Histological forms of myocarditis

Article written and reviewed by Dr Luca Moretti

The histological classification of myocarditis describes how inflammation and injury appear in cardiac tissue by identifying the predominant cell population, its distribution and its relationship to necrosis, cardiomyocyte degeneration, granulomas, vasculitis and fibrosis. It is not purely descriptive nomenclature: distinguishing a limited lymphocytic infiltrate from a diffusely destructive giant cell process, a necrotizing eosinophilic lesion or a granulomatous disease can, within hours, change diagnostic urgency, use of immunosuppression and evaluation for circulatory support.

Histological subtype, however, is not equivalent to etiology, because lymphocytic myocarditis can accompany infections, autoimmunity, drugs and checkpoint inhibitors; eosinophils may reflect hypersensitivity, a hypereosinophilic syndrome, vasculitis or a parasite; granulomas require differentiation of sarcoidosis from infection. Different components may even coexist in the same heart, while a very small biopsy may show only part of the process; the report therefore acquires meaning when integrated with clinical phenotype, imaging, exposures, microbiology and time from onset.

Endomyocardial biopsy is the main tool for obtaining this information in a living patient, but it is not an infallible binary test; a focal lesion may be missed, a crushed fragment may become unreadable and inappropriate preservation may preclude immunohistochemistry or molecular analysis. The decision to perform biopsy is justified when knowledge of the histological subtype or causative agent can concretely modify treatment and prognosis, particularly in fulminant presentations, advanced block, ventricular arrhythmias, rapidly progressive heart failure and refractory forms.

Diagnostic terminology has evolved from the Dallas morphological criteria to integration with immunohistochemical markers and molecular techniques, and ultimately to contemporary criteria proposed by cardiovascular pathology societies. This development does not make microscopy obsolete, but refines its interpretation: a higher leukocyte density alone does not prove active myocarditis, just as a few foci with genuine myocyte injury may be clinically decisive. The central finding remains the morphological correlation among inflammation, nonischemic injury and context.

Etiology, Pathogenesis and Pathophysiology

The myocardial immune response begins with recognition of microbial components or signals released by injured cells. Interferons, complement, inflammasomes and chemokines recruit innate immune cells, followed by an adaptive response capable of eliminating the agent or prolonging the injury. The visible pattern depends on the interaction among the nature of the stimulus, temporal phase, host predisposition and treatments already received; an early biopsy may therefore be dominated by edema and necrosis, whereas a late sample may show fibrosis and a much more limited infiltrate.

In the lymphocytic pattern, T lymphocytes predominate and are accompanied in variable proportions by macrophages and rarer B cells or plasma cells. When the infiltrate is associated with cardiomyocyte injury not explained by ischemia, biopsy trauma or other causes, the finding supports active myocarditis. Lymphocytic foci without convincing injury require greater caution, because resident immune cells and small aggregates may also occur in other cardiac diseases or stressed tissues; quantity, distribution and quality of injury must be interpreted together.

Giant cell myocarditis is characterized by an often extensive and destructive process with necrosis, a mixed infiltrate and multinucleated cells not organized into well-formed granulomas. T-cell and macrophage activation causes rapid myocyte loss capable of producing shock, conduction blocks and malignant tachycardias. Superficial resemblance to sarcoidosis is resolved by examining architecture, necrosis, infiltrate composition and distribution rather than relying solely on the presence of giant cells.

In eosinophilic myocarditis, eosinophil granule contents, rich in cationic proteins, can directly injure myocytes and endothelium; the spectrum includes relatively limited interstitial or perivascular infiltrates of hypersensitivity reactions and rapidly fatal necrotizing forms. The blood eosinophil count does not necessarily reflect the tissue burden, especially at onset or after corticosteroids, and absence of peripheral eosinophilia does not exclude cardiac injury.

Granulomatous myocarditis organizes epithelioid macrophages, giant cells and lymphocytes into more clearly defined structures. In cardiac sarcoidosis, typically noncaseating granulomas are patchily distributed and heal with dense scars, often in the basal septal segments and free wall; however, mycobacteria, fungi and other infectious causes must be excluded with appropriate stains, cultures or molecular tests before immunosuppression is started. Necrosis and the epidemiological context contribute to the differential diagnosis, but no single feature is absolute.

Other less frequent findings include neutrophilic infiltrates in bacterial infections or in the very early phase of certain lesions, plasma cells in particular infections and immune conditions, and a histiocytic component in systemic processes. An unusual cell predominance should not be forced into common categories: it may provide a causal clue and require special stains, immunophenotyping, in situ hybridization or hematopathology assessment. The mixed pattern is itself informative when described precisely.

