◆

Subtypes

5

Viral myocarditis MONDO:0023161

Myocarditis in which a cardiotropic virus is the initiating insult. Enteroviruses (notably coxsackievirus B), parvovirus B19, human herpesvirus 6, adenovirus, influenza and SARS-CoV-2 are the agents most often recovered from myocardium. The endomyocardial-biopsy virome has shifted over time from enterovirus-dominant to parvovirus B19- and HHV-6-dominant, and detection of viral nucleic acid alone does not establish that the virus is causing the current inflammation rather than sitting latent in endothelium.

Show evidence (1 reference)

PMID:35533750 SUPPORT Human Clinical

"Most frequently, virus DNA was detected by PCR from parvovirus B19 (PVB19, 59%) and human herpesvirus 6 (HHV6, 26%)."

Reports the contemporary distribution of viral genomes recovered by PCR from endomyocardial biopsies in biopsy-proven viral myocarditis.

Lymphocytic myocarditis

The commonest histological form: a T-cell-rich mononuclear infiltrate with associated myocyte injury. It is the histological correlate of most presumed-viral and idiopathic myocarditis, and is the form in which the Myocarditis Treatment Trial found no benefit from routine immunosuppression. It has no distinct MONDO identifier; it is a biopsy-defined pattern rather than an aetiology.

Show evidence (1 reference)

PMID:31319912 SUPPORT Human Clinical

"In a subanalysis including only adults with lymphocytic myocarditis, the main endpoints occurred more frequently in FM compared with in NFM both at 60 days (19.5% vs. 0%, p = 0.005) and at 7-year follow up (41.4% vs. 3.1%, p = 0.0004)."

Treats lymphocytic myocarditis as a distinct histological stratum with its own outcome profile, supporting it as a curated subtype.

Giant cell myocarditis MONDO:0023232

A destructive T-cell and macrophage myocarditis containing multinucleated giant cells and extensive myocyte necrosis, occurring in relatively young, previously healthy adults and frequently associated with other autoimmune disease. It is the aetiological form for which the lump/split decision matters most clinically: untreated it is near-uniformly fatal within months, it responds to combination immunosuppression, and it can recur in the transplanted heart.

Show evidence (2 references)

PMID:9197214 SUPPORT Human Clinical

"Giant cell myocarditis is a disease of relatively young, predominantly healthy adults."

The multicenter natural-history series that defined giant cell myocarditis as a distinct clinical entity.

PMID:9197214 SUPPORT Human Clinical

"Nineteen percent had associated autoimmune disorders."

Supports the association of the giant cell form with systemic autoimmunity, which distinguishes it from presumed-viral lymphocytic myocarditis.

Eosinophilic and hypersensitivity myocarditis

Myocarditis with an eosinophil-rich infiltrate, most often provoked by a drug (hypersensitivity myocarditis) or occurring in the setting of a systemic eosinophilic disorder such as eosinophilic granulomatosis with polyangiitis. Peripheral eosinophilia is usual but not obligatory. The hypersensitivity form has the highest in-hospital mortality of the eosinophilic subgroups, and the first therapeutic step is withdrawal of the offending agent rather than a drug.

Show evidence (1 reference)

PMID:29096807 SUPPORT Human Clinical

"The disorders most frequently associated with EM were hypersensitivity and eosinophilic granulomatosis with polyangiitis, which accounted for 34.1% and 12.8% of cases, respectively, whereas idiopathic or undefined forms accounted for 35.7% of cases."

Establishes the aetiological composition of the eosinophilic form from a systematic review of histologically proven cases.

Immune checkpoint inhibitor-associated myocarditis

Myocarditis precipitated by cancer immunotherapy targeting CTLA-4, PD-1 or PD-L1. It is uncommon but has the highest case fatality of any immune-related adverse event, typically presents within weeks of the first doses, and frequently overlaps with myositis and myasthenia gravis. Mechanistically it is not a hypersensitivity reaction: the myocardial infiltrate carries the same T cell clones found in the tumour and skeletal muscle. Combination CTLA-4 plus PD-1 blockade is the best-established risk factor.

Show evidence (1 reference)

PMID:30242316 SUPPORT Human Clinical

"Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities"

Establishes checkpoint-inhibitor myocarditis as the most lethal immune-related adverse event in a global pharmacovigilance analysis.

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Mechanistic Hypotheses

2

Post-infectious autoimmunity against cardiac myosin sustains chronic injury

postinfectious_autoimmunity CANONICAL

Evidence balance 1 support

Under this model the initiating virus is cleared, but antigen release and the inflammatory context break tolerance to cardiac myosin. Cross-reactive T cells and autoantibodies then sustain myocardial injury after the virus is gone, which is why virus-negative inflammatory cardiomyopathy responds to immunosuppression.

Pathograph links

Anti-Cardiac Myosin Autoimmunity -> Adaptive T Cell-Mediated Myocardial Injury DIRECT Under the post-infectious autoimmunity model, anti-myosin reactivity is what keeps the adaptive infiltrate running after the virus is cleared.

Cardiomyocyte Necrosis and Contractile Failure -> Anti-Cardiac Myosin Autoimmunity INDIRECT KNOWN INTERMEDIATES Cardiac myosin released by dying myocytes is presented in an inflamed, adjuvant-rich myocardium, which is how tolerance is broken. This closes an amplification loop - injury releases the autoantigen, autoimmunity sustains the injury - and is why the chronic phase persists after the initiating virus is gone. The loop is intentional and mechanistically load-bearing, not an artefact of edge curation.

Show evidence (1 reference)

PMID:11334481 SUPPORT Model Organism

"The chronic phase of myocarditis is associated with mononuclear infiltration of the myocardium and the production of autoantibodies to cardiac myosin, although infectious virus cannot be detected past day 14 of infection."

Describes the defining observation of this hypothesis: chronic myocardial inflammation and anti-myosin autoantibodies persisting after the virus has become undetectable.

Persistent myocardial viral genome drives ongoing injury and remodelling

viral_persistence ALTERNATIVE

Evidence balance 1 support

The competing model holds that low-level viral persistence in the myocardium, rather than autoimmunity, drives continuing injury; the corollary is that clearance predicts recovery and persistence predicts deterioration, and that immunosuppression could be harmful. The two hypotheses are not mutually exclusive and probably apply to different patients, which is exactly why endomyocardial biopsy with viral PCR governs whether immunosuppression is offered.

Pathograph links

Cardiotropic Viral Infection of the Myocardium -> Post-Inflammatory Ventricular Remodeling INDIRECT UNKNOWN INTERMEDIATES Under the viral-persistence model, failure to clear myocardial virus sustains injury and remodelling directly, without requiring an autoimmune intermediate.

Show evidence (1 reference)

PMID:14722762 SUPPORT Human Clinical

"Advances in molecular diagnosis have indicated beyond doubt that persistence of viral infection is associated with disease deterioration and poor prognosis."

States the central claim of the viral-persistence model: continued presence of viral genome in myocardium tracks with clinical deterioration.

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Discussions and Knowledge Gaps

3

Why do some patients with acute myocarditis recover with no residual myocardial injury while others progress to dilated cardiomyopathy?

KNOWLEDGE GAP OPEN why_some_progress_to_dcm

Attached to

pathophysiology#Post-Inflammatory Ventricular Remodeling pathophysiology#Inflammatory Dilated Cardiomyopathy

This is the determining question for the whole entry: the acute phase is usually survivable and the chronic phase is not reversible, so everything that matters clinically turns on which patients cross between them. The relative contributions of the pathogen, host genotype and environment are unsettled, which is also why no treatment strategy is established for preventing the transition. The two hypothesis groups curated above - post-infectious autoimmunity and viral persistence - are the leading competing explanations and are not mutually exclusive.

Show evidence (1 reference)

PMID:33046850 SUPPORT Other

"The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders."

Names the gap explicitly, including the unresolved question of which detected viruses are actually causal.

Do the two standard rodent models - coxsackievirus B3 infection and cardiac myosin-induced experimental autoimmune myocarditis - reproduce the mechanisms that actually drive human myocarditis, given that enterovirus is now a minority cause and that no human disease begins with adjuvanted self-antigen immunization?

HUMAN MODEL MISMATCH OPEN eam_cvb3_translational_validity

Attached to

pathophysiology#Cardiotropic Viral Infection of the Myocardium pathophysiology#Anti-Cardiac Myosin Autoimmunity

Most of the mechanistic content in this entry - innate sensing, dystrophin cleavage, anti-myosin autoimmunity, IL-17-driven fibrosis - rests on these two models, and both have a specific translational problem. CVB3 models an agent that contemporary human endomyocardial biopsy recovers far less often than parvovirus B19 or HHV-6, and its outcome is strongly conditioned on strain, sex and viral passage. Experimental autoimmune myocarditis reproduces the effector autoimmunity faithfully but starts from a deliberate adjuvanted immunization that has no human counterpart, so it cannot speak to how tolerance is broken in the first place. Evidence exists in these models; what is uncertain is how far it carries.

Show evidence (1 reference)

PMID:35533750 SUPPORT Human Clinical

"Most frequently, virus DNA was detected by PCR from parvovirus B19 (PVB19, 59%) and human herpesvirus 6 (HHV6, 26%)."

Shows that the viruses recovered from contemporary human myocardium are not the one modelled by the standard CVB3 system.

Should the immune_checkpoint_blockade module gain an immune-related-adverse-event arm so that checkpoint-inhibitor myocarditis, colitis, pneumonitis and hepatitis can declare conformance to a shared off-target-toxicity mechanism?

CURATION TODO OPEN ici_myocarditis_module_gap

Attached to

pathophysiology#Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity

The checkpoint-inhibitor form of myocarditis is a textbook treatment-toxicity conformer, but the existing module models only the anti-tumour arm - neoantigen generation, anti-tumour T cell response, adaptive immune resistance, T cell exhaustion - and has no node describing loss of peripheral tolerance in a non-tumour tissue. Rather than anchor this node to a tumour-immunity node it does not describe, no conforms_to is asserted here. Adding a shared irAE node to the module would let several disorder entries converge on it.

⚙

Pathophysiology

14

Cardiotropic Viral Infection of the Myocardium

A cardiotropic virus reaches and infects the myocardium. Enteroviruses such as coxsackievirus B enter cardiomyocytes through the coxsackievirus and adenovirus receptor; parvovirus B19 and HHV-6 are recovered most often from contemporary biopsies and are largely endothelial in tropism; SARS-CoV-2 can be detected in myocardium in fatal COVID-19, but usually as very rare infected cells. Direct viral replication is only the opening move - in most cases the burden of injury is delivered by what the host does next.

Persistent myocardial viral genome drives ongoing injury and remodelling

Cardiomyocyte CL:0000746

Viral entry into the cardiomyocyte GO:0046718 ↑ INCREASED

Animal models

Wild-type BALB/c infected with coxsackievirus B3 Mouse Mouse recapitulates Reproduces cardiotropic enteroviral infection of the myocardium and the biphasic acute-then-chronic inflammatory course.

Downstream

Direct Cardiomyocyte Cytoskeletal Injury

Innate Immune Sensing and Cytokine Amplification

Post-Inflammatory Ventricular Remodeling Under the viral-persistence model, failure to clear myocardial virus sustains injury and remodelling directly, without requiring an autoimmune intermediate.

Show evidence (2 references)

PMID:33046850 SUPPORT Other

"Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases."

Establishes viral infection as the predominant trigger while naming the non-viral triggers modelled elsewhere in this entry.

PMID:33727695 SUPPORT Human Clinical

"In the cases with cardiac infection, SARS-CoV-2+ cells in the myocardium were rare, with a median density of 1 cell/cm2."

Supports myocardial viral presence while qualifying its extent - the density of infected cells is too low for direct cytolysis alone to explain the injury.

Direct Cardiomyocyte Cytoskeletal Injury

Coxsackievirus B3 protease 2A cleaves dystrophin, and the cleaved carboxyl terminus and its associated sarcoglycan complex are lost from the sarcolemma. The result is functional membrane fragility that phenocopies the hereditary sarcoglycanopathies, giving enteroviral myocarditis a mechanism of contractile failure that is independent of immune-mediated killing.

Cardiomyocyte CL:0000746

Sarcolemma GO:0042383

Animal models

Wild-type BALB/c infected with coxsackievirus B3 Mouse Mouse recapitulates Murine CVB3 hearts show loss of sarcolemmal dystrophin and dissociation of the sarcoglycan complex, the structural lesion this node asserts.

Downstream

Cardiomyocyte Necrosis and Contractile Failure

Show evidence (2 references)

PMID:10988241 SUPPORT Model Organism

"We found that in cultured cardiac myocytes and murine hearts infected with coxsackievirus B3, the sarcolemmal localization of the dystrophin carboxyl terminus is lost."

Demonstrates the loss of sarcolemmal dystrophin in coxsackievirus B3-infected cardiomyocytes both in culture and in vivo.

PMID:10988241 SUPPORT Model Organism

"In vivo, the sarcolemmal integrity was functionally impaired with Evans blue dye uptake even though there was no generalized disruption of the sarcolemma of infected myocytes"

Shows the loss is functional membrane fragility rather than gross membrane destruction, which is what makes it a distinct injury mechanism.

Innate Immune Sensing and Cytokine Amplification

Cytosolic and membrane pattern-recognition receptors sense viral RNA and released damage-associated molecules. NOD2 is induced in the myocardium of virus-positive patients and drives NLRP3-caspase-1-IL-1beta signalling and viral uptake; monocytes and macrophages are recruited and generate IL-1, IL-6, TNF and reactive oxygen species. This is the step that converts a focal infection into diffuse myocardial inflammation, and it is the target of IL-1 blockade.

Macrophage CL:0000235

Innate immune response GO:0045087 ↑ INCREASED Inflammatory response GO:0006954 ↑ INCREASED

Animal models

NOD2 knockout, coxsackievirus B3 infected Mouse Mouse perturbs Genetic removal of the innate sensor establishes that this node is causally required for the downstream inflammation, fibrosis and contractile loss.

Downstream

Adaptive T Cell-Mediated Myocardial Injury

Cardiomyocyte Necrosis and Contractile Failure

Show evidence (3 references)

PMID:28912259 SUPPORT Human Clinical

"Endomyocardial biopsy NOD2 mRNA expression was higher in CVB3-positive patients compared with patients with myocarditis but without evidence of persistent CVB3 infection."

Human biopsy evidence that innate viral sensing through NOD2 is upregulated specifically in virus-positive myocarditis.

PMID:28912259 SUPPORT Model Organism

"NOD2 knockdown(-/-) mice were rescued from the detrimental CVB3-mediated effects as shown by a reduced cardiac inflammation (less cardiac infiltrates and suppression of proinflammatory cytokines), cardiac fibrosis, apoptosis, lower CAR (Coxsackievirus and adenovirus receptor) expression and CVB3..."

Loss-of-function evidence that innate sensing is causally required for the inflammation, fibrosis and contractile loss downstream of it.

PMID:33727695 SUPPORT Human Clinical

"Virus+ cases showed higher densities of myocardial CD68+ macrophages and CD3+ lymphocytes, as well as more electrocardiographic changes (23/27 vs 4/10; P = 0.01)."

Links myocardial viral presence to macrophage and lymphocyte recruitment and, in turn, to electrical abnormality in human hearts.

Anti-Cardiac Myosin Autoimmunity

Antigen release in an inflamed myocardium, together with viral epitopes that cross-react with the cardiac myosin heavy chain, breaks tolerance. The resulting anti-cardiac-myosin response outlives the infection and is itself sufficient to cause myocardial inflammation and necrosis - passive transfer of the antibodies reproduces the lesion in uninfected animals. This node is the mechanistic content of the post-infectious autoimmunity hypothesis and the rationale for immunosuppressing virus-negative inflammatory cardiomyopathy.

Post-infectious autoimmunity against cardiac myosin sustains chronic injury

Adaptive immune response against cardiac myosin GO:0002250 ↑ INCREASED

Animal models

Cardiac myosin-immunized susceptible strain (experimental autoimmune myocarditis) Mouse Mouse recapitulates Immunization against cardiac myosin reproduces the autoimmune arm and shows that anti-myosin reactivity alone is sufficient to cause myocarditis.

Downstream

Adaptive T Cell-Mediated Myocardial Injury Under the post-infectious autoimmunity model, anti-myosin reactivity is what keeps the adaptive infiltrate running after the virus is cleared.

Show evidence (2 references)

PMID:1315309 SUPPORT Model Organism

"Passive transfer of anti-cardiac myosin antibodies from Day 56 post-infection sera of the BALB/c strain induced inflammation and necrosis of the myocardium of uninfected BALB/c recipients."

Transfer experiment showing the autoantibody response is sufficient, not merely correlated, to produce myocardial inflammation and necrosis.

PMID:1315309 SUPPORT Model Organism

"These affinity-purified anti-cardiac myosin antibodies cross-react with MCMV protein(s)."

Direct demonstration of the molecular mimicry between viral protein and cardiac myosin that this node asserts.

Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity

Blockade of CTLA-4, PD-1 or PD-L1 removes the inhibitory signalling that normally restrains T cell activation, including in the heart. The myocardial infiltrate in checkpoint-inhibitor myocarditis carries the same clonally expanded T cell populations found in the tumour and in skeletal muscle, so this is not hypersensitivity to a drug but a loss of peripheral tolerance that lets a tumour-directed T cell response spill onto a shared cardiac and skeletal-muscle antigen. It explains the frequent myositis and myasthenic overlap.

CD8-positive cytotoxic T cell CL:0000625

Negative regulation of T cell activation GO:0050868 ↓ DECREASED

Downstream

Adaptive T Cell-Mediated Myocardial Injury

Show evidence (2 references)

PMID:27806233 SUPPORT Human Clinical

"Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle."

The clonal identity between tumour, skeletal muscle and myocardial T cells is the direct evidence that this is shared-antigen off-target reactivity.

PMID:38982146 SUPPORT Other

"Inflammation of the heart muscle, known as myocarditis, resulting from ICI targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1) and PD1 ligand 1 (PDL1) is an infrequent but potentially fatal complication."

Attributes the myocarditis specifically to pharmacological targeting of the CTLA4 and PD1/PDL1 checkpoint axes.

Eosinophil-Mediated Myocardial Injury

In the eosinophilic and hypersensitivity forms the infiltrate is eosinophil-rich and the injury is driven by eosinophil degranulation products rather than by cytotoxic T cells. It arises either as a drug hypersensitivity reaction or as cardiac involvement of a systemic eosinophilic disorder, and peripheral eosinophilia accompanies about three-quarters of cases.

Eosinophil CL:0000771

Inflammatory response GO:0006954 ↑ INCREASED

Downstream

Cardiomyocyte Necrosis and Contractile Failure

Show evidence (2 references)

PMID:29096807 SUPPORT Human Clinical

"Eosinophilic myocarditis (EM) is an acute life-threatening inflammatory disease of the heart."

Establishes the eosinophilic form as a distinct, severe inflammatory myocardial disease.

PMID:29096807 SUPPORT Human Clinical

"with peripheral eosinophilia observed in 75.9%"

Quantifies how often the systemic eosinophil expansion accompanies the myocardial lesion.

Giant Cell Destructive Myocardial Necrosis

In giant cell myocarditis the infiltrate contains multinucleated giant cells and the myocyte necrosis is unusually extensive and rapidly progressive. Clinically it converges on the same endpoints as other forms - heart failure, ventricular arrhythmia and heart block - but at a pace that makes it the histological subtype with the worst prognosis, and it is the one form in which combination immunosuppression clearly prolongs survival.

Multinucleated giant cell CL:0000647 Macrophage CL:0000235

Downstream

Cardiomyocyte Necrosis and Contractile Failure

Electrical Instability and Arrhythmogenesis

Show evidence (2 references)

PMID:9197214 SUPPORT Human Clinical

"Most presented with congestive heart failure (47 patients, or 75 percent), ventricular arrhythmia (9 patients, or 14 percent), or heart block (3 patients, or 5 percent)"

Shows the giant cell form converging on the same heart-failure, arrhythmia and conduction endpoints as other myocarditis subtypes.

PMID:31319912 SUPPORT Human Clinical

"the histologic subtype emerged as a further variable affecting the outcome in FM patients, with giant cell myocarditis having a significantly worse prognosis compared with eosinophilic and lymphocytic myocarditis"

Establishes that the giant cell histology carries independent prognostic weight beyond the severity of presentation.

Genetically Susceptible Myocardium

A minority of patients carry a pathogenic or likely pathogenic variant in an inherited-cardiomyopathy gene, and that background modifies how the myocardium responds to an inflammatory insult. Such variants are found in around 4% of uncomplicated acute myocarditis but in roughly a fifth of adults and nearly half of children whose myocarditis is complicated by heart failure, reduced ejection fraction, or life-threatening ventricular arrhythmia, with desmosomal genes predominating in the milder group and sarcomeric genes in the severe one. This is a susceptibility and severity modifier, not a cause of myocarditis - the inflammatory episode still needs its own trigger.

Cardiomyocyte CL:0000746

Downstream

Cardiomyocyte Necrosis and Contractile Failure A vulnerable structural background lowers the threshold at which an inflammatory insult produces clinically significant myocyte loss and contractile failure. The intermediate steps are not established, and the evidence is an association between genotype and severity rather than a demonstrated mechanism.

Post-Inflammatory Ventricular Remodeling

Show evidence (2 references)

PMID:38573261 SUPPORT Human Clinical

"For uncomplicated myocarditis, the pooled prevalence was 4.2% (95% CI: 1.8%-7.4%; I2 = 1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95% CI: 14.3%-30.5%; I2 = 38.8%) and 44.5% (95% CI: 22.7%-67.4%; I2 = 52.8%) in adults and children, respectively."

Quantifies the enrichment of cardiomyopathy-gene variants in severe versus mild acute myocarditis, which is the severity-modifier claim this node makes.

PMID:38573261 SUPPORT Human Clinical

"P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children)."

Establishes that the gene classes involved differ by clinical severity, which is why this node is curated as a modifier rather than as a single susceptibility gene.

Adaptive T Cell-Mediated Myocardial Injury

The defining lesion of myocarditis: a T cell and macrophage infiltrate in the myocardium accompanied by injury to the adjacent myocytes. This is the node at which all of the aetiological entry points converge, and it is the node the histological definition of myocarditis actually names - an inflammatory infiltrate with myocyte injury, in multiple foci, not explained by another cause. Cytotoxic CD8 T cells kill infected or autoantigen-presenting myocytes; CD4 T cells and macrophages sustain the response.

CD8-positive cytotoxic T cell CL:0000625 CD4-positive helper T cell CL:0000624 Macrophage CL:0000235

T cell mediated cytotoxicity against cardiomyocytes GO:0001913 ↑ INCREASED Adaptive immune response GO:0002250 ↑ INCREASED

Myocardium UBERON:0002349

Downstream

Cardiomyocyte Necrosis and Contractile Failure

Electrical Instability and Arrhythmogenesis

Post-Inflammatory Ventricular Remodeling

Show evidence (2 references)

PMID:33727695 SUPPORT Human Clinical

"Myocarditis was defined as an inflammatory infiltrate associated with myocyte injury, which was not due to some other cause and was present in multiple foci"

States the operational histological definition this node encodes: infiltrate plus adjacent myocyte injury, multifocal, not otherwise explained.

PMID:27806233 SUPPORT Human Clinical

"In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates."

Documents the T cell and macrophage composition of the infiltrate in human myocarditis and its coupling to electrical instability.

Cardiomyocyte Necrosis and Contractile Failure

Myocyte death - by immune killing, by eosinophil granule toxicity, or by direct viral cytoskeletal disruption - releases troponin, removes contractile units, and together with interstitial oedema impairs systolic performance. This is the inflammatory instance of the generic primary cardiomyocyte insult that opens the maladaptive remodelling pathway shared with the inherited and toxic cardiomyopathies.

Post-infectious autoimmunity against cardiac myosin sustains chronic injury

Cardiomyocyte CL:0000746

Cardiomyocyte death GO:0010659 ↑ INCREASED Muscle contraction GO:0006936 ⚠ ABNORMAL

Downstream

Acute Contractile Failure and Cardiogenic Shock

Post-Inflammatory Ventricular Remodeling

Electrical Instability and Arrhythmogenesis

Anti-Cardiac Myosin Autoimmunity Cardiac myosin released by dying myocytes is presented in an inflamed, adjuvant-rich myocardium, which is how tolerance is broken. This closes an amplification loop - injury releases the autoantigen, autoimmunity sustains the injury - and is why the chronic phase persists after the initiating virus is gone. The loop is intentional and mechanistically load-bearing, not an artefact of edge curation.

Show evidence (2 references)

PMID:33046850 SUPPORT Other

"Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology."

Couples the myocardial infiltrate to deteriorating cardiac function, which is the claim this node makes.

PMID:10988241 SUPPORT Model Organism

"Enteroviral infection can cause an acquired form of dilated cardiomyopathy."

