TRIM18 is a critical regulator of viral myocarditis and organ inflammation.

BACKGROUND: Infections by viruses including severe acute respiratory syndrome coronavirus 2 could cause organ inflammations such as myocarditis, pneumonia and encephalitis. Innate immunity to viral nucleic acids mediates antiviral immunity as well as inflammatory organ injury. However, the innate immune mechanisms that control viral induced organ inflammations are unclear. METHODS: To understand the role of the E3 ligase TRIM18 in controlling viral myocarditis and organ inflammation, wild-type and Trim18 knockout mice were infected with coxsackievirus B3 for inducing viral myocarditis, influenza A virus PR8 strain and human adenovirus for inducing viral pneumonia, and herpes simplex virus type I for inducing herpes simplex encephalitis. Mice survivals were monitored, and heart, lung and brain were harvested for histology and immunohistochemistry analysis. Real-time PCR, co-immunoprecipitation, immunoblot, enzyme-linked immunosorbent assay, luciferase assay, flow cytometry, over-expression and knockdown techniques were used to understand the molecular mechanisms of TRIM18 in regulating type I interferon (IFN) production after virus infection in this study. RESULTS: We find that knockdown or deletion of TRIM18 in human or mouse macrophages enhances production of type I IFN in response to double strand (ds) RNA and dsDNA or RNA and DNA virus infection. Importantly, deletion of TRIM18 protects mice from viral myocarditis, viral pneumonia, and herpes simplex encephalitis due to enhanced type I IFN production in vivo. Mechanistically, we show that TRIM18 recruits protein phosphatase 1A (PPM1A) to dephosphorylate TANK binding kinase 1 (TBK1), which inactivates TBK1 to block TBK1 from interacting with its upstream adaptors, mitochondrial antiviral signaling (MAVS) and stimulator of interferon genes (STING), thereby dampening antiviral signaling during viral infections. Moreover, TRIM18 stabilizes PPM1A by inducing K63-linked ubiquitination of PPM1A. CONCLUSIONS: Our results indicate that TRIM18 serves as a negative regulator of viral myocarditis, lung inflammation and brain damage by downregulating innate immune activation induced by both RNA and DNA viruses. Our data reveal that TRIM18 is a critical regulator of innate immunity in viral induced diseases, thereby identifying a potential therapeutic target for treatment.

The Spontaneous Course of Human Herpesvirus 6 DNA-Associated Myocarditis and the Effect of Immunosuppressive Intervention.

INTRODUCTION: This study investigated the spontaneous clinical course of patients with endomyocardial biopsy (EMB)-proven lymphocytic myocarditis and cardiac human herpesvirus 6 (HHV6) DNA presence, and the effectiveness of steroid-based intervention in HHV6-positive patients. RESULTS: 756 heart failure (HF) patients underwent an EMB procedure to determine the underlying cause of unexplained HF. Low levels of HHV6 DNA, detectable by nested PCR only, were found in 10.4% of the cases (n = 79) of which 62% (n = 49) showed myocardial inflammation. The spontaneous course of patients with EMB-proven HHV6 DNA-associated lymphocytic myocarditis (n = 26) showed significant improvements in the left ventricular ejection fraction (LVEF) and clinical symptoms, respectively, in 15/26 (60%) patients, 3-12 months after disease onset. EMB mRNA expression of components of the NLRP3 inflammasome pathway and protein analysis of cardiac remodeling markers, analyzed by real-time PCR and MALDI mass spectrometry, respectively, did not differ between HHV6-positive and -negative patients. In another cohort of patients with ongoing symptoms related to lymphocytic myocarditis associated with cardiac levels of HHV6-DNA copy numbers <500 copies/µg cardiac DNA, quantified by real-time PCR, the efficacy and safety of steroid-based immunosuppression for six months was investigated. Steroid-based immunosuppression improved the LVEF (≥5%) in 8/10 patients and reduced cardiac inflammation in 7/10 patients, without an increase in cardiac HHV6 DNA levels in follow-up EMBs. CONCLUSION: Low HHV6 DNA levels are frequently detected in the myocardium, independent of inflammation. In patients with lymphocytic myocarditis with low levels of HHV6 DNA, the spontaneous clinical improvement is nearby 60%. In selected symptomatic patients with cardiac HHV6 DNA copy numbers less than 500 copies/µg cardiac DNA and without signs of an active systemic HHV6 infection, steroid-based therapy was found to be effective and safe. This finding needs to be further confirmed in large, randomized trials.