Distribution adds an essential layer to the description, because focal, multifocal or diffuse, interstitial, perivascular, subendocardial or replacement lesions carry different sampling errors and functional consequences. Conduction-system involvement causes block disproportionate to dysfunction, while patchy scar facilitates ventricular re-entry; microvascular involvement may generate ischemia without epicardial coronary disease. Morphology thus explains why patients with the same ejection fraction can have radically different electrical risks.

Healing does not consist simply of disappearance of the infiltrate, because macrophages clear debris, fibroblasts deposit matrix and scar replaces lost cardiomyocytes, sometimes leaving a permanent substrate even after remission. The report may therefore describe active, resolving or previous myocarditis, but the phase must be correlated with troponin, CMR edema and the clinical course. Mature fibrosis does not prove that the process remains immune-mediated, just as edema and cytokines can depress function before extensive necrosis appears.

Clinical Manifestations

No symptom identifies a histological subtype with certainty, because chest pain with troponin elevation, dyspnea, palpitations, syncope and shock occur in many forms and presentation depends more on the location and speed of injury than on the predominant cell alone. Uncomplicated lymphocytic myocarditis often presents with an infarct-like phenotype and preserved function, but it can also be fulminant; giant cells and eosinophils increase suspicion in an aggressive course without making a definitive clinical diagnosis possible.

The combination of rapidly progressive heart failure, ventricular tachycardias and atrioventricular block should accelerate biopsy because it makes forms in which early treatment is decisive plausible. Giant cell myocarditis can progress despite initial conventional support, whereas sarcoidosis and granulomatous diseases may present with block or arrhythmia before function declines. Electrocardiography and continuous monitoring are therefore part of indirect histopathological characterization because they help determine the urgency and site of tissue sampling.

Rash, fever, eosinophilia, asthma, neuropathy, renal or hepatic failure and recent introduction of a drug suggest an eosinophilic or hypersensitivity form, although the complete constellation is uncommon. Similarly, lymphadenopathy, pulmonary nodules, uveitis and hypercalcemia may point toward sarcoidosis, although they may be absent in isolated cardiac disease. An accessible extracardiac biopsy can provide the diagnosis with lower risk, provided that the finding is truly representative of the suspected systemic process.

Immunosuppression, travel or origin from endemic areas, contact with tuberculosis and exposure to parasites or fungi modify the interpretation of granulomas, eosinophils and necrosis. In these contexts, empirical immunosuppression can worsen an unrecognized infection, and samples must be allocated in advance for microbiology and molecular analysis. The mere absence of fever or positive blood cultures is insufficient to consider the myocardial process sterile.

Checkpoint inhibitors can produce myocarditis with a predominantly lymphocytic and macrophagic infiltrate, sometimes associated with myositis, myasthenia and conduction disturbances. The presentation can be severe even with a nondiagnostic CMR and preserved ejection fraction, making biopsy particularly important when clinical probability remains high. The pathologist should know the exposure because morphology may overlap with conventional lymphocytic myocarditis, and the diagnosis arises from convergence of tissue findings and the oncology timeline.

In children the histological spectrum is similar, but causes, presentation and ability to tolerate sampling differ. Tachypnea, feeding difficulties, irritability and shock may precede a specific description of symptoms; in adolescents, pain and arrhythmias become more prominent. The choice to perform biopsy should balance procedural risk and potential diagnostic benefit, recognizing that a fulminant form cannot be reliably classified from age or echocardiography alone.

The clinical course after the acute phase completes the meaning of the finding. Persistent troponin elevation, new dysfunction, increased LGE or arrhythmias indicate activity or structural consequences that may require reassessment; normalization of biomarkers does not erase scar. A second biopsy is not performed routinely, but it may be useful when response to treatment is unexpected, the initial diagnosis is uncertain or the decision to continue high-risk therapy depends on demonstrating residual activity.

Investigations and Diagnosis

The work-up begins with electrocardiography, troponin, natriuretic peptides, complete blood count with differential, inflammatory markers, renal and hepatic function and echocardiography; these tests define severity and possible causal clues, but none establishes the histological subtype. Eosinophilia, conduction blocks, effusion, biventricular dysfunction or regional abnormalities increase the value of biopsy; normal results, especially if obtained after therapy, do not exclude a focal or early lesion.

