Myocarditis

Article written and reviewed by Dr Luca Moretti

Myocarditis is an inflammatory disease of the myocardium in which an immune infiltrate is associated with injury, degeneration or necrosis of cardiomyocytes not explained solely by coronary ischemia. The pathological definition does not correspond to a single clinical syndrome: the same process may present with chest pain, heart failure, arrhythmias, conduction blocks, shock, or remain subclinical. Involvement may be focal, multifocal or diffuse and may affect both ventricles, the conduction system, small vessels and the pericardium. The heterogeneity of cause, site, intensity and biological phase explains why troponin, ECG, echocardiography and cardiac magnetic resonance may be normal or discordant in individual patients.

The clinical diagnosis is broader than histologically proven myocarditis because biopsy is performed only when the diagnostic benefit outweighs risks and sampling limitations. CMR has made many non-fulminant forms recognizable, but it documents a pattern of inflammation or non-ischemic injury and does not automatically identify etiology or histotype. Diagnostic certainty should therefore be expressed in graded terms, distinguishing confirmed disease from compatible findings and keeping the differential diagnosis active.

From a temporal standpoint, the spectrum includes recent, persistent and recurrent phases: acute myocarditis presents with newly developed symptoms and evidence of activity, whereas in the chronic form inflammation, dysfunction or clinical manifestations persist beyond the initial phase. The term fulminant instead describes an extreme hemodynamic condition rather than a duration. This interpretation is complemented by the ACC pathway, which classifies the spectrum as stage A, exposure or risk without demonstrated disease; B, evidence of disease without symptoms; C, symptomatic myocarditis; and D, symptomatic disease accompanied by electrical or hemodynamic instability.

Epidemiologic estimates are influenced by coding, availability of CMR and case selection. Global Burden of Disease analyses estimated approximately 1.3 million incident cases in 2021, but clinical prevalence is lower than the actual frequency of inflammatory injury because many mild forms are not diagnosed. Myocarditis is also relevant as a cause of sudden death in young people and as a precursor of dilated cardiomyopathy; an apparent concentration in adolescents and young adults does not exclude neonates, older adults or immunosuppressed patients.

In registries of acute myocarditis, the uncomplicated phenotype with pain and preserved function generally has a favorable prognosis; an ejection fraction below 50%, ventricular tachyarrhythmias or low-output syndrome instead identify a higher-risk trajectory. Persistence of LGE, particularly when septal and without edema at follow-up, retains prognostic value even after clinical recovery. This distinction prevents both trivializing a patient with preserved function and an arrhythmogenic scar and inevitably assigning a poor prognosis to severe but reversible initial dysfunction.

Etiology, Pathogenesis and Pathophysiology

Infectious causes vary according to geographic area, age and immune competence. Enteroviruses, adenoviruses, parvovirus B19, human herpesvirus 6, influenza viruses, HIV and SARS-CoV-2 have been associated with myocardial injury, but the relationship between systemic presence, tissue genome and causality must be demonstrated cautiously. Bacterial infections, rickettsioses, spirochetoses, fungi and parasites are less common in high-income countries but become central in specific exposures; diphtheria, Lyme disease and Chagas disease have their own mechanisms and therapies.

A cardiotropic virus may bind to membrane receptors, enter the cell, use the replicative machinery and produce cytolysis or proteases that damage contractile and junctional structures. Pattern-recognition receptors such as Toll-like receptors, RIG-I and MDA5 recognize microbial components and activate type I interferons, NF-kB and cytokines; innate immunity contains the pathogen, but production of radicals, proteases and inflammatory mediators amplifies collateral damage.

Neutrophils and monocytes reach the tissue through activated endothelium; macrophages assume dynamic proinflammatory and reparative phenotypes. Natural killer cells eliminate infected cells, while dendritic cells present antigens in lymph nodes and connect innate and adaptive immunity. Microvascular permeability causes edema; microthrombi, altered vasomotor tone and endothelial dysfunction may add non-atherothrombotic ischemia to the inflammatory injury.

CD8 T lymphocytes recognize antigens displayed by cardiomyocytes and induce apoptosis through perforin, granzymes and Fas pathways. T helper cells coordinate Th1 and Th17 responses, while regulatory T-cell defects favor persistence; B lymphocytes produce antibodies and present antigens. Mimicry between microbial epitopes and cardiac proteins, epitope spreading and myosin release may convert a protective response into cardiac autoimmunity.