The mechanism underlying extrapulmonary complications of the coronavirus disease 2019 and its therapeutic implication.

The coronavirus disease 2019 (COVID-19) is a highly transmissible disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that poses a major threat to global public health. Although COVID-19 primarily affects the respiratory system, causing severe pneumonia and acute respiratory distress syndrome in severe cases, it can also result in multiple extrapulmonary complications. The pathogenesis of extrapulmonary damage in patients with COVID-19 is probably multifactorial, involving both the direct effects of SARS-CoV-2 and the indirect mechanisms associated with the host inflammatory response. Recognition of features and pathogenesis of extrapulmonary complications has clinical implications for identifying disease progression and designing therapeutic strategies. This review provides an overview of the extrapulmonary complications of COVID-19 from immunological and pathophysiologic perspectives and focuses on the pathogenesis and potential therapeutic targets for the management of COVID-19.

Morphologically, immunohistochemically and PCR proven lymphocytic viral peri-, endo-, myocarditis in patients with fatal COVID-19.

BACKGROUND: Despite a reported cardiac injury in patients with new coronavirus infection, the possibility and specifics of genuine viral myocarditis in COVID-19 remains not fully clear. PURPOSE: To study the presence of SARS-CoV-2 in the myocardium and the morphological properties of myocarditis in patients with severe coronavirus infection (COVID-19). METHODS: Autopsy data of eight elderly patients (75.6 ± 7.4 years), four male and four female, with severe new coronavirus infection were studied. The lifetime diagnosis of COVID-19 is based on a positive result of the PCR study. The inclusion criterion was the presence of morphological signs of myocarditis according to the Dallas criteria. A standard histological examination included staining by hematoxylin and eosin, toluidin blue and Van Gieson. An immunohistochemical study was performed using antibodies to CD3, CD 68, CD20, perforin, toll-like receptor (TLR) types 4 and 9. PCR in real-time was performed to determine the viral RNA in the myocardium. RESULTS: All patients had severe bilateral viral pneumonia. In all cases, myocarditis was not clinically diagnosed. Morphological examination of the heart found signs of active lymphocytic myocarditis. PCR identified the SARS-Cov2 RNA in all cases. There were also signs of destructive coronaritis in all cases, thrombovasculitis, lymphocytic pericarditis (in 3 cases) and endocarditis (in 2 cases). The absence of neutrophils confirms the aseptic nature of inflammation. An immunohistochemical study showed the CD3-positive T lymphocytes in the infiltrates. Increased expression of TLR type 4 and less 9 was also detected. CONCLUSION: Morphological and immunohistochemical evidence of myocarditis in COVID-19 was presented. Lymphocytic infiltrations and positive PCR confirm the viral nature of inflammation. Myocarditis in COVID-19 is also characterized by coronaritis with microvascular thrombosis and associated with lymphocytic endo- and pericarditis.

