key: cord-1031137-t6dxlkbq authors: Van Linthout, Sophie; Klingel, Karin; Tschöpe, Carsten title: SARS‐CoV2‐related myocarditis‐like syndroms: Shakespeare´s question: What´s in a name? date: 2020-05-19 journal: Eur J Heart Fail DOI: 10.1002/ejhf.1899 sha: 03de2efca9626ef64af9042923bfeed86de6e610 doc_id: 1031137 cord_uid: t6dxlkbq nan The current pandemic coronavirus disease 2019 (COVID-19) is primary a respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological data from China show that approximately 20% of COVID-19 patients have concomitant established cardiovascular diseases and are more likely to develop lifethreatening complications in the course of infection 1 . In some cases, the development of myocarditis, a cardiac disorder characterized by inflammatory cell infiltration of the heart and greater risk of deterioration of cardiac function 2 , has been clinically suggested. However, endomyocardial biopsy (EMB) analysis as the gold standard diagnostic tool to verify the clinical diagnosis 3 and to understand the underlying pathomechanisms at the cellular level, had rarely been used. To the best of our knowledge, only 11 single cases, including the case of Tavazzi et al. 4 have been reported so far of probable SARS-CoV2-associated myocarditis [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] (Table 1 ). In most of the cases, a SARS-CoV2-related myocarditis was clinically suspected based on cardiac biomarkers, combined with echocardiography and ECG, and in 5 cases combined with magnetic resonance imaging findings. One group also provided a case in the absence of any clinical symptoms or cardiac functional limitations 12 . In a post-mortem examination, endothelial inflammation was found in a patient with suspected myocarditis 14 . In the same case series, global endotheliitis was associated with viral inclusion structures in endothelial cells in severe COVID-19-diseased patients. This indicates that the findings and definitions are not completely consistent and that several clinical-based "myocarditis-like syndromes" are described. Thus, in most of these reports, no pathophysiological confirmation of the suspected diagnosis occurred. Only in one report, EMB analysis was performed, describing a mild lymphocytic myocarditis in the absence of myocardial SARS-CoV2 RNA presence 9 . In the previous issue of the Journal, Tavazzi et al. 4 provide the first case of EMB-proven localization of viral particles in the heart with morphology and size typical of SARS-CoV2 in a COVID-19 patient presenting with cardiogenic shock. Viral particles are observed in interstitial macrophages and their surroundings, but not in cardiomyocytes or endothelial Accepted Article This article is protected by copyright. All rights reserved. cells, excluding the direct damage of the heart due to virus replication. In contrast to the clinical presentation suggestive for severe and necrotizing acute myocarditis, only low-grade myocardial inflammation and absence of myocyte necrosis was observed. This is in agreement with Xu et al. who also only found low-grade inflammatory responses in cardiac autopsy species of a COVID-19 patient with acute respiratory distress syndrome 15 . Furthermore, cardiac myocytes showed only non-specific features such as myofibrillar lysis, and no signs of myocyte hypertrophy. There were no indications of vasculitis or thrombosis and fibrosis was mainly perivascular. This case report is of important value since it demonstrates for the first time the cardiac presence of SARS-CoV2 in a COVID-19 patient with cardiogenic shock. Despite the tropism of SARS-CoV2 for ACE2, which is expressed by cardiomyocytes, fibroblasts, endothelial cells and particularly by pericytes 16 , viral particles were interestingly not found in these cells, but in macrophages, which may have reached the heart during transient viremia or by migration e.g. from the infected lung. The cellular serine proteases TMPRSS2, which is coexpressed on lung cells expressing ACE2, and essential for viral entry 17 , is not co-expressed in cardiomyocytes, pericytes and fibroblasts 18 , suggesting also its relevance for viral uptake in cardiac cells, without excluding the potential need of other co-receptors like cathepsin B and L, for spike protein priming. Though, the absence of viral particles in cardiomyocytes, pericytes and fibroblasts seen in this patient may not be generalized, not knowing the cardiac (cellular)-specific expression levels of ACE2 in this patient, the clinical history of this patient -ACE2 is increased in heart failure patients 19 , -and the SARS-CoV2 viral load in the heart or other organs (lung). Investigations in model systems are needed to assess correlations between ACE2 and co-receptor expression and viral uptake in specific cardiac cells and to evaluate whether SARS-CoV2 can damage cardiac cells dependent or independent of virus replication in the myocardium. This article is protected by copyright. All rights reserved. nasopharyngeal swab, and in EMB in combination with immunohistological analysis of EMB according to ESC guidelines 3 and biomarker analysis. In COVID-19 patients without any signs of cardiovascular involvement, SARS-CoV2 copy numbers in nasopharyngeal swab and the collection of plasma/serum for potential subsequent (antibody) analyses are needed, not to rule out the potential occurrence of myocarditis due to a SARS-CoV2-triggered autoantibody production, which might take place 3-4 weeks post infection. In conclusion, this case reports for the first time cardiac presence of SARS-CoV2 in a COVID-19 patient with cardiogenic shock mimicking fulminant myocarditis. Many questions about COVID-19-related heart disease remain unanswered, calling for profound COVID19 patient characterization and model systems, stressing also basic virology studies enabling to study the pathogenesis of multifaced SARS-CoV2-related heart disease and to differentiate cardiac inflammatory-like pathologies triggered by SARS-CoV2 (Figure 1) This article is protected by copyright. All rights reserved. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Potential Effects of Coronaviruses on the Cardiovascular System: A Review European Society of Cardiology Working Group on M and Pericardial D. 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