Systemic diseases may cause myocarditis through different and sometimes concomitant mechanisms: lupus and other connective tissue diseases involve immune complexes, complement and autoantibodies, vasculitides cause small-vessel ischemia together with infiltration, and eosinophilic granulomatosis with polyangiitis combines eosinophil cytotoxicity and necrotizing vasculitis. In sarcoidosis, by contrast, noncaseating granulomas are distributed in patches, often in the basal segments and septum, interrupting the conduction system and creating arrhythmic circuits.

Drugs can act as haptens, induce systemic hypersensitivity or directly alter immune homeostasis. PD-1, PD-L1 and CTLA-4 inhibitors remove antitumor tolerance signals and may allow autoreactive T-cell clones to attack the heart and skeletal muscle; overlap with myositis and myasthenia increases severity. The timing of exposure is essential, but an atypical latency does not exclude the relationship when pharmacokinetics and immunobiology are compatible.

In eosinophilic myocarditis, major basic protein, eosinophil cationic protein and peroxidase damage membranes and the microcirculation. The eosinophilic necrotizing form may rapidly cause shock; more indolent phases favor endocardial thrombosis and restrictive fibrosis. Giant-cell myocarditis is dominated by T lymphocytes and multinucleated macrophages with extensive necrosis and carries a high risk of arrhythmia, block, transplantation and death without combined immunosuppression.

Variants in DSP, PKP2, DSG2, FLNC, TTN and other genes may reduce myocardial resilience to stress. In desmoplakin cardiomyopathy, episodes of pain and elevated troponin may precede the structural phenotype and leave ring-like subepicardial LGE; inflammation is therefore not always external to a cardiomyopathy: it may represent a phenotypic phase of the disease and contribute to progression.

Cellular injury reduces the strength and synchrony of contraction; cytokines transiently depress function beyond the amount of necrosis. Edema and increased interstitial volume alter compliance, while right-sided involvement reduces left ventricular filling and tolerance to preload changes; heterogeneous distribution creates conduction and refractoriness gradients that explain arrhythmias disproportionate to global dysfunction.

The reparative phase may restore nearly normal structure or deposit replacement collagen. The non-ischemic scar tends to be subepicardial or intramural and does not follow a coronary territory; persistent inflammation fuels further necrosis and remodeling. Dilatation, increased wall stress and neurohormonal activation transform the process into chronic inflammatory cardiomyopathy.

Clinical Manifestations

History taking begins by reconstructing onset, placing acute chest pain, progressive dyspnea, palpitations or syncope in relation to fever, respiratory or gastrointestinal infection, rash, arthralgia and new treatments. An interval of days or weeks between systemic and cardiac manifestations is common but not required. Medication review must include antibiotics, anticonvulsants, antipsychotics, immunotherapies and supplements and document not only exposure but also start and stop dates and any re-exposure, from which a more convincing causal relationship may emerge.

Infarct-like pain is often retrosternal and persistent, may be associated with ST elevation and elevated troponin and requires exclusion of an acute coronary syndrome. Pericarditic pain worsens with inspiration and recumbency and improves when sitting forward; the two patterns may coexist. Simple reproducibility on palpation does not exclude a cardiac process when abnormal biomarkers or ECG findings are present.

Dyspnea results from increased pulmonary pressures, reduced output or concomitant respiratory involvement. Orthopnea and paroxysmal nocturnal dyspnea indicate congestion; asthenia, confusion, cold extremities and oliguria indicate hypoperfusion. The speed of progression is informative: a transition over hours from influenza-like symptoms to shock suggests a fulminant phenotype; brief palpitations may correspond to ectopy, but sustained episodes with dizziness or syncope require admission and monitoring. Atrioventricular block may present with bradycardia, exercise intolerance or syncope; onset with monomorphic ventricular tachycardia also points toward sarcoidosis or arrhythmogenic cardiomyopathy. Sudden death in the family changes the pre-test probability of a genetic substrate.

