Chronic myocarditis

Article written and reviewed by Dr Luca Moretti

Chronic myocarditis describes persistence of myocarditis beyond three months, but the clinical meaning of this definition cannot be reduced to symptom duration alone. In the traditional ESC classification, persistence of heart failure or clinical manifestations beyond three months constituted a subacute or chronic presentation, whereas contemporary assessment requires determining whether active inflammation, ongoing cardiomyocyte injury and dysfunction are still present or whether only the scarred sequela of an episode that has already resolved remains. This distinction is essential because persistent LGE after the acute phase may correspond to healed fibrosis and, when considered in isolation, does not demonstrate continuing myocarditic activity.

Chronic myocarditis does not necessarily coincide with inflammatory cardiomyopathy: the former identifies myocarditis persisting beyond three months that may still be accompanied by preserved ventricular function, whereas the latter requires chronic myocarditis associated with cardiac dysfunction and ventricular remodeling. As myocyte loss, fibrotic deposition and dilation progress, the condition may acquire the appearance of dilated cardiomyopathy in which the original mechanism can no longer be recognized from morphology alone. Separating these levels is not a terminological exercise, because neurohormonal heart failure therapy, immunosuppression and any etiologic treatment pursue different targets and require different evidence before they are initiated.

The natural history may follow profoundly different trajectories: slow remission after the acute episode, persistent immune activity that continues to cause injury, relapses separated by intervals of apparent well-being, or the hot phases of a genetic cardiomyopathy. Because similar symptoms may accompany all of these pathways, biopsy, serial CMR, molecular analysis and genetic testing are not requested as an undifferentiated panel but are selected to identify the mechanism that remains modifiable. The frequency of the condition also remains uncertain: persistence of symptoms or dysfunction after acute myocarditis does not necessarily imply active inflammation, whereas immunohistochemistry may demonstrate immune activation in cardiomyopathies previously considered idiopathic. Consequently, epidemiology depends on how intensively the tissue substrate is sought, and the chronic form emerges particularly in centers dedicated to heart failure and cardiomyopathies rather than in registries built around acute chest pain.

Prognosis ranges from stability for decades to progression toward advanced heart failure and therefore cannot be inferred from the chronological label. Much more important determinants are the function of both ventricles, the extent and location of fibrosis, arrhythmic burden, genotype, cause and response observed over time. For this reason, truly effective management requires deep phenotyping: immunosuppressing an inactive scar or an uncharacterized viral persistence exposes the patient to toxicity without offering a definite target, whereas failure to recognize an immune process that remains active allows potentially reversible injury to become irreversible remodeling.

Etiology, Pathogenesis and Pathophysiology

One possible mechanism is antigen persistence, in which microbial genetic material or a biologically active infection continues to sustain the host response. Detection of a viral genome in the myocardium does not, however, have a uniform meaning, because it must be interpreted by considering the agent, viral load, cellular compartment, possible transcriptional activity and immunologic context. Parvovirus B19, located mainly in the endothelium, may also be detected in control subjects, and an isolated qualitative PCR therefore does not demonstrate active viral cardiomyopathy; enteroviruses and adenoviruses, by contrast, have historically shown more direct associations among replication, persistence and functional impairment in carefully selected subgroups.

In other patients, the autoimmune response continues even after the initial trigger has disappeared, sustained by molecular mimicry, persistent exposure of cardiac antigens, inadequate control by regulatory T lymphocytes and autoantibody production. Lymphocytes and macrophages may therefore remain in the tissue, accompanied by abnormal HLA expression on cardiomyocytes, while low-grade injury may at times escape both troponin testing and CMR. Chronic inflammation may also result from systemic autoimmune diseases, sarcoidosis, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndromes through mechanisms that include immune complexes, granulomas, vasculitis and eosinophil degranulation. Because the cardiac course does not necessarily parallel extracardiac markers, an apparently quiescent systemic disease does not exclude myocardial activity.

Drugs and toxins may perpetuate injury when exposure continues, but withdrawal of the agent does not always guarantee immediate cessation of the response because some immunologic circuits outlast discontinuation. Checkpoint inhibitors have prolonged functional effects and may require extended immunosuppression, while clozapine and other drugs may produce acute or subacute syndromes destined to leave fibrotic remodeling; in this setting, re-exposure may lead to a faster and more severe recurrence. A different mechanism operates in genetic cardiomyopathies, in which desmosomal fragility and mechanical stress promote cell death and inflammatory signaling. DSP variants are particularly associated with episodes of pain, troponin elevation and subepicardial LGE, but TTN, FLNC and other genes may also contribute to complicated phenotypes in which inflammation accelerates a vulnerable substrate without necessarily representing its sole cause.

