Myocarditis and inflammatory heart diseases

Article written and reviewed by Dr Luca Moretti

Inflammatory heart diseases constitute a heterogeneous spectrum in which inflammation may predominantly involve the myocardium, the pericardium or both. The term myocarditis denotes an inflammatory process of the heart muscle associated with cardiomyocyte injury not explained solely by ischemia; distribution may be focal or diffuse and the clinical expression ranges from subclinical disease to cardiogenic shock. The contemporary framework of inflammatory myopericardial syndromes integrates clinical presentation, biomarkers, multimodality imaging, histology and etiologic investigation. It avoids treating myocardium and pericardium as invariably separate compartments and allows precise description of phenotypes in which pericarditic pain, myocardial injury and ventricular dysfunction carry different weights.

True incidence remains difficult to determine because mild forms do not reach clinical observation, cardiac magnetic resonance is not uniformly available and endomyocardial biopsy is reserved for presentations in which it can change management. The most recent global analyses estimate more than one million new cases annually, but values depend on the definition adopted and do not fully measure paucisymptomatic disease. Distribution is influenced by age, sex, environment, circulation of infectious agents, immune competence, drug exposures and genetic predisposition. In adult clinical registries, young men with painful presentations are common, whereas pediatric, autoimmune, eosinophilic, granulomatous or immunotherapy-associated forms have their own epidemiology and prognosis.

A clinically useful classification must answer different questions: which compartment is involved, how recent the process is, which clinical syndrome it produces, whether hemodynamic or electrical instability exists, which cause is plausible and whether inflammation is still active. Morphology, duration and etiology are therefore not interchangeable categories, because myocarditis may simultaneously be acute, lymphocytic, immune-mediated and fulminant, or chronic, eosinophilic and still hemodynamically stable. The same clinical presentation may result from different histologic substrates and, conversely, the same substrate may produce different clinical phenotypes.

Forms with chest pain, elevated troponin and non-obstructive coronary arteries can mimic myocardial infarction; arrhythmic forms may present with palpitations, syncope, atrioventricular block or ventricular tachycardia; those with pump failure cause dyspnea, congestion and low output. Fulminant myocarditis identifies the extreme phenotype with hemodynamic compromise requiring inotropic or circulatory support, not simply high troponin or a reduced ejection fraction. Clinical resolution does not always coincide with complete biological normalization; edema and necrosis may decrease while a non-ischemic scar persists, capable of maintaining arrhythmic risk even after ventricular function has recovered.

The condition in which pericarditis predominates with modest myocardial injury and preserved systolic function is defined as myopericarditis; when myocardial involvement predominates and is associated with ventricular dysfunction it is called perimyocarditis. This distinction guides anti-inflammatory treatment, monitoring, prognosis and duration of exercise restriction; terminology must remain tied to objective data and should not be used as a generic synonym for chest pain with positive troponin.

Etiology, Pathogenesis and Pathophysiology

Established causes include infectious agents demonstrated in the appropriate context, immune-mediated reactions to drugs, immune checkpoint inhibitors, eosinophilic and granulomatous diseases, autoimmune disorders and specific toxic agents. Etiologic attribution requires consistency among exposure, chronology, phenotype and tissue or microbiologic findings; isolated positive serology does not demonstrate cardiac infection. In infectious forms, injury may result from direct invasion and replication, toxins, the host response or a combination of these mechanisms; RNA and DNA viruses, bacteria, spirochetes, protozoa, helminths and fungi differ profoundly in tropism, persistence and treatment.

Viruses may enter cardiomyocytes or vascular cells through specific receptors, activate cytosolic and endosomal nucleic-acid sensors, and induce interferons, chemokines and cytokines. The innate response recruits neutrophils, monocytes, macrophages and natural killer cells, limits replication but amplifies edema and membrane injury; subsequent adaptive immunity mobilizes cytotoxic T lymphocytes, T helper cells and B lymphocytes. Molecular mimicry, epitope spreading and exposure of previously sequestered cardiac antigens may maintain an autoreactive response even after the initial trigger has diminished.

