Coronavirus Disease 2019 (COVID-19) Coronary Vascular Thrombosis: Correlation with Neutrophil but Not Endothelial
Justin E Johnson1, Declan McGuone2, Mina L Xu2
1Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut.
Insights
Severe coronavirus disease 2019 (COVID-19) causes heart injury and death. Autopsy studies found frequent blood clots in COVID-19 hearts, driven by neutrophil activation, not endothelial damage, suggesting new therapeutic targets for COVID-19 complications.
Area of Science:
- Cardiovascular Pathology
- Immunology
- Infectious Diseases
Background:
- Severe coronavirus disease 2019 (COVID-19) is linked to myocardial injury and mortality.
- The precise mechanisms underlying COVID-19-associated cardiac pathology remain incompletely understood.
- Previous studies have not definitively identified viral presence or myocarditis in COVID-19 hearts.
Purpose of the Study:
- To investigate the pathological mechanisms of myocardial injury in fatal COVID-19 cases.
- To compare cardiac autopsy findings in COVID-19 patients with control groups.
- To identify the cellular and molecular contributors to thrombosis in COVID-19 hearts.
Main Methods:
- Multiparameter immunofluorescence analysis of heart autopsy tissues.
- Comparison of 7 COVID-19 cases with 12 control specimens (with or without cardiovascular disease).
- Assessment of viral infection, inflammation, endothelial activation, and neutrophil activation markers.
Main Results:
- No evidence of viral infection or lymphocytic myocarditis was found in COVID-19 hearts.
- Frequent and extensive thrombosis was observed in both large and small cardiac vessels of COVID-19 patients.
- Thrombosed vessels showed preserved endothelium without signs of cytokine-mediated activation, but frequent markers of neutrophil activation, including NET formation, were present.
Conclusions:
- The increased thrombotic diathesis in COVID-19 hearts is primarily attributed to alterations in circulating neutrophils, not endothelial activation.
- Neutrophil activation and extracellular trap formation are key contributors to cardiac thrombosis in severe COVID-19.
- These findings suggest potential therapeutic strategies targeting neutrophil pathways to mitigate cardiac complications of COVID-19.
Abstract:
Severe coronavirus disease 2019 (COVID-19) increases the risk of myocardial injury that contributes to mortality. This study used multiparameter immunofluorescence to extensively examine heart autopsy tissue of 7 patients who died of COVID-19 compared to 12 control specimens, with or without cardiovascular disease. Consistent with prior reports, no evidence of viral infection or lymphocytic infiltration indicative of myocarditis was found. However, frequent and extensive thrombosis was observed in large and small vessels in the hearts of the COVID-19 cohort, findings that were infrequent in controls. The endothelial lining of thrombosed vessels typically lacked evidence of cytokine-mediated endothelial activation, assessed as nuclear expression of transcription factors p65 (RelA), pSTAT1, or pSTAT3, or evidence of inflammatory activation assessed by expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), tissue factor, or von Willebrand factor (VWF). Intimal EC lining was also generally preserved with little evidence of cell death or desquamation. In contrast, there were frequent markers of neutrophil activation within myocardial thrombi in patients with COVID-19, including neutrophil-platelet aggregates, neutrophil-rich clusters within macrothrombi, and evidence of neutrophil extracellular trap (NET) formation. These findings point to alterations in circulating neutrophils rather than in the endothelium as contributors to the increased thrombotic diathesis in the hearts of COVID-19 patients.
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