Activation of Immune System May Cause Pathophysiological Changes in the Myocardium of SARS-CoV-2 Infected Monkey Model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is an extremely contagious disease whereby the virus damages the host's respiratory tract via entering through the ACE2 receptor. Cardiovascular disorder is being recognized in the majority of COVID-19 patients; yet, the relationship between SARS-CoV-2 and heart failure has not been established. In the present study, SARS-CoV-2 infection was induced in the monkey model. Thereafter, heart tissue samples were collected, and pathological changes were analyzed in the left ventricular tissue by hematoxylin and eosin, trichrome, and immunohistochemical staining specific to T lymphocytes and macrophages. The findings revealed that SARS-CoV-2 infection induces several pathological changes in the heart, which cause cardiomyocyte disarray, mononuclear infiltrates of inflammatory cells, and hypertrophy. Furthermore, collagen-specific staining showed the development of cardiac fibrosis in the interstitial and perivascular regions in the hearts of infected primates. Moreover, the myocardial tissue samples displayed multiple foci of inflammatory cells positive for T lymphocytes and macrophages within the myocardium. These findings suggest the progression of the disease, which can lead to the development of severe complications, including heart failure. Additionally, SARS-CoV-2 antigen staining detected the presence of virus particles in the myocardium. Thus, we found that SARS-CoV-2 infection is characterized by an exaggerated inflammatory immune response in the heart, which possibly contributes to myocardial remodeling and subsequent fibrosis.

Sex-Specific Effects of Plastic Caging in Murine Viral Myocarditis.

BACKGROUND: Myocarditis is an inflammatory heart disease caused by viral infections that can lead to heart failure, and occurs more often in men than women. Since animal studies have shown that myocarditis is influenced by sex hormones, we hypothesized that endocrine disruptors, which interfere with natural hormones, may play a role in the progression of the disease. The human population is exposed to the endocrine disruptor bisphenol A (BPA) from plastics, such as water bottles and plastic food containers. METHODS: Male and female adult BALB/c mice were housed in plastic versus glass caging, or exposed to BPA in drinking water versus control water. Myocarditis was induced with coxsackievirus B3 on day 0, and the endpoints were assessed on day 10 post infection. RESULTS: We found that male BALB/c mice that were exposed to plastic caging had increased myocarditis due to complement activation and elevated numbers of macrophages and neutrophils, whereas females had elevated mast cell activation and fibrosis. CONCLUSIONS: These findings show that housing mice in traditional plastic caging increases viral myocarditis in males and females, but using sex-specific immune mechanisms.

3D virtual histopathology of cardiac tissue from Covid-19 patients based on phase-contrast X-ray tomography.

For the first time, we have used phase-contrast X-ray tomography to characterize the three-dimensional (3d) structure of cardiac tissue from patients who succumbed to Covid-19. By extending conventional histopathological examination by a third dimension, the delicate pathological changes of the vascular system of severe Covid-19 progressions can be analyzed, fully quantified and compared to other types of viral myocarditis and controls. To this end, cardiac samples with a cross-section of 3.5mm were scanned at a laboratory setup as well as at a parallel beam setup at a synchrotron radiation facility the synchrotron in a parallel beam configuration. The vascular network was segmented by a deep learning architecture suitable for 3d datasets (V-net), trained by sparse manual annotations. Pathological alterations of vessels, concerning the variation of diameters and the amount of small holes, were observed, indicative of elevated occurrence of intussusceptive angiogenesis, also confirmed by high-resolution cone beam X-ray tomography and scanning electron microscopy. Furthermore, we implemented a fully automated analysis of the tissue structure in the form of shape measures based on the structure tensor. The corresponding distributions show that the histopathology of Covid-19 differs from both influenza and typical coxsackie virus myocarditis.

Evidence of SARS-CoV-2-Specific T-Cell-Mediated Myocarditis in a MIS-A Case.

A 26-year-old otherwise healthy man died of fulminant myocarditis. Nasopharyngeal specimens collected premortem tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Histopathological evaluation of the heart showed myocardial necrosis surrounded by cytotoxic T-cells and tissue-repair macrophages. Myocardial T-cell receptor (TCR) sequencing revealed hyper-dominant clones with highly similar sequences to TCRs that are specific for SARS-CoV-2 epitopes. SARS-CoV-2 RNA was detected in the gut, supporting a diagnosis of multisystem inflammatory syndrome in adults (MIS-A). Molecular targets of MIS-associated inflammation are not known. Our data indicate that SARS-CoV-2 antigens selected high-frequency T-cell clones that mediated fatal myocarditis.