Cardiomyocyte necrosis and apoptosis release DAMPs capable of activating inflammasomes and proinflammatory pathways. Interleukin-1, interleukin-6, TNF, interferons and oxidative mediators alter contractility, energy metabolism, excitation-contraction coupling and endothelial function; interstitial edema increases stiffness, alters oxygen diffusion and may transiently thicken the walls. Disorganization of gap junctions and heterogeneity of action potentials slow conduction and create substrates for reentry and ectopic ventricular activity.

In immune-mediated forms, the immune system recognizes self cardiac antigens or modified antigens. Autoantibodies against beta-adrenergic receptors, myosin, troponin and other structures have been described, but their individual diagnostic significance is not uniform and does not replace tissue characterization. Immune-mediated and toxic forms include conditions in which removal of the exposure and timely immunosuppressive therapy may be decisive, as in hypersensitivity myocarditis or immune checkpoint inhibitor-associated myocarditis.

Eosinophilic myocarditis combines cytotoxicity of granule proteins, oxidative stress, thrombosis and necrosis; giant-cell myocarditis features a particularly destructive T-cell attack; sarcoidosis forms noncaseating granulomas that interrupt conduction tissue and leave arrhythmogenic scars. Histological forms are not merely microscopic variants because they identify different natural histories and treatments. The distribution of injury explains part of the phenotype: septal and basal involvement favors conduction blocks, inferolateral subepicardial lesions often produce pain and a typical CMR pattern, and diffuse involvement causes pump failure.

Genetic predisposition modifies the threshold at which an inflammatory stimulus becomes clinically manifest. Pathogenic variants in cardiomyopathy genes, especially desmosomal genes and desmoplakin, are more frequent in complicated myocarditis and may present with recurrent inflammatory episodes, the so-called hot phases. In these patients, inflammation may be the cause, an accelerator or an expression of the cardiomyopathic process; a family history of cardiomyopathy or sudden death, relapses, disproportionate arrhythmias and persistent LGE should therefore prompt consideration of a genetic cardiomyopathy.

If the process resolves, reparative macrophages, fibroblasts and extracellular matrix replace necrotic tissue with a scar of variable extent. If immune activation persists, myocyte loss, collagen deposition, dilatation and neurohormonal remodeling continue. Inflammatory cardiomyopathy represents the condition in which chronic myocarditis is associated with cardiac dysfunction and ventricular remodeling, with a dilated or non-dilated hypokinetic phenotype and a possible arrhythmogenic substrate.

Risk factors should not be confused with demonstrated causes. Young age, male sex for some forms, immunodeficiency, autoimmune diseases, cancer therapy, exposure to sensitizing drugs, travel or residence in endemic areas, and cardiomyopathy variants increase probability, but none of them alone establishes the diagnosis. Final pathophysiology depends on the balance among injury, immune response, reparative capacity and pre-existing cardiac reserve.

Clinical Manifestations

History taking should reconstruct the chronology and relationship between systemic and cardiac symptoms. Fever, sore throat, cough, diarrhea, rash, arthralgia or documented infection in the preceding weeks support a trigger, but their absence does not reduce probability to zero. New drugs, dose increases, recent vaccines, immunotherapies, toxic agents, tick bites, travel, immunosuppression, rheumatologic diseases, known eosinophilia, pregnancy and the postpartum period should be sought.

Pain may be pleuritic and positional when the pericardium predominates, or pressure-like and indistinguishable from ischemia when myocardial injury dominates. The infarct-like presentation is typical of relatively young patients with elevated troponin, ST-T changes and no culprit coronary lesion; dyspnea, orthopnea, asthenia, edema and reduced exercise tolerance signal increased filling pressures and reduced output.

Palpitations, presyncope and syncope may result from ventricular tachyarrhythmias, atrial fibrillation or atrioventricular block; syncope without prodromes during exertion or at rest, especially with a family history of sudden death, is a high-risk sign. The patient may report only a decline in performance, while arrhythmias or functional abnormalities are discovered during evaluations performed for other reasons.