Subclinical forms are discovered because of troponin, ECG, imaging or arrhythmias during assessment of infections, oncologic therapies or sports screening. Absence of symptoms does not imply absence of risk when extensive injury or electrical abnormalities are present. In the ACC pathway these patients may fall within stage B and require characterization and surveillance proportionate to the findings; on physical examination, consciousness, blood pressure, heart rate, perfusion and work of breathing are assessed immediately. Tachycardia may be the first sign; hypotension, thready pulse, mottled skin and reduced peripheral temperature indicate shock. Blood pressure may remain initially normal because of compensatory vasoconstriction, so urine output and lactate complete the assessment.

Crackles, hypoxemia and tachypnea document pulmonary congestion; jugular venous distension, hepatomegaly and edema signal elevated right-sided pressures. A third heart sound reflects rapid filling of a dysfunctional ventricle; a new mitral murmur may result from dilatation or papillary dysfunction. Pulsus paradoxus and echocardiographic signs become relevant if a hemodynamically significant pericardial effusion coexists; fever, rash, lymphadenopathy, arthritis, purpura, neuropathy, hepatosplenomegaly or signs of infection help orient the cause. Proximal weakness, ptosis, diplopia and dysphagia in a patient treated with checkpoint inhibitors suggest myocarditis-myositis-myasthenia overlap and require urgent treatment; peripheral eosinophilia supports an eosinophilic form, but its absence does not exclude it.

In infants, tachypnea, feeding difficulty, sweating, irritability and poor growth predominate, whereas in older children abdominal pain and vomiting may precede cardiac signs; lower reserve permits rapid progression to shock and congenital heart disease, metabolic disorders and sepsis broaden the pediatric differential diagnosis. The course must be documented serially because symptomatic improvement with falling troponin does not guarantee resolution of edema or arrhythmic risk, and a rapidly recovering ejection fraction may coexist with residual LGE. Assessment therefore concerns the combined trajectory of symptoms, biomarkers, function, rhythm and tissue rather than an isolated snapshot.

Investigations and Diagnosis

The ECG is performed immediately but has no pathognomonic pattern. ST elevation or depression, T-wave inversion, PR depression, wide QRS, low voltages, Q waves, blocks and arrhythmias are possible; a normal ECG reduces but does not eliminate probability. Serial changes and continuous monitoring have greater diagnostic and prognostic value than a single recording; troponin documents cardiomyocyte injury and should be measured serially with a high-sensitivity assay. CRP and ESR measure systemic inflammation but may be normal; BNP or NT-proBNP quantify hemodynamic stress; complete blood count with differential looks for eosinophilia and cytopenias. Renal, hepatic and thyroid function, CK, electrolytes, lactate and blood gas analysis define severity, overlap and treatment safety.

Echocardiography establishes left and right ventricular function, regional abnormalities, wall thickening due to edema, effusion, functional regurgitation, pressures and thrombi; global longitudinal strain may be abnormal before the ejection fraction. In shock, bedside examination guides fluids, inotropes and support while also looking for alternative causes such as tamponade, pulmonary embolism or ischemic complications. CMR should be performed early in stable patients because edema diminishes over time. Cine imaging, T2-weighted imaging, T1 and T2 mapping, extracellular volume and LGE distinguish edema, injury and scar; a subepicardial or mid-wall distribution supports a non-ischemic cause. A subendocardial or transmural pattern in a vascular territory instead requires an ischemic explanation.

The 2018 Lake Louise criteria consider tissue characterization positive for acute inflammation when at least one T2-based criterion and at least one T1-based criterion are present. A single positive domain makes the picture less specific; pericarditis, effusion and dysfunction are supportive but not substitutive. Mapping values must be compared with scanner- and sequence-specific local reference ranges; diffuse edema may escape techniques based on comparison with apparently normal myocardium.

In the absence of a single universal clinical diagnostic criterion, according to the 2025 ESC guidelines and the 2024 ACC consensus, diagnosis requires a compatible presentation associated with objective evidence of injury or inflammation obtained through biomarkers, ECG, imaging or biopsy, after assessment of alternatives. Diagnosis is more robust when several independent domains are concordant and becomes histologically definitive when biopsy demonstrates a relevant myocarditic process.

Coronary angiography or CCTA is indicated when the probability of acute coronary syndrome is not negligible. In young stable patients CCTA may exclude obstructive anatomy; when acute myocardial infarction or instability is suspected, invasive coronary angiography takes precedence. Demonstration of non-obstructive coronary arteries opens the MINOCA pathway and does not authorize myocarditis to be assigned automatically.