Spectrum of Viral Pathogens Identified in Children with Clinical Myocarditis (Pre-Coronavirus Disease-2019, 2000-2018): Etiologic Agent Versus Innocent Bystander.

OBJECTIVE: To identify the etiologies of viral myocarditis in children in the pre-coronavirus disease 2019 era. STUDY DESIGN: This was a retrospective review of all patients (age <18 years) diagnosed with myocarditis and hospitalized at Rady Children's Hospital San Diego between 2000 and 2018. RESULTS: Twenty-nine patients met inclusion criteria. Of 28 (97%) patients who underwent testing for viruses, polymerase chain reaction was used in 24 of 28 (86% of cases), and 16 of 24 (67%) detected a virus. Pathogens were rhinovirus (6), influenza A/B (4), respiratory syncytial virus (RSV) (3), coronavirus (3), parvovirus B19 (2), adenovirus (2), and coxsackie B5 virus, enterovirus, and parainfluenza virus type 2 in one case each. Six (21%) patients had no pathogen detected but imaging and other laboratory test results were compatible with myocarditis. Age 0-2 years was associated with RSV, influenza A/B, coronavirus, and enteroviruses (P < .001). Twenty-one patients (72%) experienced full clinical recovery. Three patients (10%) required venoarterial extracorporeal membrane oxygenation (VA-ECMO), and all 3 recovered. Three others (10%) required and underwent successful cardiac transplantation without complications. Two patients (7%) died 9-10 days after hospitalization (1 had RSV and 1 had influenza A/B). Two other patients presented with complete atrioventricular block; 1 case (rhinovirus) resolved spontaneously, and 1 (coronavirus) resolved after support with VA-ECMO. Age <2 years, female sex, lower ejection fraction at admission, and greater initial and peak levels of brain natriuretic peptide were significant predictors of critical outcomes (use of VA-ECMO, listing for cardiac transplantation, and death). CONCLUSIONS: Viral nucleic acid-based testing revealed a wider spectrum of viruses that could be associated with myocarditis in children than previously reported and traditionally anticipated. A predilection of certain pathogens in the very young patients was observed. Whether the observed range of viral agents reflects an undercurrent of change in viral etiology or viral detection methods is unclear, but the wider spectrum of viral pathogens found underscores the usefulness of polymerase chain reaction testing to explore possible viral etiologies of myocarditis in children.

Taming the Storm in the Heart: Exploring Different Therapeutic Choices Against Myocardial Inflammation in COVID-19.

Mechanism of cardiac injury in COVID-19 is a serious problem and plays critical role in mediating the severity of the disease. However, the mechanistic insights of the induction of the inflammatory signal leading to cardiac injury was poorly understood. However, few recent studies have indicated the involvement of Toll-Like Receptors (TLRs) as the major 'culprit' behind eliciting the initial signal of 'cytokine storm'. As a result, TLRs are now considered as the therapeutic targets to develop efficacious therapeutics. Herein, we present an overall summary on the mechanistic insight of cardiac injury in COVID-19 patients and the therapeutic promises of TLR-targeted therapies.

COVID-19 associated myocarditis: A systematic review.

BACKGROUND: Most COVID-19 infections result in a viral syndrome characterized by fever, cough, shortness of breath, and myalgias. A small but significant proportion of patients develop severe COVID-19 resulting in respiratory failure. Many of these patients also develop multi-organ dysfunction as a byproduct of their critical illness. Although heart failure can be a part of this, there also appears to be a subset of patients who have primary cardiac collapse from COVID-19. OBJECTIVE: Conduct a systematic review of COVID-19-associated myocarditis, including clinical presentation, risk factors, and prognosis. DISCUSSION: Our review demonstrates two distinct etiologies of primary acute heart failure in surprisingly equal incidence in patients with COVID-19: viral myocarditis and Takotsubo cardiomyopathy. COVID myocarditis, Takotsubo cardiomyopathy, and severe COVID-19 can be clinically indistinguishable. All can present with dyspnea and evidence of cardiac injury, although in myocarditis and Takotsubo this is due to primary cardiac dysfunction as compared to respiratory failure in severe COVID-19. CONCLUSION: COVID-19-associated myocarditis differs from COVID-19 respiratory failure by an early shock state. However, not all heart failure from COVID-19 is from direct viral infection; some patient's develop takotsubo cardiomyopathy. Regardless of etiology, steroids may be a beneficial treatment, similar to other critically ill COVID-19 patients. Evidence of cardiac injury in the form of ECG changes or elevated troponin in patients with COVID-19 should prompt providers to consider concurrent myocarditis.

Cardiovascular consequences of viral infections: from COVID to other viral diseases.

Infection of the heart muscle with cardiotropic viruses is one of the major aetiologies of myocarditis and acute and chronic inflammatory cardiomyopathy (DCMi). However, viral myocarditis and subsequent dilated cardiomyopathy is still a challenging disease to diagnose and to treat and is therefore a significant public health issue globally. Advances in clinical examination and thorough molecular genetic analysis of intramyocardial viruses and their activation status have incrementally improved our understanding of molecular pathogenesis and pathophysiology of viral infections of the heart muscle. To date, several cardiotropic viruses have been implicated as causes of myocarditis and DCMi. These include, among others, classical cardiotropic enteroviruses (Coxsackieviruses B), the most commonly detected parvovirus B19, and human herpes virus 6. A newcomer is the respiratory virus that has triggered the worst pandemic in a century, SARS-CoV-2, whose involvement and impact in viral cardiovascular disease is under scrutiny. Despite extensive research into the pathomechanisms of viral infections of the cardiovascular system, our knowledge regarding their treatment and management is still incomplete. Accordingly, in this review, we aim to explore and summarize the current knowledge and available evidence on viral infections of the heart. We focus on diagnostics, clinical relevance and cardiovascular consequences, pathophysiology, and current and novel treatment strategies.

Association Between COVID-19 and Myocarditis Using Hospital-Based Administrative Data - United States, March 2020-January 2021.

Viral infections are a common cause of myocarditis, an inflammation of the heart muscle (myocardium) that can result in hospitalization, heart failure, and sudden death (1). Emerging data suggest an association between COVID-19 and myocarditis (2-5). CDC assessed this association using a large, U.S. hospital-based administrative database of health care encounters from >900 hospitals. Myocarditis inpatient encounters were 42.3% higher in 2020 than in 2019. During March 2020-January 2021, the period that coincided with the COVID-19 pandemic, the risk for myocarditis was 0.146% among patients diagnosed with COVID-19 during an inpatient or hospital-based outpatient encounter and 0.009% among patients who were not diagnosed with COVID-19. After adjusting for patient and hospital characteristics, patients with COVID-19 during March 2020-January 2021 had, on average, 15.7 times the risk for myocarditis compared with those without COVID-19 (95% confidence interval [CI] = 14.1-17.2); by age, risk ratios ranged from approximately 7.0 for patients aged 16-39 years to >30.0 for patients aged <16 years or ≥75 years. Overall, myocarditis was uncommon among persons with and without COVID-19; however, COVID-19 was significantly associated with an increased risk for myocarditis, with risk varying by age group. These findings underscore the importance of implementing evidence-based COVID-19 prevention strategies, including vaccination, to reduce the public health impact of COVID-19 and its associated complications.

Echocardiographic characteristics of patients with SARS-CoV-2 infection.

