Acute Myocarditis: From Pathophysiology to Risk‐Stratified Management—A Clinical Review

FIGURE 1. The innate immune response in acute myocarditis: The auto‐inflammatory hypothesis. Cardiotropic viruses (e.g., coxsackievirus B3 [CVB3], human herpes virus 6 [HHV6], adenovirus [ADV], severe acute respiratory syndrome‐coronavirus‐2 [SARS‐CoV‐2]) invade the myocardium via the bloodstream, causing cardiomyocyte damage. Additionally, viruses (e.g., ADV) can also lead to the phosphorylation of Connexin (Cx) 43, impairing gap junction function and increasing arrhythmic risk. Damaged cardiomyocytes release interleukin (IL)‐1α and intracellular ‘alarmins’ which in turn bind the IL‐1 receptor 1 (IL‐1R1) on macrophages, triggering the activation of a cytosolic macromolecular structure named ‘inflammasome’, responsible for the cleavage of pro‐IL‐1β into its final biologically active form IL‐1β. Once activated, IL‐1β is released into the blood and amplifies the inflammatory process by further damaging cardiomyocytes and releasing additional cytokines and ‘alarmins’ (a process referred to as ‘autoinflammation’). IL‐1β also induces Cx43 phosphorylation, further affecting direct and anisotropic electrical coupling in the heart. Over time, persistent autoinflammation can precipitate…

FIGURE 2. The adaptive immune response in acute myocarditis. Central to the development of acute myocarditis is the priming and activation of the adaptive immune system. This can occur via (anticlockwise from top left): Myocyte injury with subsequent release and processing of myocardial antigens, molecular mimicry of (cardiotropic) viral and gut bacterial proteins or direct activation by immune‐checkpoint inhibitors. Immune activation leads to the development of pathological B‐ and T‐cell subsets that can migrate to the heart and exacerbate inflammation by releasing cytokines, exerting direct cytotoxic effects and forming and secreting autoantibodies against myocardial proteins. B19V, parvovirus B19; HHV6, human herpesvirus 6; APC, antigen presenting cell; MHC II, major histocompatibility complex class II; CTLs, cytotoxic T‐lymphocytes; TH1/TH17, T‐helper 1/T‐helper 17 cells, β1AR, β1 adrenoreceptor (Created with BioRender.com). Reproduced from Golino et al. [15].

FIGURE 3. GRASP mnemonic for complex myocarditis presentations and look‐alikes. The GRASP mnemonic is presented as a practical clinical memory aid to support the early recognition of complex or atypical presentations of myocarditis and important mimickers requiring distinct diagnostic and therapeutic approaches. G (Giant cell myocarditis) is characterized by rapidly progressive heart failure and life‐threatening arrhythmias, often requiring urgent diagnosis and aggressive management. R (Related to immune checkpoint inhibitors) highlights myocarditis associated with cancer immunotherapy, mediated by T‐cell activation and immune dysregulation. A (Allergic/eosinophilic myocarditis) includes hypersensitivity reactions, eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndromes, parasitic infections and malignancy‐related eosinophilia. S (Systemic immune‐mediated inflammatory diseases) encompasses connective tissue and inflammatory disorders such as systemic lupus erythematosus, systemic sclerosis, vasculitis, adult‐onset Still's disease and inflammatory bowel disease, which may involve the myocardium. P (Pathogenic genetic mutations) refers to inherited cardiomyopathies,…