Supports the route from myocyte structural injury to acquired contractile failure, though from enteroviral models rather than from all aetiologies.

Acute Contractile Failure and Cardiogenic Shock

When myocyte loss and oedema are extensive and abrupt, ventricular systolic function collapses over hours to days and the patient presents in cardiogenic shock requiring inotropes or mechanical circulatory support. This fulminant presentation is where the acute mortality of myocarditis is concentrated, and it is also the point at which endomyocardial biopsy changes management, because the histological subtype independently predicts outcome.

Heart contraction GO:0060047 ↓ DECREASED

Show evidence (1 reference)

PMID:31319912 SUPPORT Human Clinical

"Fulminant myocarditis (FM) is a form of acute myocarditis characterized by severe left ventricular systolic dysfunction requiring inotropes and/or mechanical circulatory support."

Defines the fulminant haemodynamic phenotype this node represents.

Electrical Instability and Arrhythmogenesis

Inflammation, oedema and patchy necrosis disturb conduction and repolarisation directly, and the scar left behind provides a fixed re-entrant substrate. The result is ventricular tachyarrhythmia and high-grade atrioventricular block, and it is this arm rather than pump failure that accounts for myocarditis being a recognised cause of sudden death in young people with previously normal hearts.

Cardiomyocyte CL:0000746

Cardiac conduction GO:0061337 ⚠ ABNORMAL

Show evidence (2 references)

PMID:33727695 SUPPORT Human Clinical

"Cardiac infection by SARS-CoV-2 is associated with more cardiac inflammation and electrocardiographic changes."

Links myocardial inflammation to electrocardiographic abnormality in human hearts, supporting the inflammation-to-electrical-disturbance step.

PMID:9197214 SUPPORT Human Clinical

"Patients usually die of heart failure and ventricular arrhythmia unless cardiac transplantation is performed."

Establishes ventricular arrhythmia, alongside pump failure, as a principal mode of death in myocarditis.

Post-Inflammatory Ventricular Remodeling

Where inflammation does not resolve, cardiac fibroblasts are activated and lay down extracellular matrix, replacing lost myocardium with scar. IL-17 from Th17 cells is a direct fibrogenic signal in experimental autoimmune myocarditis, acting through PKC-beta, Erk1/2 and NF-kappaB. This node is the inflammatory entry into the conserved ventricular-remodelling step shared across the cardiomyopathies.

Cardiac fibroblast CL:0002548

Extracellular matrix deposition GO:0030198 ↑ INCREASED Collagen fibril organization GO:0030199 ↑ INCREASED Cardiomyocyte death GO:0010659 ↑ INCREASED

Animal models

Cardiac myosin-immunized susceptible strain (experimental autoimmune myocarditis) Mouse Mouse recapitulates The model develops post-myocarditis cardiac fibrosis and was used to establish IL-17 as a direct fibrogenic driver of it.

Downstream

Inflammatory Dilated Cardiomyopathy

Electrical Instability and Arrhythmogenesis Replacement fibrosis leaves a fixed scar that supports macro-re-entrant ventricular arrhythmia after the acute inflammation has settled.

Show evidence (2 references)

PMID:22531062 SUPPORT Model Organism

"The results indicated that IL-17 induced cardiac fibrosis both in vitro and in vivo."

Direct experimental evidence that a myocarditis-associated cytokine drives the fibrotic remodelling this node asserts.

PMID:22531062 SUPPORT Model Organism

"The protein kinase C (PKC)β/Erk1/2/NF-κB (Nuclear Factor κappa B) pathway was involved in the development of myocardial fibrosis and IL-17 contributed to cardiac fibrosis following EAM via this pathway."

Names the signalling route from the inflammatory cytokine to matrix deposition.

Inflammatory Dilated Cardiomyopathy

The chronic endpoint: a dilated, hypokinetic ventricle with persisting inflammation and established fibrosis, clinically indistinguishable from other dilated cardiomyopathy and carrying the same trajectory to heart failure, transplantation or death. Which patients arrive here rather than recovering is the central open question of the field.

Heart contraction GO:0060047 ⚠ ABNORMAL

Show evidence (2 references)

PMID:22531062 SUPPORT Other

"Myocarditis is a common clinical cardiovascular disease, and some patients progress to dilated cardiomyopathy (DCM) with chronic heart failure."

States the progression from myocarditis to dilated cardiomyopathy with chronic heart failure that this node represents.

PMID:33046850 SUPPORT Other

"Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis."

Supports the poor prognosis attached to the chronic inflammatory-cardiomyopathy endpoint.

✶

Histopathology

3

Lymphocytic Infiltrate of the Myocardium

Mononuclear, T-cell-predominant infiltration of the myocardium with injury to adjacent myocytes; the commonest histological pattern and the substrate of the Dallas-criteria diagnosis.

Show evidence (1 reference)

PMID:33727695 SUPPORT Human Clinical

"Virus+ cases showed higher densities of myocardial CD68+ macrophages and CD3+ lymphocytes, as well as more electrocardiographic changes (23/27 vs 4/10; P = 0.01)."

Quantifies the CD3+ lymphocyte and CD68+ macrophage composition of the myocardial infiltrate on human autopsy histology.

Eosinophilic Infiltrate of the Myocardium

Eosinophil-rich myocardial infiltration defining the eosinophilic and hypersensitivity forms on biopsy.

Show evidence (1 reference)

PMID:29096807 SUPPORT Human Clinical

"Based on a systematic revision of all published histologically proven cases, this study aimed to describe the clinical presentation, treatment, and outcome of EM."

Confirms that the eosinophilic form is defined and assembled histologically rather than clinically.

Cardiac Fibrosis

Replacement and interstitial fibrosis following myocyte loss, the histological correlate of chronic remodelling and of the arrhythmogenic scar substrate.

Show evidence (1 reference)

PMID:22531062 SUPPORT Model Organism

"western blot, immunofluorescence and sirius red staining were used to analyze the collagen expression"

Names the histological methods by which the post-myocarditis collagen deposition was demonstrated in the experimental model.

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Pathograph

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Phenotypes

13

Blood 1

Peripheral Eosinophilia VERY_FREQUENT Increased total eosinophil count HP:0001880

Show evidence (1 reference)

PMID:29096807 SUPPORT Human Clinical

"with peripheral eosinophilia observed in 75.9%"

Quantifies the frequency of peripheral eosinophilia in histologically proven eosinophilic myocarditis.

Cardiovascular 7

Myocarditis OBLIGATE HP:0012819

Show evidence (1 reference)

PMID:33727695 SUPPORT Human Clinical

"Myocarditis was defined as an inflammatory infiltrate associated with myocyte injury, which was not due to some other cause and was present in multiple foci"

Gives the histological definition of the defining phenotype.

Reduced Left Ventricular Ejection Fraction FREQUENT HP:0012664

Show evidence (1 reference)

PMID:29096807 SUPPORT Human Clinical

"Median left ventricular ejection fraction at presentation was 35% (interquartile range: 25% to 50%)."

Quantifies the degree of systolic impairment at presentation.

Congestive Heart Failure FREQUENT HP:0001635

Show evidence (1 reference)

PMID:9197214 SUPPORT Human Clinical

"Most presented with congestive heart failure (47 patients, or 75 percent), ventricular arrhythmia (9 patients, or 14 percent), or heart block (3 patients, or 5 percent)"

Quantifies heart failure as the dominant presentation in the giant cell form.

Ventricular Arrhythmia OCCASIONAL HP:0004308

Show evidence (1 reference)

PMID:9197214 SUPPORT Human Clinical

"Patients usually die of heart failure and ventricular arrhythmia unless cardiac transplantation is performed."

Establishes ventricular arrhythmia as a leading cause of death in myocarditis.

Atrioventricular Block OCCASIONAL HP:0001678

Show evidence (1 reference)

PMID:9197214 SUPPORT Human Clinical

"Most presented with congestive heart failure (47 patients, or 75 percent), ventricular arrhythmia (9 patients, or 14 percent), or heart block (3 patients, or 5 percent)"

Documents heart block as a presenting manifestation in the giant cell series.

Sudden Cardiac Death VERY_RARE HP:0001645

Show evidence (1 reference)

PMID:37955565 SUPPORT Human Clinical

"Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection."

Quantifies myocarditis as an adjudicated cause of sudden cardiac death in a 20-year athlete cohort, and notes it did not increase during the pandemic period.

Dilated Cardiomyopathy OCCASIONAL HP:0001644

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:14722762 SUPPORT Human Clinical

"Myocarditis is considered as a potent predisposing factor for dilated cardiomyopathy (DCM)."

Establishes dilated cardiomyopathy as a recognised sequela of myocarditis.

Respiratory 1

Dyspnea FREQUENT HP:0002094

Show evidence (1 reference)

PMID:29096807 SUPPORT Human Clinical

"The main symptom at presentation was dyspnea (59.4%)"

Quantifies dyspnea as the leading presenting symptom in a large series of histologically proven eosinophilic myocarditis.

Constitutional 1

Chest Pain FREQUENT HP:0100749

Temporal: ACUTE

Show evidence (1 reference)

PMID:35533750 SUPPORT Human Clinical

"Coronary spasm is a frequent finding in patients with biopsy-proven viral myocarditis supporting the hypothesis that coronary spasm may contribute to chest pain in these patients."

Documents chest pain as a presenting feature of biopsy-proven viral myocarditis and offers a mechanism for it.

Other 3

Cardiogenic Shock OCCASIONAL HP:0030149

Temporal: ACUTE

Show evidence (1 reference)

PMID:31319912 SUPPORT Human Clinical

"Fulminant myocarditis (FM) is a form of acute myocarditis characterized by severe left ventricular systolic dysfunction requiring inotropes and/or mechanical circulatory support."

Defines the shock phenotype and the support requirement that identifies it.

Elevated Cardiac Troponin VERY_FREQUENT Increased circulating troponin I concentration HP:0410173

Show evidence (1 reference)

PMID:37640625 SUPPORT Human Clinical

"symptomatic patients with elevated cardiac troponin and cardiac magnetic resonance-proven acute myocarditis"

Shows elevated cardiac troponin used as a defining criterion for acute myocarditis in a randomized trial population.

Myositis HP:0100614

Show evidence (1 reference)

PMID:27806233 SUPPORT Human Clinical

"In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates."

Documents the myositis overlap that characterises checkpoint-inhibitor myocarditis.

🧬

Genetic Associations

1

Cardiomyopathy-associated gene variants (Pathogenic or likely pathogenic variants in inherited-cardiomyopathy genes - desmosomal genes such as DSP and PKP2, and sarcomeric and cytoskeletal genes such as TTN, MYH7 and FLNC - are found in a substantial minority of patients with acute myocarditis and are markedly enriched in those with a complicated course. There is no myocarditis gene; the genotype modifies susceptibility and severity rather than causing the inflammatory episode, and it is one reason a myocarditis-like presentation can be the first manifestation of an inherited cardiomyopathy.)

relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:38573261 SUPPORT Human Clinical

"Genetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation."

States both the frequency of cardiomyopathy-gene variants in acute myocarditis and their dependence on age and presentation.

PMID:38573261 SUPPORT Human Clinical

"Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy."

Supports the overlap between acute myocarditis and inherited cardiomyopathy that makes genetic evaluation relevant; it does not itself establish causality.

💊

Medical Actions

9

Guideline-Directed Heart Failure Therapy and Supportive Care

Action: Supportive Care NCIT:C15747

The baseline for most patients. Ventricular dysfunction is treated with standard heart-failure therapy - in the ARAMIS trial population an ACE inhibitor and a beta-blocker were given as standard of care - alongside rhythm monitoring and haemodynamic support. Most uncomplicated cases are self-limited and need nothing more.

Show evidence (1 reference)

PMID:37640625 SUPPORT Human Clinical

"in addition to standard of care, including an angiotensin-converting enzyme inhibitor and a beta-blocker"

Documents ACE inhibition plus beta-blockade as the standard-of-care backbone in a contemporary randomized acute-myocarditis trial.

Immunosuppression for Virus-Negative Inflammatory Cardiomyopathy

Action: Immunosuppressive Therapy NCIT:C15261

Agent: prednisone CHEBI:8382 azathioprine CHEBI:2948

Prednisone plus azathioprine in patients with biopsy-proven myocarditis, chronic heart failure refractory to conventional therapy, and no myocardial viral genome. The TIMIC trial showed a significant improvement in ejection fraction and a reduction in ventricular dimensions in the treated arm while the placebo arm deteriorated. The pathogen-exclusion step is not optional - it is what separates this indication from the unselected population in which immunosuppression failed.

Mechanism Target:

Adaptive T Cell-Mediated Myocardial Injury — Suppresses the adaptive infiltrate that drives ongoing myocyte injury once the myocardium has been shown to be virus-free.

Show evidence (1 reference)

PMID:19556262 SUPPORT Human Clinical

"Group 1 showed a significant improvement of left-ventricular ejection fraction and a significant decrease in left-ventricular dimensions and volumes compared with baseline."

Randomized evidence that suppressing the immune infiltrate reverses the contractile and dimensional consequences of the mechanism.

Show evidence (2 references)

PMID:19556262 SUPPORT Human Clinical

"These data confirm the efficacy of immunosuppression in virus-negative inflammatory cardiomyopathy."

The trial conclusion supporting this indication.

PMID:7596370 REFUTE Human Clinical

"Our results do not support routine treatment of myocarditis with immunosuppressive drugs."

Recorded as a refuting item because it is the negative trial that bounds this indication: in unselected myocarditis, without virus exclusion, immunosuppression did not improve ejection fraction or survival.

Combination Immunosuppression for Giant Cell Myocarditis

Action: Immunosuppressive Therapy NCIT:C15261

Agent: prednisone CHEBI:8382 cyclosporine CHEBI:4031 azathioprine CHEBI:2948

Corticosteroids combined with cyclosporine, azathioprine, or both. In the multicenter registry, treated patients survived on average 12.3 months versus 3.0 months untreated. This is the clearest survival benefit from immunosuppression in any myocarditis subtype and is the practical reason the giant cell form must be identified on biopsy.

Mechanism Target:

Giant Cell Destructive Myocardial Necrosis — Suppresses the T cell and macrophage response responsible for the destructive giant cell lesion.

Show evidence (1 reference)

PMID:9197214 SUPPORT Human Clinical

"The 22 patients treated with corticosteroids and cyclosporine, azathioprine, or both therapies survived for an average of 12.3 months, as compared with an average of 3.0 months for the 30 patients who received no immunosuppressive therapy (P=0.001)."

Quantifies the survival gain from suppressing the giant cell lesion.

Show evidence (1 reference)

PMID:9197214 SUPPORT Human Clinical

"The 22 patients treated with corticosteroids and cyclosporine, azathioprine, or both therapies survived for an average of 12.3 months, as compared with an average of 3.0 months for the 30 patients who received no immunosuppressive therapy (P=0.001)."

The observational comparison supporting combination immunosuppression in the giant cell form.

Corticosteroid Therapy for Eosinophilic Myocarditis

Action: Pharmacotherapy NCIT:C15986

Agent: prednisone CHEBI:8382

Withdrawal of the offending agent where one is identified, plus corticosteroids; steroids were given to more than three-quarters of patients in the largest published series. In-hospital mortality remains high, and is highest in the hypersensitivity form.

Mechanism Target:

Eosinophil-Mediated Myocardial Injury — Corticosteroids suppress the eosinophil-driven infiltrate responsible for the myocardial injury in this form.

Show evidence (1 reference)

PMID:29096807 SUPPORT Human Clinical

"Steroids were administered in 77.7% of patients."

Documents corticosteroid use as near-universal practice in this form; the series is observational and reports no controlled effect estimate, so the support is partial.

Show evidence (1 reference)

PMID:29096807 SUPPORT Human Clinical

"In-hospital death was 22.3% (n = 40), with the highest occurrence in the hypersensitivity form (36.1%; p = 0.026)."

Records the residual mortality despite widespread steroid use, bounding the claim that this treatment is sufficient.

High-Dose Corticosteroids and Drug Withdrawal for Checkpoint-Inhibitor Myocarditis

Action: Pharmacotherapy NCIT:C15986

Agent: methylprednisolone NCIT:C647

Immediate discontinuation of the checkpoint inhibitor with early high-dose corticosteroids. The evidence base is observational; the two index cases were refractory and fatal despite treatment, which is the origin of the recommendation to act early rather than escalate late.

Mechanism Target:

Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity — Stopping the drug removes the ongoing checkpoint blockade; corticosteroids suppress the T cell response it released.

Show evidence (1 reference)

PMID:30242316 SUPPORT Human Clinical

"Median time from symptom onset to death was 32 days."

Supports the urgency rationale by showing how short the window between symptom onset and death is; it does not itself measure corticosteroid efficacy.

Show evidence (1 reference)

PMID:27806233 SUPPORT Human Clinical

"In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates."

Documents the refractory course that motivates immediate drug withdrawal and early high-dose steroids; it does not demonstrate steroid efficacy.

Second-Line Immunosuppression for Steroid-Refractory Checkpoint-Inhibitor Myocarditis

Action: Immunosuppressive Therapy NCIT:C15261

Agent: abatacept NCIT:C28898 ruxolitinib CHEBI:66919 mycophenolate mofetil CHEBI:8764 tocilizumab NCIT:C84217

Methylprednisolone pulse therapy at 500-1,000 mg/day is the guideline-recommended first step for checkpoint-inhibitor myocarditis, and a substantial fraction of patients do not respond to it. Abatacept is the proposed preferred second agent for isolated steroid-refractory disease; alemtuzumab or tocilizumab/tofacitinib are proposed for rapidly progressive or IL-6-high disease, and abatacept combined with ruxolitinib, mycophenolate mofetil or IVIG for cases overlapping myositis or myasthenia gravis. The evidence base is 45 case reports and case series, not a trial, and the authors of the proposed algorithm say so themselves.

Mechanism Target:

Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity — Abatacept restores CTLA-4-mediated co-stimulation blockade, the checkpoint the drug removed; the other agents suppress the resulting T cell and cytokine response by different routes.

Show evidence (1 reference)

PMID:39263485 SUPPORT Human Clinical

"Abatacept is the preferred choice for the treatment of isolated steroid-refractory IRM."

States the proposed first choice for suppressing the checkpoint-released T cell response; the recommendation rests on case series, so the support is partial.

Show evidence (2 references)

PMID:39263485 SUPPORT Human Clinical

"Methylprednisolone pulse therapy (500-1,000 mg/day) is the initial treatment for IRM recommended by almost all relevant guidelines."

Establishes the first-line therapy against which steroid-refractory disease is defined.

PMID:39263485 SUPPORT Human Clinical

"The pathogenesis of steroid-refractory IRM and the treatment regimen remain unclear. A large number of studies need to be conducted to validate or update our proposed treatment approach."

The authors' own statement that the proposed algorithm is unvalidated, which is why this treatment is curated as proposed rather than established.

Temporary Mechanical Circulatory Support

Action: Extracorporeal Membrane Oxygenation NCIT:C171507

Extracorporeal membrane oxygenation or a temporary ventricular assist device to carry the patient through fulminant cardiogenic shock, either to myocardial recovery or to transplantation. It was used in about one in six patients in the eosinophilic series and is the established bridge in giant cell disease.

Mechanism Target:

Acute Contractile Failure and Cardiogenic Shock — Mechanical support substitutes for the failed ventricle while the inflammatory injury resolves or a donor organ is found.

Show evidence (1 reference)

PMID:12057701 SUPPORT Human Clinical

"In our experience, these patients can be bridged successfully to transplant with mechanical circulatory assist."

Direct evidence that mechanical support addresses the shock node as a bridge to definitive therapy.

Show evidence (1 reference)

PMID:29096807 SUPPORT Human Clinical

"A temporary mechanical circulatory support (n = 30) was instituted in 16.8% of patients."

Quantifies how often temporary mechanical support is required in severe myocarditis.

Heart Transplantation

Action: Heart Transplantation NCIT:C15246

Definitive therapy for irreversible myocardial failure. In giant cell myocarditis transplantation is the treatment of choice for most patients despite a real risk of the giant cell infiltrate recurring in the graft, which can respond to augmented immunosuppression.

Mechanism Target:

Inflammatory Dilated Cardiomyopathy — Replaces the irreversibly remodelled ventricle when medical therapy has failed.

Show evidence (1 reference)

PMID:9197214 SUPPORT Human Clinical

"Despite the possibility of fatal disease recurrence, transplantation is the treatment of choice for most patients."

States transplantation as definitive therapy while recording the recurrence risk that qualifies it.

Show evidence (1 reference)

PMID:12057701 SUPPORT Human Clinical

"Giant cell myocarditis may recur after transplantation but may respond to augmented immunosuppression."

Records both the recurrence risk after transplantation and its responsiveness to augmented immunosuppression.

Interleukin-1 Blockade

Action: Pharmacotherapy NCIT:C15986

Agent: anakinra NCIT:C38717

Anakinra, an IL-1 receptor antagonist, targets the NLRP3-caspase-1-IL-1beta arm of the innate amplification step. It is investigational in acute myocarditis; ARAMIS is the randomized trial designed to test it, and the indication should not be treated as established.

Mechanism Target:

Innate Immune Sensing and Cytokine Amplification — Blocks IL-1 receptor signalling downstream of inflammasome activation, the cytokine amplification step of this node.

Show evidence (1 reference)

PMID:37640625 SUPPORT Human Clinical

"Recently, experimental studies have suggested that specific blockade of the interleukin-1β immune innate pathway could be effective in acute myocarditis."

States the mechanistic rationale for targeting this node; the evidence is a trial protocol, so the support is partial and the efficacy claim is untested.

Show evidence (3 references)

PMID:42397625 REFUTE Other

"Clinically, the randomized trial of anakinra in acute myocarditis (ARAMIS) did not improve outcomes in a largely low-risk cohort, but accumulating case reports and small series suggest potential benefit in fulminant/hyperinflammatory myocarditis and chronic active refractory myocarditis."

Records the negative randomized result in the enrolled low-risk population. Carried as REFUTE for the general indication; the residual case-series signal in fulminant disease is noted but is not randomized evidence.

PMID:42397625 SUPPORT Other

"However, evidence is mainly derived from case reports and small series, and robust randomized data are lacking."

Bounds the residual claim: outside the negative trial population the support for IL-1 blockade in myocarditis is uncontrolled.

PMID:37640625 SUPPORT Human Clinical

"ARAMIS is the first trial evaluating inhibition of the interleukin-1β immune innate pathway in the setting of acute myocarditis."

Establishes what the trial set out to test; it is a design paper and reports no result.

🌍

Environmental Factors

3

mRNA COVID-19 vaccination

No exposure_term is bound. ECTO was searched and carries no vaccination-exposure term suitable for this concept; a free-text preferred_term with no ontology binding would render as an unbound node without adding meaning, so it is omitted deliberately rather than left un-researched.

Myocarditis occurs rarely after mRNA COVID-19 vaccination, concentrated in adolescent and young adult males and mostly after the second dose. The clinical course is usually mild and self-limited, unlike infection-associated myocarditis.

Show evidence (2 references)

PMID:34614328 SUPPORT Human Clinical

"The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients."

National active-surveillance evidence for the association and for its concentration in young males after the second dose.

PMID:34614328 SUPPORT Human Clinical

"The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal."

Establishes that the vaccine-associated form is usually mild, while recording that fulminant disease occurred.

Mechanism Target:

TRIGGERS Adaptive T Cell-Mediated Myocardial Injury — Vaccination is followed by myocardial inflammation in a small excess of recipients. The intermediate steps are not established - molecular mimicry and cytokine dysregulation are both proposed and neither is settled - so the link is recorded as indirect with unknown intermediates.

Show evidence (1 reference)

PMID:34614328 SUPPORT Human Clinical

"As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20)."

Quantifies the excess of myocarditis over background incidence following vaccination, which is the evidence that the exposure acts on this node.

Immune checkpoint inhibitor therapy

Therapeutic blockade of CTLA-4, PD-1 or PD-L1 for cancer. Combination CTLA-4 plus PD-1 blockade carries the highest risk, and myocarditis is the most lethal of the immune-related adverse events it provokes.

Show evidence (1 reference)

PMID:30242316 SUPPORT Human Clinical

"Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%])."

Establishes checkpoint-inhibitor exposure, particularly combination therapy, as a cause of fatal myocarditis.

Mechanism Target:

TRIGGERS Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity — The drug exposure is the proximate cause of the loss of checkpoint restraint on myocardial T cells.

Show evidence (1 reference)

PMID:27806233 SUPPORT Human Clinical

"We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab."

Direct clinical evidence linking the checkpoint-inhibitor exposure to the myocardial T cell lesion.

Strenuous exercise during active myocarditis

The mechanistic link is inferred rather than demonstrated: the cited athlete cohort establishes that half of sudden cardiac deaths are exertional across all causes, not that exertion causes deterioration specifically in myocarditis. The evidence is graded PARTIAL for that reason and no influences_mechanisms link is asserted.

