Inflammation and vascular remodeling in COVID-19 hearts

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.

The D405N Mutation in the Spike Protein of SARS-CoV-2 Omicron BA.5 Inhibits Spike/Integrins Interaction and Viral Infection of Human Lung Microvascular Endothelial Cells

“…Both clinical studies and autopsy findings have also shown vascular damage and thrombotic complications in different organs, as seen in myocardial, liver, kidney, and intestinal injury [ 4 , 12 ]. Increasing clinical evidence suggests a key role of ECs in triggering and sustaining these phenomena by promoting inflammatory, angiogenic, and clotting cascades [ 40 , 41 , 42 ]. Initial dysfunction of the endothelial barrier and vascular leakage have also been considered responsible for an indirect immune-mediated mechanism of endothelial injury [ 12 , 37 ].…”

Effect of coronaviruses on blood vessel permeability: potential therapeutic targets

“… 141 , 142 This type of angiogenesis is characterized by blood vessels splitting into two lumens after forming an intraluminal septum (inside to outside growing) mainly due to microthrombi presence, and it was reported to be macrophage-dependent in COVID-19 patients. 143 , 144 In fact, enhanced circulating levels of VEGF were observed in COVID-19 patients and even correlated with disease severity. 145 Intussusceptive angiogenesis may contribute to COVID-19 abnormalities as it disturbs the regular blood flow, leading to further microthrombi formation.…”

A Post-Pandemic Enigma: The Cardiovascular Impact of Post-Acute Sequelae of SARS-CoV-2

“… 59 Histopathology from 24 confirmed SARS-CoV-2 cardiac autopsy samples compared with 16 age-matched influenza H1N1 A cardiac samples, 8 lymphocytic noninfluenza myocarditis, and 9 noninflamed heart tissues revealed that viral myocarditis was not evident in the SARs-CoV-2 samples; rather, there was a significant increase in perivascular CD11b/TIE2+ macrophages, a finding not seen in the 3 comparison groups, suggesting that cardiac involvement in SARS-CoV-2 may be predicated upon a macrophage-driven inflammatory process. 60 Additional studies suggest that the inflammatory response in acute SARS-CoV-2 infection provokes AutoAb (autoantibody) production targeting cardiac antigens. In one study of 104 patients hospitalized with COVID-19, 68% (71) had anticardiac autoAbs: 39% had anticardiac IgG autoAbs, 51% had anticardiac IgM autoAbs, and 22% had both.…”