Multiparametric CMR identifies edema and nonischemic injury using T1 and T2 mapping, extracellular volume and late gadolinium enhancement. The LGE pattern may suggest distributions more compatible with certain diseases, but overlap is broad and does not permit a cellular diagnosis. Its most concrete contribution is to localize active segments, avoid purely scarred areas and integrate function and prognosis; a negative CMR does not exclude focal, early or already treated high-risk disease.

Fluorodeoxyglucose PET, prepared by suppressing physiological myocardial uptake, is particularly useful in sarcoidosis and some persistent inflammatory conditions; focal uptake can guide sampling and monitor response, but preparation artifacts and nonspecific activity limit precision. PET and CMR answer different questions from tissue: they document metabolism, edema and scar, whereas biopsy shows cells, injury and potential agents.

The biopsy procedure should be planned collaboratively, because in diffuse diseases the right ventricle can provide adequate samples with established expertise; in predominantly left-sided or localized lesions, left ventricular or biventricular sampling may increase yield, provided the center has the necessary experience. Guidance with CMR, PET or electroanatomical mapping reduces sampling error in focal phenotypes without eliminating it; multiple fragments are taken from different sites, avoiding consumption of all material in a single method.

Some samples are fixed for histology and immunohistochemistry, while others must be kept sterile and rapidly frozen or processed according to the laboratory protocol for PCR, culture or electron microscopy. Formalin can compromise some molecular analyses, and lack of planning makes them impossible to recover later. Hematoxylin-eosin, trichrome and microorganism-specific stains form the basis; antibodies against leukocyte, lymphocyte, macrophage, endothelial and HLA markers define the quantity and phenotype of the infiltrate.

The Dallas criteria codified active myocarditis through an inflammatory infiltrate associated with myocyte necrosis or injury not typical of ischemia, distinguishing it from less defined findings. The main limitations are sampling, interobserver variability and poor sensitivity for small but biologically significant infiltrates. Immunohistochemistry increases the ability to detect and quantify inflammation, but thresholds must be applied to adequate tissue and do not replace morphological evidence of injury.

The 2025 Seaport criteria propose three grades of lymphocytic myocarditis and a SITUS category for endomyocardial biopsy; for surgical or autopsy specimens they instead distinguish active myocarditis and LIUS. Specific criteria are provided for endomyocardial biopsy and for surgical or autopsy specimens, which differ in size and evaluability. The advantage is to avoid labeling every small aggregate as myocarditis and to describe severity more reproducibly while preserving the requirement for clinicopathological correlation.

Testing for viral or microbial genomes should use controls, validated methods and quantitative or contextual interpretation. A positive result may indicate causal infection, persistence, latency or contamination depending on the agent and cellular site; a negative result may reflect an insufficient sample, late timing or limited sensitivity. Routine viral serology rarely identifies the myocardial agent and does not replace tissue testing, while cultures and systemic tests are selected according to pretest probability.

The ideal report describes adequacy and number of fragments, infiltrate and immunophenotype, distribution, cardiomyocyte injury, necrosis, granulomas, vasculitis, deposits and fibrosis, specifying stains and limitations. It should also integrate molecular results without overinterpreting them and indicate residual differential diagnoses. Direct discussion among cardiologist, pathologist, radiologist, infectious-disease specialist and immunologist is often more informative than an isolated formula, especially when a negative result conflicts with a high-risk clinical phenotype.

Treatment and Prognosis

Hemodynamic stabilization precedes definitive classification; oxygenation, treatment of congestion, correction of arrhythmias and circulatory support are tailored to the patient's profile, avoiding drugs that worsen hypotension or organ failure. In refractory shock, early transfer to a center capable of biopsy, ventricular assist support and transplantation creates the time needed to obtain the diagnosis and start specific treatment before irreversible deterioration occurs.

An uncomplicated lymphocytic form is treated mainly with temporary rest, arrhythmia control and heart-failure therapy when necessary; immunosuppression is not automatic, because many acute forms improve spontaneously and active infection may be worsened by treatment. In selected patients with biopsy-documented, virus-negative inflammatory cardiomyopathy and persistent dysfunction, studies such as TIMIC support a benefit from combination regimens; this evidence should not be indiscriminately extended to every lymphocytic infiltrate.

Giant cell disease, severe eosinophilic forms and checkpoint inhibitor myocarditis require a rapid and specific immune strategy, often started while characterization is being completed when immediate risk is high. Regimen, intensity and duration depend on histological subtype and cause, and corticosteroid monotherapy may be insufficient in giant cell myocarditis; clinical response does not eliminate the need to monitor opportunistic infections, toxicity, recurrence and persistence of the arrhythmic substrate.

In granulomatous forms, treatment depends on distinguishing sarcoidosis from infection. The former may require corticosteroids and steroid-sparing agents guided by activity, function and arrhythmias; tuberculosis, mycoses and other infections instead require targeted antimicrobial therapy and make unprotected immunosuppression potentially dangerous. Etiologic investigation is therefore not an academic step but a component of histological-subtype-guided treatment.

The prognosis of a histological form cannot be expressed as a simple hierarchy. Giant cell myocarditis and necrotizing eosinophilic myocarditis are associated with an often aggressive course, but early diagnosis and treatment modify outcomes; the lymphocytic form has, on average, a greater probability of recovery while still including fulminant presentations and arrhythmogenic scars. Sarcoidosis and granulomatous diseases may preserve pump function while causing conduction block and ventricular tachycardias, making ejection fraction alone insufficient.

Follow-up integrates symptoms, ECG, Holter monitoring, echocardiography, troponin, natriuretic peptides and CMR according to severity and etiology. PET is useful when granulomatous activity must be distinguished from scar, while a repeat biopsy is reserved for questions capable of changing treatment. Return to physical and sports activity requires clinical remission, stable biomarkers, adequate function and absence of significant arrhythmias; any residual LGE is interpreted together with electrical burden.

Long-term prognosis arises from the intersection of reversible activity and permanent injury. Therapy may eliminate the infiltrate without removing scar, and a heart with normalized function may retain arrhythmic risk; conversely, edema and cytokine-mediated depression can produce severe initial dysfunction followed by recovery. Decisions about devices and transplantation should therefore consider trajectory, histological subtype, fibrosis distribution, genotype and rhythm events, not a single snapshot.

Complications

Acute heart failure results from myocyte loss, edema and immune-mediated contractile depression and may progress to shock with multiorgan failure; diffusely necrotizing forms rapidly reduce contractile mass, while focal processes in strategic sites may cause instability disproportionate to their extent. Mechanical support can serve as a bridge to recovery, decision or transplantation, but its success depends on timeliness and protection of neurological and other organ function.

Ventricular arrhythmias arise both from active inflammation, which changes automaticity and refractoriness, and from scar, which creates re-entry circuits. Tachycardia, ventricular fibrillation and sudden death can occur with preserved function, especially in patchy diseases or septal involvement; controlling inflammation may reduce arrhythmic burden but does not replace evaluation for a defibrillator when clinical indications persist.

Atrioventricular block is particularly relevant in giant cell, granulomatous and checkpoint inhibitor-associated forms. It may be transient as edema decreases or reflect permanent destruction and fibrosis of the conduction system; the need for pacing is decided according to stability and probability of recovery. Unexplained block in a young or middle-aged adult warrants etiologic investigation before being treated as isolated degenerative disease.

Chronic progression leads to inflammatory cardiomyopathy, dilation, functional mitral regurgitation and persistent heart failure. Reduction of the infiltrate does not automatically stop remodeling already sustained by wall stress and neurohormonal pathways, making comprehensive heart-failure therapy necessary. Interstitial and replacement fibrosis limit reverse remodeling and maintain electrical risk even when troponin and inflammatory markers are normal.

Endocardial injury, severe dysfunction and eosinophilia can promote intracardiac thrombi and systemic or pulmonary embolism. In hypereosinophilic syndromes, progression toward endomyocardial fibrosis and valvular impairment is a specific complication, whereas a large aneurysm or markedly dilated ventricle creates stasis in other histological subtypes as well. Anticoagulation is based on documented thrombus, atrial fibrillation and embolic risk profile, not on the diagnosis of myocarditis alone.

Immunosuppression and antimicrobials have their own complications: opportunistic infections, cytopenias, renal or hepatic injury, metabolic abnormalities and drug interactions. Screening, prophylaxis and monitoring should be built into the plan from the outset, because toxicity can become the main determinant of prognosis during prolonged treatment. In infectious etiologies, incomplete therapy may promote persistence or recurrence, whereas in immune disease an overly rapid taper may reactivate the process.

The subtler risk is an incorrect diagnostic conclusion derived from a nonrepresentative sample; a false negative may delay life-saving therapy, whereas interpreting a small nonspecific infiltrate as active disease unnecessarily exposes the patient to immunosuppression. Sample quality, review by a cardiovascular pathologist, comparison with imaging and willingness to reconsider the diagnosis are therefore concrete safety measures, not merely academic refinements.