Vigorous exertion while the myocardium is actively inflamed is believed to amplify injury and arrhythmic risk, which is why exercise restriction is standard advice during the acute phase. Half of sudden cardiac deaths in athletes are exertional.

Show evidence (1 reference)

PMID:37955565 SUPPORT Human Clinical

"SCD events were exertional in 50% of cases."

Supports the association between exertion and sudden cardiac death across causes; it does not by itself establish that exertion worsens myocarditis specifically.

🔬

Diagnosis

2

Endomyocardial Biopsy

The reference standard for histological, immunophenotypic and pathogen-directed diagnosis. It is the only test that distinguishes lymphocytic from giant cell and eosinophilic disease and that separates virus-positive from virus-negative inflammation - and because those distinctions decide whether immunosuppression is offered, biopsy changes management rather than merely confirming it.

Show evidence (1 reference)

PMID:31319912 SUPPORT Human Clinical

"we provide evidence that the histologic subtype of FM carries independent prognostic value, highlighting the need for timely endomyocardial biopsy in this condition"

Supports biopsy as management-changing by showing the histological subtype carries prognostic information beyond clinical severity.

Cardiac Magnetic Resonance

The principal non-invasive tissue-characterisation test, combining T2-based markers of oedema with T1-based markers of injury under the updated Lake Louise criteria.

Show evidence (1 reference)

PMID:30545455 SUPPORT Human Clinical

"While having both a positive T2-based marker and a T1-based marker will increase specificity for diagnosing acute myocardial inflammation, having only one (i.e., T2-based OR T1-based) marker may still support a diagnosis of acute myocardial inflammation in an appropriate clinical scenario,..."

States the diagnostic logic and the specificity trade-off of the CMR criteria.

🩻

Imaging Findings

1

Myocardial Late Gadolinium Enhancement

Non-ischaemic, typically subepicardial or mid-wall late gadolinium enhancement on cardiac magnetic resonance. Under the updated Lake Louise criteria it is one of the T1-based markers which, combined with a T2-based marker of oedema, supports a diagnosis of acute myocardial inflammation.

Mri Diagnostic

Myocardial late gadolinium enhancement HP:4000004

Show evidence (1 reference)

PMID:30545455 SUPPORT Human Clinical

"This is based on at least one T2-based criterion (global or regional increase of myocardial T2 relaxation time or an increased signal intensity in T2-weighted CMR images), with at least one T1-based criterion (increased myocardial T1, extracellular volume, or late gadolinium enhancement)."

Places late gadolinium enhancement within the consensus CMR criteria for diagnosing myocardial inflammation.

📈

Progression

2

Acute injury and inflammation

Duration: Approximately the first month after symptom onset

Trigger and prodrome, followed by myocardial oedema, myocyte injury with troponin release, and the peak risk of shock, malignant arrhythmia and high-grade AV block.

Show evidence (1 reference)

PMID:11334481 SUPPORT Model Organism

"Infection of susceptible BALB/c mice with either Coxsackievirus or murine cytomegalovirus results in the development of acute myocarditis from day 7-14 after infection, and chronic myocarditis from day 28 onwards."

Supports the separation of an acute from a chronic phase, though the timing is taken from murine models rather than from human natural history.

Chronic inflammatory cardiomyopathy

In the subset that does not resolve, persistent mononuclear infiltration and fibrotic remodelling produce ventricular dilation and heart failure. Whether the persisting driver is residual virus or post-infectious autoimmunity is unsettled; both hypotheses are curated below.

Show evidence (1 reference)

PMID:33046850 SUPPORT Other

"At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear."

States directly that the determinants of progression from acute myocarditis to dilated cardiomyopathy remain unresolved.

📊

Prevalence

3

General population, Sweden

Annual Incidence 7.45 per 100,000 (6.3–8.6) 1–9 per 100,000

Swedish national registry incidence of 6.3-8.6 per 100,000 inhabitants, mostly in young men; rate_per_100000 is the midpoint of that range. True incidence is almost certainly higher, because mild cases are never diagnosed and case definitions differ between studies.

Show evidence (1 reference)

PMID:42397625 SUPPORT Other

"A large Swedish registry reported an incidence of 6.3–8.6 per 100,000 inhabitants, mostly in young men"

Source of the population-level incidence estimate and of the male predominance.

Male BNT162b2 mRNA COVID-19 vaccine recipients aged 16-19, Israel

Period Prevalence 13.73 per 100,000 (8.11–19.46) 1–9 per 10,000

Risk difference between the second and first dose in Israeli national active surveillance; the highest-risk stratum identified. This is an excess over the first-dose rate per 100,000 vaccinated persons, not a general-population prevalence. 13.73 per 100,000 is 1.4 per 10,000, which places it in the BAND_1_5_PER_10000 Orphanet class.

Show evidence (1 reference)

PMID:34614328 SUPPORT Human Clinical

"The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46)."

Source of the stratified risk-difference estimate and its confidence interval.

Patients receiving combined ipilimumab plus nivolumab

Period Prevalence 270.0 per 100,000 >1 in 1,000

Pharmacovigilance estimate of 0.27% of treated patients, converted to 270 per 100,000, which is 2.7 per 1,000 and so falls in the ABOVE_1_IN_1000 class. This is an occurrence rate within a drug-exposed population, not a population prevalence.

Show evidence (1 reference)

PMID:27806233 SUPPORT Human Clinical

"Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction."

Source of the 0.27% occurrence figure in combination checkpoint blockade.

⚖️

Clinical Burden

High

Myocarditis is a leading identified cause of sudden cardiac death in young people, and the fulminant presentation carries high short- and long-term rates of cardiac death or transplantation. Giant cell myocarditis is near-uniformly fatal without immunosuppression or transplantation.

Show evidence (1 reference)

PMID:31319912 SUPPORT Human Clinical

"Patients with FM (n = 165) had significantly higher rates of cardiac death and heart transplantation compared with those with NFM (n = 55), both at 60 days (28.0% vs. 1.8%, p = 0.0001) and at 7-year follow-up (47.7% vs. 10.4%, p < 0.0001)."

Quantifies the burden of the fulminant presentation in an international registry of biopsy-proven acute myocarditis.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Myocarditis:

Acute Myocardial Infarction MONDO:0005068

Overlapping Features The infarct-like presentation of myocarditis - chest pain, ST/T change and troponin release - is indistinguishable from acute coronary syndrome until coronary imaging shows unobstructed arteries.

Distinguishing Features

Unobstructed coronary arteries on angiography
Non-ischaemic (subepicardial or mid-wall rather than subendocardial) distribution of late gadolinium enhancement

Show evidence (1 reference)

PMID:35533750 SUPPORT Human Clinical

"A total of 618 consecutive patients with unobstructed coronary arteries who underwent endomyocardial biopsy between 2008 and 2018 were screened."

Describes the clinical population in which myocarditis is separated from coronary disease - patients presenting like infarction but with unobstructed coronaries.

Cardiac Sarcoidosis MONDO:0001707

Overlapping Features Granulomatous myocardial inflammation that presents with the same high-grade AV block, ventricular arrhythmia and heart failure, and is curated separately in this knowledge base.

Distinguishing Features

Non-caseating epithelioid granulomas rather than a lymphocytic, eosinophilic or giant-cell-with-necrosis infiltrate
Extracardiac sarcoid involvement
Patchy distribution favouring the basal septum on imaging

Show evidence (1 reference)

PMID:36924191 SUPPORT Human Clinical

"Cardiac sarcoidosis (CS) results from epithelioid cell granulomas infiltrating the myocardium and predisposing to conduction disturbances, ventricular tachyarrhythmias, and heart failure."

Names the granulomatous histology that distinguishes cardiac sarcoidosis from the infiltrates curated here, while confirming the overlapping clinical endpoints that make it a differential.

📊

Related Datasets

4

Spatial transcriptomic profiling of human heart tissue obtained from mRNA vaccine-associated myocarditis cases geo:GSE316643

human SPATIAL TRANSCRIPTOMICS n=13

PMID:41922346

Human myocardial tissue from mRNA vaccine-associated myocarditis, profiled spatially. Directly relevant to the vaccine-associated exposure curated in the environmental section. Discovered via just discover-datasets and verified with just verify-datasets; relevance triaged manually.

An Interferon-gamma-Driven Myeloid Inflammatory Signature defines Glucocorticoid-Resistance of Immune Checkpoint Inhibitor-Associated Myocarditis geo:GSE329991

human SINGLE CELL RNA SEQ n=6

Human single-cell profiling of checkpoint-inhibitor myocarditis, relevant to the ICI-Associated subtype and to the corticosteroid treatment entry. No linked publication was available at the time of curation.

Immune checkpoint inhibitor-induced myocarditis is dependent on CD8 T cell-derived TNF and TNFR2 signaling geo:GSE302512

house mouse BULK RNA SEQ n=6

PMID:41718716

Murine model of checkpoint-inhibitor myocarditis, supporting the CD8 T cell arm of the Checkpoint Withdrawal node. Model-organism data, not human.

IL-17A Neutralization Prevents Immune Checkpoint Inhibitor-Associated Myocarditis geo:GSE297745

house mouse SPATIAL TRANSCRIPTOMICS n=4

Murine spatial transcriptomics of checkpoint-inhibitor myocarditis under IL-17A neutralization. Complements the IL-17 fibrosis evidence curated on the Post-Inflammatory Ventricular Remodeling node, from a different disease context.

🔬

Clinical Trials

1

NCT03018834 PHASE_II COMPLETED

ARAMIS: anakinra versus placebo, a double-blind randomized controlled trial of IL-1 receptor blockade in acute myocarditis with elevated troponin and CMR-confirmed disease. Primary endpoint is days alive free of myocarditis complications.

Target Phenotypes: Myocarditis HP:0012819

Show evidence (3 references)

PMID:37640625 SUPPORT Human Clinical

"The "Anakinra versus placebo double blind Randomized controlled trial for the treatment of Acute MyocarditIS" (ARAMIS) trial (ClinicalTrials.gov identifier: NCT03018834) is a national multicentre randomized parallel-group double blind study among symptomatic patients with elevated cardiac..."

Identifies the trial, its registration identifier, and its enrolled population.

clinicaltrials:NCT03018834 SUPPORT Other

"ANAKINRA, an IL-1β Blocker, is a new treatment that has never been evaluated in myocarditis."

The trial registration record states the intervention and confirms that IL-1 blockade was untested in myocarditis when the study was designed.

PMID:42397625 REFUTE Other

"Clinically, the randomized trial of anakinra in acute myocarditis (ARAMIS) did not improve outcomes in a largely low-risk cohort, but accumulating case reports and small series suggest potential benefit in fulminant/hyperinflammatory myocarditis and chronic active refractory myocarditis."

Reports the outcome of this completed trial, so its COMPLETED status is not read as a result still pending.

🐁

Animal Models

3

Wild-type BALB/c infected with coxsackievirus B3 Mouse Infection model

Intraperitoneal coxsackievirus B3 infection of susceptible BALB/c mice produces acute myocarditis at days 7-14 and chronic myocarditis from day 28, with viral replication, innate and adaptive infiltration, myocyte necrosis and later fibrosis. It is the workhorse model for enteroviral myocarditis.

Species

Mouse

Genotype

Wild-type BALB/c infected with coxsackievirus B3

Publication

PMID:11334481

Pathograph links

Cardiotropic Viral Infection of the Myocardium recapitulates fidelity: moderate Reproduces cardiotropic enteroviral infection of the myocardium and the biphasic acute-then-chronic inflammatory course.

Limitations: Enterovirus accounts for a minority of contemporary human myocarditis, where parvovirus B19 and HHV-6 dominate the biopsy virome; outcome in the model is also strongly dependent on mouse strain, sex, age and viral passage.

Show evidence (1 reference)

PMID:11334481 SUPPORT Model Organism

"Infection of susceptible BALB/c mice with either Coxsackievirus or murine cytomegalovirus results in the development of acute myocarditis from day 7-14 after infection, and chronic myocarditis from day 28 onwards."

Establishes that the model reproduces the acute and chronic phases of viral myocarditis.

Direct Cardiomyocyte Cytoskeletal Injury recapitulates fidelity: moderate Murine CVB3 hearts show loss of sarcolemmal dystrophin and dissociation of the sarcoglycan complex, the structural lesion this node asserts.

Limitations: Specific to enteroviral protease 2A; it does not generalise to parvovirus B19, HHV-6, drug-induced or checkpoint-inhibitor myocarditis.

Show evidence (1 reference)

PMID:10988241 SUPPORT Model Organism

"The dystrophin-associated glycoproteins alpha-, beta-, gamma-, and delta-sarcoglycan and beta-dystroglycan were markedly decreased in the membrane fraction of infected cells in culture, and the typical sarcolemmal localization for each of these proteins was lost in coxsackievirus-B3-infected..."

Demonstrates the sarcolemmal lesion in the model in vivo.

Show evidence (1 reference)

PMID:11334481 SUPPORT Model Organism

"We have investigated two models of virally-induced autoimmune myocarditis in mice using widely different infectious agents."

Establishes the murine coxsackievirus system as an accepted experimental model of virally induced myocarditis.

NOD2 knockout, coxsackievirus B3 infected Mouse Genetic perturbation of an infection model

NOD2-deficient mice infected with CVB3 show reduced cardiac inflammation, fibrosis and apoptosis, lower CAR expression and viral copy number, and improved left ventricular function relative to wild-type infected controls.

Species

Mouse

Genotype

NOD2 knockout, coxsackievirus B3 infected

Publication

PMID:28912259

Pathograph links

Innate Immune Sensing and Cytokine Amplification perturbs fidelity: moderate Genetic removal of the innate sensor establishes that this node is causally required for the downstream inflammation, fibrosis and contractile loss.

Limitations: A single-gene knockout in an enteroviral model; NOD2 dependence has not been shown for the non-enteroviral or drug-induced forms of human myocarditis.

Show evidence (1 reference)

PMID:28912259 SUPPORT Model Organism

"NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3 myocarditis."

States the causal role of the innate sensing node established by the knockout.

Show evidence (1 reference)

PMID:28912259 SUPPORT Model Organism

"Left ventricular NOD2 mRNA expression was also induced in CVB3-induced myocarditis versus healthy control mice."

Establishes that the murine CVB3 system reproduces the innate-sensing induction seen in human biopsies, which is what makes the knockout informative.

Cardiac myosin-immunized susceptible strain (experimental autoimmune myocarditis) Mouse Autoimmune induction model

Immunization with cardiac myosin plus adjuvant produces T-cell-driven myocarditis and later dilated cardiomyopathy, and is the standard system for studying post-infectious autoimmunity, Th17/IL-17 biology and post-myocarditis fibrosis.

Species

Mouse

Genotype

Cardiac myosin-immunized susceptible strain (experimental autoimmune myocarditis)

Publication

PMID:22531062

Pathograph links

Anti-Cardiac Myosin Autoimmunity recapitulates fidelity: moderate Immunization against cardiac myosin reproduces the autoimmune arm and shows that anti-myosin reactivity alone is sufficient to cause myocarditis.

Limitations: Deliberate immunization with adjuvant is not how human myocarditis begins, so the model reproduces the effector autoimmunity without reproducing the initiating event or the tolerance breach.

Show evidence (1 reference)

PMID:1315309 SUPPORT Model Organism

"immunization with cardiac myosin induced myocarditis and high titres of cardiac myosin antibodies in uninfected mice of the susceptible BALB/c strain only"

Shows that cardiac myosin immunization alone induces myocarditis in susceptible animals.

Post-Inflammatory Ventricular Remodeling recapitulates fidelity: moderate The model develops post-myocarditis cardiac fibrosis and was used to establish IL-17 as a direct fibrogenic driver of it.

Limitations: Fibrosis in this model follows an artificially induced autoimmune insult; the IL-17/PKC-beta/Erk1/2/NF-kappaB route has not been shown to carry the same weight in human post-myocarditis remodelling.

Show evidence (1 reference)

PMID:22531062 SUPPORT Model Organism

"We therefore investigated whether IL-17 directly induced cardiac fibrosis in experimental autoimmune myocarditis (EAM) and explored the possible molecular mechanisms."

Identifies the model as the system in which the fibrotic remodelling mechanism was established.

Show evidence (1 reference)

PMID:22531062 SUPPORT Model Organism

"The EAM model was induced and serum IL-17 level was detected by ELISA"

Identifies experimental autoimmune myocarditis as the induced model system used for the mechanistic work cited on the linked nodes.