On physical examination, stability, mental status, perfusion, blood pressure, heart rate and oxygen saturation are assessed first, because cold extremities, weak pulse, oliguria, hypotension, narrowed pulse pressure and elevated lactate suggest low output and require immediate escalation. Tachycardia disproportionate to fever, bradycardia from block, irregular rhythm or ectopic beats point toward electrical involvement, while tachypnea, crackles and pulmonary edema signal the respiratory component. Elevated jugular venous pressure, hepatojugular reflux, hepatomegaly, ascites and peripheral edema document systemic congestion and possible right ventricular involvement; a third heart sound, functional mitral regurgitation murmur and diffuse apical impulse reflect ventricular dysfunction, while a friction rub supports pericardial involvement despite being transient and poorly sensitive.

Severity is not proportional to ejection fraction alone, because apparently preserved function may coexist with edema, extensive LGE and malignant arrhythmias, while severe reversible systolic depression may recover after adequately supported fulminant disease. Assessment must therefore distinguish hemodynamic stability, electrical stability, myocardial injury and functional impairment. In young children, irritability, poor growth, feeding difficulty, tachypnea, pallor and signs of shock predominate, and in adolescents the presentation more often approaches that of adults; in older adults and immunosuppressed patients, by contrast, presentation may be subtle or dominated by the systemic disease. Rash, eosinophilia, neuropathy, muscle weakness, ptosis, arthritis or lymphadenopathy may finally indicate a specific cause and alter the urgency of biopsy.

The temporal course pragmatically distinguishes acute myocarditis, characterized by recent symptoms and signs of activity, from chronic myocarditis, in which inflammation, symptoms or dysfunction persist or recur. The date of clinical onset does not necessarily coincide with the biological beginning of disease; every visit should look for previous unexplained episodes because recurrence changes the differential diagnosis, indication for genetic testing and prognosis.

Investigations and Diagnosis

First-line assessment includes a 12-lead ECG, high-sensitivity troponin, complete blood count with differential, CRP, renal and hepatic function, electrolytes, natriuretic peptide and echocardiography. These tests define injury, congestion and instability, but no single result has sufficient sensitivity to exclude disease. ECG may show diffuse or territorial ST-T changes, PR depression if pericarditis coexists, low voltages, QRS prolongation, premature beats, tachycardias or atrioventricular block.

Echocardiography assesses global and regional function of both ventricles, wall thickness, dimensions, effusion, valves, pressures and thrombi. Segmental abnormalities do not necessarily respect a coronary territory; longitudinal strain may reveal subclinical dysfunction with preserved ejection fraction. Serial echocardiograms are essential in unstable presentations because function and wall thickness may change rapidly with edema, loading conditions and treatment.

Acute coronary syndrome should be excluded according to age, risk, pain characteristics, ECG and hemodynamic picture using CT angiography or invasive coronary angiography when appropriate. Normal coronary arteries do not automatically demonstrate myocarditis: Takotsubo syndrome, pulmonary embolism, coronary dissection, vasospasm and ischemic MINOCA remain alternatives; diagnosis proceeds by probabilistic integration, not by exclusion of a single disease.

Multiparametric CMR integrates function, edema, hyperemia, injury and scar and, according to the Lake Louise criteria updated in 2018, supports acute inflammation with greater specificity when at least one T2-based marker of edema and one T1-based marker of non-ischemic injury coexist, with effusion, pericarditis and dysfunction as supportive elements. T2 mapping or elevated T2 signal satisfies the edema domain, while native T1, extracellular volume or non-ischemic LGE satisfies the injury domain; sensitivity nevertheless decreases in chronic, focal and predominantly arrhythmic forms, in which absence of complete criteria does not exclude the process.

There is no single universal criterion capable of replacing clinical judgment and tissue confirmation. The 2025 ESC guidelines and ACC consensus propose a graded diagnosis combining a compatible syndrome with laboratory, ECG, imaging or biopsy findings. In suspected inflammatory myocardial disease, it is necessary to document a compatible clinical presentation, seek objective evidence of injury or inflammation and systematically assess alternative diagnoses.

Endomyocardial biopsy is the reference for defining histology, immunohistochemistry and microbial genomes in tissue; sampling should include multiple fragments, correctly fixed or frozen, and interpretation should be entrusted to experienced pathologists. Biopsy is a priority in shock, sustained ventricular arrhythmias, advanced block, rapid progression, failure to respond, eosinophilia or suspected giant-cell myocarditis, sarcoidosis, immunotherapy toxicity and other treatable causes.

