By: Prof. Dr. Seyed Saeid Zamanieh Shahri, MD and Prof. Dr. Sonia Sayyedalhosseini, MD
1) Definition of Myocarditis: Myocarditis refers to a group of disorders in which the heart muscle (the myocardium) becomes inflamed. This inflammation may arise from infectious causes (such as viruses) or non-infectious causes (such as autoimmune processes, medications, or hypersensitivity reactions). In many references, myocarditis is described as “non-ischemic inflammation of the myocardium”—that is, myocardial injury not caused by reduced coronary blood flow as in myocardial infarction, but rather driven primarily by an inflammatory process.
Conceptually, several layers of definition may be considered:
• Histologic definition: the presence of inflammatory cell infiltrates within the myocardium together with evidence of cardiomyocyte injury on biopsy specimens.
• Clinical–imaging definition: a compatible clinical syndrome (e.g., chest pain, heart failure, arrhythmia) accompanied by noninvasive evidence of myocardial inflammation on imaging—particularly cardiac MRI—or by elevated disease-relevant biomarkers.
Myocarditis may be acute, subacute, or chronic, and it spans a wide spectrum from a mild, transient illness to advanced stages that progress to dilated cardiomyopathy and chronic heart failure.
2) Pathophysiology: The pathophysiology of myocarditis is complex and multi-stage, typically involving a combination of direct myocardial injury and the host immune response.
-Early phase: entry of the trigger and initial injury
In many cases, the initiating factor is a viral infection. Viruses such as enteroviruses, adenovirus, parvovirus B19, herpesviruses, influenza, and SARS-CoV-2 are among the most frequently reported. Other viruses have also been implicated.
The virus may directly enter cardiomyocytes, replicate within them, and cause primary injury through cell lysis. During this stage, the innate immune system (macrophages and neutrophils) is activated and releases inflammatory mediators and cytokines.
-Adaptive immune phase:
Over time, adaptive immune responses become prominent. Lymphocytes, by recognizing viral antigens or altered cardiac antigens, generate a broader immune reaction. In some models, cytotoxic cells have been shown to destroy infected cardiomyocytes.
If viral clearance is complete and immune activation is appropriately down-regulated, inflammation may resolve. However, if the virus persists or immune regulation becomes dysregulated, a chronic phase may develop.
-Chronic phase and transition to cardiomyopathy:
In persistent or chronic myocarditis, a combination of the following may be observed:
• Persistent viral genetic material in the myocardium
• Continued inflammatory cell infiltration
• Ongoing autoimmune pathways targeting cardiac antigens
• Myocardial remodeling and fibrosis
This process may alter cardiac geometry and drive progression toward inflammatory dilated cardiomyopathy.
-Non-infectious mechanisms:
In non-infectious myocarditis (e.g., drug-induced, immune-checkpoint inhibitor–associated, or autoimmune myocarditis), the primary trigger is not an external antigen but rather disproportionate immune activation against cardiac structures or disruption of immune balance. For example, myocarditis associated with immune checkpoint inhibitors is characterized by extensive lymphocytic infiltration of the myocardium and is classified as a distinct subtype in recent guidance.
3) Causes:
Infectious causes: Viruses are considered the most common cause in many studies. Key pathogens include enteroviruses, adenovirus, parvovirus, herpesviruses, respiratory viruses (influenza, respiratory syncytial virus, etc.), and coronaviruses. In addition to viruses, the following may also contribute:
• Bacteria (e.g., Corynebacterium diphtheriae in diphtheria, or Borrelia burgdorferi in Lyme disease)
• Parasites (e.g., Trypanosoma cruzi in Chagas disease)
• Certain fungi, particularly in immunocompromised patients
Non-infectious causes: Systemic autoimmune disorders such as lupus, rheumatoid arthritis, and vasculitis may involve the myocardium. Drug-related or hypersensitivity myocarditis can occur following exposure to certain medications and is characterized by eosinophilic infiltration.
Myocarditis related to cancer immunotherapy has been emphasized as an important subgroup in recent Japanese and European guidance . T o be continued