When cardiomyocyte loss becomes progressive, contractile reserve decreases and fibroblast activation deposits replacement and interstitial collagen, with wall thinning, chamber dilation and altered mitral geometry. Increased wall stress activates the renin-angiotensin system, sympathetic nervous system and profibrotic pathways, allowing remodeling to acquire dynamics that are at least partly autonomous from the initial infiltrate. In parallel, fibrosis fragments electrical propagation and creates slow-conduction corridors, so ventricular arrhythmias may increase precisely while troponin and edema decline; during relapses, new inflammation transiently alters refractoriness and facilitates triggers. Separation between the scar substrate and biological activity thus becomes the principle guiding arrhythmic protection and any immunotherapy, respectively.

Persistent microvascular and endothelial dysfunction may accompany myocyte loss, reducing coronary reserve and contributing both to pain and exercise intolerance. Cytokines interfere with mitochondrial metabolism and intracellular calcium handling, while functional autoantibodies may modify beta-adrenergic and muscarinic receptor responses; none of these mechanisms is adequately represented by a single clinical biomarker. Moreover, reparative and inflammatory phases may coexist in different regions of the same heart, so that a biopsy documents fibrosis together with immune activation while CMR detects LGE without global edema. Because sampling error also remains possible, only multimodal characterization reduces the risk of confusing a disease that is now inactive with a process that remains modifiable.

Biological prognosis ultimately depends on the balance between the reversible component and established injury: edema, cytokine-mediated contractile depression and immune activation may improve, whereas replacement necrosis and structural abnormalities determined by a genetic variant do not regress. Even a clear therapeutic response may therefore restore function without eliminating all scar. The realistic objective is to interrupt injury that is still ongoing and promote reverse remodeling, without confusing functional recovery with complete anatomical restitution.

Clinical Manifestations

The history should reconstruct the index episode, recovery and subsequent course as a single trajectory, determining whether troponin and function normalized, what distribution any LGE had, which treatments were continued and when symptoms or arrhythmias reappeared. Previous medical records and images therefore become an integral part of diagnosis, because they allow unresolved persistence to be separated from a new event. Fatigue and reduced exercise tolerance remain common but nonspecific, whereas progressive dyspnea, orthopnea, weight gain and edema indicate the development of heart failure; recurrent pain accompanied by a new troponin rise instead suggests cardiomyocyte activity, provided ischemia and other causes of injury are excluded. Fluctuation in symptoms must also be interpreted in light of arrhythmias, anemia, thyroid dysfunction, deconditioning and comorbidities, avoiding automatic attribution of every deterioration to inflammation.

Palpitations may reflect simple premature beats or sustained tachycardias, but the appearance of sudden syncope, exertional arrhythmias or appropriate ICD therapies identifies a high-risk phenotype in which increasing arrhythmic burden may precede ventricular deterioration. Correlation between symptoms and rhythm, obtained with prolonged Holter monitoring or a loop recorder, avoids assuming that every episodic manifestation is arrhythmic. From a hemodynamic perspective, chronic congestion presents with jugular venous distension, hepatomegaly, ascites and edema, while crackles may be absent when heart failure is chronically compensated; a third heart sound and functional mitral or tricuspid murmurs reflect remodeling, and the combination of low blood pressure, cool extremities and sarcopenia signals an advanced stage with reduced reserve.

Rash, arthritis, Raynaud phenomenon, neuropathy, asthma, eosinophilia, uveitis, lymphadenopathy and muscle weakness suggest systemic activity and, when present, may also provide a safer biopsy site that is more representative than the heart. Their absence, however, does not exclude a form confined to the myocardium. In parallel, family history should extend over at least three generations and investigate cardiomyopathies, sudden deaths, transplants, early pacemaker implantation and previous diagnoses labeled as myocarditis, because familial recurrence or a phenotype similar to that associated with DSP increases the likelihood of a genetic basis. The test result acquires meaning only after counseling and rigorous variant classification, without turning an uncertain finding into a causal explanation.

