocardial infarction. Elife 10:e66808 Kawaguchi M, Takahashi M, Hata T et al (2011) Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123:594–604. https://doi.org/10.1161/CIRCULATIONAHA.110.982777 Bröcker V, Länger F, Fellous TG et al (2006) Fibroblasts of recipient origin contribute to bronchiolitis obliterans in human lung transplants. Am J Respir Crit Care Med 173:1276–1282. https://doi.org/10.1164/rccm.200509-1381OC Shantsila E, Watson T, Lip GYH (2007) Endothelial progenitor cells in cardiovascular disorders. J Am Coll Cardiol 49:741–752. https://doi.org/10.1016/j.jacc.2006.09.050 Merad M, Martin JC (2020) Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 20:355–362. https://doi.org/10.1038/s41577-020-0331-4 Ackermann M, Stark H, Neubert L et al (2020) Morphomolecular motifs of pulmonary neoangiogenesis in interstitial lung diseases. Eur Respir J. https://doi.org/10.1183/13993003.00933-2019 Mentzer SJ, Konerding MA (2014) Intussusceptive angiogenesis: expansion and remodeling of microvascular networks. Angiogenesis 17:499–509. https://doi.org/10.1007/s10456-014-9428-3 Napoli C, Ignarro LJ (2009) Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Arch Pharm Res 32:1103–1108. https://doi.org/10.1007/s12272-009-1801-1 Ackermann M, Tsuda A, Secomb TW et al (2013) Intussusceptive remodeling of vascular branch angles in chemically-induced murine colitis. Microvasc Res 87:75–82. https://doi.org/10.1016/j.mvr.2013.02.002 Pandita A, Ekstrand M, Bjursten S et al (2021) Intussusceptive angiogenesis in human metastatic malignant melanoma. Am J Pathol 191:2023–2038. https://doi.org/10.1016/j.ajpath.2021.07.009 Ackermann M, Wagner WL, Rellecke P et al (2020) Parvovirus B19-induced angiogenesis in fulminant myocarditis. Eur Heart J 41:1309. https://doi.org/10.1093/eurheartj/ehaa092 Schmaier AA, Pajares Hurtado GM, Manickas-Hill ZJ et al (2021) Tie2 activation protects against prothrombotic endothelial dysfunction in COVID-19. JCI Insight. https://doi.org/10.1172/jci.insight.151527 Dimova I, Karthik S, Makanya A et al (2019) SDF-1/CXCR4 signalling is involved in blood vessel growth and remodelling by intussusception. J Cell Mol Med 23:3916–3926. https://doi.org/10.1111/jcmm.14269 Chamoto K, Gibney BC, Lee GS et al (2013) Migration of CD11b+ accessory cells during murine lung regeneration. Stem Cell Res 10:267–277. https://doi.org/10.1016/j.scr.2012.12.006 Peled A, Grabovsky V, Habler L et al (1999) The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow. J Clin Invest 104:1199–1211. https://doi.org/10.1172/JCI7615 Thomas M, Augustin HG (2009) The role of the angiopoietins in vascular morphogenesis. Angiogenesis 12:125–137. https://doi.org/10.1007/s10456-009-9147-3 Penn MS (2009) Editorial: Importance of the SDF-1: CXCR4 axis in myocardial repair. Circ Res 104:1133–1135. https://doi.org/10.1161/CIRCRESAHA.109.198929 Zisa D, Shabbir A, Mastri M et al (2011) Intramuscular VEGF activates an SDF1-dependent progenitor cell cascade and an SDF1-independent muscle paracrine cascade for cardiac repair. Am J Physiol - Hear Circ Physiol 301:2422–2432. https://doi.org/10.1152/ajpheart.00343.2011 Zuern CS, Walker B, Sauter M et al (2015) Endomyocardial expression of SDF-1 predicts mortality in patients with suspected myocarditis. Clin Res Cardiol 104:1033–1043. https://doi.org/10.1007/s00392-015-0871-y
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Angiogenesis

Tập 26

233-248

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