{ }

Source YAML

click to show

name: Myocarditis
creation_date: "2026-08-28T00:00:00Z"
category: Immune
description: >-
  Myocarditis is inflammatory injury of the myocardium, defined histologically as
  an inflammatory infiltrate of the heart muscle together with injury or necrosis
  of the adjacent myocytes. It is a syndrome with many entry points rather than a
  single disease: most cases begin with an insult to the myocardium - most often a
  cardiotropic virus, but also a drug, a systemic immune-mediated disease, or
  release of T cell checkpoint restraint by cancer immunotherapy - which is
  followed by an immune-mediated phase in which the host response, not the
  original insult, becomes the dominant driver of myocyte injury. In a subset the
  process does not resolve, and persistent inflammation with fibrotic remodelling
  produces chronic inflammatory cardiomyopathy and dilated cardiomyopathy. Clinical
  expression ranges from a self-limited chest-pain syndrome to fulminant
  cardiogenic shock, high-grade atrioventricular block, ventricular tachyarrhythmia,
  and sudden cardiac death in otherwise healthy young people. The aetiological and
  histological forms carried here as subtypes share this downstream chain but
  differ sharply in their trigger, their infiltrate, and - critically - in whether
  immunosuppression helps or harms.
disease_term:
  preferred_term: myocarditis
  term:
    id: MONDO:0004496
    label: myocarditis
synonyms:
- inflammatory myocardial disease
- inflammatory cardiomyopathy
- myopericarditis
parents:
- Cardiovascular Disease
- Inflammatory Disease
- Immune-Mediated Disease
notes: >-
  Two curation decisions worth recording. First, the subtypes below deliberately
  mix two axes - aetiology (viral, checkpoint-inhibitor-associated) and histology
  (lymphocytic, eosinophilic, giant cell) - because that is how the clinical
  literature and the endomyocardial-biopsy report are actually organised; a viral
  case is usually lymphocytic on histology, so the two overlap rather than
  partition. Second, this entry does NOT declare conformance to the
  immune_checkpoint_blockade module for the checkpoint-inhibitor form. That module
  models anti-tumour efficacy (neoantigen generation, anti-tumour T cell response,
  adaptive immune resistance, T cell exhaustion) and carries no off-target-toxicity
  or immune-related-adverse-event node, so every available anchor would misdescribe
  what happens in the myocardium. Adding an irAE arm to that module is the right
  fix and is left as follow-up work.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Myocarditis is a leading identified cause of sudden cardiac death in young
    people, and the fulminant presentation carries high short- and long-term rates
    of cardiac death or transplantation. Giant cell myocarditis is near-uniformly
    fatal without immunosuppression or transplantation.
  evidence:
  - reference: PMID:31319912
    reference_title: "Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with FM (n = 165) had significantly higher rates of cardiac death and heart transplantation compared with those with NFM (n = 55), both at 60 days (28.0% vs. 1.8%, p = 0.0001) and at 7-year follow-up (47.7% vs. 10.4%, p < 0.0001)."
    explanation: >-
      Quantifies the burden of the fulminant presentation in an international
      registry of biopsy-proven acute myocarditis.
has_subtypes:
- name: Viral
  display_name: Viral myocarditis
  subtype_term:
    preferred_term: viral myocarditis
    term:
      id: MONDO:0023161
      label: viral myocarditis
  description: >-
    Myocarditis in which a cardiotropic virus is the initiating insult. Enteroviruses
    (notably coxsackievirus B), parvovirus B19, human herpesvirus 6, adenovirus,
    influenza and SARS-CoV-2 are the agents most often recovered from myocardium.
    The endomyocardial-biopsy virome has shifted over time from enterovirus-dominant
    to parvovirus B19- and HHV-6-dominant, and detection of viral nucleic acid alone
    does not establish that the virus is causing the current inflammation rather
    than sitting latent in endothelium.
  evidence:
  - reference: PMID:35533750
    reference_title: "Epicardial and microvascular coronary artery spasm in biopsy-proven viral myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most frequently, virus DNA was detected by PCR from parvovirus B19 (PVB19, 59%) and human herpesvirus 6 (HHV6, 26%)."
    explanation: >-
      Reports the contemporary distribution of viral genomes recovered by PCR from
      endomyocardial biopsies in biopsy-proven viral myocarditis.
- name: Lymphocytic
  display_name: Lymphocytic myocarditis
  description: >-
    The commonest histological form: a T-cell-rich mononuclear infiltrate with
    associated myocyte injury. It is the histological correlate of most presumed-viral
    and idiopathic myocarditis, and is the form in which the Myocarditis Treatment
    Trial found no benefit from routine immunosuppression. It has no distinct MONDO
    identifier; it is a biopsy-defined pattern rather than an aetiology.
  evidence:
  - reference: PMID:31319912
    reference_title: "Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a subanalysis including only adults with lymphocytic myocarditis, the main endpoints occurred more frequently in FM compared with in NFM both at 60 days (19.5% vs. 0%, p = 0.005) and at 7-year follow up (41.4% vs. 3.1%, p = 0.0004)."
    explanation: >-
      Treats lymphocytic myocarditis as a distinct histological stratum with its own
      outcome profile, supporting it as a curated subtype.
- name: Giant Cell
  display_name: Giant cell myocarditis
  subtype_term:
    preferred_term: giant cell myocarditis
    term:
      id: MONDO:0023232
      label: giant cell myocarditis
  description: >-
    A destructive T-cell and macrophage myocarditis containing multinucleated giant
    cells and extensive myocyte necrosis, occurring in relatively young, previously
    healthy adults and frequently associated with other autoimmune disease. It is
    the aetiological form for which the lump/split decision matters most clinically:
    untreated it is near-uniformly fatal within months, it responds to combination
    immunosuppression, and it can recur in the transplanted heart.
  evidence:
  - reference: PMID:9197214
    reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Giant cell myocarditis is a disease of relatively young, predominantly healthy adults."
    explanation: >-
      The multicenter natural-history series that defined giant cell myocarditis as a
      distinct clinical entity.
  - reference: PMID:9197214
    reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nineteen percent had associated autoimmune disorders."
    explanation: >-
      Supports the association of the giant cell form with systemic autoimmunity,
      which distinguishes it from presumed-viral lymphocytic myocarditis.
- name: Eosinophilic
  display_name: Eosinophilic and hypersensitivity myocarditis
  description: >-
    Myocarditis with an eosinophil-rich infiltrate, most often provoked by a drug
    (hypersensitivity myocarditis) or occurring in the setting of a systemic
    eosinophilic disorder such as eosinophilic granulomatosis with polyangiitis.
    Peripheral eosinophilia is usual but not obligatory. The hypersensitivity form
    has the highest in-hospital mortality of the eosinophilic subgroups, and the
    first therapeutic step is withdrawal of the offending agent rather than a drug.
  evidence:
  - reference: PMID:29096807
    reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorders most frequently associated with EM were hypersensitivity and eosinophilic granulomatosis with polyangiitis, which accounted for 34.1% and 12.8% of cases, respectively, whereas idiopathic or undefined forms accounted for 35.7% of cases."
    explanation: >-
      Establishes the aetiological composition of the eosinophilic form from a
      systematic review of histologically proven cases.
- name: ICI-Associated
  display_name: Immune checkpoint inhibitor-associated myocarditis
  description: >-
    Myocarditis precipitated by cancer immunotherapy targeting CTLA-4, PD-1 or PD-L1.
    It is uncommon but has the highest case fatality of any immune-related adverse
    event, typically presents within weeks of the first doses, and frequently
    overlaps with myositis and myasthenia gravis. Mechanistically it is not a
    hypersensitivity reaction: the myocardial infiltrate carries the same T cell
    clones found in the tumour and skeletal muscle. Combination CTLA-4 plus PD-1
    blockade is the best-established risk factor.
  evidence:
  - reference: PMID:30242316
    reference_title: "Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities"
    explanation: >-
      Establishes checkpoint-inhibitor myocarditis as the most lethal immune-related
      adverse event in a global pharmacovigilance analysis.
prevalence:
- population: General population, Sweden
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 7.45
  rate_low: 6.3
  rate_high: 8.6
  notes: >-
    Swedish national registry incidence of 6.3-8.6 per 100,000 inhabitants, mostly in
    young men; rate_per_100000 is the midpoint of that range. True incidence is almost
    certainly higher, because mild cases are never diagnosed and case definitions
    differ between studies.
  evidence:
  - reference: PMID:42397625
    reference_title: "Cardioimmunology of Myocarditis: Targeting the IL-1 Pathway."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A large Swedish registry reported an incidence of 6.3–8.6 per 100,000 inhabitants, mostly in young men"
    explanation: >-
      Source of the population-level incidence estimate and of the male predominance.
- population: Male BNT162b2 mRNA COVID-19 vaccine recipients aged 16-19, Israel
  measure_type: PERIOD_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 13.73
  rate_low: 8.11
  rate_high: 19.46
  notes: >-
    Risk difference between the second and first dose in Israeli national active
    surveillance; the highest-risk stratum identified. This is an excess over the
    first-dose rate per 100,000 vaccinated persons, not a general-population
    prevalence. 13.73 per 100,000 is 1.4 per 10,000, which places it in the
    BAND_1_5_PER_10000 Orphanet class.
  evidence:
  - reference: PMID:34614328
    reference_title: "Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46)."
    explanation: >-
      Source of the stratified risk-difference estimate and its confidence interval.
- population: Patients receiving combined ipilimumab plus nivolumab
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 270.0
  notes: >-
    Pharmacovigilance estimate of 0.27% of treated patients, converted to 270 per
    100,000, which is 2.7 per 1,000 and so falls in the ABOVE_1_IN_1000 class. This
    is an occurrence rate within a drug-exposed population, not a population
    prevalence.
  evidence:
  - reference: PMID:27806233
    reference_title: "Fulminant Myocarditis with Combination Immune Checkpoint Blockade."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction."
    explanation: >-
      Source of the 0.27% occurrence figure in combination checkpoint blockade.
progression:
- phase: Acute injury and inflammation
  duration: Approximately the first month after symptom onset
  notes: >-
    Trigger and prodrome, followed by myocardial oedema, myocyte injury with troponin
    release, and the peak risk of shock, malignant arrhythmia and high-grade AV block.
  evidence:
  - reference: PMID:11334481
    reference_title: "From infection to autoimmunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Infection of susceptible BALB/c mice with either Coxsackievirus or murine cytomegalovirus results in the development of acute myocarditis from day 7-14 after infection, and chronic myocarditis from day 28 onwards."
    explanation: >-
      Supports the separation of an acute from a chronic phase, though the timing is
      taken from murine models rather than from human natural history.
- phase: Chronic inflammatory cardiomyopathy
  notes: >-
    In the subset that does not resolve, persistent mononuclear infiltration and
    fibrotic remodelling produce ventricular dilation and heart failure. Whether the
    persisting driver is residual virus or post-infectious autoimmunity is unsettled;
    both hypotheses are curated below.
  evidence:
  - reference: PMID:33046850
    reference_title: "Myocarditis and inflammatory cardiomyopathy: current evidence and future directions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear."
    explanation: >-
      States directly that the determinants of progression from acute myocarditis to
      dilated cardiomyopathy remain unresolved.
mechanistic_hypotheses:
- hypothesis_group_id: postinfectious_autoimmunity
  hypothesis_label: Post-infectious autoimmunity against cardiac myosin sustains chronic injury
  status: CANONICAL
  description: >-
    Under this model the initiating virus is cleared, but antigen release and the
    inflammatory context break tolerance to cardiac myosin. Cross-reactive T cells
    and autoantibodies then sustain myocardial injury after the virus is gone, which
    is why virus-negative inflammatory cardiomyopathy responds to immunosuppression.
  evidence:
  - reference: PMID:11334481
    reference_title: "From infection to autoimmunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The chronic phase of myocarditis is associated with mononuclear infiltration of the myocardium and the production of autoantibodies to cardiac myosin, although infectious virus cannot be detected past day 14 of infection."
    explanation: >-
      Describes the defining observation of this hypothesis: chronic myocardial
      inflammation and anti-myosin autoantibodies persisting after the virus has
      become undetectable.
- hypothesis_group_id: viral_persistence
  hypothesis_label: Persistent myocardial viral genome drives ongoing injury and remodelling
  status: ALTERNATIVE
  description: >-
    The competing model holds that low-level viral persistence in the myocardium,
    rather than autoimmunity, drives continuing injury; the corollary is that
    clearance predicts recovery and persistence predicts deterioration, and that
    immunosuppression could be harmful. The two hypotheses are not mutually exclusive
    and probably apply to different patients, which is exactly why endomyocardial
    biopsy with viral PCR governs whether immunosuppression is offered.
  evidence:
  - reference: PMID:14722762
    reference_title: "Viral heart disease: molecular diagnosis, clinical prognosis, and treatment strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Advances in molecular diagnosis have indicated beyond doubt that persistence of viral infection is associated with disease deterioration and poor prognosis."
    explanation: >-
      States the central claim of the viral-persistence model: continued presence of
      viral genome in myocardium tracks with clinical deterioration.
pathophysiology:
- name: Cardiotropic Viral Infection of the Myocardium
  description: >-
    A cardiotropic virus reaches and infects the myocardium. Enteroviruses such as
    coxsackievirus B enter cardiomyocytes through the coxsackievirus and adenovirus
    receptor; parvovirus B19 and HHV-6 are recovered most often from contemporary
    biopsies and are largely endothelial in tropism; SARS-CoV-2 can be detected in
    myocardium in fatal COVID-19, but usually as very rare infected cells. Direct
    viral replication is only the opening move - in most cases the burden of injury
    is delivered by what the host does next.
  role: trigger
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Viral entry into the cardiomyocyte
    term:
      id: GO:0046718
      label: symbiont entry into host cell
    modifier: INCREASED
  evidence:
  - reference: PMID:33046850
    reference_title: "Myocarditis and inflammatory cardiomyopathy: current evidence and future directions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases."
    explanation: >-
      Establishes viral infection as the predominant trigger while naming the
      non-viral triggers modelled elsewhere in this entry.
  - reference: PMID:33727695
    reference_title: "Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the cases with cardiac infection, SARS-CoV-2+ cells in the myocardium were rare, with a median density of 1 cell/cm2."
    explanation: >-
      Supports myocardial viral presence while qualifying its extent - the density of
      infected cells is too low for direct cytolysis alone to explain the injury.
  downstream:
  - target: Direct Cardiomyocyte Cytoskeletal Injury
    causal_link_type: DIRECT
  - target: Innate Immune Sensing and Cytokine Amplification
    causal_link_type: DIRECT
  - target: Post-Inflammatory Ventricular Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - viral_persistence
    description: >-
      Under the viral-persistence model, failure to clear myocardial virus sustains
      injury and remodelling directly, without requiring an autoimmune intermediate.
    evidence:
    - reference: PMID:14722762
      reference_title: "Viral heart disease: molecular diagnosis, clinical prognosis, and treatment strategies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Myocarditis is considered as a potent predisposing factor for dilated cardiomyopathy (DCM)."
      explanation: >-
        Supports the link from myocarditis to subsequent dilated remodelling in the
        molecular-virology framing of this hypothesis group.
- name: Direct Cardiomyocyte Cytoskeletal Injury
  description: >-
    Coxsackievirus B3 protease 2A cleaves dystrophin, and the cleaved carboxyl
    terminus and its associated sarcoglycan complex are lost from the sarcolemma.
    The result is functional membrane fragility that phenocopies the hereditary
    sarcoglycanopathies, giving enteroviral myocarditis a mechanism of contractile
    failure that is independent of immune-mediated killing.
  role: mediator
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: Sarcolemma
    term:
      id: GO:0042383
      label: sarcolemma
    modifier: ABNORMAL
  evidence:
  - reference: PMID:10988241
    reference_title: "Dissociation of sarcoglycans and the dystrophin carboxyl terminus from the sarcolemma in enteroviral cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found that in cultured cardiac myocytes and murine hearts infected with coxsackievirus B3, the sarcolemmal localization of the dystrophin carboxyl terminus is lost."
    explanation: >-
      Demonstrates the loss of sarcolemmal dystrophin in coxsackievirus B3-infected
      cardiomyocytes both in culture and in vivo.
  - reference: PMID:10988241
    reference_title: "Dissociation of sarcoglycans and the dystrophin carboxyl terminus from the sarcolemma in enteroviral cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vivo, the sarcolemmal integrity was functionally impaired with Evans blue dye uptake even though there was no generalized disruption of the sarcolemma of infected myocytes"
    explanation: >-
      Shows the loss is functional membrane fragility rather than gross membrane
      destruction, which is what makes it a distinct injury mechanism.
  downstream:
  - target: Cardiomyocyte Necrosis and Contractile Failure
    causal_link_type: DIRECT
- name: Innate Immune Sensing and Cytokine Amplification
  description: >-
    Cytosolic and membrane pattern-recognition receptors sense viral RNA and released
    damage-associated molecules. NOD2 is induced in the myocardium of virus-positive
    patients and drives NLRP3-caspase-1-IL-1beta signalling and viral uptake;
    monocytes and macrophages are recruited and generate IL-1, IL-6, TNF and reactive
    oxygen species. This is the step that converts a focal infection into diffuse
    myocardial inflammation, and it is the target of IL-1 blockade.
  role: amplifier
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Innate immune response
    term:
      id: GO:0045087
      label: innate immune response
    modifier: INCREASED
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:28912259
    reference_title: "NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Endomyocardial biopsy NOD2 mRNA expression was higher in CVB3-positive patients compared with patients with myocarditis but without evidence of persistent CVB3 infection."
    explanation: >-
      Human biopsy evidence that innate viral sensing through NOD2 is upregulated
      specifically in virus-positive myocarditis.
  - reference: PMID:28912259
    reference_title: "NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "NOD2 knockdown(-/-) mice were rescued from the detrimental CVB3-mediated effects as shown by a reduced cardiac inflammation (less cardiac infiltrates and suppression of proinflammatory cytokines), cardiac fibrosis, apoptosis, lower CAR (Coxsackievirus and adenovirus receptor) expression and CVB3 copy number, and an improved left ventricular function in NOD2-/- CVB3 mice compared with wild-type CVB3 mice."
    explanation: >-
      Loss-of-function evidence that innate sensing is causally required for the
      inflammation, fibrosis and contractile loss downstream of it.
  - reference: PMID:33727695
    reference_title: "Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Virus+ cases showed higher densities of myocardial CD68+ macrophages and CD3+ lymphocytes, as well as more electrocardiographic changes (23/27 vs 4/10; P = 0.01)."
    explanation: >-
      Links myocardial viral presence to macrophage and lymphocyte recruitment and,
      in turn, to electrical abnormality in human hearts.
  downstream:
  - target: Adaptive T Cell-Mediated Myocardial Injury
    causal_link_type: DIRECT
  - target: Cardiomyocyte Necrosis and Contractile Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Anti-Cardiac Myosin Autoimmunity
  description: >-
    Antigen release in an inflamed myocardium, together with viral epitopes that
    cross-react with the cardiac myosin heavy chain, breaks tolerance. The resulting
    anti-cardiac-myosin response outlives the infection and is itself sufficient to
    cause myocardial inflammation and necrosis - passive transfer of the antibodies
    reproduces the lesion in uninfected animals. This node is the mechanistic content
    of the post-infectious autoimmunity hypothesis and the rationale for
    immunosuppressing virus-negative inflammatory cardiomyopathy.
  role: amplifier
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: Adaptive immune response against cardiac myosin
    term:
      id: GO:0002250
      label: adaptive immune response
    modifier: INCREASED
  evidence:
  - reference: PMID:1315309
    reference_title: "Mouse cytomegalovirus infection induces antibodies which cross-react with virus and cardiac myosin: a model for the study of molecular mimicry in the pathogenesis of viral myocarditis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Passive transfer of anti-cardiac myosin antibodies from Day 56 post-infection sera of the BALB/c strain induced inflammation and necrosis of the myocardium of uninfected BALB/c recipients."
    explanation: >-
      Transfer experiment showing the autoantibody response is sufficient, not merely
      correlated, to produce myocardial inflammation and necrosis.
  - reference: PMID:1315309
    reference_title: "Mouse cytomegalovirus infection induces antibodies which cross-react with virus and cardiac myosin: a model for the study of molecular mimicry in the pathogenesis of viral myocarditis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These affinity-purified anti-cardiac myosin antibodies cross-react with MCMV protein(s)."
    explanation: >-
      Direct demonstration of the molecular mimicry between viral protein and cardiac
      myosin that this node asserts.
  downstream:
  - target: Adaptive T Cell-Mediated Myocardial Injury
    causal_link_type: DIRECT
    hypothesis_groups:
    - postinfectious_autoimmunity
    description: >-
      Under the post-infectious autoimmunity model, anti-myosin reactivity is what
      keeps the adaptive infiltrate running after the virus is cleared.
- name: Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity
  description: >-
    Blockade of CTLA-4, PD-1 or PD-L1 removes the inhibitory signalling that normally
    restrains T cell activation, including in the heart. The myocardial infiltrate in
    checkpoint-inhibitor myocarditis carries the same clonally expanded T cell
    populations found in the tumour and in skeletal muscle, so this is not
    hypersensitivity to a drug but a loss of peripheral tolerance that lets a
    tumour-directed T cell response spill onto a shared cardiac and skeletal-muscle
    antigen. It explains the frequent myositis and myasthenic overlap.
  role: trigger
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: CD8-positive cytotoxic T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  biological_processes:
  - preferred_term: Negative regulation of T cell activation
    term:
      id: GO:0050868
      label: negative regulation of T cell activation
    modifier: DECREASED
  evidence:
  - reference: PMID:27806233
    reference_title: "Fulminant Myocarditis with Combination Immune Checkpoint Blockade."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle."
    explanation: >-
      The clonal identity between tumour, skeletal muscle and myocardial T cells is
      the direct evidence that this is shared-antigen off-target reactivity.
  - reference: PMID:38982146
    reference_title: "Immune-checkpoint inhibitor-mediated myocarditis: CTLA4, PD1 and LAG3 in the heart."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inflammation of the heart muscle, known as myocarditis, resulting from ICI targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), programmed cell death protein 1 (PD1) and PD1 ligand 1 (PDL1) is an infrequent but potentially fatal complication."
    explanation: >-
      Attributes the myocarditis specifically to pharmacological targeting of the
      CTLA4 and PD1/PDL1 checkpoint axes.
  downstream:
  - target: Adaptive T Cell-Mediated Myocardial Injury
    causal_link_type: DIRECT
- name: Eosinophil-Mediated Myocardial Injury
  description: >-
    In the eosinophilic and hypersensitivity forms the infiltrate is eosinophil-rich
    and the injury is driven by eosinophil degranulation products rather than by
    cytotoxic T cells. It arises either as a drug hypersensitivity reaction or as
    cardiac involvement of a systemic eosinophilic disorder, and peripheral
    eosinophilia accompanies about three-quarters of cases.
  role: trigger
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Eosinophil
    term:
      id: CL:0000771
      label: eosinophil
  biological_processes:
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:29096807
    reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eosinophilic myocarditis (EM) is an acute life-threatening inflammatory disease of the heart."
    explanation: >-
      Establishes the eosinophilic form as a distinct, severe inflammatory myocardial
      disease.
  - reference: PMID:29096807
    reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with peripheral eosinophilia observed in 75.9%"
    explanation: >-
      Quantifies how often the systemic eosinophil expansion accompanies the
      myocardial lesion.
  downstream:
  - target: Cardiomyocyte Necrosis and Contractile Failure
    causal_link_type: DIRECT
- name: Giant Cell Destructive Myocardial Necrosis
  description: >-
    In giant cell myocarditis the infiltrate contains multinucleated giant cells and
    the myocyte necrosis is unusually extensive and rapidly progressive. Clinically
    it converges on the same endpoints as other forms - heart failure, ventricular
    arrhythmia and heart block - but at a pace that makes it the histological subtype
    with the worst prognosis, and it is the one form in which combination
    immunosuppression clearly prolongs survival.
  role: trigger
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Multinucleated giant cell
    term:
      id: CL:0000647
      label: multinucleated giant cell
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  evidence:
  - reference: PMID:9197214
    reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most presented with congestive heart failure (47 patients, or 75 percent), ventricular arrhythmia (9 patients, or 14 percent), or heart block (3 patients, or 5 percent)"
    explanation: >-
      Shows the giant cell form converging on the same heart-failure, arrhythmia and
      conduction endpoints as other myocarditis subtypes.
  - reference: PMID:31319912
    reference_title: "Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the histologic subtype emerged as a further variable affecting the outcome in FM patients, with giant cell myocarditis having a significantly worse prognosis compared with eosinophilic and lymphocytic myocarditis"
    explanation: >-
      Establishes that the giant cell histology carries independent prognostic weight
      beyond the severity of presentation.
  downstream:
  - target: Cardiomyocyte Necrosis and Contractile Failure
    causal_link_type: DIRECT
  - target: Electrical Instability and Arrhythmogenesis
    causal_link_type: DIRECT
- name: Genetically Susceptible Myocardium
  description: >-
    A minority of patients carry a pathogenic or likely pathogenic variant in an
    inherited-cardiomyopathy gene, and that background modifies how the myocardium
    responds to an inflammatory insult. Such variants are found in around 4% of
    uncomplicated acute myocarditis but in roughly a fifth of adults and nearly half
    of children whose myocarditis is complicated by heart failure, reduced ejection
    fraction, or life-threatening ventricular arrhythmia, with desmosomal genes
    predominating in the milder group and sarcomeric genes in the severe one. This
    is a susceptibility and severity modifier, not a cause of myocarditis - the
    inflammatory episode still needs its own trigger.
  role: modifier
  biological_scale: MOLECULAR
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:38573261
    reference_title: "Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Acute Myocarditis: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For uncomplicated myocarditis, the pooled prevalence was 4.2% (95% CI: 1.8%-7.4%; I2 = 1.4%), whereas for complicated myocarditis, the pooled prevalence was 21.9% (95% CI: 14.3%-30.5%; I2 = 38.8%) and 44.5% (95% CI: 22.7%-67.4%; I2 = 52.8%) in adults and children, respectively."
    explanation: >-
      Quantifies the enrichment of cardiomyopathy-gene variants in severe versus mild
      acute myocarditis, which is the severity-modifier claim this node makes.
  - reference: PMID:38573261
    reference_title: "Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Acute Myocarditis: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "P/LP variants in desmosomal genes were predominant in uncomplicated myocarditis (64%), whereas sarcomeric gene variants were more prevalent in complicated myocarditis (58% in adults and 71% in children)."
    explanation: >-
      Establishes that the gene classes involved differ by clinical severity, which is
      why this node is curated as a modifier rather than as a single susceptibility gene.
  downstream:
  - target: Cardiomyocyte Necrosis and Contractile Failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A vulnerable structural background lowers the threshold at which an inflammatory
      insult produces clinically significant myocyte loss and contractile failure. The
      intermediate steps are not established, and the evidence is an association between
      genotype and severity rather than a demonstrated mechanism.
  - target: Post-Inflammatory Ventricular Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Adaptive T Cell-Mediated Myocardial Injury
  description: >-
    The defining lesion of myocarditis: a T cell and macrophage infiltrate in the
    myocardium accompanied by injury to the adjacent myocytes. This is the node at
    which all of the aetiological entry points converge, and it is the node the
    histological definition of myocarditis actually names - an inflammatory infiltrate
    with myocyte injury, in multiple foci, not explained by another cause. Cytotoxic
    CD8 T cells kill infected or autoantigen-presenting myocytes; CD4 T cells and
    macrophages sustain the response.
  role: central_effector
  biological_scale: TISSUE
  cell_types:
  - preferred_term: CD8-positive cytotoxic T cell
    term:
      id: CL:0000625
      label: CD8-positive, alpha-beta T cell
  - preferred_term: CD4-positive helper T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: Macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: T cell mediated cytotoxicity against cardiomyocytes
    term:
      id: GO:0001913
      label: T cell mediated cytotoxicity
    modifier: INCREASED
  - preferred_term: Adaptive immune response
    term:
      id: GO:0002250
      label: adaptive immune response
    modifier: INCREASED
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:33727695
    reference_title: "Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myocarditis was defined as an inflammatory infiltrate associated with myocyte injury, which was not due to some other cause and was present in multiple foci"