During physical activity, symptoms may emerge because of reduced hemodynamic reserve or arrhythmias, but not every episode of fatigue after an infection indicates cardiac inflammation, nor does stable LGE in the absence of other markers by itself justify an indefinite sports restriction. Cardiopulmonary exercise testing and rhythm monitoring help distinguish central limitation, reduced peripheral capacity and deconditioning. In children, progression may present with poor growth, reduced activity and conditions interpreted as recurrent respiratory infections, while repeated painful episodes are possible in adolescents; neuromuscular and metabolic diseases further broaden the differential diagnosis. For this very reason, a familial cardiomyopathy should not be attributed to a succession of infections without first evaluating a genetic origin.

The clinical trajectory may remain silent, because ventricular function and dimensions sometimes worsen without symptoms in young people who spontaneously reduce activity, whereas in other cases intense symptoms coexist with stable functional parameters. Planned follow-up based on quantitative measurements therefore prevents reliance on subjective perception alone. At each visit, adherence, blood pressure, heart rate, volume status, adverse effects and new exposures should be reassessed, bearing in mind that withdrawal of heart failure therapy after recovery may precede relapse and that infections or pregnancy may unmask reduced reserve. Chronic myocarditis should therefore be interpreted as a dynamic condition in which the relative weight of activity, scar and remodeling changes over time.

Investigations and Diagnosis

The diagnostic pathway begins with ECG, troponin, natriuretic peptide, complete blood count with differential, CRP, renal, liver and thyroid function and electrolytes, adding CK, autoimmune testing and infectious investigations only when the phenotype makes them relevant. Normal values do not exclude low-grade inflammation, whereas elevated values should be compared with baseline and alternative causes. Echocardiography quantifies volumes, biventricular function, strain, regurgitation, pressures and thrombi, allowing progressive dilation, wall thinning and mitral regurgitation to be recognized as signs of remodeling; at the same time, a preserved ejection fraction does not exclude focal disease or arrhythmic risk. To interpret modest changes, serial measurements obtained with consistent methods and, where possible, the same laboratory are preferable, reducing nonbiological variability.

CMR can distinguish, with limitations that become more evident in chronic disease, active edema, diffuse increases in T1 or extracellular volume and scar documented by LGE. The T2 domain loses sensitivity when activity is modest, whereas LGE without edema may simply represent a sequela; mapping values also require local reference ranges and must be interpreted with the possibility of diffuse fibrosis in mind. Serial changes are often more informative than a single study, but CMR does not reliably identify cell populations or genomes. Because chronic myocarditis is defined by persistence of myocarditis beyond three months, guidelines and consensus documents require confirmation of a persistent compatible phenotype and a search for objective evidence of inflammation, distinguishing it from irreversible injury; when that distinction changes therapy, endomyocardial biopsy remains the reference, whereas symptom duration alone is insufficient.

Biopsy becomes particularly relevant when persistent or progressive dysfunction remains unexplained, arrhythmias or recurrences occur, a granulomatous or eosinophilic process is suspected, or targeted immunosuppression is being considered. Multiple samples should permit histology, fibrosis quantification, immunohistochemistry and appropriate molecular investigation, including, in specialist settings, messenger RNA or replicative intermediates of specific viruses. Dallas criteria retain specificity but have limited sensitivity in focal and chronic forms; immunohistochemistry adds leukocyte quantification, characterization of subpopulations and HLA expression, provided thresholds are applied with validated methods and in clinical context. A negative biopsy does not automatically close the diagnostic pathway, because review of slides, guided sampling of another site or reassessment of an alternative diagnosis may be necessary.

Any viral genome must be interpreted in relation to the agent and its biological activity: a low B19V load may be incidental, whereas transcriptionally active replication, high load and coherent cellular localization confer greater significance. The decision to immunosuppress therefore cannot rest on the generic label of “positive PCR.” When sarcoidosis or focal inflammation is suspected, 18F-FDG PET may reveal activity and direct sampling, provided preparation adequately suppresses physiological myocardial metabolism; CT, lymph-node imaging and extracardiac biopsy further increase yield and may avoid repeated cardiac procedures. Lack of uptake, however, does not exclude all lymphocytic forms and does not replace integration with CMR and tissue findings.