Endomyocardial biopsy should be obtained as soon as possible when shock, advanced block, sustained arrhythmia, rapid progression or etiologic suspicion make a treatment-changing result likely. Biventricular or imaging-/mapping-guided sampling may increase yield in focal processes; histology, immunohistochemistry and molecular testing should be planned before sampling to avoid unusable specimens. Dallas criteria identify inflammatory infiltrate with non-ischemic myocyte injury, but a negative biopsy does not exclude patchy disease. Immunohistochemistry quantifies leukocytes and HLA molecules; special stains distinguish eosinophils, giant cells, granulomas, amyloid and selected agents. Tissue PCR for viral genomes is essential before immunosuppression in some inflammatory cardiomyopathies, but requires an experienced laboratory and correct interpretation.

Etiologic investigation does not consist of indiscriminately ordering a panel: blood cultures precede antibiotics if sepsis is present; serology and molecular tests for HIV, Borrelia, Trypanosoma or other agents are selected according to exposure, and PET is most useful when sarcoidosis is suspected and for identifying extracardiac sites for biopsy. Routine viral serology, by contrast, correlates poorly with any virus present in the myocardium and does not constitute proof of cardiac causality.

The differential diagnosis includes acute coronary syndrome, spontaneous coronary dissection, Takotsubo syndrome, pulmonary embolism, sepsis, tachycardia-induced cardiomyopathy, peripartum cardiomyopathy, infiltrative diseases and genetic cardiomyopathies. A non-ischemic scar pattern without edema may represent a remote sequela rather than active inflammation; relapse, ring-like LGE, family history and arrhythmias should prompt distinction of a genetic hot phase from isolated acquired myocarditis.

Treatment and Prognosis

Treatment depends on syndrome and cause, because there is no single drug for all myocarditis. The unstable patient is admitted to intensive care and, if shock or refractory arrhythmias are present, transferred without delay to a center with circulatory support and transplantation capabilities. Stabilization precedes complete definition, but biopsy should not be delayed when the result may guide urgent immunosuppression.

Congestion is treated with diuretics; vasodilation may be used if blood pressure permits. In the stable phase with reduced ejection fraction, the pillars of heart failure therapy are introduced and titrated over time; after recovery, early discontinuation may expose the patient to recurrent dysfunction. The duration of neurohormonal therapy is individualized according to recovery, scar, etiology and risk of relapse.

In shock, inotropes and vasopressors are used at the lowest effective dose as a bridge, while the biventricular profile and oxygenation requirements guide the choice among VA-ECMO, an axial-flow pump and ventricular assist support, bearing in mind that VA-ECMO can increase left ventricular afterload and may require unloading. Escalation should precede irreversible multiorgan failure and is based on the trend in lactate and perfusion as well as blood pressure. Unstable tachyarrhythmias require cardioversion, amiodarone is often used when pharmacologic treatment is needed, and symptomatic block may require temporary pacing; implantable defibrillator and ablation are generally reassessed after the acute phase, although persistent arrhythmias, extensive scar or high-risk etiologies may justify earlier definitive protection.

A bacterial, fungal or parasitic cause receives targeted antimicrobial therapy and source control. In Lyme carditis, monitoring and appropriate antibiotic therapy often allow recovery of conduction; in Chagas disease, phase and parasite burden influence treatment. There is no evidence for empiric antivirals in common presumed viral lymphocytic myocarditis. Combined immunosuppression improves survival in giant-cell myocarditis compared with supportive therapy alone; corticosteroids are central in eosinophilic, sarcoid and immune checkpoint inhibitor-associated forms, often with other immunomodulators according to severity. In virus-negative lymphocytic inflammatory cardiomyopathy, the TIMIC trial showed benefit from prednisone and azathioprine in biopsy-selected patients.

NSAIDs and colchicine may control pericarditic pain when function is preserved and heart failure is absent. In isolated myocarditis they are not treatment for myocardial inflammation, and NSAIDs are avoided in forms with heart failure. Immunoglobulins and plasmapheresis are not routine interventions but may have a role in specific subtypes or immune overlaps; vigorous exercise increases adrenergic stress, mechanical load and arrhythmic susceptibility during inflammatory activity. Symptomatic patients suspend competitive sport and intense training; return requires absence of symptoms, functional recovery, stable biomarkers and rhythm assessment. Follow-up includes ECG, echocardiography or CMR, Holter monitoring and exercise testing according to risk.

