The Pathogenesis of COVID-19 Myocardial Injury: An Immunohistochemical Study of Postmortem Biopsies.

Camila Hartmann,Lidia Zytynski Moura,Caroline Busatta Vaz De Paula,Lucas Baena Carstens,Anna Flavia Ribeiro Dos Santos Miggiolaro,Lucia De Noronha,Sarah Fagundes Grobe,Cristina Pellegrino Baena,Jarbas Da Silva Motta,Larissa Hermann De Souza Nunes,Gustavo Lenci Marques,Peter Libby

doi:10.3389/fimmu.2021.748417

Abstract

RationaleMyocardial injury associates significantly and independently with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 remains unclear, and cardiac involvement by SARS-CoV-2 presents a major challenge worldwide.ObjectiveThis histological and immunohistochemical study sought to clarify the pathogenesis and propose a mechanism with pathways involved in COVID-19 myocardial injury.Methods and ResultsPostmortem minimally invasive autopsies were performed in six patients who died from COVID-19, and the myocardium samples were compared to a control group (n=11). Histological analysis was performed using hematoxylin-eosin and toluidine blue staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: caspase-1, caspase-9, gasdermin-d, ICAM-1, IL-1β, IL-4, IL-6, CD163, TNF-α, TGF-β, MMP-9, type 1 and type 3 collagen. The samples were also assessed for apoptotic cells by TUNEL. Histological analysis showed severe pericardiocyte interstitial edema and higher mast cells counts per high-power field in all COVID-19 myocardium samples. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-1β, IL-6, MMP-9, TNF-α, and other markers in the hearts of COVID-19 patients. Expression of caspase-9 did not differ from the controls, while gasdermin-d expression was less. The TUNEL assay was positive in all the COVID-19 samples supporting endothelial apoptosis.ConclusionsThe pathogenesis of COVID-19 myocardial injury does not seem to relate to primary myocardiocyte involvement but to local inflammation with associated interstitial edema. We found heightened TGF-β and interstitial collagen expression in COVID-affected hearts, a potential harbinger of chronic myocardial fibrosis. These results suggest a need for continued clinical surveillance of patients for myocardial dysfunction and arrythmias after recovery from the acute phase of COVID-19.

Highlights

Since its emergence in December 2019 [1], the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to grow despite unprecedented worldwide efforts in the search of treatments and vaccines
Given that the cardiac manifestations play a major role in adverse outcomes and discordant pathological studies regarding the mechanism of myocardial injury in COVID-19, we investigated myocardium samples in a histological and immunohistochemical study to help clarify its pathogenesis in lethal cases
Our findings provide new insight into the mechanisms involved in COVID-19-related myocardial injury

Summary

Introduction

Since its emergence in December 2019 [1], the coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), continues to grow despite unprecedented worldwide efforts in the search of treatments and vaccines. COVID-19 is initially a respiratory disease, causing viral pneumonia and adult respiratory distress syndrome. Cardiovascular manifestations occur commonly and relate to poor outcomes [2]. Common cardiac complications among hospitalized patients with COVID-19 include arrhythmias and acute heart failure. Heart failure may contribute up to 40% of deaths, and circulatory failure may cause death even without respiratory failure [3]. A prothrombotic coagulopathy can occur in 25% of patients resulting in venous and arterial thromboembolic events [5]

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