The differential diagnosis must be reopened even when there is an old diagnosis of myocarditis, because coronary artery disease, valvular disease, hypertension, tachycardia-induced cardiomyopathy, alcohol, toxins and endocrinopathies may supervene and explain new dysfunction. LGE patterns, coronary anatomy and response to rhythm control help separate these mechanisms. Genetic testing should also be considered in recurrent, complicated, familial, arrhythmic or morphologically suggestive forms, remembering that a variant of uncertain significance does not prove causality and cannot by itself guide devices or invasive screening. Conversely, a pathogenic or likely pathogenic variant consistent with the phenotype changes counseling, assessment of relatives and the interpretation of the inflammatory episodes themselves.

Prolonged Holter monitoring, exercise testing and, in selected cases, loop recorders quantify electrical risk over a period that a single ECG cannot represent, while cardiopulmonary exercise testing measures functional capacity, the VE/VCO2 slope and hemodynamic reserve. Right-heart catheterization is reserved for advanced heart failure or discrepancies in which defining pressures and cardiac output changes a therapeutic decision. The final diagnosis therefore does not coincide with a single test, but integrates inflammatory activity, function, rhythm, etiology and genotype in a formulation intended to be updated during follow-up.

Treatment and Prognosis

In patients with dysfunction, guideline-directed heart failure therapy forms the background structure onto which etiologic interventions are added. An ARNI, or an ACE inhibitor or ARB, beta-blocker, mineralocorticoid receptor antagonist and SGLT2 inhibitor are introduced and titrated according to ejection fraction, blood pressure, renal function and potassium, while diuretics maintain volume control. In many cases therapy is continued even after recovery, especially when scar persists or the cause has not been eliminated. Atrial fibrillation, tachycardias and conduction disorders are treated according to their respective guidelines without overlooking possible inflammatory activity; ventricular tachycardia ablation may be effective in a mature scar but is less stable during an active phase, while ICD and CRT indications and timing must integrate function, arrhythmias, genotype and response to optimal treatment.

Immunosuppression should be reserved for a documented target, because giant cell myocarditis, sarcoidosis, eosinophilic myocarditis and autoimmune diseases require different regimens, whereas in lymphocytic inflammatory cardiomyopathy selection is based mainly on a positive biopsy and absence of clinically relevant viral genomes. The decision therefore requires discussion among the cardiologist, pathologist, infectious disease specialist and immunology specialist. In the TIMIC trial, patients with chronic heart failure, biopsy-proven virus-negative myocarditis and lack of response to conventional therapy were randomized to prednisone and azathioprine or placebo: function improved in most treated patients, and follow-up extending to twenty years confirmed a lower incidence of cardiovascular death or transplantation compared with matched controls. These results support a tissue-guided strategy but cannot be extended to patients without biopsy or with unresolved viral persistence.

Observational virus-negative cohorts have likewise documented improvements in inflammation and function with immunosuppression, although patient selection and center expertise limit extrapolation. The earlier Myocarditis Treatment Trial, which did not demonstrate benefit from nonpersonalized immunosuppression, clarifies why the uniform approach was replaced by a biopsy-guided strategy based on etiology and immunophenotype. In chronic viral cardiomyopathy due to enterovirus or adenovirus, some interferon-beta studies achieved clearance or reduction in viral load together with clinical improvements, whereas BICC, which also included B19V, yielded more complex virologic results. These are, however, strategies for dedicated centers and laboratories rather than standard empirical treatments, and for many viruses there is still no validated therapy capable of eradicating the myocardial reservoir.

Sarcoidosis is treated with corticosteroids and steroid-sparing agents, following PET activity, rhythm and function over time, whereas eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndromes require a hematology-rheumatology strategy. In checkpoint inhibitor toxicity, possible resumption of oncologic immunotherapy is an exceptional decision that must balance cancer prognosis and cardiac risk; in other drug-induced forms, removal of the trigger remains the first measure. Exercise is also modulated according to activity, function and arrhythmic risk: intense exertion is suspended during recurrence or biomarker elevation, whereas rehabilitation during a stable phase limits deconditioning. Isolated and stable LGE therefore requires individualized interpretation, not an automatic permanent prohibition.