Initial follow-up reassesses function after two to four weeks in symptomatic presentations and repeats imaging within several months. Follow-up CMR distinguishes resolving edema from LGE without edema, which is closer to permanent scar; longer monitoring is required for arrhythmias, relapses or a genetic substrate. Genetic counseling is appropriate particularly in complicated, recurrent or familial forms.

The prognosis of uncomplicated acute forms is generally favorable, as shown by the contemporary cohort reported by Ammirati, in which major events at five years were concentrated among patients with dysfunction, ventricular arrhythmias or low output at presentation, whereas risk in uncomplicated forms remained very low. Extensive, anteroseptal or persistent LGE, right ventricular dysfunction, stage D disease and aggressive histology instead constitute adverse markers requiring closer surveillance even after initial improvement.

Normalization of troponin does not equal histologic healing, and normalization of ejection fraction does not eliminate arrhythmic risk. Conversely, severe initial dysfunction due to inflammatory stunning may recover completely; reliable prognosis arises from serial observations and the cause, not from a single value at admission.

Complications

Acute heart failure results from contractile depression, stiffness and edema, functional valvular regurgitation and arrhythmias. The right ventricle may be directly involved or fail because of elevated pulmonary pressures; biventricular dysfunction reduces compensatory capacity. Congestion causes hypoxemia, renal and hepatic injury and worsens drug absorption. Cardiogenic shock combines insufficient output, vasoconstriction, acidosis and progressive multiorgan dysfunction; in some forms the inflammatory response adds vasoplegia, creating a mixed picture. Delaying mechanical support increases the risk that lactate, coagulopathy and neurologic injury will compromise recovery or transplantation.

Ventricular arrhythmias may be triggered by acute edema, abnormal automaticity, microvascular ischemia or reentry in scar. Ventricular fibrillation causes sudden cardiac arrest; late monomorphic tachycardia suggests an organized fibrotic circuit. Septal or ring-like LGE and desmosomal variants increase concern about electrical risk; conduction disorders include fascicular and atrioventricular blocks up to complete dissociation. Advanced block may resolve as edema decreases or persist because of necrosis of the conduction system; sarcoidosis, Lyme disease, giant-cell myocarditis and immune checkpoint inhibitor-associated myocarditis require particular diagnostic urgency.

Residual fibrosis creates a chronic substrate even when symptoms disappear. Scar reduces contractile reserve, fragments conduction and may explain palpitations, syncope and late sudden death. LGE without edema on follow-up CMR has greater prognostic significance than an exclusively edematous finding destined to resolve. If myocyte loss exceeds reparative capacity, ventricular dilatation and sphericity develop. Functional mitral regurgitation increases volume overload and neurohormonal activation accelerates progression toward chronic heart failure; some patients reach an end-stage phenotype despite disappearance of the inflammatory infiltrate.

Ventricular stasis, endocardial injury and the inflammatory state favor intracavitary thrombi, from which cerebral, renal, splenic or peripheral emboli may arise, while atrial fibrillation adds an independent risk; anticoagulation is decided on the basis of the thrombus or standard indications, balancing bleeding and biopsy requirements. Relapse may recur with the same phenotype or with a different expression, but each episode can add scar and increase arrhythmic risk and requires a renewed search for drugs, autoimmunity, infections, sarcoidosis and genetic cardiomyopathy. An initial diagnosis of idiopathic myocarditis should therefore be reopened when a second hot phase occurs.

Associated pericarditis may be complicated by effusion and, rarely, tamponade; more often it causes persistent or recurrent pain. Use of anti-inflammatory drugs must be balanced against ventricular function and must not obscure the course of myocardial injury. A dominant pericardial component generally has a different prognosis from perimyocarditis with dysfunction. Psychological and functional consequences include fear of recurrence, deconditioning and difficulty returning to work or sport. Excessive and indefinite restriction is not harmless, but premature resumption increases risk; rehabilitation should be progressive and based on objective evidence of remission.

The terminal complication is death from shock, arrhythmia, multiorgan failure or advanced heart failure; risk is reduced by recognizing dangerous phenotypes early, performing biopsy when it can change treatment, and ensuring timely access to support. Myocarditis should therefore be regarded as a dynamic diagnosis whose severity and nature may emerge over time.