Association of Complement and MAPK Activation With SARS-CoV-2–Associated Myocardial Inflammation

Abstract

IMPORTANCE Myocardial injury is a common feature of patients with SARS-CoV-2 infection. However, the cardiac inflammatory processes associated with SARS-CoV-2 infection are not completely understood.OBJECTIVE To investigate the inflammatory cardiac phenotype associated with SARS-CoV-2 infection compared with viral myocarditis, immune-mediated myocarditis, and noninflammatory cardiomyopathy by integrating histologic, transcriptomic, and proteomic profiling.DESIGN, SETTING, AND PARTICIPANTS This case series was a cooperative study between the Ludwig Maximilian University Hospital Munich and the Cardiopathology Referral Center at the University of Tübingen in Germany. A cohort of 19 patients with suspected myocarditis was examined; of those, 5 patients were hospitalized with SARS-CoV-2 infection between March and May 2020. Cardiac tissue specimens from those 5 patients were compared with specimens from 5 patients with immune-mediated myocarditis, 4 patients with non-SARS-CoV-2 viral myocarditis, and 5 patients with noninflammatory cardiomyopathy, collected from January to August 2019. EXPOSURES Endomyocardial biopsy. MAIN OUTCOMES AND MEASURESThe inflammatory cardiac phenotypes were measured by immunohistologic analysis, RNA exome capture sequencing, and mass spectrometry-based proteomic analysis of endomyocardial biopsy specimens. RESULTS Among 19 participants, the median age was 58 years (range, 37-76 years), and 15 individuals (79%) were male. Data on race and ethnicity were not collected. The abundance of CD163+ macrophages was generally higher in the cardiac tissue of patients with myocarditis, whereas lymphocyte counts were lower in the tissue of patients with SARS-CoV-2 infection vs patients with non-SARS-CoV-2 virus-associated and immune-mediated myocarditis. Among those with SARS-CoV-2 infection, components of the complement cascade, including C1q subunits (transcriptomic analysis: 2.5-fold to 3.6-fold increase; proteomic analysis: 2.0-fold to 3.4-fold increase) and serine/cysteine proteinase inhibitor clade G member 1 (transcriptomic analysis: 1.7-fold increase; proteomic analysis: 2.6-fold increase), belonged to the most commonly upregulated transcripts and differentially abundant proteins. In cardiac macrophages, the abundance of C1q was highest in SARS-CoV-2 infection. Assessment of important signaling cascades identified an upregulation of the serine/threonine mitogen-activated protein kinase pathways.CONCLUSIONS AND RELEVANCE This case series found that the cardiac immune signature varied in inflammatory conditions with different etiologic characteristics. Future studies are needed to examine the role of these immune pathways in myocardial inflammation.

Myocarditis following COVID‐19 vaccine: incidence, presentation, diagnosis, pathophysiology, therapy, and outcomes put into perspective. A clinical consensus document supported by the Heart Failure Association of the European Society of Cardiology (ESC) and the ESC Working Group on Myocardial and Pericardial Diseases

“…Immunohistochemical staining of myocardial tissue of patients who died of SARS‐CoV infection revealed a significant amount of CD68 + macrophages, whereas infiltration by CD3 + T cells was minimal 81 . Similar observations were reported among patients with SARS‐CoV‐2 infection 77,82,83 . Whereas lymphocytic myocarditis was present in only 14% ( n = 3) of patients who died with COVID‐19, interstitial macrophage infiltration was noted in 86% ( n = 18) of cases 84 …”

“…81 Similar observations were reported among patients with SARS-CoV-2 infection. 77,82,83 Whereas lymphocytic myocarditis was present in only 14% (n = 3) of patients who died with COVID-19, interstitial macrophage infiltration was noted in 86% (n = 18) of cases. 84 Despite the fact that in electron microscopy studies SARS-CoV-2 viruses were visualized in endothelial cells, 77 cardiomyocytes 15 and macrophages 85 mostly in the early viremic phase of the infection, it is not clear whether SARS-CoV-2 can directly induce myocardial injury and, subsequently, inflammation.…”

“… 81 Similar observations were reported among patients with SARS‐CoV‐2 infection. 77 , 82 , 83 Whereas lymphocytic myocarditis was present in only 14% ( n = 3) of patients who died with COVID‐19, interstitial macrophage infiltration was noted in 86% ( n = 18) of cases. 84 …”

Systematic analysis of alternative splicing in time course data using Spycone

“…NOTCH signaling pathways are found up-regulated in the lungs of infected macaques [31]. The MAPK pathway has a pro-inflammatory effect by interacting with SARS-CoV-2 downstream pathogenesis, especially in patients suffering from cardiovascular disease [32]. TLR 7/8 cascades are related to ssRNA, and there are studies supporting the association of TLR 7/8 with SARS-CoV-2 infection [33,34].…”

Microbiological and Clinical Findings of SARS-CoV-2 Infection after 2 Years of Pandemic: From Lung to Gut Microbiota

“…Cardiovascular complications can occur in patients with heart failure or coronary artery disease. One of the most common is myocarditis that may be characterized by myocardial damage in the absence of ischemic causes and inflammatory infiltrates [ 65 , 66 ]. In almost a third of COVID-19 patients with myocardial involvement, cardiogenic shock occurred [ 67 ] with a mortality of about 26% [ 68 ].…”