Follow-up should measure symptoms, NYHA class, blood pressure, volume status, troponin, natriuretic peptide, function and arrhythmias in a coordinated manner, repeating CMR or PET when the result may change immunotherapy or risk estimation and reserving serial biopsies for selected situations. Response does not coincide solely with an increase in ejection fraction, but includes remission of inflammatory activity and electrical stabilization. Prognosis is better when the reversible component is treated before extensive fibrosis develops; by contrast, extensive LGE, right ventricular dysfunction, arrhythmias, a high-risk genotype, advanced NYHA class and lack of response indicate a greater likelihood of death or transplantation. Because recurrence may occur even after an apparently complete response, surveillance should continue beyond initial normalization.

When heart failure reaches an advanced stage, assessment for ventricular assist support or transplantation should not be delayed until irreversible organ damage develops. Infectious or autoimmune activity, malignancy and extracardiac involvement influence candidacy, so etiologic definition retains value even in the terminal stage. Transplantation replaces the compromised pump but does not necessarily eliminate the risk of recurrence of a systemic disease and therefore requires planning shared with specialists in the underlying condition.

Complications

The most common and clinically relevant progression leads to inflammatory cardiomyopathy with dysfunction and remodeling, in which myocyte loss, fibrosis and increased wall stress dilate the ventricle and worsen functional mitral regurgitation. This cascade may continue even after the infiltrate has decreased, ultimately causing chronic congestion, renal injury, liver disease, cachexia and repeated hospitalizations. Each acute deterioration must nevertheless be broken down into its possible determinants, including arrhythmia, intercurrent infection, poor adherence, ischemia and renewed inflammatory activity; automatically attributing every deterioration to myocarditis exposes the patient to inappropriate immunotherapy and delays correction of the true cause.

Intramural or subepicardial scar fragments conduction and creates reentry circuits through which premature ventricular complexes and ventricular tachycardia may progress to cardiac arrest and sudden death, maintaining residual risk even after ejection fraction recovers. LGE extent and septal location therefore contribute to stratification together with the clinical phenotype and genotype. Atrioventricular block and sinus-node dysfunction may result from fibrosis as well as renewed activity in the conduction system, with a particular propensity in sarcoidosis and giant cell myocarditis; development of a new block in known disease therefore requires investigation for reactivation, and the choice between pacemaker and ICD must also take ventricular risk into account.

Each inflammatory recurrence may add edema, necrosis and new scar to an already vulnerable substrate; although some episodes are preceded by recognizable infections or exposures, repeated events often suggest autoimmunity or genetic cardiomyopathy and are associated with progressively less favorable prognosis. Prevention therefore depends on the cause and no universal prophylaxis exists. On the thromboembolic side, stasis and dilation promote ventricular thrombus formation, to which atrial fibrillation adds an independent risk: stroke and peripheral emboli may therefore be the first manifestation of advanced cardiomyopathy, while contrast echocardiography and CMR increase sensitivity for apical thrombi that are difficult to visualize.

Prolonged immunosuppression adds its own risks, including opportunistic infections, malignancies, osteoporosis, diabetes, cytopenias, infertility and renal or hepatic toxicity, making vaccination, prophylaxis and scheduled monitoring necessary before and during treatment. The cumulative burden of these events reinforces the need for a solid tissue diagnosis. Viral persistence incorrectly treated with immunosuppression may promote replication or prevent clearance, whereas the opposite choice, withholding treatment from a virus-negative autoimmune form, allows injury to progress. This dilemma is one of the most important consequences of incomplete diagnosis and makes the quality of the sample, immunohistochemistry and the molecular laboratory integral to therapeutic safety.

An unrecognized genetic cardiomyopathy exposes relatives to unmonitored risk and the patient to inappropriate restrictions or treatments, because a hot phase interpreted as an isolated infection may be followed by malignant arrhythmias that were not prevented. Genetic counseling then transforms individual management into family prevention, organizing clinical assessment and, when indicated, cascade testing for the variant. In the terminal stage, a VAD or transplantation may become necessary, but pulmonary hypertension, right ventricular failure and organ damage progressively reduce options; early assessment prevents referral from occurring when candidacy is already compromised. Prognosis improves when heart failure therapy and etiologic characterization proceed together rather than being considered alternative pathways.

Even apparent stability may conceal evolving risk, because scar, silent arrhythmias and slow progression do not necessarily produce symptoms before a complication. This justifies follow-up proportionate to the phenotype, but not indiscriminate testing without a clinical question, which would increase false positives and medicalization. The goal is personalized surveillance that is sufficiently sensitive to recognize treatable activity and sufficiently selective to focus interventions on preventing irreversible complications.