    explanation: >-
      States the operational histological definition this node encodes: infiltrate
      plus adjacent myocyte injury, multifocal, not otherwise explained.
  - reference: PMID:27806233
    reference_title: "Fulminant Myocarditis with Combination Immune Checkpoint Blockade."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates."
    explanation: >-
      Documents the T cell and macrophage composition of the infiltrate in human
      myocarditis and its coupling to electrical instability.
  downstream:
  - target: Cardiomyocyte Necrosis and Contractile Failure
    causal_link_type: DIRECT
  - target: Electrical Instability and Arrhythmogenesis
    causal_link_type: DIRECT
  - target: Post-Inflammatory Ventricular Remodeling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Cardiomyocyte Necrosis and Contractile Failure
  description: >-
    Myocyte death - by immune killing, by eosinophil granule toxicity, or by direct
    viral cytoskeletal disruption - releases troponin, removes contractile units, and
    together with interstitial oedema impairs systolic performance. This is the
    inflammatory instance of the generic primary cardiomyocyte insult that opens the
    maladaptive remodelling pathway shared with the inherited and toxic
    cardiomyopathies.
  role: effector
  biological_scale: CELLULAR
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiomyocyte death
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
    modifier: INCREASED
  - preferred_term: Muscle contraction
    term:
      id: GO:0006936
      label: muscle contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33046850
    reference_title: "Myocarditis and inflammatory cardiomyopathy: current evidence and future directions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology."
    explanation: >-
      Couples the myocardial infiltrate to deteriorating cardiac function, which is
      the claim this node makes.
  - reference: PMID:10988241
    reference_title: "Dissociation of sarcoglycans and the dystrophin carboxyl terminus from the sarcolemma in enteroviral cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Enteroviral infection can cause an acquired form of dilated cardiomyopathy."
    explanation: >-
      Supports the route from myocyte structural injury to acquired contractile
      failure, though from enteroviral models rather than from all aetiologies.
  downstream:
  - target: Acute Contractile Failure and Cardiogenic Shock
    causal_link_type: DIRECT
  - target: Post-Inflammatory Ventricular Remodeling
    causal_link_type: DIRECT
  - target: Electrical Instability and Arrhythmogenesis
    causal_link_type: DIRECT
  - target: Anti-Cardiac Myosin Autoimmunity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - postinfectious_autoimmunity
    description: >-
      Cardiac myosin released by dying myocytes is presented in an inflamed,
      adjuvant-rich myocardium, which is how tolerance is broken. This closes an
      amplification loop - injury releases the autoantigen, autoimmunity sustains the
      injury - and is why the chronic phase persists after the initiating virus is
      gone. The loop is intentional and mechanistically load-bearing, not an artefact
      of edge curation.
    evidence:
    - reference: PMID:11334481
      reference_title: "From infection to autoimmunity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The chronic phase of myocarditis is associated with mononuclear infiltration of the myocardium and the production of autoantibodies to cardiac myosin, although infectious virus cannot be detected past day 14 of infection."
      explanation: >-
        Places the anti-myosin autoantibody response after, and downstream of, the acute
        injury phase rather than at the start of it, which is what this edge asserts.
- name: Acute Contractile Failure and Cardiogenic Shock
  description: >-
    When myocyte loss and oedema are extensive and abrupt, ventricular systolic
    function collapses over hours to days and the patient presents in cardiogenic
    shock requiring inotropes or mechanical circulatory support. This fulminant
    presentation is where the acute mortality of myocarditis is concentrated, and it
    is also the point at which endomyocardial biopsy changes management, because the
    histological subtype independently predicts outcome.
  role: consequence
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:31319912
    reference_title: "Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fulminant myocarditis (FM) is a form of acute myocarditis characterized by severe left ventricular systolic dysfunction requiring inotropes and/or mechanical circulatory support."
    explanation: >-
      Defines the fulminant haemodynamic phenotype this node represents.
- name: Electrical Instability and Arrhythmogenesis
  description: >-
    Inflammation, oedema and patchy necrosis disturb conduction and repolarisation
    directly, and the scar left behind provides a fixed re-entrant substrate. The
    result is ventricular tachyarrhythmia and high-grade atrioventricular block, and
    it is this arm rather than pump failure that accounts for myocarditis being a
    recognised cause of sudden death in young people with previously normal hearts.
  role: consequence
  biological_scale: TISSUE
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33727695
    reference_title: "Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac infection by SARS-CoV-2 is associated with more cardiac inflammation and electrocardiographic changes."
    explanation: >-
      Links myocardial inflammation to electrocardiographic abnormality in human
      hearts, supporting the inflammation-to-electrical-disturbance step.
  - reference: PMID:9197214
    reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients usually die of heart failure and ventricular arrhythmia unless cardiac transplantation is performed."
    explanation: >-
      Establishes ventricular arrhythmia, alongside pump failure, as a principal mode
      of death in myocarditis.
- name: Post-Inflammatory Ventricular Remodeling
  description: >-
    Where inflammation does not resolve, cardiac fibroblasts are activated and lay
    down extracellular matrix, replacing lost myocardium with scar. IL-17 from Th17
    cells is a direct fibrogenic signal in experimental autoimmune myocarditis,
    acting through PKC-beta, Erk1/2 and NF-kappaB. This node is the inflammatory
    entry into the conserved ventricular-remodelling step shared across the
    cardiomyopathies.
  role: effector
  biological_scale: TISSUE
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  cell_types:
  - preferred_term: Cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Extracellular matrix deposition
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: Collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  - preferred_term: Cardiomyocyte death
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:22531062
    reference_title: "IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The results indicated that IL-17 induced cardiac fibrosis both in vitro and in vivo."
    explanation: >-
      Direct experimental evidence that a myocarditis-associated cytokine drives the
      fibrotic remodelling this node asserts.
  - reference: PMID:22531062
    reference_title: "IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The protein kinase C (PKC)β/Erk1/2/NF-κB (Nuclear Factor κappa B) pathway was involved in the development of myocardial fibrosis and IL-17 contributed to cardiac fibrosis following EAM via this pathway."
    explanation: >-
      Names the signalling route from the inflammatory cytokine to matrix deposition.
  downstream:
  - target: Inflammatory Dilated Cardiomyopathy
    causal_link_type: DIRECT
  - target: Electrical Instability and Arrhythmogenesis
    causal_link_type: DIRECT
    description: >-
      Replacement fibrosis leaves a fixed scar that supports macro-re-entrant
      ventricular arrhythmia after the acute inflammation has settled.
- name: Inflammatory Dilated Cardiomyopathy
  description: >-
    The chronic endpoint: a dilated, hypokinetic ventricle with persisting
    inflammation and established fibrosis, clinically indistinguishable from other
    dilated cardiomyopathy and carrying the same trajectory to heart failure,
    transplantation or death. Which patients arrive here rather than recovering is
    the central open question of the field.
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22531062
    reference_title: "IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Myocarditis is a common clinical cardiovascular disease, and some patients progress to dilated cardiomyopathy (DCM) with chronic heart failure."
    explanation: >-
      States the progression from myocarditis to dilated cardiomyopathy with chronic
      heart failure that this node represents.
  - reference: PMID:33046850
    reference_title: "Myocarditis and inflammatory cardiomyopathy: current evidence and future directions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis."
    explanation: >-
      Supports the poor prognosis attached to the chronic inflammatory-cardiomyopathy
      endpoint.
phenotypes:
- category: Cardiac
  name: Myocarditis
  description: >-
    Inflammatory infiltration of the myocardium with associated myocyte injury; the
    defining finding of the disease.
  phenotype_term:
    preferred_term: Myocarditis
    term:
      id: HP:0012819
      label: Myocarditis
  frequency: OBLIGATE
  diagnostic: true
  evidence:
  - reference: PMID:33727695
    reference_title: "Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myocarditis was defined as an inflammatory infiltrate associated with myocyte injury, which was not due to some other cause and was present in multiple foci"
    explanation: >-
      Gives the histological definition of the defining phenotype.
- category: Cardiac
  name: Chest Pain
  description: >-
    Acute chest pain, often with ST/T-wave change and troponin elevation but
    unobstructed coronary arteries - the infarct-like presentation. Coronary spasm is
    frequently demonstrable on provocative testing in biopsy-proven viral disease and
    may contribute.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
    temporality: ACUTE
  frequency: FREQUENT
  evidence:
  - reference: PMID:35533750
    reference_title: "Epicardial and microvascular coronary artery spasm in biopsy-proven viral myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coronary spasm is a frequent finding in patients with biopsy-proven viral myocarditis supporting the hypothesis that coronary spasm may contribute to chest pain in these patients."
    explanation: >-
      Documents chest pain as a presenting feature of biopsy-proven viral myocarditis
      and offers a mechanism for it.
- category: Cardiac
  name: Dyspnea
  description: >-
    Breathlessness from congestion and impaired systolic function; the commonest
    presenting symptom in the eosinophilic form.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  frequency: FREQUENT
  evidence:
  - reference: PMID:29096807
    reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The main symptom at presentation was dyspnea (59.4%)"
    explanation: >-
      Quantifies dyspnea as the leading presenting symptom in a large series of
      histologically proven eosinophilic myocarditis.
- category: Cardiac
  name: Reduced Left Ventricular Ejection Fraction
  description: >-
    Impaired systolic function, ranging from mild reduction to profound dysfunction.
    Median ejection fraction at presentation was 35% in a large eosinophilic
    myocarditis series.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  frequency: FREQUENT
  evidence:
  - reference: PMID:29096807
    reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median left ventricular ejection fraction at presentation was 35% (interquartile range: 25% to 50%)."
    explanation: >-
      Quantifies the degree of systolic impairment at presentation.
  subtype: Eosinophilic
- category: Cardiac
  name: Congestive Heart Failure
  description: >-
    Congestive heart failure is the commonest mode of presentation in giant cell
    myocarditis and a frequent one across all forms.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  frequency: FREQUENT
  evidence:
  - reference: PMID:9197214
    reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most presented with congestive heart failure (47 patients, or 75 percent), ventricular arrhythmia (9 patients, or 14 percent), or heart block (3 patients, or 5 percent)"
    explanation: >-
      Quantifies heart failure as the dominant presentation in the giant cell form.
- category: Cardiac
  name: Cardiogenic Shock
  description: >-
    Severe left ventricular systolic dysfunction requiring inotropes or mechanical
    circulatory support - the fulminant presentation.
  phenotype_term:
    preferred_term: Cardiogenic shock
    term:
      id: HP:0030149
      label: Cardiogenic shock
    temporality: ACUTE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:31319912
    reference_title: "Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fulminant myocarditis (FM) is a form of acute myocarditis characterized by severe left ventricular systolic dysfunction requiring inotropes and/or mechanical circulatory support."
    explanation: >-
      Defines the shock phenotype and the support requirement that identifies it.
- category: Cardiac
  name: Ventricular Arrhythmia
  description: >-
    Ventricular tachyarrhythmia arising from inflamed or scarred myocardium; a
    principal mode of death.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:9197214
    reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients usually die of heart failure and ventricular arrhythmia unless cardiac transplantation is performed."
    explanation: >-
      Establishes ventricular arrhythmia as a leading cause of death in myocarditis.
- category: Cardiac
  name: Atrioventricular Block
  description: >-
    High-grade conduction block from inflammatory or fibrotic involvement of the
    atrioventricular conduction axis, sometimes the presenting event.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:9197214
    reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most presented with congestive heart failure (47 patients, or 75 percent), ventricular arrhythmia (9 patients, or 14 percent), or heart block (3 patients, or 5 percent)"
    explanation: >-
      Documents heart block as a presenting manifestation in the giant cell series.
- category: Cardiac
  name: Sudden Cardiac Death
  description: >-
    Myocarditis is a recognised, if uncommon, adjudicated cause of sudden cardiac
    death in young competitive athletes.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  frequency: VERY_RARE
  evidence:
  - reference: PMID:37955565
    reference_title: "Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eight cases of death were attributable to myocarditis over the study period (1 case from January 1, 2020, through June 30, 2022), with none attributed to COVID-19 infection."
    explanation: >-
      Quantifies myocarditis as an adjudicated cause of sudden cardiac death in a
      20-year athlete cohort, and notes it did not increase during the pandemic
      period.
- category: Laboratory
  name: Elevated Cardiac Troponin
  description: >-
    Troponin release from injured myocytes; elevated cardiac troponin is an entry
    criterion for contemporary acute-myocarditis trials.
  phenotype_term:
    preferred_term: Increased circulating troponin I concentration
    term:
      id: HP:0410173
      label: Increased circulating troponin I concentration
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:37640625
    reference_title: "Rationale and design of the ARAMIS trial: Anakinra versus placebo, a double blind randomized controlled trial for the treatment of acute myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "symptomatic patients with elevated cardiac troponin and cardiac magnetic resonance-proven acute myocarditis"
    explanation: >-
      Shows elevated cardiac troponin used as a defining criterion for acute
      myocarditis in a randomized trial population.
- category: Laboratory
  name: Peripheral Eosinophilia
  description: >-
    Blood eosinophil expansion accompanying the eosinophilic and hypersensitivity
    forms; present in about three-quarters of cases but not obligatory.
  phenotype_term:
    preferred_term: Increased total eosinophil count
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  frequency: VERY_FREQUENT
  subtype: Eosinophilic
  evidence:
  - reference: PMID:29096807
    reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with peripheral eosinophilia observed in 75.9%"
    explanation: >-
      Quantifies the frequency of peripheral eosinophilia in histologically proven
      eosinophilic myocarditis.
- category: Musculoskeletal
  name: Myositis
  description: >-
    Skeletal muscle inflammation, sometimes with rhabdomyolysis, overlapping the
    myocarditis in checkpoint-inhibitor disease and reflecting the shared antigen
    targeted by the same T cell clones.
  phenotype_term:
    preferred_term: Myositis
    term:
      id: HP:0100614
      label: Myositis
  subtype: ICI-Associated
  evidence:
  - reference: PMID:27806233
    reference_title: "Fulminant Myocarditis with Combination Immune Checkpoint Blockade."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates."
    explanation: >-
      Documents the myositis overlap that characterises checkpoint-inhibitor
      myocarditis.
- category: Cardiac
  name: Dilated Cardiomyopathy
  description: >-
    The chronic sequela: a dilated, hypokinetic ventricle following unresolved
    myocarditis.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    clinical_course: PROGRESSIVE
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:14722762
    reference_title: "Viral heart disease: molecular diagnosis, clinical prognosis, and treatment strategies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Myocarditis is considered as a potent predisposing factor for dilated cardiomyopathy (DCM)."
    explanation: >-
      Establishes dilated cardiomyopathy as a recognised sequela of myocarditis.
histopathology:
- name: Lymphocytic Infiltrate of the Myocardium
  finding_term:
    preferred_term: Lymphocytic infiltrate
    term:
      id: NCIT:C35983
      label: Lymphocytic Infiltrate
  description: >-
    Mononuclear, T-cell-predominant infiltration of the myocardium with injury to
    adjacent myocytes; the commonest histological pattern and the substrate of the
    Dallas-criteria diagnosis.
  diagnostic: true
  subtype: Lymphocytic
  evidence:
  - reference: PMID:33727695
    reference_title: "Factors associated with myocardial SARS-CoV-2 infection, myocarditis, and cardiac inflammation in patients with COVID-19."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Virus+ cases showed higher densities of myocardial CD68+ macrophages and CD3+ lymphocytes, as well as more electrocardiographic changes (23/27 vs 4/10; P = 0.01)."
    explanation: >-
      Quantifies the CD3+ lymphocyte and CD68+ macrophage composition of the
      myocardial infiltrate on human autopsy histology.
- name: Eosinophilic Infiltrate of the Myocardium
  finding_term:
    preferred_term: Eosinophilic infiltrate
    term:
      id: NCIT:C35981
      label: Eosinophilic Infiltrate
  description: >-
    Eosinophil-rich myocardial infiltration defining the eosinophilic and
    hypersensitivity forms on biopsy.
  diagnostic: true
  subtype: Eosinophilic
  evidence:
  - reference: PMID:29096807
    reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on a systematic revision of all published histologically proven cases, this study aimed to describe the clinical presentation, treatment, and outcome of EM."
    explanation: >-
      Confirms that the eosinophilic form is defined and assembled histologically
      rather than clinically.
- name: Cardiac Fibrosis
  finding_term:
    preferred_term: Cardiac fibrosis
    term:
      id: NCIT:C178564
      label: Cardiac Fibrosis
  description: >-
    Replacement and interstitial fibrosis following myocyte loss, the histological
    correlate of chronic remodelling and of the arrhythmogenic scar substrate.
  evidence:
  - reference: PMID:22531062
    reference_title: "IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "western blot, immunofluorescence and sirius red staining were used to analyze the collagen expression"
    explanation: >-
      Names the histological methods by which the post-myocarditis collagen
      deposition was demonstrated in the experimental model.
imaging_findings:
- name: Myocardial Late Gadolinium Enhancement
  modality: MRI
  imaging_finding_term:
    preferred_term: Myocardial late gadolinium enhancement
    term:
      id: HP:4000004
      label: Myocardial late gadolinium enhancement
  description: >-
    Non-ischaemic, typically subepicardial or mid-wall late gadolinium enhancement on
    cardiac magnetic resonance. Under the updated Lake Louise criteria it is one of
    the T1-based markers which, combined with a T2-based marker of oedema, supports a
    diagnosis of acute myocardial inflammation.
  diagnostic: true
  evidence:
  - reference: PMID:30545455
    reference_title: "Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is based on at least one T2-based criterion (global or regional increase of myocardial T2 relaxation time or an increased signal intensity in T2-weighted CMR images), with at least one T1-based criterion (increased myocardial T1, extracellular volume, or late gadolinium enhancement)."
    explanation: >-
      Places late gadolinium enhancement within the consensus CMR criteria for
      diagnosing myocardial inflammation.
diagnosis:
- name: Endomyocardial Biopsy
  description: >-
    The reference standard for histological, immunophenotypic and pathogen-directed
    diagnosis. It is the only test that distinguishes lymphocytic from giant cell and
    eosinophilic disease and that separates virus-positive from virus-negative
    inflammation - and because those distinctions decide whether immunosuppression is
    offered, biopsy changes management rather than merely confirming it.
  evidence:
  - reference: PMID:31319912
    reference_title: "Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we provide evidence that the histologic subtype of FM carries independent prognostic value, highlighting the need for timely endomyocardial biopsy in this condition"
    explanation: >-
      Supports biopsy as management-changing by showing the histological subtype
      carries prognostic information beyond clinical severity.
- name: Cardiac Magnetic Resonance
  description: >-
    The principal non-invasive tissue-characterisation test, combining T2-based
    markers of oedema with T1-based markers of injury under the updated Lake Louise
    criteria.
  evidence:
  - reference: PMID:30545455
    reference_title: "Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While having both a positive T2-based marker and a T1-based marker will increase specificity for diagnosing acute myocardial inflammation, having only one (i.e., T2-based OR T1-based) marker may still support a diagnosis of acute myocardial inflammation in an appropriate clinical scenario, albeit with less specificity."
    explanation: >-
      States the diagnostic logic and the specificity trade-off of the CMR criteria.
differential_diagnoses:
- name: Acute Myocardial Infarction
  description: >-
    The infarct-like presentation of myocarditis - chest pain, ST/T change and
    troponin release - is indistinguishable from acute coronary syndrome until
    coronary imaging shows unobstructed arteries.
  disease_term:
    preferred_term: myocardial infarction
    term:
      id: MONDO:0005068
      label: myocardial infarction
  distinguishing_features:
  - Unobstructed coronary arteries on angiography
  - Non-ischaemic (subepicardial or mid-wall rather than subendocardial) distribution of late gadolinium enhancement
  evidence:
  - reference: PMID:35533750
    reference_title: "Epicardial and microvascular coronary artery spasm in biopsy-proven viral myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 618 consecutive patients with unobstructed coronary arteries who underwent endomyocardial biopsy between 2008 and 2018 were screened."
    explanation: >-
      Describes the clinical population in which myocarditis is separated from
      coronary disease - patients presenting like infarction but with unobstructed
      coronaries.
- name: Cardiac Sarcoidosis
  description: >-
    Granulomatous myocardial inflammation that presents with the same high-grade AV
    block, ventricular arrhythmia and heart failure, and is curated separately in
    this knowledge base.
  disease_term:
    preferred_term: cardiac sarcoidosis
    term:
      id: MONDO:0001707
      label: cardiac sarcoidosis
  distinguishing_features:
  - Non-caseating epithelioid granulomas rather than a lymphocytic, eosinophilic or giant-cell-with-necrosis infiltrate
  - Extracardiac sarcoid involvement
  - Patchy distribution favouring the basal septum on imaging
  evidence:
  - reference: PMID:36924191
    reference_title: "Cardiac sarcoidosis: phenotypes, diagnosis, treatment, and prognosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac sarcoidosis (CS) results from epithelioid cell granulomas infiltrating the myocardium and predisposing to conduction disturbances, ventricular tachyarrhythmias, and heart failure."
    explanation: >-
      Names the granulomatous histology that distinguishes cardiac sarcoidosis from
      the infiltrates curated here, while confirming the overlapping clinical
      endpoints that make it a differential.
environmental:
- name: mRNA COVID-19 vaccination
  description: >-
    Myocarditis occurs rarely after mRNA COVID-19 vaccination, concentrated in
    adolescent and young adult males and mostly after the second dose. The clinical
    course is usually mild and self-limited, unlike infection-associated myocarditis.
  effect: Increases the short-term incidence of myocarditis, concentrated in young males after dose 2
  notes: >-
    No exposure_term is bound. ECTO was searched and carries no vaccination-exposure
    term suitable for this concept; a free-text preferred_term with no ontology
    binding would render as an unbound node without adding meaning, so it is omitted
    deliberately rather than left un-researched.
  evidence:
  - reference: PMID:34614328
    reference_title: "Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients."
    explanation: >-
      National active-surveillance evidence for the association and for its
      concentration in young males after the second dose.
  - reference: PMID:34614328
    reference_title: "Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal."
    explanation: >-
      Establishes that the vaccine-associated form is usually mild, while recording
      that fulminant disease occurred.
  influences_mechanisms:
  - target: Adaptive T Cell-Mediated Myocardial Injury
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Vaccination is followed by myocardial inflammation in a small excess of
      recipients. The intermediate steps are not established - molecular mimicry and
      cytokine dysregulation are both proposed and neither is settled - so the link is
      recorded as indirect with unknown intermediates.
    evidence:
    - reference: PMID:34614328
      reference_title: "Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20)."
      explanation: >-
        Quantifies the excess of myocarditis over background incidence following
        vaccination, which is the evidence that the exposure acts on this node.
- name: Immune checkpoint inhibitor therapy
  description: >-
    Therapeutic blockade of CTLA-4, PD-1 or PD-L1 for cancer. Combination CTLA-4 plus
    PD-1 blockade carries the highest risk, and myocarditis is the most lethal of the
    immune-related adverse events it provokes.
  effect: Triggers off-target myocardial T cell reactivity by removing checkpoint restraint
  exposure_term:
    preferred_term: exposure to immune checkpoint inhibitor drug
    term:
      id: ECTO:0000509
      label: exposure to drug
  evidence:
  - reference: PMID:30242316
    reference_title: "Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%])."
    explanation: >-
      Establishes checkpoint-inhibitor exposure, particularly combination therapy, as
      a cause of fatal myocarditis.
  influences_mechanisms:
  - target: Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The drug exposure is the proximate cause of the loss of checkpoint restraint on
      myocardial T cells.
    evidence:
    - reference: PMID:27806233
      reference_title: "Fulminant Myocarditis with Combination Immune Checkpoint Blockade."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab."
      explanation: >-
        Direct clinical evidence linking the checkpoint-inhibitor exposure to the
        myocardial T cell lesion.
- name: Strenuous exercise during active myocarditis
  description: >-
    Vigorous exertion while the myocardium is actively inflamed is believed to amplify
    injury and arrhythmic risk, which is why exercise restriction is standard advice
    during the acute phase. Half of sudden cardiac deaths in athletes are exertional.
  effect: Believed to amplify myocardial injury and arrhythmic risk during active inflammation
  exposure_term:
    preferred_term: exposure to strenuous exercise
    term:
      id: ECTO:6000031
      label: exposure to strenuous exercise
  notes: >-
    The mechanistic link is inferred rather than demonstrated: the cited athlete
    cohort establishes that half of sudden cardiac deaths are exertional across all
    causes, not that exertion causes deterioration specifically in myocarditis. The
    evidence is graded PARTIAL for that reason and no influences_mechanisms link is
    asserted.
  evidence:
  - reference: PMID:37955565
    reference_title: "Sudden Cardiac Death in National Collegiate Athletic Association Athletes: A 20-Year Study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SCD events were exertional in 50% of cases."
    explanation: >-
      Supports the association between exertion and sudden cardiac death across
      causes; it does not by itself establish that exertion worsens myocarditis
      specifically.
genetic:
- name: Cardiomyopathy-associated gene variants
  relationship_type: SUSCEPTIBILITY
  association: >-
    Pathogenic or likely pathogenic variants in inherited-cardiomyopathy genes -
    desmosomal genes such as DSP and PKP2, and sarcomeric and cytoskeletal genes
    such as TTN, MYH7 and FLNC - are found in a substantial minority of patients
    with acute myocarditis and are markedly enriched in those with a complicated
    course. There is no myocarditis gene; the genotype modifies susceptibility and
    severity rather than causing the inflammatory episode, and it is one reason a
    myocarditis-like presentation can be the first manifestation of an inherited
    cardiomyopathy.
  notes: >-
    No gene_term is bound because the evidence curated here is at the level of gene
    classes (desmosomal versus sarcomeric) from a meta-analysis, not a variant-level
    claim about a named gene. Binding a specific HGNC gene would assert more than the
    cited source supports.
  evidence:
  - reference: PMID:38573261
    reference_title: "Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Acute Myocarditis: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic variants are present in a large proportion of patients with acute myocarditis. The prevalence of genetic variants and the genes involved vary according to age and clinical presentation."
    explanation: >-
      States both the frequency of cardiomyopathy-gene variants in acute myocarditis
      and their dependence on age and presentation.
  - reference: PMID:38573261
    reference_title: "Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Acute Myocarditis: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Acute myocarditis is an inflammatory condition that may precede the development of dilated or arrhythmogenic cardiomyopathy."
    explanation: >-
      Supports the overlap between acute myocarditis and inherited cardiomyopathy that
      makes genetic evaluation relevant; it does not itself establish causality.
treatments:
- name: Guideline-Directed Heart Failure Therapy and Supportive Care
  description: >-
    The baseline for most patients. Ventricular dysfunction is treated with standard
    heart-failure therapy - in the ARAMIS trial population an ACE inhibitor and a
    beta-blocker were given as standard of care - alongside rhythm monitoring and
    haemodynamic support. Most uncomplicated cases are self-limited and need nothing
    more.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  therapeutic_modality: OTHER
  evidence:
  - reference: PMID:37640625
    reference_title: "Rationale and design of the ARAMIS trial: Anakinra versus placebo, a double blind randomized controlled trial for the treatment of acute myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to standard of care, including an angiotensin-converting enzyme inhibitor and a beta-blocker"