Dallas criteria require inflammatory infiltrate with myocyte necrosis or degeneration not typical of ischemic injury, but they suffer from sampling error and interpretive variability. Immunohistochemistry increases sensitivity and characterizes the amount and phenotype of cells; tissue PCR must be interpreted with quality controls and in the clinical context. The mere presence of a viral genome does not always demonstrate causality, particularly for agents that can persist in non-myocyte cells.

Etiologic investigation is selective and uses blood cultures, targeted serology, molecular tests, autoantibodies, immunophenotyping, eosinophils, ACE, 18F-FDG PET and extracardiac imaging only when exposures and phenotype make them relevant, because indiscriminate viral serology panels have low utility. The differential diagnosis includes ischemia, Takotsubo syndrome, genetic cardiomyopathies, sarcoidosis, amyloidosis, sepsis, tachycardia-induced cardiomyopathy, non-inflammatory toxicity and transplant rejection. Stratification integrates low output, biventricular dysfunction, sustained arrhythmias, advanced block, syncope, septal or extensive LGE, failure to recover and aggressive histotypes, remembering that absence of dysfunction does not eliminate risk if an arrhythmogenic scar persists. Telemetry, Holter monitoring, exercise testing and repeat imaging are therefore scheduled according to the risk profile.

Treatment and Prognosis

Treatment begins with stabilization, and patients with shock, major arrhythmias or advanced block should be managed in an intensive care unit with access to electrophysiology, advanced heart failure care, cardiac surgery and cardiovascular pathology; early transfer prevents multiorgan injury from making late support ineffective. Oxygenation, ventilation, correction of electrolytes, control of congestion and support of perfusion are modulated according to the hemodynamic phenotype rather than applied as an identical sequence to every presentation.

When stable ventricular dysfunction is present, guideline-based heart failure therapy is used and adapted to blood pressure, renal function and clinical phase. Diuretics treat congestion; renin-angiotensin system inhibition, beta-blockade, mineralocorticoid antagonists and SGLT2 inhibitors are introduced when tolerated. The beta-blocker is not initiated or up-titrated during shock or severe hypoperfusion, but becomes valuable after stabilization for remodeling and arrhythmic control.

In cardiogenic shock, inotropes may temporarily support output but increase oxygen consumption and arrhythmic risk. Deterioration despite initial therapy requires early assessment for VA-ECMO, a microaxial pump or ventricular support, selected according to right- and left-sided involvement, oxygenation and the need for unloading. The goal of mechanical circulatory support is to create a bridge to recovery, decision, durable support or transplantation.

Ventricular arrhythmias and conduction disorders are treated according to instability and mechanism, remembering that the substrate may be transient. Cardioversion, antiarrhythmics, temporary pacing and a wearable defibrillator may be necessary; permanent implantation is reassessed after the inflammatory phase unless there are indications that cannot be deferred. Persistence of LGE and arrhythmias after recovery requires stratification distinct from ejection fraction alone.

Etiologic therapy is appropriate only when the target is documented or highly probable and the treatment has recognized efficacy. Antibiotics, antiparasitic drugs or antifungals are essential in the corresponding infections; empiric antiviral therapy is not standard in common uncharacterized viral myocarditis. Withdrawal of the causal drug is immediate in hypersensitivity reactions and iatrogenic toxicities.

Immunosuppression is urgent in giant-cell myocarditis, severe eosinophilic myocarditis, active cardiac sarcoidosis and immune checkpoint inhibitor-associated myocarditis, with specific regimens. In chronic lymphocytic inflammatory cardiomyopathy, the strongest evidence concerns patients with positive biopsy and absence of viral genomes in the myocardium; empiric corticosteroids are not a universal therapy and may be harmful if they mask or worsen an unrecognized infection.

NSAIDs may be used to control pain in uncomplicated myocarditis in the absence of symptomatic heart failure; colchicine is reserved for presentations with a pericardial component, while high doses of NSAIDs are not used as routine treatment for isolated myocarditis. Intravenous immunoglobulin is not systematically recommended in adults in the absence of a specific indication; anticoagulation depends on intracardiac thrombus, atrial fibrillation or another indication, not on the diagnosis of myocarditis itself.

