This Review is the result of a scientific cooperation of members from the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society. The aim of the Review is to help clinicians and scientists apply the best diagnostic and therapeutic approaches to solve individual patient problems in clinical practice. We outline patient-specific therapeutic options that are based on an accurate diagnosis, covering current and novel strategies. We assess the relevance of histology, immunohistology and molecular biology techniques for the analysis of endomyocardial biopsy (EMB) samples, as well as advanced imaging methods and the role of inflammatory and immune cell markers, immune cell ratios, microRNAs and antibodies for the diagnosis, guidance of therapeutic decisions and management in patients with myocarditis and inflammatory cardiomyopathy. We discuss the role of viruses as active inducers or as potential bystanders of myocarditis and inflammatory cardiomyopathy. In this Review, we discuss the available evidence and identify the gaps in our understanding of the pathogenesis, diagnosis, treatment and prognosis of myocarditis and inflammatory cardiomyopathy, appraise the available animal and cell models of these conditions and propose future directions for the field. These gaps in knowledge highlight the need for advanced experimental systems that can better model the human immune system and the need to improve the characterization and classification of the patients, for example, with the use of phenomapping and phenomics, which involve detailed evaluation of immune status, viral presence and/or other biomarkers. Many questions remain unanswered regarding the pathogenesis of inflammatory cardiomyopathy and the role of the viral infection, the immune system, the host genetic background and the environment in disease progression and prognosis. Prompt diagnosis and specific treatment strategies are needed to reduce mortality and the need for heart transplantation in these patients 4, 5. Furthermore, fulminant myocarditis, a rare, sudden and severe cardiac inflammation, is one of the main causes of cardiogenic shock in young adults 4, 5. Despite extensive research and improved diagnosis and understanding of the pathogenesis of inflammatory cardiomyopathy, this disorder is still associated with a poor prognosis when complicated by left ventricular (LV) dysfunction, heart failure (HF) or arrhythmia 3. Inflammatory cardiomyopathy is defined as myocarditis in association with cardiac dysfunction and ventricular remodelling 1, 2. 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. 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. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. 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. As a consequence, treatment strategies are not well established. 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. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. 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. Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology.
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