    explanation: >-
      Documents ACE inhibition plus beta-blockade as the standard-of-care backbone in
      a contemporary randomized acute-myocarditis trial.
- name: Immunosuppression for Virus-Negative Inflammatory Cardiomyopathy
  description: >-
    Prednisone plus azathioprine in patients with biopsy-proven myocarditis, chronic
    heart failure refractory to conventional therapy, and no myocardial viral genome.
    The TIMIC trial showed a significant improvement in ejection fraction and a
    reduction in ventricular dimensions in the treated arm while the placebo arm
    deteriorated. The pathogen-exclusion step is not optional - it is what separates
    this indication from the unselected population in which immunosuppression failed.
  treatment_term:
    preferred_term: Immunosuppressive Therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Adaptive T Cell-Mediated Myocardial Injury
    description: >-
      Suppresses the adaptive infiltrate that drives ongoing myocyte injury once the
      myocardium has been shown to be virus-free.
    evidence:
    - reference: PMID:19556262
      reference_title: "Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Group 1 showed a significant improvement of left-ventricular ejection fraction and a significant decrease in left-ventricular dimensions and volumes compared with baseline."
      explanation: >-
        Randomized evidence that suppressing the immune infiltrate reverses the
        contractile and dimensional consequences of the mechanism.
  evidence:
  - reference: PMID:19556262
    reference_title: "Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data confirm the efficacy of immunosuppression in virus-negative inflammatory cardiomyopathy."
    explanation: >-
      The trial conclusion supporting this indication.
  - reference: PMID:7596370
    reference_title: "A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results do not support routine treatment of myocarditis with immunosuppressive drugs."
    explanation: >-
      Recorded as a refuting item because it is the negative trial that bounds this
      indication: in unselected myocarditis, without virus exclusion, immunosuppression
      did not improve ejection fraction or survival.
- name: Combination Immunosuppression for Giant Cell Myocarditis
  description: >-
    Corticosteroids combined with cyclosporine, azathioprine, or both. In the
    multicenter registry, treated patients survived on average 12.3 months versus 3.0
    months untreated. This is the clearest survival benefit from immunosuppression in
    any myocarditis subtype and is the practical reason the giant cell form must be
    identified on biopsy.
  treatment_term:
    preferred_term: Immunosuppressive Therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
    - preferred_term: cyclosporine
      term:
        id: CHEBI:4031
        label: cyclosporin A
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Giant Cell Destructive Myocardial Necrosis
    description: >-
      Suppresses the T cell and macrophage response responsible for the destructive
      giant cell lesion.
    evidence:
    - reference: PMID:9197214
      reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The 22 patients treated with corticosteroids and cyclosporine, azathioprine, or both therapies survived for an average of 12.3 months, as compared with an average of 3.0 months for the 30 patients who received no immunosuppressive therapy (P=0.001)."
      explanation: >-
        Quantifies the survival gain from suppressing the giant cell lesion.
  evidence:
  - reference: PMID:9197214
    reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 22 patients treated with corticosteroids and cyclosporine, azathioprine, or both therapies survived for an average of 12.3 months, as compared with an average of 3.0 months for the 30 patients who received no immunosuppressive therapy (P=0.001)."
    explanation: >-
      The observational comparison supporting combination immunosuppression in the
      giant cell form.
  notes: Applies to the Giant Cell subtype.
- name: Corticosteroid Therapy for Eosinophilic Myocarditis
  description: >-
    Withdrawal of the offending agent where one is identified, plus corticosteroids;
    steroids were given to more than three-quarters of patients in the largest
    published series. In-hospital mortality remains high, and is highest in the
    hypersensitivity form.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Eosinophil-Mediated Myocardial Injury
    description: >-
      Corticosteroids suppress the eosinophil-driven infiltrate responsible for the
      myocardial injury in this form.
    evidence:
    - reference: PMID:29096807
      reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Steroids were administered in 77.7% of patients."
      explanation: >-
        Documents corticosteroid use as near-universal practice in this form; the
        series is observational and reports no controlled effect estimate, so the
        support is partial.
  evidence:
  - reference: PMID:29096807
    reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In-hospital death was 22.3% (n = 40), with the highest occurrence in the hypersensitivity form (36.1%; p = 0.026)."
    explanation: >-
      Records the residual mortality despite widespread steroid use, bounding the
      claim that this treatment is sufficient.
  notes: Applies to the Eosinophilic subtype.
- name: High-Dose Corticosteroids and Drug Withdrawal for Checkpoint-Inhibitor Myocarditis
  description: >-
    Immediate discontinuation of the checkpoint inhibitor with early high-dose
    corticosteroids. The evidence base is observational; the two index cases were
    refractory and fatal despite treatment, which is the origin of the recommendation
    to act early rather than escalate late.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: methylprednisolone
      term:
        id: NCIT:C647
        label: Methylprednisolone
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity
    description: >-
      Stopping the drug removes the ongoing checkpoint blockade; corticosteroids
      suppress the T cell response it released.
    evidence:
    - reference: PMID:30242316
      reference_title: "Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Median time from symptom onset to death was 32 days."
      explanation: >-
        Supports the urgency rationale by showing how short the window between symptom
        onset and death is; it does not itself measure corticosteroid efficacy.
  evidence:
  - reference: PMID:27806233
    reference_title: "Fulminant Myocarditis with Combination Immune Checkpoint Blockade."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates."
    explanation: >-
      Documents the refractory course that motivates immediate drug withdrawal and
      early high-dose steroids; it does not demonstrate steroid efficacy.
  notes: Applies to the ICI-Associated subtype.
- name: Second-Line Immunosuppression for Steroid-Refractory Checkpoint-Inhibitor Myocarditis
  description: >-
    Methylprednisolone pulse therapy at 500-1,000 mg/day is the guideline-recommended
    first step for checkpoint-inhibitor myocarditis, and a substantial fraction of
    patients do not respond to it. Abatacept is the proposed preferred second agent
    for isolated steroid-refractory disease; alemtuzumab or tocilizumab/tofacitinib
    are proposed for rapidly progressive or IL-6-high disease, and abatacept combined
    with ruxolitinib, mycophenolate mofetil or IVIG for cases overlapping myositis or
    myasthenia gravis. The evidence base is 45 case reports and case series, not a
    trial, and the authors of the proposed algorithm say so themselves.
  treatment_term:
    preferred_term: Immunosuppressive Therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
    therapeutic_agent:
    - preferred_term: abatacept
      term:
        id: NCIT:C28898
        label: Abatacept
    - preferred_term: ruxolitinib
      term:
        id: CHEBI:66919
        label: ruxolitinib
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
    - preferred_term: tocilizumab
      term:
        id: NCIT:C84217
        label: Tocilizumab
  therapeutic_modality: OTHER
  notes: >-
    Curated as a proposed, uncontrolled treatment approach. The source is an explicitly
    narrative review synthesizing case reports; nothing here has randomized support, and
    the agents span several modalities (a fusion protein, a JAK inhibitor, a small
    molecule and a monoclonal antibody), so therapeutic_modality is OTHER rather than
    any single platform.
  target_mechanisms:
  - target: Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity
    description: >-
      Abatacept restores CTLA-4-mediated co-stimulation blockade, the checkpoint the
      drug removed; the other agents suppress the resulting T cell and cytokine
      response by different routes.
    evidence:
    - reference: PMID:39263485
      reference_title: "Therapeutic agents for steroid-refractory immune checkpoint inhibitor-related myocarditis: a narrative review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Abatacept is the preferred choice for the treatment of isolated steroid-refractory IRM."
      explanation: >-
        States the proposed first choice for suppressing the checkpoint-released T cell
        response; the recommendation rests on case series, so the support is partial.
  evidence:
  - reference: PMID:39263485
    reference_title: "Therapeutic agents for steroid-refractory immune checkpoint inhibitor-related myocarditis: a narrative review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Methylprednisolone pulse therapy (500-1,000 mg/day) is the initial treatment for IRM recommended by almost all relevant guidelines."
    explanation: >-
      Establishes the first-line therapy against which steroid-refractory disease is
      defined.
  - reference: PMID:39263485
    reference_title: "Therapeutic agents for steroid-refractory immune checkpoint inhibitor-related myocarditis: a narrative review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathogenesis of steroid-refractory IRM and the treatment regimen remain unclear. A large number of studies need to be conducted to validate or update our proposed treatment approach."
    explanation: >-
      The authors' own statement that the proposed algorithm is unvalidated, which is
      why this treatment is curated as proposed rather than established.
- name: Temporary Mechanical Circulatory Support
  description: >-
    Extracorporeal membrane oxygenation or a temporary ventricular assist device to
    carry the patient through fulminant cardiogenic shock, either to myocardial
    recovery or to transplantation. It was used in about one in six patients in the
    eosinophilic series and is the established bridge in giant cell disease.
  treatment_term:
    preferred_term: Extracorporeal Membrane Oxygenation
    term:
      id: NCIT:C171507
      label: Extracorporeal Membrane Oxygenation
  therapeutic_modality: DEVICE
  target_mechanisms:
  - target: Acute Contractile Failure and Cardiogenic Shock
    description: >-
      Mechanical support substitutes for the failed ventricle while the inflammatory
      injury resolves or a donor organ is found.
    evidence:
    - reference: PMID:12057701
      reference_title: "Giant cell myocarditis: clinical presentation, bridge to transplantation with mechanical circulatory support, and long-term outcome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In our experience, these patients can be bridged successfully to transplant with mechanical circulatory assist."
      explanation: >-
        Direct evidence that mechanical support addresses the shock node as a bridge
        to definitive therapy.
  evidence:
  - reference: PMID:29096807
    reference_title: "Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A temporary mechanical circulatory support (n = 30) was instituted in 16.8% of patients."
    explanation: >-
      Quantifies how often temporary mechanical support is required in severe
      myocarditis.
- name: Heart Transplantation
  description: >-
    Definitive therapy for irreversible myocardial failure. In giant cell myocarditis
    transplantation is the treatment of choice for most patients despite a real risk
    of the giant cell infiltrate recurring in the graft, which can respond to
    augmented immunosuppression.
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  therapeutic_modality: SURGERY
  target_mechanisms:
  - target: Inflammatory Dilated Cardiomyopathy
    description: >-
      Replaces the irreversibly remodelled ventricle when medical therapy has failed.
    evidence:
    - reference: PMID:9197214
      reference_title: "Idiopathic giant-cell myocarditis--natural history and treatment. Multicenter Giant Cell Myocarditis Study Group Investigators."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Despite the possibility of fatal disease recurrence, transplantation is the treatment of choice for most patients."
      explanation: >-
        States transplantation as definitive therapy while recording the recurrence
        risk that qualifies it.
  evidence:
  - reference: PMID:12057701
    reference_title: "Giant cell myocarditis: clinical presentation, bridge to transplantation with mechanical circulatory support, and long-term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Giant cell myocarditis may recur after transplantation but may respond to augmented immunosuppression."
    explanation: >-
      Records both the recurrence risk after transplantation and its responsiveness to
      augmented immunosuppression.
- name: Interleukin-1 Blockade
  description: >-
    Anakinra, an IL-1 receptor antagonist, targets the NLRP3-caspase-1-IL-1beta arm of
    the innate amplification step. It is investigational in acute myocarditis; ARAMIS
    is the randomized trial designed to test it, and the indication should not be
    treated as established.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  therapeutic_modality: OTHER
  target_mechanisms:
  - target: Innate Immune Sensing and Cytokine Amplification
    description: >-
      Blocks IL-1 receptor signalling downstream of inflammasome activation, the
      cytokine amplification step of this node.
    evidence:
    - reference: PMID:37640625
      reference_title: "Rationale and design of the ARAMIS trial: Anakinra versus placebo, a double blind randomized controlled trial for the treatment of acute myocarditis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recently, experimental studies have suggested that specific blockade of the interleukin-1β immune innate pathway could be effective in acute myocarditis."
      explanation: >-
        States the mechanistic rationale for targeting this node; the evidence is a
        trial protocol, so the support is partial and the efficacy claim is untested.
  notes: >-
    ARAMIS has reported and was negative in its enrolled population, so IL-1 blockade
    is NOT an established treatment for acute myocarditis. It is retained here because
    the mechanism target is real and the residual signal is confined to fulminant or
    hyperinflammatory disease, where the evidence is case series only.
  evidence:
  - reference: PMID:42397625
    reference_title: "Cardioimmunology of Myocarditis: Targeting the IL-1 Pathway."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "Clinically, the randomized trial of anakinra in acute myocarditis (ARAMIS) did not improve outcomes in a largely low-risk cohort, but accumulating case reports and small series suggest potential benefit in fulminant/hyperinflammatory myocarditis and chronic active refractory myocarditis."
    explanation: >-
      Records the negative randomized result in the enrolled low-risk population.
      Carried as REFUTE for the general indication; the residual case-series signal in
      fulminant disease is noted but is not randomized evidence.
  - reference: PMID:42397625
    reference_title: "Cardioimmunology of Myocarditis: Targeting the IL-1 Pathway."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, evidence is mainly derived from case reports and small series, and robust randomized data are lacking."
    explanation: >-
      Bounds the residual claim: outside the negative trial population the support for
      IL-1 blockade in myocarditis is uncontrolled.
  - reference: PMID:37640625
    reference_title: "Rationale and design of the ARAMIS trial: Anakinra versus placebo, a double blind randomized controlled trial for the treatment of acute myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ARAMIS is the first trial evaluating inhibition of the interleukin-1β immune innate pathway in the setting of acute myocarditis."
    explanation: >-
      Establishes what the trial set out to test; it is a design paper and reports no
      result.
datasets:
- accession: geo:GSE316643
  title: Spatial transcriptomic profiling of human heart tissue obtained from mRNA vaccine-associated myocarditis cases
  data_type: SPATIAL_TRANSCRIPTOMICS
  sample_count: 13
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:41922346
  notes: >-
    Human myocardial tissue from mRNA vaccine-associated myocarditis, profiled
    spatially. Directly relevant to the vaccine-associated exposure curated in the
    environmental section. Discovered via just discover-datasets and verified with
    just verify-datasets; relevance triaged manually.
- accession: geo:GSE329991
  title: An Interferon-gamma-Driven Myeloid Inflammatory Signature defines Glucocorticoid-Resistance of Immune Checkpoint Inhibitor-Associated Myocarditis
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 6
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: >-
    Human single-cell profiling of checkpoint-inhibitor myocarditis, relevant to the
    ICI-Associated subtype and to the corticosteroid treatment entry. No linked
    publication was available at the time of curation.
- accession: geo:GSE302512
  title: Immune checkpoint inhibitor-induced myocarditis is dependent on CD8 T cell-derived TNF and TNFR2 signaling
  data_type: BULK_RNA_SEQ
  sample_count: 6
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:41718716
  notes: >-
    Murine model of checkpoint-inhibitor myocarditis, supporting the CD8 T cell arm
    of the Checkpoint Withdrawal node. Model-organism data, not human.
- accession: geo:GSE297745
  title: IL-17A Neutralization Prevents Immune Checkpoint Inhibitor-Associated Myocarditis
  data_type: SPATIAL_TRANSCRIPTOMICS
  sample_count: 4
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  notes: >-
    Murine spatial transcriptomics of checkpoint-inhibitor myocarditis under IL-17A
    neutralization. Complements the IL-17 fibrosis evidence curated on the
    Post-Inflammatory Ventricular Remodeling node, from a different disease context.
clinical_trials:
- name: NCT03018834
  phase: PHASE_II
  status: COMPLETED
  notes: >-
    ClinicalTrials.gov registers ARAMIS as a phase 2/3 study. The schema's phase slot
    is single-valued, so the earlier of the two is recorded here rather than claiming
    the phase III designation alone.
  description: >-
    ARAMIS: anakinra versus placebo, a double-blind randomized controlled trial of
    IL-1 receptor blockade in acute myocarditis with elevated troponin and
    CMR-confirmed disease. Primary endpoint is days alive free of myocarditis
    complications.
  target_phenotypes:
  - preferred_term: Myocarditis
    term:
      id: HP:0012819
      label: Myocarditis
  evidence:
  - reference: PMID:37640625
    reference_title: "Rationale and design of the ARAMIS trial: Anakinra versus placebo, a double blind randomized controlled trial for the treatment of acute myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The \"Anakinra versus placebo double blind Randomized controlled trial for the treatment of Acute MyocarditIS\" (ARAMIS) trial (ClinicalTrials.gov identifier: NCT03018834) is a national multicentre randomized parallel-group double blind study among symptomatic patients with elevated cardiac troponin and cardiac magnetic resonance-proven acute myocarditis."
    explanation: >-
      Identifies the trial, its registration identifier, and its enrolled population.
  - reference: clinicaltrials:NCT03018834
    reference_title: "Anakinra Versus Placebo Double Blind Randomized Controlled Trial for the Treatment of Acute MyocarditIS"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ANAKINRA, an IL-1β Blocker, is a new treatment that has never been evaluated in myocarditis."
    explanation: >-
      The trial registration record states the intervention and confirms that IL-1
      blockade was untested in myocarditis when the study was designed.
  - reference: PMID:42397625
    reference_title: "Cardioimmunology of Myocarditis: Targeting the IL-1 Pathway."
    supports: REFUTE
    evidence_source: OTHER
    snippet: "Clinically, the randomized trial of anakinra in acute myocarditis (ARAMIS) did not improve outcomes in a largely low-risk cohort, but accumulating case reports and small series suggest potential benefit in fulminant/hyperinflammatory myocarditis and chronic active refractory myocarditis."
    explanation: >-
      Reports the outcome of this completed trial, so its COMPLETED status is not read
      as a result still pending.
animal_models:
- species: Mouse
  genotype: Wild-type BALB/c infected with coxsackievirus B3
  category: Infection model
  description: >-
    Intraperitoneal coxsackievirus B3 infection of susceptible BALB/c mice produces
    acute myocarditis at days 7-14 and chronic myocarditis from day 28, with viral
    replication, innate and adaptive infiltration, myocyte necrosis and later
    fibrosis. It is the workhorse model for enteroviral myocarditis.
  publication: PMID:11334481
  evidence:
  - reference: PMID:11334481
    reference_title: "From infection to autoimmunity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We have investigated two models of virally-induced autoimmune myocarditis in mice using widely different infectious agents."
    explanation: >-
      Establishes the murine coxsackievirus system as an accepted experimental model
      of virally induced myocarditis.
  modeled_mechanisms:
  - target: Cardiotropic Viral Infection of the Myocardium
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces cardiotropic enteroviral infection of the myocardium and the biphasic
      acute-then-chronic inflammatory course.
    limitations: >-
      Enterovirus accounts for a minority of contemporary human myocarditis, where
      parvovirus B19 and HHV-6 dominate the biopsy virome; outcome in the model is
      also strongly dependent on mouse strain, sex, age and viral passage.
    evidence:
    - reference: PMID:11334481
      reference_title: "From infection to autoimmunity."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Infection of susceptible BALB/c mice with either Coxsackievirus or murine cytomegalovirus results in the development of acute myocarditis from day 7-14 after infection, and chronic myocarditis from day 28 onwards."
      explanation: >-
        Establishes that the model reproduces the acute and chronic phases of viral
        myocarditis.
  - target: Direct Cardiomyocyte Cytoskeletal Injury
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Murine CVB3 hearts show loss of sarcolemmal dystrophin and dissociation of the
      sarcoglycan complex, the structural lesion this node asserts.
    limitations: >-
      Specific to enteroviral protease 2A; it does not generalise to parvovirus B19,
      HHV-6, drug-induced or checkpoint-inhibitor myocarditis.
    evidence:
    - reference: PMID:10988241
      reference_title: "Dissociation of sarcoglycans and the dystrophin carboxyl terminus from the sarcolemma in enteroviral cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The dystrophin-associated glycoproteins alpha-, beta-, gamma-, and delta-sarcoglycan and beta-dystroglycan were markedly decreased in the membrane fraction of infected cells in culture, and the typical sarcolemmal localization for each of these proteins was lost in coxsackievirus-B3-infected cardiomyocytes in vivo."
      explanation: >-
        Demonstrates the sarcolemmal lesion in the model in vivo.
- species: Mouse
  genotype: NOD2 knockout, coxsackievirus B3 infected
  category: Genetic perturbation of an infection model
  description: >-
    NOD2-deficient mice infected with CVB3 show reduced cardiac inflammation,
    fibrosis and apoptosis, lower CAR expression and viral copy number, and improved
    left ventricular function relative to wild-type infected controls.
  publication: PMID:28912259
  evidence:
  - reference: PMID:28912259
    reference_title: "NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Left ventricular NOD2 mRNA expression was also induced in CVB3-induced myocarditis versus healthy control mice."
    explanation: >-
      Establishes that the murine CVB3 system reproduces the innate-sensing induction
      seen in human biopsies, which is what makes the knockout informative.
  modeled_mechanisms:
  - target: Innate Immune Sensing and Cytokine Amplification
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Genetic removal of the innate sensor establishes that this node is causally
      required for the downstream inflammation, fibrosis and contractile loss.
    limitations: >-
      A single-gene knockout in an enteroviral model; NOD2 dependence has not been
      shown for the non-enteroviral or drug-induced forms of human myocarditis.
    evidence:
    - reference: PMID:28912259
      reference_title: "NOD2 (Nucleotide-Binding Oligomerization Domain 2) Is a Major Pathogenic Mediator of Coxsackievirus B3-Induced Myocarditis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "NOD2 is an important mediator in the viral uptake and inflammatory response during the pathogenesis of CVB3 myocarditis."
      explanation: >-
        States the causal role of the innate sensing node established by the knockout.
- species: Mouse
  genotype: Cardiac myosin-immunized susceptible strain (experimental autoimmune myocarditis)
  category: Autoimmune induction model
  description: >-
    Immunization with cardiac myosin plus adjuvant produces T-cell-driven myocarditis
    and later dilated cardiomyopathy, and is the standard system for studying
    post-infectious autoimmunity, Th17/IL-17 biology and post-myocarditis fibrosis.
  publication: PMID:22531062
  evidence:
  - reference: PMID:22531062
    reference_title: "IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The EAM model was induced and serum IL-17 level was detected by ELISA"
    explanation: >-
      Identifies experimental autoimmune myocarditis as the induced model system used
      for the mechanistic work cited on the linked nodes.
  modeled_mechanisms:
  - target: Anti-Cardiac Myosin Autoimmunity
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Immunization against cardiac myosin reproduces the autoimmune arm and shows that
      anti-myosin reactivity alone is sufficient to cause myocarditis.
    limitations: >-
      Deliberate immunization with adjuvant is not how human myocarditis begins, so the
      model reproduces the effector autoimmunity without reproducing the initiating
      event or the tolerance breach.
    evidence:
    - reference: PMID:1315309
      reference_title: "Mouse cytomegalovirus infection induces antibodies which cross-react with virus and cardiac myosin: a model for the study of molecular mimicry in the pathogenesis of viral myocarditis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "immunization with cardiac myosin induced myocarditis and high titres of cardiac myosin antibodies in uninfected mice of the susceptible BALB/c strain only"
      explanation: >-
        Shows that cardiac myosin immunization alone induces myocarditis in susceptible
        animals.
  - target: Post-Inflammatory Ventricular Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model develops post-myocarditis cardiac fibrosis and was used to establish
      IL-17 as a direct fibrogenic driver of it.
    limitations: >-
      Fibrosis in this model follows an artificially induced autoimmune insult; the
      IL-17/PKC-beta/Erk1/2/NF-kappaB route has not been shown to carry the same weight
      in human post-myocarditis remodelling.
    evidence:
    - reference: PMID:22531062
      reference_title: "IL-17 contributes to cardiac fibrosis following experimental autoimmune myocarditis by a PKCβ/Erk1/2/NF-κB-dependent signaling pathway."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We therefore investigated whether IL-17 directly induced cardiac fibrosis in experimental autoimmune myocarditis (EAM) and explored the possible molecular mechanisms."
      explanation: >-
        Identifies the model as the system in which the fibrotic remodelling mechanism
        was established.
discussions:
- discussion_id: why_some_progress_to_dcm
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do some patients with acute myocarditis recover with no residual myocardial
    injury while others progress to dilated cardiomyopathy?
  attaches_to:
  - pathophysiology#Post-Inflammatory Ventricular Remodeling
  - pathophysiology#Inflammatory Dilated Cardiomyopathy
  rationale: >-
    This is the determining question for the whole entry: the acute phase is usually
    survivable and the chronic phase is not reversible, so everything that matters
    clinically turns on which patients cross between them. The relative contributions
    of the pathogen, host genotype and environment are unsettled, which is also why
    no treatment strategy is established for preventing the transition. The two
    hypothesis groups curated above - post-infectious autoimmunity and viral
    persistence - are the leading competing explanations and are not mutually
    exclusive.
  evidence:
  - reference: PMID:33046850
    reference_title: "Myocarditis and inflammatory cardiomyopathy: current evidence and future directions."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders."
    explanation: >-
      Names the gap explicitly, including the unresolved question of which detected
      viruses are actually causal.
- discussion_id: eam_cvb3_translational_validity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the two standard rodent models - coxsackievirus B3 infection and cardiac
    myosin-induced experimental autoimmune myocarditis - reproduce the mechanisms that
    actually drive human myocarditis, given that enterovirus is now a minority cause
    and that no human disease begins with adjuvanted self-antigen immunization?
  attaches_to:
  - pathophysiology#Cardiotropic Viral Infection of the Myocardium
  - pathophysiology#Anti-Cardiac Myosin Autoimmunity
  rationale: >-
    Most of the mechanistic content in this entry - innate sensing, dystrophin
    cleavage, anti-myosin autoimmunity, IL-17-driven fibrosis - rests on these two
    models, and both have a specific translational problem. CVB3 models an agent that
    contemporary human endomyocardial biopsy recovers far less often than parvovirus
    B19 or HHV-6, and its outcome is strongly conditioned on strain, sex and viral
    passage. Experimental autoimmune myocarditis reproduces the effector autoimmunity
    faithfully but starts from a deliberate adjuvanted immunization that has no human
    counterpart, so it cannot speak to how tolerance is broken in the first place.
    Evidence exists in these models; what is uncertain is how far it carries.
  evidence:
  - reference: PMID:35533750
    reference_title: "Epicardial and microvascular coronary artery spasm in biopsy-proven viral myocarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most frequently, virus DNA was detected by PCR from parvovirus B19 (PVB19, 59%) and human herpesvirus 6 (HHV6, 26%)."
    explanation: >-
      Shows that the viruses recovered from contemporary human myocardium are not the
      one modelled by the standard CVB3 system.
- discussion_id: ici_myocarditis_module_gap
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Should the immune_checkpoint_blockade module gain an immune-related-adverse-event
    arm so that checkpoint-inhibitor myocarditis, colitis, pneumonitis and hepatitis
    can declare conformance to a shared off-target-toxicity mechanism?
  attaches_to:
  - pathophysiology#Checkpoint Withdrawal and Off-Target Myocardial T Cell Reactivity
  rationale: >-
    The checkpoint-inhibitor form of myocarditis is a textbook treatment-toxicity
    conformer, but the existing module models only the anti-tumour arm - neoantigen
    generation, anti-tumour T cell response, adaptive immune resistance, T cell
    exhaustion - and has no node describing loss of peripheral tolerance in a
    non-tumour tissue. Rather than anchor this node to a tumour-immunity node it does
    not describe, no conforms_to is asserted here. Adding a shared irAE node to the
    module would let several disorder entries converge on it.
references:
- reference: PMID:33046850
  title: "Myocarditis and inflammatory cardiomyopathy: current evidence and future directions."
- reference: PMID:23824828
  title: "Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases."
- reference: PMID:30545455
  title: "Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations."