During the active phase, sport and intense activity are suspended and, in symptomatic forms, the ACC consensus generally indicates three to six months of abstention from vigorous exertion; return requires clinical remission, recovered function, stabilized biomarkers and absence of relevant arrhythmias on monitoring and exercise testing. The most recent ESC recommendations, however, favor a personalized assessment in which elapsed time is only one of the elements rather than an identical threshold for everyone.

Early follow-up monitors symptoms, ECG, troponin, natriuretic peptides and echocardiography. In symptomatic presentations it is reasonable to reassess clinical status and function after a few weeks and repeat imaging later, choosing CMR in patients with greater risk or persistent findings. Relapses, family history or an arrhythmic phenotype justify genetic counseling and prolonged monitoring; prognosis is excellent in many uncomplicated acute forms but cannot be generalized. Reduced ejection fraction, low output, ventricular arrhythmias, right ventricular dysfunction, septal or persistent LGE and aggressive histotypes increase the risk of death, transplantation, heart failure and relapse. Recovery of function does not automatically eliminate scar or electrical risk.

Complications

The most immediate hemodynamic complication is acute heart failure, in which loss of contractility and increased stiffness raise filling pressures and cause pulmonary edema and systemic congestion, while right ventricular involvement worsens hepatic and renal perfusion. When output is no longer sufficient to support the organs, cardiogenic shock develops, often worsened by the combination of inflammatory vasoplegia and arrhythmias.

Arrhythmias include premature beats, monomorphic or polymorphic ventricular tachycardia, ventricular fibrillation, atrial fibrillation and supraventricular tachycardias. Edema and cytokines acutely alter conduction and refractoriness; necrosis and fibrosis subsequently create stable reentry circuits. Sudden cardiac death may therefore occur during the active phase or later; the conduction system may be directly involved by infiltrate or septal lesions. High-grade atrioventricular block is particularly suggestive of sarcoidosis, giant-cell myocarditis, Lyme disease or some immunotherapy-associated forms, although it is not specific. Recovery of conduction may make pacing temporary, but a persistent scar may require a permanent device.

Extensive myocardial necrosis may progress to dilatation, functional mitral regurgitation and inflammatory cardiomyopathy, because sympathetic and renin-angiotensin system activation, wall stress and fibrosis fuel a remodeling loop that continues even after inflammation decreases and may culminate in refractory heart failure, durable support or transplantation. Akinesia and low output also favor ventricular thrombi, which may cause stroke or peripheral ischemia; atrial fibrillation and intracardiac catheters add further thrombotic mechanisms. Searching for thrombus becomes particularly important when function is severely reduced or the apex is akinetic.

The pericardial component may produce an effusion that rarely progresses to tamponade: a modest collection does not measure myocardial severity, whereas rapid increase accompanied by compromise of the right-sided chambers requires urgent drainage, and pericardial inflammation may recur even after ventricular recovery. Renal and hepatic injury, meanwhile, results from the interaction among hypoperfusion, venous congestion, hemolysis and drugs and may limit therapeutic options; if shock continues, lactic acidosis, coagulopathy, intestinal ischemia and multiorgan failure define a point of no return that early escalation of support seeks to prevent.

Relapses may reflect a new exposure, persistent autoimmunity, an infection that has not been eradicated or genetic cardiomyopathy with inflammatory phases, and each episode may add fibrosis and increase cumulative arrhythmic risk; recurrence therefore requires a new etiologic assessment, not simple repetition of the previous therapy. Misdiagnosis is also an indirect but relevant clinical complication, because treating an acute coronary syndrome, dissection, genetic cardiomyopathy or systemic infection as myocarditis delays specific therapy, while failing to recognize an aggressive form can lose the window for biopsy and immunosuppression. The quality of the pathway depends on continuous reassessment of diagnostic alternatives.

Final prognosis emerges from the interaction among cause, initial severity, timeliness of support, amount of myocardium lost and persistence of scar. The goal is not merely survival and normalization of ejection fraction, but prevention of heart failure, arrhythmias, relapses and long-term functional limitation. Risk-proportionate follow-up is therefore an integral part of treatment, not an ancillary phase.