BACKGROUND: Myocardial involvement induced by SARS-CoV-2 infection might be important for long-term prognosis. The aim of this observational study was to characterize the myocardial effects during SARS-CoV-2 infections by echocardiography. RESULTS AND METHODS: An extended echocardiographic image acquisition protocol was performed in 18 patients with SARS-CoV-2 infection assessing LV longitudinal, radial, and circumferential deformation including rotation, twist, and untwisting. Furthermore, LV deformation was analyzed in an age-matched control group of healthy individuals (n = 20). The most prevalent finding was a reduced longitudinal strain observed predominantly in more than one basal LV segment (n = 10/14 patients, 71%). This pattern reminded of a "reverse tako-tsubo" morphology that is not typical for other viral myocarditis. Additional findings included a biphasic pattern with maximum post-systolic or negative regional radial strain predominantly basal (n = 5/14 patients, 36%); the absence or dispersion of basal LV rotation (n = 6/14 patients, 43%); a reduced or positive regional circumferential strain in more than one segment (n = 7/14 patients, 50%); a net rotation showing late post-systolic twist or biphasic pattern (n = 8/14 patients, 57%); a net rotation showing polyphasic pattern and/or higher maximum net values during diastole (n = 8/14 patients, 57%). CONCLUSION: Myocardial involvement due to SARS-CoV-2-infection was highly prevalent in the present cohort-even in patients with mild symptoms. It appears to be characterized by specific speckle tracking deformation abnormalities in the basal LV segments. These data set the stage to prospectively test whether these parameters are helpful for risk stratification and for the long-term follow-up of these patients.

Clinical and cardiac magnetic resonance findings in post-COVID patients referred for suspected myocarditis.

OBJECTIVES: We assessed possible myocardial involvement in previously cardiac healthy post-COVID patients referred for persisting symptoms with suspected myocarditis. BACKGROUND: Prior studies suggested myocardial inflammation in patients with coronavirus-induced disease 2019 (COVID-19). However, the prevalence of cardiac involvement among COVID patients varied between 1.4 and 78%. METHODS: A total of 56 post-COVID patients without previous heart diseases were included consecutively into this study. All patients had positive antibody titers against SARS-CoV-2. Patients were referred for persistent symptoms such as chest pain/discomfort, shortness of breath, or intolerance to activity. All patients underwent standardized cardiac assessment including electrocardiogram (ECG), cardiac biomarkers, echocardiography, and cardiac magnetic resonance (CMR). RESULTS: 56 Patients (46 ± 12 years, 54% females) presented 71 ± 66 days after their COVID-19 disease. In most patients, the course of COVID-19 was mild, with hospital treatment being necessary in five (9%). At presentation, patients most often reported persistent fatigue (75%), chest pain (71%), and shortness of breath (66%). Acute myocarditis was confirmed by T1/T2-weighed CMR and elevated NTpro-BNP levels in a single patient (2%). Left ventricular ejection fraction was 56% in this patient. Additional eight patients (14%) showed suspicious CMR findings, including myocardial edema without fibrosis (n = 3), or non-ischemic myocardial injury suggesting previous inflammation (n = 5). However, myocarditis could ultimately not be confirmed according to 2018 Lake Louise criteria; ECG, echo and lab findings were inconspicuous in all eight patients. CONCLUSIONS: Among 56 post-COVID patients with persistent thoracic complaints final diagnosis of myocarditis could be confirmed in a single patient using CMR.

Longitudinally Extensive Transverse Myelitis (LETM) and Myopericarditis in a 7-Month-Old Child with SARs-CoV-2 Infection.

INTRODUCTION: In the last few months, some pediatric cases with neurological and neuroradiological pictures related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been reported, often associated with multisystem inflammatory syndrome (MIS-C). The most frequently encountered pediatric neurological complications seem to be postinfectious immune-mediated acute disseminated encephalomyelitis (ADEM)-like changes of the brain, myelitis, neural enhancement, and splenial lesions. Concomitant neurological and cardiac involvement has been reported only in MIS-C, although specific clinical details are often not fully available. METHODS: In this case report, a very young child infected with SARs-CoV-2 and diagnosed as longitudinal extensive transverse myelitis with concomitant myo-pericarditis is presented. RESULTS: A previously healthy 7-month-old girl presented with abrupt onset of generalized weakness with inability to sit up. She had had mild respiratory symptoms 1 week earlier. Spinal magnetic resonance imaging (MRI) showed a T2-hyperintense intramedullary lesion extending from C4 to T2, compatible with acute longitudinally extensive transverse myelitis (LETM). Cerebrospinal fluid analysis was negative.Echocardiography and blood tests were suggestive for myo-pericarditis. Real time polymerase chain reaction for SARS-CoV-2 on nasopharyngeal swab sample tested positive. She was promptly treated with high dose of steroids and immunoglobulin with satisfactory clinical response. CONCLUSION: To the evolving literature of neurological complications of SARs-CoV-2 infection, we add the youngest patient described to date with isolated LETM and concomitant cardiac involvement. Our case suggests that clinicians should be aware of this association, although difficult to recognize in infants. Practitioners are encouraged to consider aggressive first-line immunotherapies with the final aim to prevent permanent disability.

SARS-CoV-2, myocardial injury and inflammation: insights from a large clinical and autopsy study.

OBJECTIVE: Despite growing evidence about myocardial injury in hospitalized COronaVIrus Disease 2019 (COVID-19) patients, the mechanism behind this injury is only poorly understood and little is known about its association with SARS-CoV-2-mediated myocarditis. Furthermore, definite evidence of the presence and role of SARS-CoV-2 in cardiomyocytes in the clinical scenario is still lacking. METHODS: We histologically characterized myocardial tissue of 40 patients deceased with severe SARS-CoV-2 infection during the first wave of the pandemic. Clinical data were also recorded and analyzed. In case of findings supportive of myocardial inflammation, histological analysis was complemented by RT-PCR and immunohistochemistry for SARS-CoV-2 viral antigens and in situ RNA hybridization for the detection of viral genomes. RESULTS: Both chronic and acute myocardial damage was invariably present, correlating with the age and comorbidities of our population. Myocarditis of overt entity was found in one case (2.5%). SARS-CoV-2 genome was not found in the cardiomyocytes of the patient with myocarditis, while it was focally and negligibly present in cardiomyocytes of patients with known viral persistence in the lungs and no signs of myocardial inflammation. The presence of myocardial injury was not associated with myocardial inflammatory infiltrates. CONCLUSIONS: In this autopsy cohort of COVID-19 patients, myocarditis is rarely found and not associated with SARS-CoV-2 presence in cardiomyocytes. Chronic and acute forms of myocardial damage are constantly found and correlate with the severity of COVID-19 disease and pre-existing comorbidities.

COVID-19 myocarditis: quantitative analysis of the inflammatory infiltrate and a proposed mechanism.

COVID-19 has a significant effect upon the cardiovascular system. While a number of different cardiovascular histopathologies have been described at post-mortem examination, the incidence of typical viral myocarditis in COVID-19 positive patients appears very low [1-3]. In this study, we further characterize and quantify the inflammatory cell infiltrate in a COVID-19 study cohort and compare the findings to both an age and disease matched control cohort and a cohort of patients diagnosed with typical inflammatory myocarditis. All study and control cohorts had 1 or more of the comorbidities most commonly associated with severe disease (hypertension, type II diabetes, obesity, or known cardiovascular disease). The results demonstrate a skewed distribution of the number of CD68+ cells in COVID-19 hearts, with upper quantiles showing a significant increase as compared to both matched control hearts, and those with myocarditis. In contrast, hearts from typical inflammatory myocarditis contained increased numbers of CD4+, and CD8+ cells compared to both COVID-19 and control cohorts. In conclusion, the presence of an increased number of CD68+ cells suggests that COVID-19 may incite a form of myocarditis different from typical viral myocarditis, and associated with diffusely infiltrative cells of monocytes/macrophage lineage.