📚

References & Deep Research

References

3

PMID:33046850

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.

No top-level findings curated for this source.

PMID:23824828

Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.

No top-level findings curated for this source.

PMID:30545455

Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 29 citations 2026-08-28T15:12:33.085222

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Myocarditis
MONDO ID: (if available)
Category: Immune

Research Objectives

Please provide a comprehensive research report on Myocarditis covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Myocarditis: comprehensive disease-characteristics report

Executive summary

Myocarditis is an etiologically heterogeneous inflammatory disease of the myocardium. It ranges from a mild, self-limited chest-pain syndrome to fulminant cardiogenic shock, malignant ventricular arrhythmia, chronic inflammatory cardiomyopathy, transplantation, or death. Modern practice treats myocarditis as a syndrome requiring etiologic and risk stratification, rather than as one uniform disease. Cardiac magnetic resonance (CMR) is the principal noninvasive tissue-characterization test, while endomyocardial biopsy (EMB) remains the reference method for histologic, immunophenotypic, and pathogen-directed diagnosis—especially in high-risk disease. Recent work emphasizes overlap with inherited cardiomyopathies, immune-checkpoint-inhibitor toxicity, and inflammatory endotypes potentially amenable to targeted therapy. (lauriero2025acutemyocarditisand pages 1-2, caforio2024…prognosticutility pages 2-3, peretto2023myocardialinflammationas pages 2-3)

Evidence note. Human clinical evidence is identified as such below. Mechanistic claims are separated from animal, in-vitro, and computational evidence. The retrieved corpus did not reliably expose PMIDs for every article; therefore, DOI URLs and publication dates are supplied rather than inventing PMIDs. The brief quotations are exact wording available from retrieved abstracts.

1. Disease information

Definition and scope

Acute myocarditis is focal or diffuse myocardial inflammation caused by direct infectious or toxic injury and/or a dysregulated immune response. A practical temporal definition places acute disease within approximately one month of onset; persistent inflammation with cardiac dysfunction can evolve into chronic inflammatory cardiomyopathy. “Inflammatory cardiomyopathy” generally denotes myocarditis accompanied by ventricular dysfunction, often operationalized as LVEF below 50%. (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 2-3)

A recent diagnostic review summarized the clinical reality: “Most cases of myocarditis can be self-limiting without specific treatment”, while stressing that early risk identification determines monitoring and escalation. Martens, Cooper, and Tang, Journal of the American Heart Association, September 2023, DOI: 10.1161/JAHA.123.031454. (caforio2024…prognosticutility pages 2-3)

Identifiers and synonyms

MONDO: MONDO:0004496, myocarditis; validate against the current MONDO release before ingestion.
MeSH: D009205, Myocarditis.
ICD-10-CM: I40.-, acute myocarditis; I51.4, myocarditis, unspecified. Specific infectious forms may be coded under infection-plus-manifestation conventions.
ICD-11: myocarditis is represented within inflammatory diseases of the heart; the exact extension/subtype code should be checked against the deployment’s current ICD-11 release.
Synonyms: inflammatory myocardial disease; acute myocarditis; chronic myocarditis; inflammatory cardiomyopathy when dysfunction is present; myopericarditis when myocardial injury accompanies predominant pericarditis; perimyocarditis when myocardial disease predominates.
OMIM/Orphanet: no single identifier adequately represents all myocarditis. Specific inherited cardiomyopathies or rare histologic entities may have separate entries, but generic myocarditis is not one Mendelian disorder.

The information here is aggregated disease-level evidence from registries, cohorts, guidelines, reviews, trials, biopsy series, and experimental studies—not an individual-patient EHR abstraction.

2. Etiology, risk, protection, and gene–environment interaction

Causal or triggering factors

Infectious: enteroviruses including coxsackievirus B, adenovirus, influenza, SARS-CoV-2, HHV-6, EBV, CMV, HSV, parvovirus B19, HIV, hepatitis viruses, and less commonly bacteria, fungi, protozoa, or helminths. Detection of viral nucleic acid—particularly latent/endothelial-tropic viruses—does not by itself prove causal myocardial infection.
Immune-mediated: systemic lupus erythematosus, systemic sclerosis, vasculitis, inflammatory myopathy, eosinophilic syndromes, giant-cell myocarditis, sarcoidosis, and postinfectious autoimmunity.
Drugs and toxins: immune checkpoint inhibitors (anti-PD-1/PD-L1 and anti-CTLA-4), hypersensitivity-causing medicines, some chemotherapies, clozapine, cocaine/amphetamines, and other toxic exposures.
Vaccination-associated: myocarditis occurs rarely after mRNA COVID-19 vaccination, particularly in adolescent and young-adult males and commonly after dose 2. Reviews characterize it as generally milder and more self-limited than infection-associated myocarditis; vaccination also prevents COVID-19 and its cardiac complications. Proposed molecular mimicry and cytokine dysregulation remain hypotheses rather than settled causal mechanisms. Costa and Moniati, Advances in Medicine, April 2024, DOI: 10.1155/2024/4470326. (costa2024theepidemiologyof pages 1-2)

Genetic susceptibility—not usually simple causation

Myocarditis is usually multifactorial. Rare germline variants in cardiomyopathy genes can create a myocardium vulnerable to inflammatory “hot phases,” recurrent myocarditis, arrhythmias, or adverse remodeling. Repeatedly implicated genes include DSP, PKP2, DSG2, DSC2, JUP, TTN, BAG3, LMNA, FLNC, DES, DMD, DYSF, MYH7, MYBPC3, RBM20, SCN5A, RYR2, LAMA4, and LDB3. Desmosomal disease—especially DSP—is particularly important when recurrent episodes, ring-like or subepicardial LGE, ventricular arrhythmia, or family history are present. (lutokhina2025incidenceandimpact pages 1-2, peretto2023myocardialinflammationas pages 2-3)

TTN truncating variants illustrate susceptibility rather than a myocarditis-specific allele: they account for approximately 25% of familial and 18% of idiopathic DCM in the cited synthesis. Variant interpretation must follow ACMG/AMP and disease-specific ClinGen rules; the mere presence of a rare variant or VUS does not establish causality. (peretto2023myocardialinflammationas pages 11-13)

Variant fields: no universal recurrent pathogenic variant, allele frequency, founder mutation, or carrier frequency exists for myocarditis as a whole. Most relevant variants are rare, germline, heterozygous loss-of-function or missense alleles inherited according to the underlying cardiomyopathy—often autosomal dominant with incomplete, age-dependent penetrance and variable expressivity. Somatic mutation, anticipation, germline mosaicism, chromosomal aneuploidy, and repeat expansion are not established generic myocarditis mechanisms.

Environmental and lifestyle risks

Male sex, adolescence/young adulthood, recent infection, autoimmune disease, cardiotoxic treatment, and intense exercise during active infection/inflammation are clinically important contexts. In one pre-pandemic estimate, incidence among people aged 35–39 was 6.1/100,000 in men versus 4.4/100,000 in women; one 2020 cohort was 82% male. (costa2024theepidemiologyof pages 1-2)

Smoking, alcohol, diet, and air pollution are important general cardiovascular exposures, but robust myocarditis-specific causal estimates are lacking. Strenuous exercise during acute myocarditis may amplify injury and arrhythmic risk; it should not be confused with habitual moderate exercise after documented recovery.

Protective factors and gene–environment interactions

There is no validated protective germline allele or diet that prevents myocarditis. Practical protection consists of infection prevention, vaccination according to public-health guidance, avoidance of illicit stimulants and unnecessary cardiotoxic exposure, and refraining from strenuous exercise during systemic infection or active myocarditis. In genetically susceptible myocardium, infection or mechanical/adrenergic stress can act as a second hit. DMD/DYSF-associated membrane fragility has been linked to susceptibility to coxsackievirus injury, while inflammatory episodes may unmask desmosomal or DCM phenotypes. (lutokhina2025incidenceandimpact pages 2-4, peretto2023myocardialinflammationas pages 2-3)

3. Phenotypes

Clinical expression is variable across all ages. Pediatric cases may present with nonspecific respiratory or gastrointestinal symptoms; adults more often have chest pain, dyspnea, palpitations, or exercise intolerance. Older adults and patients with comorbidities may have worse hemodynamic tolerance.

Infarct-like phenotype: acute chest pain, ST/T-wave changes, elevated troponin, and unobstructed coronary arteries. Suggested HPO: chest pain, elevated troponin, ST-segment abnormality.
Heart-failure phenotype: dyspnea, fatigue, edema, tachycardia, reduced LVEF, elevated BNP/NT-proBNP. Severity ranges from mild dysfunction to cardiogenic shock. Suggested HPO: dyspnea, fatigue, peripheral edema, left ventricular systolic dysfunction, cardiomegaly, cardiogenic shock.
Arrhythmic phenotype: palpitations, premature ventricular beats, ventricular tachycardia/fibrillation, atrial arrhythmia, high-grade atrioventricular block, syncope, or sudden death. Suggested HPO: palpitations, ventricular arrhythmia, atrioventricular block, syncope, sudden cardiac death.
Inflammatory/systemic phenotype: fever, myalgia, elevated CRP/ESR, leukocytosis or eosinophilia, depending on cause. Suggested HPO: fever, elevated CRP, eosinophilia.
Imaging/pathology phenotype: myocardial edema, nonischemic LGE, inflammatory infiltrates, myocyte necrosis; chronic cases develop fibrosis, ventricular dilation, or nondilated hypokinetic cardiomyopathy.

The ESC registry included biopsy-proven myocarditis (n=233), clinically suspected disease with abnormal CMR (n=222), and suspected disease with normal/inconclusive CMR (n=126), demonstrating that no single phenotype or test captures the whole spectrum. (caforio2024…prognosticutility pages 2-3)

Frequency and quality of life: reliable universal percentages for individual symptoms are unavailable because cohorts differ by referral threshold and diagnostic definition. Acute pain, hospitalization, activity restriction, arrhythmia anxiety, and reduced exercise capacity can markedly impair short-term quality of life. Persistent ventricular dysfunction, ICD implantation, or recurrent “hot phases” can produce long-term physical and psychological burden; myocarditis-specific EQ-5D/SF-36 reference norms are not established in the retrieved evidence.

4. Genetic and molecular information

Causal genes and testing interpretation

There is no single “myocarditis gene.” Genes listed above cause inherited cardiomyopathy or membrane/cytoskeletal vulnerability and modify the response to environmental injury. Testing is most informative in recurrent myocarditis, family history of cardiomyopathy/sudden death, persistent dysfunction, extensive or characteristic LGE, malignant arrhythmia, conduction disease, or an arrhythmogenic-cardiomyopathy phenotype. (lutokhina2025incidenceandimpact pages 1-2, peretto2023myocardialinflammationas pages 2-3)

Recommended analysis is a curated cardiomyopathy/arrhythmia panel with copy-number detection; WES/WGS may be appropriate in unresolved familial disease. Results should be classified as pathogenic, likely pathogenic, VUS, likely benign, or benign. Cascade testing is appropriate only for pathogenic/likely pathogenic variants, not for VUS. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine unless syndromic features independently indicate them.

Modifier and epigenetic evidence

Sex hormones, common genetic background, immune-response loci, and viral receptor expression probably modify penetrance, but clinically actionable modifiers are unvalidated. Altered microRNAs, chromatin state, and DNA methylation have been described experimentally; no epigenetic biomarker is approved for routine diagnosis or treatment selection. Large recurrent chromosomal abnormalities are not characteristic.

5. Environmental and infectious information

Cardiotropic pathogens may injure cardiomyocytes directly, activate endothelial and innate immune pathways, or trigger postinfectious autoimmunity. A 2025 cardiomyopathy cohort detected PVB19, HHV-6, EBV, CMV, HSV-1, and SARS-CoV-2 genomes, but its high inflammation prevalence reflects a selected referral population and should not be generalized to community myocarditis. (lutokhina2025incidenceandimpact pages 4-6, lutokhina2025incidenceandimpact pages 11-13, lutokhina2025incidenceandimpact pages 13-14)

Important noninfectious exposures include ICIs, hypersensitivity-provoking medications, stimulants, and selected occupational/toxic agents. Routine broad viral serology is generally less informative than targeted testing driven by clinical context; myocardial PCR is most meaningful when interpreted with histology, viral load/replication, cell localization, and immune findings.

6. Mechanism and pathophysiology

Causal chain

Upstream trigger → pathogen-associated or damage-associated molecular recognition → endothelial activation and innate immune recruitment → cytokine and inflammasome amplification → antigen presentation and adaptive T-cell/B-cell responses → cardiomyocyte necrosis/apoptosis and electrical instability → edema and impaired contraction → resolution or persistent immune activation → fibroblast activation, extracellular-matrix deposition, scar, ventricular remodeling, arrhythmia, and chronic inflammatory cardiomyopathy. (lauriero2025acutemyocarditisand pages 1-2, vosko2026giantcellmyocarditis pages 1-2, peretto2023myocardialinflammationas pages 11-13)

Relevant processes include GO inflammatory response, innate immune response, adaptive immune response, leukocyte migration, cytokine production, apoptotic process, necrotic cell death, extracellular-matrix organization, and cardiac muscle contraction.

Cells and pathways

Cardiomyocytes are the primary injured cells; death releases troponin and danger signals and impairs contraction/conduction.
Macrophages/monocytes clear debris but also generate IL-1, IL-6, TNF, reactive oxygen species, and profibrotic signals.
CD4/CD8 T cells mediate adaptive cytotoxic and autoimmune injury; Th17 biology is prominent in experimental giant-cell disease.
B cells/plasma cells may generate anticardiac antibodies, including antibodies against DSG2 or titin, although direct pathogenicity varies.
Fibroblasts execute downstream scar formation; endothelial cells and pericytes regulate vascular permeability and leukocyte trafficking.

NF-κB is a central inflammatory regulator; downstream TGF-β signaling promotes extracellular-matrix expression and suppresses matrix degradation. NLRP3–caspase-1–IL-1 signaling provides a mechanistic rationale for IL-1 blockade, but broad clinical efficacy is unproven. CVB3 models show abnormal titin phosphorylation, increased IL-6, and fibrosis; IL-6-receptor blockade improved experimental outcomes. (ricci2026severemyocardialinflammation pages 34-37, peretto2023myocardialinflammationas pages 11-13)

Suggested cell terms: cardiomyocyte, cardiac fibroblast, endothelial cell, pericyte, monocyte, macrophage, neutrophil, CD4-positive T cell, CD8-positive T cell, B cell, plasma cell, eosinophil, and multinucleated giant cell.

Histologic endotypes

Lymphocytic: most common; T-cell-rich infiltrates with associated myocyte injury.
Eosinophilic/hypersensitivity: eosinophils, often associated with drugs or systemic eosinophilic disease.
Giant-cell: destructive T-cell/macrophage inflammation with multinucleated giant cells and extensive necrosis; often rapidly progressive.
Granulomatous/cardiac sarcoidosis: noncaseating granulomas; patchy distribution complicates biopsy.
ICI-associated: frequently CD4/CD8 T-cell-rich injury, sometimes overlapping myositis and myasthenia gravis.

Omics and advanced technologies

Bulk and single-cell studies support immune activation, altered contraction/conduction programs, fibroblast activation, and metabolic reprogramming. Giant-cell myocarditis profiling found adaptive/innate pathways upregulated and cardiac contraction/conduction genes downregulated; rat single-cell data identified Th17 cells and distinct macrophage states. (vosko2026giantcellmyocarditis pages 1-2)

Spatial transcriptomics and single-cell work in inherited arrhythmogenic cardiomyopathy—relevant to myocarditis-like “hot phases”—identifies regional cardiomyocyte degeneration, inflammatory macrophages, and fibro-inflammatory niches. These results are hypothesis-generating and not yet diagnostic assays. Proteomic, metabolomic, lipidomic, liquid-biopsy, and epigenomic signatures remain investigational; no profile has replaced CMR or EMB.

7. Anatomy

Primary organ/system: heart/cardiovascular system; myocardium of one or both ventricles and sometimes atria.
Tissue: cardiac muscle, interstitium, microvasculature, conduction tissue, and—in myopericarditis—the pericardium.
Distribution: focal, multifocal, or diffuse; no fixed lateralization. CMR often shows subepicardial or mid-wall nonischemic injury, commonly inferolateral, but genetic and immune subtypes may differ.
Secondary involvement: pulmonary/systemic congestion, hepatic and renal hypoperfusion, cerebral consequences of embolism or arrest, skeletal muscle/myasthenic overlap in ICI disease.
Subcellular compartments: sarcolemma/desmosomes, sarcomere, mitochondria, cytosol/inflammasome, nucleus, extracellular matrix, and intercalated disc.

Suggested UBERON terms: heart, myocardium, left-ventricular myocardium, right-ventricular myocardium, interventricular septum, cardiac conduction system, coronary microvasculature, and pericardium.

8. Temporal development

Onset can be neonatal, pediatric, adult, or geriatric, but recognized disease is enriched in younger males. Presentation may be acute or fulminant over hours to weeks, subacute, recurrent/episodic, or chronic/insidious. Acute disease occurs within roughly one month; persistent hypokinetic disease beyond that interval may be classified as inflammatory cardiomyopathy. (lauriero2025acutemyocarditisand pages 1-2)

A useful conceptual sequence is: trigger/prodrome → acute injury/edema → early recovery or fulminant failure → convalescence with residual scar → complete resolution, recurrent inflammatory episodes, or chronic ventricular remodeling. The first days of shock, malignant arrhythmia, or AV block are the critical treatment window. Follow-up at approximately 3–6 months commonly reassesses symptoms, biomarkers, ECG/rhythm, ventricular function, and CMR where results alter management.

9. Inheritance and population epidemiology

Myocarditis itself is usually sporadic and multifactorial. When an underlying cardiomyopathy is found, inheritance follows that disorder—often autosomal dominant with incomplete penetrance and variable expressivity. X-linked inheritance is relevant to DMD-associated disease; recessive or mitochondrial disorders are uncommon contexts. There is no general carrier frequency, anticipation pattern, founder effect, or consanguinity estimate for myocarditis.

True population incidence is underestimated because mild cases escape diagnosis and definitions differ. A contemporary review cited 4.4/100,000 women and 6.1/100,000 men aged 35–39. Male predominance is consistent across conventional and vaccine-associated myocarditis. (costa2024theepidemiologyof pages 1-2)

Selected cardiomyopathy cohorts report much higher inflammation frequencies—ARVC 74.3%, DCM 56.7%, LVNC 54.4%, RCM 37.5%, and HCM 30.9%—but these figures derive from a specialized cohort using biopsy or a noninvasive antibody/CMR algorithm and are not general-population prevalence estimates. (lutokhina2025incidenceandimpact pages 16-17, lutokhina2025incidenceandimpact pages 1-2)

10. Diagnostics

Clinical workflow

Recognize a compatible syndrome: chest pain, new heart failure, arrhythmia/AV block, shock, or unexplained troponin elevation.
Initial tests: high-sensitivity troponin, BNP/NT-proBNP, CBC with differential, CRP/ESR, metabolic profile, ECG, continuous rhythm monitoring, and echocardiography.
Exclude alternatives: acute coronary syndrome, Takotsubo syndrome, pulmonary embolism, sepsis-related injury, tachycardia-mediated cardiomyopathy, inherited cardiomyopathy, cardiac sarcoidosis, giant-cell disease, amyloidosis, and pericarditis without myocardial injury.
CMR: ventricular function, edema, hyperemia/injury, T1/T2 mapping, extracellular volume, and nonischemic LGE. Updated Lake Louise assessment seeks at least one T2-based marker of edema and one T1-based marker of nonischemic injury, interpreted in clinical context.
EMB: histology, immunohistochemistry, and targeted molecular testing. EMB is especially indicated for cardiogenic shock/fulminant disease, malignant arrhythmia, high-grade AV block, suspected giant-cell/eosinophilic/ICI disease, persistent biomarker elevation or dysfunction, or failure to respond to standard care. (lauriero2025acutemyocarditisand pages 1-2, caforio2024…prognosticutility pages 2-3, peretto2023myocardialinflammationas pages 2-3)

In the ESC registry, biopsy complications occurred in 4.7% of adults and 4.9% of children, with no procedure-related deaths, supporting performance in experienced centers. Sampling error remains important because disease can be patchy. (caforio2024…prognosticutility pages 2-3)

Biomarkers and emerging diagnostics

Troponin documents injury but neither excludes myocarditis when normal nor defines etiology. BNP/NT-proBNP reflects hemodynamic stress. CRP, eosinophils, CK, autoantibodies, cytokines, microRNAs, cell-free nucleic acids, PET tracers, and AI-assisted imaging are being studied, but none independently establishes generic myocarditis. FDG-PET is useful when sarcoidosis is suspected or CMR is unavailable/contraindicated. (peretto2023myocardialinflammationas pages 2-3)

Genetic and omics testing

Genetic testing is not universal screening. Use a phenotype-driven cardiomyopathy panel in recurrent/familial/high-risk cases; WES/WGS is second-line. RNA-seq, proteomics, metabolomics, and epigenomics are research tools. Population screening, newborn screening, and routine asymptomatic CMR are not recommended. Cascade screening is appropriate when a pathogenic cardiomyopathy variant is identified.

11. Outcomes and prognosis

Many uncomplicated infarct-like cases recover clinically, but residual LGE can persist. Adverse outcomes include recurrent myocarditis, sustained ventricular arrhythmia, AV block, chronic DCM, heart failure, thromboembolism, sudden death, mechanical support, transplantation, and death.

Poor prognostic features include cardiogenic shock, reduced LVEF, biventricular dysfunction, sustained ventricular arrhythmia, high-grade AV block, giant-cell histology, extensive/persistent LGE, ongoing troponin release, failure of early recovery, and pathogenic cardiomyopathy genotype. Reduced LVEF and need for immunomodulatory treatment predicted adverse outcomes in ESC registry data. (caforio2024…prognosticutility pages 2-3)

In a selected LVNC cohort, myocarditis independently predicted mortality (HR 5.8); treated patients improved from mean LVEF 36.8% to 40.3% and had death/transplantation of 20.9% versus 44.0% without immunosuppression. These observational results are confounded and should not justify indiscriminate immunosuppression. (lutokhina2025incidenceandimpact pages 11-13)

For DCM, morphologically verified myocarditis predicted lethal outcome (HR 3.6, 95% CI 1.433–9.249). Again, this is selected-cohort evidence rather than a universal prognostic calculator. (lutokhina2025incidenceandimpact pages 14-16)

12. Treatment and real-world implementation

General strategy

Hospitalize high-risk patients; monitor rhythm and hemodynamics.
Treat congestion and ventricular dysfunction with guideline-directed heart-failure therapy as tolerated.
Manage ventricular arrhythmias and AV block according to standard electrophysiology guidance, recognizing that temporary protection may be preferable while inflammation resolves.
Treat shock with inotropes/vasopressors and early referral for VA-ECMO, temporary VAD, durable VAD, or transplantation where necessary.
Avoid NSAIDs in isolated myocarditis with heart failure; they may be used cautiously when clinically significant pericarditis predominates and ventricular function is preserved.

A 2024 treatment review states: “Treatment of myocarditis is often supportive, and the evidence for immunosuppression is scarce and debated.” Ferone et al., Journal of Cardiovascular Pharmacology, May 2024, DOI: 10.1097/FJC.0000000000001542. (ferone2024currenttreatmentand pages 11-11)

Etiology/endotype-directed treatment

Routine presumed viral/idiopathic lymphocytic myocarditis: supportive therapy; empirical immunosuppression is not universal.
Virus-negative, biopsy-proven inflammatory cardiomyopathy: corticosteroid plus azathioprine has supportive randomized evidence from TIMIC, but requires careful pathogen exclusion and specialist supervision.
Giant-cell myocarditis: urgent combination immunosuppression, commonly high-dose corticosteroid plus a calcineurin inhibitor and another T-cell-directed agent; early mechanical-support/transplant evaluation.
Eosinophilic/hypersensitivity myocarditis: remove the offending agent and begin corticosteroids when clinically significant; treat systemic eosinophilic disease.
Cardiac sarcoidosis: corticosteroid-based immunosuppression with steroid-sparing therapy and arrhythmia/device management.
ICI myocarditis: immediately hold ICI therapy, admit and monitor, and initiate early high-dose intravenous corticosteroids in significant disease. Steroid-refractory options include mycophenolate, abatacept, IVIG, antithymocyte globulin, alemtuzumab, ruxolitinib, or other targeted strategies in expert centers. Evidence remains mainly observational; infliximab is controversial and generally avoided in moderate-to-severe heart failure. (ferone2024currenttreatmentand pages 11-11)
IL-1 blockade: anakinra is biologically plausible, but ARAMIS did not show broad benefit in a largely low-risk cohort; severe hyperinflammatory cases remain an investigational niche.
Antiviral/antimicrobial therapy: only for a demonstrated treatable pathogen or systemic infection; myocardial viral nucleic acid alone does not automatically indicate therapy.

