Clinically Suspected and Biopsy-Proven Myocarditis Temporally Associated with SARS-CoV-2 Infection.

We review current data on clinically suspected [European Society of Cardiology (ESC) 2013 criteria] and biopsy-proven [ESC and World Health Organization (WHO) criteria] myocarditis that is temporally associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ESC/WHO etiological diagnosis of viral myocarditis is based on histological and immunohistological evidence of nonischemic myocyte necrosis and monolymphocytic infiltration, i.e., myocarditis, plus the identification of a specific cardiotropic virus by molecular techniques, in particular polymerase chain reaction (PCR)/in-situ hybridization, on endomyocardial biopsy (EMB)/autopsy tissue. There is not yet definitive EMB/autopsy proof that SARS-CoV-2 causes direct cardiomyocyte damage in association with histological myocarditis. Clinical epidemiology data suggest that myocarditis is uncommon for both SARS-CoV-2-positive and -negative PCR cases. We hypothesize that the rare virus-negative biopsy-proven cases may represent new-onset immune-mediated or latent pre-existing autoimmune forms,triggered or fostered by the hyperinflammatory state of severe COVID-19. We recommend the application of the ESC/WHO definitions and diagnostic criteria in future reports to avoid low-quality scientific information leading to an inaccurate estimate of myocarditis incidence based on misdiagnosis.

Management of myocarditis in clinical practice.

Myocarditis is an inflammatory heart muscle disease characterized by heterogeneous clinical presentation and outcome. Clinical heterogeneity of myocarditis, ranging from acute onset chest pain with electrocardiographic changes resembling an acute coronary syndrome, to arrhythmic storm and chronic decompensated heart failure, makes diagnosis challenging. However, a correct diagnosis is fundamental to proper patients' management and should always be seeked. Although a definite diagnosis is only provided by endomyocardial biopsy, the European Society of Cardiology task force on myocardial and pericardial diseases provided specific criteria for the diagnosis of clinically suspected myocarditis, which has been facilitated by the advent of noninvasive imaging tests (i.e. cardiovascular magnetic resonance based myocardial tissue characterization). Due to the heterogeneous presentation and disease course of myocarditis, a tailored treatment would be the best strategy, but a standardized management is still not available. However, over the years, new, promising therapies, such as antiviral and immune-suppressive treatment, have come side by side to the standard pharmacological heart treatment, i.e. antiheart failure medications. In this paper we will review the basic principles of myocarditis management in clinical practice, including diagnostic work-up, conventional and disease-specific therapy and patients' follow-up.

Recurrent autoimmune myocarditis in a young woman during the coronavirus disease 2019 pandemic.

We report a unique case of a young woman with recurrent immune-mediated (virus-negative) lymphocytic fulminant myocarditis during the coronavirus disease 2019 pandemic. At the first endomyocardial biopsy (EMB)-proven episode, she had concomitant pneumonia, and a temporary biventricular assist device implant was followed by complete and long-lasting cardiac recovery. Five years later, she was re-admitted for relapsing cardiogenic shock with a recent history of pneumonia. She was treated with extracorporeal life support with apical venting for left ventricular unloading, and full recovery was achieved. Despite negative seriate nasopharyngeal swabs and EMB during hospitalization, an antibody positivity for severe acute respiratory syndrome coronavirus 2 was discovered after 4 weeks from discharge. This is the first report of an EMB-proven, immune-mediated (virus-negative) recurrence of fulminant myocarditis. We hypothesize that in patients with a predisposing immunogenetic background, autoimmune disease may be triggered or reactivated by major infections, for example, pneumonia, that may act as adjuvants leading to an immune-mediated hyper-response.

Clinically Suspected Myocarditis in the Course of Severe Acute Respiratory Syndrome Novel Coronavirus-2 Infection: Fact or Fiction?

Cardiac complications, including clinically suspected myocarditis, have been described in novel coronavirus disease 2019. Here, we review current data on suspected myocarditis in the course of severe acute respiratory syndrome novel coronavirus-2 (SARS-CoV-2) infection. Hypothetical mechanisms to explain the pathogenesis of troponin release in patients with novel coronavirus disease 2019 include direct virus-induced myocardial injury (ie, viral myocarditis), systemic hyperinflammatory response (ie, cytokine storm), hypoxemia, downregulation of angiotensin-converting enzyme 2, systemic virus-induced endothelialitis, and type 1 and type 2 myocardial infarction. To date, despite the fact that millions of SARS-CoV-2 infections have been diagnosed worldwide, there is no definitive proof that SARS-CoV-2 is a novel cardiotropic virus causing direct cardiomyocyte damage. Diagnosis of viral myocarditis should be based on the molecular assessment of endomyocardial biopsy or autopsy by polymerase chain reaction or in-situ hybridization. Blood, sputum, or nasal and throat swab virology testing are insufficient and do not correlate with the myocardial involvement of a given pathogen. Data from endomyocardial biopsies and autopsies in clinically suspected SARS-CoV-2 myocarditis are scarce. Overall, current clinical epidemiologic data do not support the hypothesis that viral myocarditis is caused by SARS-CoV-2, or that it is common. More endomyocardial biopsy and autopsy data are also needed for a better understanding of pathogenesis of clinically suspected myocarditis in the course of SARS-CoV-2 infection, which may include virus-negative immune-mediated or already established subclinical autoimmune forms, triggered or accelerated by the hyperinflammatory state of severe novel coronavirus disease 2019.

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.

Predictors of adverse prognosis in COVID-19: A systematic review and meta-analysis.

BACKGROUND: Identification of reliable outcome predictors in coronavirus disease 2019 (COVID-19) is of paramount importance for improving patient's management. METHODS: A systematic review of literature was conducted until 24 April 2020. From 6843 articles, 49 studies were selected for a pooled assessment; cumulative statistics for age and sex were retrieved in 587 790 and 602 234 cases. Two endpoints were defined: (a) a composite outcome including death, severe presentation, hospitalization in the intensive care unit (ICU) and/or mechanical ventilation; and (b) in-hospital mortality. We extracted numeric data on patients' characteristics and cases with adverse outcomes and employed inverse variance random-effects models to derive pooled estimates. RESULTS: We identified 18 and 12 factors associated with the composite endpoint and death, respectively. Among those, a history of CVD (odds ratio (OR) = 3.15, 95% confidence intervals (CIs) 2.26-4.41), acute cardiac (OR = 10.58, 5.00-22.40) or kidney (OR = 5.13, 1.78-14.83) injury, increased procalcitonin (OR = 4.8, 2.034-11.31) or D-dimer (OR = 3.7, 1.74-7.89), and thrombocytopenia (OR = 6.23, 1.031-37.67) conveyed the highest odds for the adverse composite endpoint. Advanced age, male sex, cardiovascular comorbidities, acute cardiac or kidney injury, lymphocytopenia and D-dimer conferred an increased risk of in-hospital death. With respect to the treatment of the acute phase, therapy with steroids was associated with the adverse composite endpoint (OR = 3.61, 95% CI 1.934-6.73), but not with mortality. CONCLUSIONS: Advanced age, comorbidities, abnormal inflammatory and organ injury circulating biomarkers captured patients with an adverse clinical outcome. Clinical history and laboratory profile may then help identify patients with a higher risk of in-hospital mortality.