Suggested NCIT concepts include corticosteroid therapy, immunosuppressive therapy, intravenous immunoglobulin, extracorporeal membrane oxygenation, ventricular-assist device therapy, heart transplantation, antiarrhythmic therapy, and cardiac rehabilitation.

Pharmacogenomics and advanced therapeutics

No CPIC/PharmGKB genotype-guided myocarditis regimen is established. Gene therapy, CRISPR, ASOs, siRNA, and cell therapy are not approved treatments for myocarditis. Precision approaches currently mean identifying infectious, autoimmune, ICI-associated, eosinophilic, giant-cell, sarcoid, or inherited-cardiomyopathy endotypes—not editing a myocarditis gene.

13. Prevention

Primary prevention: vaccination and infection-control measures; prompt management of systemic infection; avoidance of cocaine/amphetamines and unnecessary cardiotoxic drugs; baseline and early surveillance protocols for selected ICI recipients. The small myocarditis risk after mRNA vaccination must be balanced against protection from COVID-19 and its complications. (costa2024theepidemiologyof pages 1-2)

Secondary prevention: rapid evaluation of chest pain, dyspnea, syncope, palpitations, or exercise intolerance after infection, vaccination, or ICI exposure; early troponin/ECG/echo testing; genetic evaluation in recurrent or familial disease.

Tertiary prevention: restrict strenuous exercise during active disease—commonly 3–6 months, individualized by phenotype and contemporary guidance. Return requires resolution of symptoms and injury markers, recovered ventricular function, and absence of clinically important arrhythmia; persistent scar or genotype-positive disease may justify stricter assessment. Optimize heart-failure therapy, rhythm surveillance, and family screening where appropriate. (ferone2024currenttreatmentand pages 11-11)

No prophylactic medication, population screening program, prenatal test, or newborn screen exists for generic myocarditis.

14. Other species and natural disease

Naturally occurring myocarditis occurs in dogs, cats, cattle, horses, pigs, nonhuman primates, and wildlife from infectious, toxic, parasitic, and immune causes. Examples include canine protozoal/vector-borne or viral myocarditis, feline infectious myocarditis, and enteroviral disease in susceptible animals. Species-specific pathogen ecology makes direct extrapolation hazardous. Generic myocarditis is not ordinarily zoonotically transmitted; zoonotic concern belongs to the causal pathogen, not myocardial inflammation itself.

Suggested taxa include Homo sapiens (NCBI:9606), Mus musculus (10090), Rattus norvegicus (10116), Canis lupus familiaris (9615), Felis catus (9685), and Danio rerio (7955). No universal VBO breed association or single conserved ortholog explains natural myocarditis.

15. Model organisms and experimental systems

Principal models

CVB3 mouse myocarditis: reproduces viral replication, innate/adaptive inflammation, necrosis, sex effects, and later fibrosis. It is valuable for antiviral and immunomodulatory studies but depends strongly on strain, sex, age, inoculum, and viral passage; many human cases are not enteroviral.
Experimental autoimmune myocarditis: cardiac-myosin peptide plus adjuvant in susceptible mice/rats produces T-cell-driven myocarditis and later DCM; useful for autoimmunity and IL-1/IL-6/Th17 biology, but the artificial immunization does not reproduce most human initiating events.
Giant-cell myocarditis models: cardiac-myosin immunization in rats reproduces destructive T-cell/macrophage disease. Rat single-cell data identify Th17 cytokines and macrophage giant-cell contributors, but species and induction differences remain substantial. (vosko2026giantcellmyocarditis pages 1-2)
Genetic models: Dsg2, Pkp2, Dsp, Dmd, Dysf, and related knock-out/knock-in animals model inflammatory “hot phases” in inherited cardiomyopathy.
Human iPSC-cardiomyocytes, engineered heart tissue, and organoids: permit patient-specific viral entry, desmosomal failure, cytokine injury, electrophysiology, and drug screening; limitations include fetal-like maturation, incomplete immune/vascular systems, and absent whole-organ hemodynamics.

The CVB3 literature links infection to impaired titin phosphorylation, IL-6 elevation, and fibrosis, with improvement after IL-6-receptor blockade—strong preclinical support, but not proof of clinical efficacy. (peretto2023myocardialinflammationas pages 11-13)

Current research and active implementation

Current programs emphasize prognosis, genotype–phenotype overlap, post-vaccine outcomes, CMR/PET molecular imaging, and biomarker-guided follow-up. Examples identified in ClinicalTrials.gov searches include:

NCT04844151: acute myocarditis registry integrating prognostic, histologic, immunologic, biological, imaging, and clinical assessment; recruiting; planned n=1,400.
NCT06010199: biomarker risk stratification; recruiting; planned n=1,000.
NCT06189053: long-term outcomes after myocarditis following Moderna mRNA vaccination; active, not recruiting; n=1,500.
NCT05125965: early CMR diagnosis of immunotherapy-induced myocarditis; active, not recruiting; n=200.
NCT05949450: prognostic role of high-sensitivity troponin during follow-up; not yet recruiting; n=244.

Registry status and enrollment should be verified at ClinicalTrials.gov before production use.

Ontology-ready summary

The following compact table is suitable for knowledge-base mapping; accession numbers marked for validation should be checked against live ontology releases.

Domain	Recommended identifier/ontology term	Meaning/use	Evidence/qualification
Disease	MONDO:0004496 (validate in live MONDO release)	Myocarditis disease concept for cross-ontology mapping and KB normalization	Commonly used MONDO identifier for myocarditis; validate against current ontology release before production use. Myocarditis is a heterogeneous inflammatory myocardial syndrome rather than a single Mendelian disorder (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 2-3)
Disease	MeSH: D009205	NLM MeSH descriptor for indexing literature on myocarditis	Stable literature-indexing term; useful for PubMed/MeSH harmonization (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 2-3)
Disease classification	ICD-10-CM: I40	Acute myocarditis diagnosis code family	Appropriate for acute presentations; aligns with clinical spectrum emphasizing recent-onset inflammatory myocardial injury (lauriero2025acutemyocarditisand pages 1-2, caforio2024…prognosticutility pages 2-3)
Disease classification	ICD-10-CM: I51.4	Myocarditis, unspecified	Use when documentation confirms myocarditis without subclassification; less specific than acute myocarditis coding (lauriero2025acutemyocarditisand pages 1-2)
Disease resources	No single OMIM/Orphanet ID recommended	Avoid forcing myocarditis into a monogenic rare-disease identifier slot	Do not invent OMIM/Orphanet IDs; myocarditis spans infectious, autoimmune, toxic/drug-related, and genetically susceptible forms (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 2-3)
Phenotype (symptom)	HPO: Chest pain (validate HP accession in live HPO)	Common presenting symptom, especially infarct-like/pseudoinfarction phenotype	Frequently reported in acute myocarditis presentations; exact HPO accession should be verified live (caforio2024…prognosticutility pages 2-3, peretto2023myocardialinflammationas pages 2-3)
Phenotype (symptom)	HPO: Dyspnea (validate HP accession in live HPO)	Symptom of heart failure/hemodynamic compromise	Seen across acute and chronic inflammatory cardiomyopathy phenotypes (lauriero2025acutemyocarditisand pages 1-2, caforio2024…prognosticutility pages 2-3)
Phenotype (symptom)	HPO: Fatigue (validate HP accession in live HPO)	Nonspecific constitutional/cardiac symptom	Common but nonspecific; useful as supportive phenotype only (lauriero2025acutemyocarditisand pages 1-2)
Phenotype (symptom)	HPO: Palpitations (validate HP accession in live HPO)	Symptom suggesting atrial/ventricular arrhythmia	Myocarditis may present with arrhythmias even without classic heart-failure syndrome (caforio2024…prognosticutility pages 2-3, peretto2023myocardialinflammationas pages 2-3)
Phenotype (symptom)	HPO: Syncope (validate HP accession in live HPO)	Transient loss of consciousness related to malignant arrhythmia/hemodynamic instability	Important high-risk presentation trigger for urgent workup (caforio2024…prognosticutility pages 2-3)
Phenotype (symptom/sign)	HPO: Fever (validate HP accession in live HPO)	Febrile inflammatory/infectious presentation	Supports inflammatory trigger but is not required for diagnosis (lauriero2025acutemyocarditisand pages 1-2)
Phenotype (laboratory)	HPO: Elevated cardiac troponin level (validate HP accession in live HPO)	Biomarker evidence of cardiomyocyte injury	Acute myocarditis commonly shows elevated high-sensitivity troponin; useful in diagnosis and follow-up (lauriero2025acutemyocarditisand pages 1-2, costa2024theepidemiologyof pages 1-2)
Phenotype (imaging/functional)	HPO: Ventricular dysfunction (validate HP accession in live HPO)	Reduced systolic performance/LV or biventricular dysfunction	Central phenotype in inflammatory cardiomyopathy and prognostic assessment (lauriero2025acutemyocarditisand pages 1-2, caforio2024…prognosticutility pages 2-3)
Phenotype (rhythm)	HPO: Cardiac arrhythmia (validate HP accession in live HPO)	Broad rhythm-disturbance phenotype	Includes atrial and ventricular arrhythmias; a recognized myocarditis presentation (caforio2024…prognosticutility pages 2-3, peretto2023myocardialinflammationas pages 2-3)
Phenotype (critical illness)	HPO: Cardiogenic shock (validate HP accession in live HPO)	Fulminant hemodynamic collapse phenotype	Indicates severe/fulminant myocarditis and is a major biopsy/treatment-escalation trigger (lauriero2025acutemyocarditisand pages 1-2, caforio2024…prognosticutility pages 2-3)
Anatomy	UBERON: heart (validate UBERON accession in live release)	Primary organ affected	Heart-level anatomical anchor for disease localization (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 2-3)
Anatomy	UBERON: myocardium (validate UBERON accession in live release)	Primary tissue targeted by inflammation	Core tissue compartment for pathology, MRI, and biopsy annotation (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 2-3)
Cell type	CL: cardiomyocyte (validate CL accession in live release)	Primary injured parenchymal cell	Cardiomyocyte injury/necrosis drives troponin release and systolic dysfunction (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 11-13)
Cell type	CL: T cell (validate CL accession in live release)	Major adaptive immune effector cell	T-cell infiltrates are central in lymphocytic myocarditis and giant-cell myocarditis biology (peretto2023myocardialinflammationas pages 2-3, vosko2026giantcellmyocarditis pages 1-2)
Cell type	CL: macrophage (validate CL accession in live release)	Major innate immune/injury-response cell	Macrophages contribute to inflammation, cytokine signaling, and remodeling (lutokhina2025incidenceandimpact pages 16-17, vosko2026giantcellmyocarditis pages 1-2)
Cell type	CL: fibroblast (validate CL accession in live release)	Matrix-producing stromal cell in repair/fibrosis	Fibroblast activation links inflammation to fibrosis and adverse remodeling (vosko2026giantcellmyocarditis pages 1-2, peretto2023myocardialinflammationas pages 11-13)
Cell type	CL: endothelial cell (validate CL accession in live release)	Vascular interface cell relevant to trafficking and edema	Important in leukocyte recruitment and myocardial inflammatory niche interactions (peretto2023myocardialinflammationas pages 2-3)
Biological process	GO: inflammatory response (validate GO accession in live release)	General disease-process umbrella term	Captures core inflammatory biology across etiologies (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 2-3)
Biological process	GO: innate immune response (validate GO accession in live release)	Early trigger/amplification program	Supported by inflammasome, macrophage, complement, and cytokine activation evidence (ricci2026severemyocardialinflammation pages 34-37, peretto2023myocardialinflammationas pages 11-13)
Biological process	GO: adaptive immune response (validate GO accession in live release)	Antigen-driven T/B-cell response	Relevant especially in autoimmune, giant-cell, and postinfectious phenotypes (peretto2023myocardialinflammationas pages 2-3, vosko2026giantcellmyocarditis pages 1-2)
Biological process	GO: cell death (validate GO accession in live release)	Cardiomyocyte injury/necrosis/apoptosis	Explains biomarker release and contractile dysfunction; downstream of immune injury or direct infection (vosko2026giantcellmyocarditis pages 1-2, peretto2023myocardialinflammationas pages 11-13)
Biological process	GO: extracellular matrix organization / fibrosis (validate GO accession in live release)	Remodeling/scarring program	Useful for chronic inflammatory cardiomyopathy and arrhythmic risk annotation (vosko2026giantcellmyocarditis pages 1-2, peretto2023myocardialinflammationas pages 11-13)
Diagnostic concept	CMR using updated Lake Louise criteria (guideline concept, not ontology ID)	Noninvasive tissue characterization for edema/injury	Strong diagnostic role, but EMB remains gold standard for definitive etiologic/histologic diagnosis (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 2-3)
Diagnostic concept	Endomyocardial biopsy (EMB) (procedure concept)	Gold-standard histology/immunohistochemistry/molecular testing	Most specific tool for subtype confirmation and therapy guidance in high-risk or unclear cases (caforio2024…prognosticutility pages 2-3, peretto2023myocardialinflammationas pages 2-3)
Intervention	NCIT-style: Corticosteroid therapy (map to local NCIT term/live code)	First-line immunosuppression in selected immune-mediated myocarditis subtypes	Not routine for all cases; subtype- and biopsy-context dependent (e.g., giant-cell, eosinophilic, ICI-associated) (ferone2024currenttreatmentand pages 11-11)
Intervention	NCIT-style: Immunosuppressive therapy (map to live NCIT)	Broad category including azathioprine, mycophenolate, calcineurin inhibitors	Evidence strongest in virus-negative inflammatory cardiomyopathy and specific severe immune phenotypes (ferone2024currenttreatmentand pages 11-11, lutokhina2025incidenceandimpact pages 14-16)
Intervention	NCIT-style: Intravenous immunoglobulin (map to live NCIT)	Immunomodulatory adjunct in selected cases	Used variably; evidence mixed and context-specific (ferone2024currenttreatmentand pages 11-11)
Intervention	NCIT-style: Interleukin-1 inhibition / anakinra therapy (map to live NCIT)	Targeted anti-inflammatory strategy under active investigation	Mechanistically linked to inflammasome/IL-1 signaling; current evidence strongest in selected severe/refractory phenotypes rather than broad low-risk use (peretto2023myocardialinflammationas pages 11-13)
Intervention	NCIT-style: Guideline-directed heart failure therapy (map to live NCIT)	Standard supportive therapy for ventricular dysfunction	Core management across many presentations regardless of etiology (ferone2024currenttreatmentand pages 11-11)
Intervention	NCIT-style: Mechanical circulatory support (map to live NCIT)	Rescue support for fulminant/cardiogenic-shock presentations	Important in fulminant myocarditis and bridge-to-recovery/decision pathways (ferone2024currenttreatmentand pages 11-11)
Intervention	NCIT-style: Exercise restriction / sports disqualification (map to local concept if NCIT unavailable)	Secondary prevention to reduce arrhythmic risk during recovery	Common expert-management principle after acute myocarditis; timing of return depends on recovery and risk reassessment (ferone2024currenttreatmentand pages 11-11)

Table: This table provides compact disease, phenotype, anatomy, cell-type, process, and intervention terms suitable for a myocarditis knowledge base. It emphasizes where identifiers should be validated live and avoids inventing single-disease Mendelian IDs for this etiologically heterogeneous condition.

Evidence gaps and expert interpretation

The strongest present-day consensus is that myocarditis management should be risk- and endotype-directed. CMR has widened noninvasive diagnosis, but EMB remains indispensable when histology changes treatment. Genetics increasingly explains recurrence and inflammatory presentations in cardiomyopathy, yet most detected variants are susceptibility factors—not proof that myocarditis is monogenic. Broad empirical immunosuppression remains unsupported; the clearest indications are giant-cell, eosinophilic, sarcoid, ICI-associated, systemic autoimmune, and carefully characterized virus-negative inflammatory disease. (lauriero2025acutemyocarditisand pages 1-2, peretto2023myocardialinflammationas pages 2-3, ferone2024currenttreatmentand pages 11-11)

Major unresolved needs are validated noninvasive endotyping, harmonized diagnostic definitions, randomized treatment trials in high-risk disease, genotype-informed surveillance, pediatric evidence, and prospective quality-of-life data. Apparent treatment benefits in selected observational cardiomyopathy cohorts—such as lower death/transplantation with immunosuppression—must not be generalized without biopsy/pathogen context and randomized confirmation. (lutokhina2025incidenceandimpact pages 11-13, lutokhina2025incidenceandimpact pages 13-14, lutokhina2025incidenceandimpact pages 14-16)

References

(lauriero2025acutemyocarditisand pages 1-2): Francesco Lauriero, Camilla Vittoria Vita, Alessio Perazzolo, Giovanni Sanseverino, Eleonora Moliterno, Giuseppe Rovere, Riccardo Marano, and Luigi Natale. Acute myocarditis and inflammatory cardiomyopathies: insights from cardiac magnetic resonance findings. Echocardiography (Mount Kisco, N.y.), Feb 2025. URL: https://doi.org/10.1111/echo.70099, doi:10.1111/echo.70099. This article has 7 citations.
(caforio2024…prognosticutility pages 2-3): ALP Caforio, JP Kaski, and JR Gimeno. … prognostic utility in paediatric and adult myocarditis in the european society of cardiology eurobservational research programme cardiomyopathy and myocarditis …. Unknown journal, 2024.
(peretto2023myocardialinflammationas pages 2-3): Giovanni Peretto, Elena Sommariva, Chiara Di Resta, Martina Rabino, Andrea Villatore, Davide Lazzeroni, Simone Sala, Giulio Pompilio, and Leslie T. Cooper. Myocardial inflammation as a manifestation of genetic cardiomyopathies: from bedside to the bench. Apr 2023. URL: https://doi.org/10.3390/biom13040646, doi:10.3390/biom13040646. This article has 36 citations.
(costa2024theepidemiologyof pages 1-2): Christos Costa and Foteini Moniati. The epidemiology of covid-19 vaccine-induced myocarditis. Advances in Medicine, 2024:1-17, Apr 2024. URL: https://doi.org/10.1155/2024/4470326, doi:10.1155/2024/4470326. This article has 13 citations.
(lutokhina2025incidenceandimpact pages 1-2): Yulia Lutokhina, Elena Zaklyazminskaya, Evgeniya Kogan, Andrei Nartov, Valeriia Nartova, and Olga Blagova. Incidence and impact of myocarditis in genetic cardiomyopathies: inflammation as a potential therapeutic target. Jan 2025. URL: https://doi.org/10.3390/genes16010051, doi:10.3390/genes16010051. This article has 4 citations.
(peretto2023myocardialinflammationas pages 11-13): Giovanni Peretto, Elena Sommariva, Chiara Di Resta, Martina Rabino, Andrea Villatore, Davide Lazzeroni, Simone Sala, Giulio Pompilio, and Leslie T. Cooper. Myocardial inflammation as a manifestation of genetic cardiomyopathies: from bedside to the bench. Apr 2023. URL: https://doi.org/10.3390/biom13040646, doi:10.3390/biom13040646. This article has 36 citations.
(lutokhina2025incidenceandimpact pages 2-4): Yulia Lutokhina, Elena Zaklyazminskaya, Evgeniya Kogan, Andrei Nartov, Valeriia Nartova, and Olga Blagova. Incidence and impact of myocarditis in genetic cardiomyopathies: inflammation as a potential therapeutic target. Jan 2025. URL: https://doi.org/10.3390/genes16010051, doi:10.3390/genes16010051. This article has 4 citations.
(lutokhina2025incidenceandimpact pages 4-6): Yulia Lutokhina, Elena Zaklyazminskaya, Evgeniya Kogan, Andrei Nartov, Valeriia Nartova, and Olga Blagova. Incidence and impact of myocarditis in genetic cardiomyopathies: inflammation as a potential therapeutic target. Jan 2025. URL: https://doi.org/10.3390/genes16010051, doi:10.3390/genes16010051. This article has 4 citations.
(lutokhina2025incidenceandimpact pages 11-13): Yulia Lutokhina, Elena Zaklyazminskaya, Evgeniya Kogan, Andrei Nartov, Valeriia Nartova, and Olga Blagova. Incidence and impact of myocarditis in genetic cardiomyopathies: inflammation as a potential therapeutic target. Jan 2025. URL: https://doi.org/10.3390/genes16010051, doi:10.3390/genes16010051. This article has 4 citations.
(lutokhina2025incidenceandimpact pages 13-14): Yulia Lutokhina, Elena Zaklyazminskaya, Evgeniya Kogan, Andrei Nartov, Valeriia Nartova, and Olga Blagova. Incidence and impact of myocarditis in genetic cardiomyopathies: inflammation as a potential therapeutic target. Jan 2025. URL: https://doi.org/10.3390/genes16010051, doi:10.3390/genes16010051. This article has 4 citations.
(vosko2026giantcellmyocarditis pages 1-2): Ivan Vosko and Markus Wallner. Giant cell myocarditis: from immune pathogenesis to contemporary management. Heart Failure Reviews, Aug 2026. URL: https://doi.org/10.1007/s10741-026-10668-6, doi:10.1007/s10741-026-10668-6. This article has 0 citations and is from a peer-reviewed journal.
(ricci2026severemyocardialinflammation pages 34-37): Jacob C Ricci, Logan P Macomb, Emily R Whelan, Katherine Gegoutchadze, Cormac J Davis, Kyra G Ritter, Priya Tomerlin, Ashley A Darakjian, Nick A Farahani, Lauren M Parrow, Danielle J Beetler, Max W Strandes, Damian N Di Florio, Sami Khatib, Jude Elsaygh, Leslie T Cooper, Jack F Price, DeLisa Fairweather, Dipankar Gupta, and Katelyn A Bruno. Severe myocardial inflammation and necrosis in juvenile mice compared with adult mice with coxsackievirus b3 myocarditis. bioRxiv, Aug 2026. URL: https://doi.org/10.64898/2026.08.20.746108, doi:10.64898/2026.08.20.746108. This article has 0 citations.
(lutokhina2025incidenceandimpact pages 16-17): Yulia Lutokhina, Elena Zaklyazminskaya, Evgeniya Kogan, Andrei Nartov, Valeriia Nartova, and Olga Blagova. Incidence and impact of myocarditis in genetic cardiomyopathies: inflammation as a potential therapeutic target. Jan 2025. URL: https://doi.org/10.3390/genes16010051, doi:10.3390/genes16010051. This article has 4 citations.
(lutokhina2025incidenceandimpact pages 14-16): Yulia Lutokhina, Elena Zaklyazminskaya, Evgeniya Kogan, Andrei Nartov, Valeriia Nartova, and Olga Blagova. Incidence and impact of myocarditis in genetic cardiomyopathies: inflammation as a potential therapeutic target. Jan 2025. URL: https://doi.org/10.3390/genes16010051, doi:10.3390/genes16010051. This article has 4 citations.
(ferone2024currenttreatmentand pages 11-11): Emma Ferone, Amitai Segev, Erika Tempo, Piero Gentile, Ahmed Elsanhoury, Chiara Baggio, Jessica Artico, Prashan Bhatti, Paul Scott, Emanuele Bobbio, Marco Merlo, Pietro Ameri, Gianfranco Sinagra, Carsten Tschöpe, Daniel Bromage, and Antonio Cannata. Current treatment and immunomodulation strategies in acute myocarditis. May 2024. URL: https://doi.org/10.1097/fjc.0000000000001542, doi:10.1097/fjc.0000000000001542. This article has 26 citations and is from a peer-reviewed journal.

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Unresolved (possible confabulation)	0
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References weighed for topical relevance	8
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OpenScientist Report

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Imaging Findings

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Related Datasets

Clinical Trials

Animal Models

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References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Myocarditis: comprehensive disease-characteristics report

Executive summary

1. Disease information

Definition and scope

Identifiers and synonyms

2. Etiology, risk, protection, and gene–environment interaction

Causal or triggering factors

Genetic susceptibility—not usually simple causation

Environmental and lifestyle risks

Protective factors and gene–environment interactions

3. Phenotypes

4. Genetic and molecular information

Causal genes and testing interpretation

Modifier and epigenetic evidence

5. Environmental and infectious information

6. Mechanism and pathophysiology

Causal chain

Cells and pathways

Histologic endotypes

Omics and advanced technologies

7. Anatomy

8. Temporal development

9. Inheritance and population epidemiology

10. Diagnostics

Clinical workflow

Biomarkers and emerging diagnostics

Genetic and omics testing

11. Outcomes and prognosis

12. Treatment and real-world implementation

General strategy

Etiology/endotype-directed treatment

Pharmacogenomics and advanced therapeutics

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems