Perimyocarditis

Article written and reviewed by Dr Luca Moretti

Perimyocarditis is an inflammatory myopericardial syndrome in which myocardial injury predominates over the pericardial component and produces new global or regional ventricular dysfunction. The term is traditionally contrasted with myopericarditis, in which pain and other signs of pericarditis predominate and function remains preserved. The two conditions belong to a continuum, but the appearance of dysfunction radically changes risk assessment, the use of anti-inflammatory drugs, monitoring intensity and follow-up.

The pericardial component may be evident through pleuritic and positional pain, a friction rub, diffuse ST-PR changes, enhancement or effusion, but it should not obscure the significance of myocardial dysfunction. Dyspnea, congestion, low output and arrhythmias may become more important than pain, and the condition may progress to shock. For this reason, perimyocarditis is essentially managed as myocarditis with pericardial involvement, adapting analgesia and pericarditis therapy to ventricular function and hemodynamic status.

Epidemiology is uncertain because many studies aggregate myopericarditis and perimyocarditis or use different definitions. Widespread use of high-sensitivity troponin and CMR has increased recognition of mixed forms, but hospital selection overrepresents phenotypes with dysfunction. Young men with infarct-like presentation are common in Western registries, whereas children, older adults, immunocompromised patients and those with systemic disease more often present with heart failure, conduction blocks or extracardiac signs.

Prognosis is less uniformly favorable than in myopericarditis with preserved function and depends on initial severity and cause; marked contractile depression may recover if it reflects edema and inflammatory stunning, whereas necrosis, fibrosis and aggressive histologic subtypes leave a persistent substrate. The trajectory must be assessed through biventricular function, electrical stability, extent and location of LGE, biomarkers and recovery over the following months.

The definition requires dysfunction to be new and plausibly related to the inflammatory process. An ejection fraction already reduced because of cardiomyopathy, ischemia or valvular disease does not automatically turn pericarditis into perimyocarditis; comparison with previous examinations, new regional abnormalities, edema or other signs of activity are required. This precision prevents chronic injury from being attributed to the acute episode and avoids overestimating the expected benefit of anti-inflammatory therapy.

Etiology, Pathogenesis and Pathophysiology

Infections and post-infectious immune responses are important causes, although the agent often remains unproven. RNA and DNA viruses may affect cardiomyocytes or endothelium, activate interferons, complement and innate cells, and induce a T-cell response that persists beyond the replicative phase. A respiratory or gastrointestinal prodrome supports the timeline but does not prove a viral etiology, and isolated serology does not demonstrate the presence of the agent in the myocardium.

The immune response causes interstitial and intracellular edema, increased permeability, microvascular dysfunction, necrosis and altered calcium handling. Contractility decreases both because of cardiomyocyte loss and because of reversible cytokine-mediated depression; consequently, a very low ejection fraction does not always imply irreversible injury. Edema may transiently increase wall thickness and reduce compliance and stroke volume even in non-dilated chambers.

Pericardial involvement reflects the continuity between the visceral pericardium and subepicardial myocardium. A superficial inferolateral distribution often produces pain and non-ischemic LGE, whereas more diffuse or septal lesions increase the probability of dysfunction, conduction block and arrhythmias. A modest effusion does not quantify myocardial severity, but rapid accumulation may impair filling and superimpose tamponade physiology on heart failure.

Autoimmune diseases, sarcoidosis, eosinophilic myocarditis and giant-cell myocarditis may present as perimyocarditis, but have different mechanisms and prognoses; immune complexes, vasculitis, granulomas, eosinophil degranulation and T-cell cytotoxicity produce non-interchangeable patterns. Advanced blocks, sustained arrhythmias, eosinophilia, myositis or rapid deterioration increase the need for biopsy because the histologic subtype changes both immunosuppression and therapeutic urgency.

Drugs, hypersensitivity reactions and checkpoint inhibitors may cause myopericardial injury. The chronology of exposure, the presence of rash or eosinophilia and association with myositis or myasthenia guide suspicion, but initially preserved function does not exclude severe electrical progression in checkpoint inhibitor-associated forms. The trigger should be removed immediately when the relationship is plausible, without delaying the characterization needed to decide on immune therapy.

Variants in cardiomyopathy genes, especially DSP and other desmosomal genes, may generate inflammatory episodes with pain, troponin elevation and subepicardial LGE. In such hot phases, inflammation is both a manifestation and an accelerator of a genetic substrate, which may leave arrhythmic risk disproportionate to functional recovery. Family history, recurrences and persistent scar should therefore prompt consideration of genetic evaluation.

Edema and necrosis alter connexins, ion channels and refractoriness, producing premature beats, ventricular tachycardia and conduction blocks. If injury resolves, reparative macrophages and fibroblasts may restore function or leave a scar; if activity persists, myocyte loss and neurohormonal remodeling lead to inflammatory cardiomyopathy. Perimyocarditis is therefore a phase diagnosis that must be updated according to evolution.

Pericardial effusion and ventricular dysfunction may coexist but follow independent dynamics; a small effusion does not exclude extensive myocarditis, whereas rapid accumulation may cause tamponade even with relatively preserved contractile function. When low output and filling limitation overlap, pressures, echocardiography and the response to interventions must distinguish the two components, because aggressive diuresis and vasodilation may be poorly tolerated in tamponade.

Clinical Manifestations

Pain may retain pericarditic features, worsening with inspiration and recumbency and improving when sitting up, or it may become oppressive and indistinguishable from ischemia. When ECG and troponin mimic myocardial infarction, exclusion of coronary occlusion or dissection remains a priority; absence of pain does not exclude the diagnosis, especially in diffuse phenotypes, children and patients in whom heart failure predominates.

Dyspnea, reduced exercise tolerance, orthopnea, fatigue, weight gain and edema reflect increased filling pressures. Progression to dyspnea at rest, oliguria, confusion, reduced pulse pressure and cold extremities indicates low output and requires intensive treatment; blood pressure may remain temporarily preserved through vasoconstriction while lactate and organ function reveal compensated shock.

Palpitations, presyncope and syncope may result from premature beats, ventricular tachycardia, atrial fibrillation or atrioventricular block; syncope without prodromes, arrhythmia during exercise, widening QRS and sustained tachycardia are high-risk signs. Arrhythmia may be both a cause and a consequence of reduced output, and worsening during observation is a reason for escalation independent of ejection fraction.

Physical examination evaluates perfusion, mental status, blood pressure, heart rate, oxygen saturation and urine output together with signs of congestion; elevated jugular venous pressure, hepatomegaly, ascites and edema indicate right-sided involvement, whereas crackles, a third heart sound and functional mitral regurgitation accompany elevated left-sided pressures. A pericardial friction rub supports the pericardial component but is transient, and its absence does not change the significance of documented dysfunction.

Etiologic history includes infections, new drugs, immunotherapy, bites or stings, travel, autoimmune diseases, occupational exposures and extracardiac symptoms. Rash and eosinophilia suggest hypersensitivity, asthma and neuropathy suggest EGPA, ptosis and weakness suggest checkpoint inhibitor overlap, and lymphadenopathy suggests sarcoidosis; a family history of cardiomyopathy, sudden death or similar episodes points toward a genetic substrate.

In young children, persistent tachycardia, tachypnea, poor appetite, irritability, hepatomegaly and pallor predominate, and the presentation may be confused with sepsis or bronchiolitis. Adolescents more often present with pain and elevated troponin. In older adults and immunocompromised patients, fever may be absent and bacterial, neoplastic, tuberculous or drug-related causes must be weighted differently from the idiopathic form of a young adult.

The course during the first hours is part of the clinical manifestation; a patient who is initially stable may develop new congestion, arrhythmias or hypotension, while rapid improvement in function suggests a reversible component. Surveillance is therefore determined by evolutionary risk, not only by the condition observed at triage.

The picture may change during the first hours, and an initially reassuring assessment does not end observation if troponin, ECG or symptoms are dynamic. Blood pressure, perfusion, urine output and rhythm are followed together with biomarkers and echocardiography because deterioration may result from myocardial progression, tamponade or arrhythmia. Persistence of pain, considered in isolation, is less informative than the onset of dyspnea, syncope, hypotension or a new conduction disorder.

Investigations and Diagnosis

ECG, serial troponin, natriuretic peptide, complete blood count with differential, CRP, electrolytes, renal and hepatic function, blood gas analysis and lactate define injury and severity. The ECG may show diffuse changes of pericarditis or territorial patterns, Q waves, wide QRS complexes, blocks and arrhythmias more typical of myocardial involvement; no tracing is pathognomonic, and a normal ECG does not exclude focal disease.

Troponin demonstrates injury but does not distinguish perimyocarditis, myocardial infarction and other causes, while BNP or NT-proBNP reflects hemodynamic stress; peak magnitude does not linearly measure prognosis and is interpreted together with function and rhythm. Eosinophilia, elevated CK, autoantibodies or positive cultures may point toward specific subtypes, but non-selective panels produce incidental findings and do not replace cardiac characterization.

Echocardiography documents the new dysfunction that distinguishes perimyocarditis from myopericarditis and assesses biventricular function, strain, wall thickness, dimensions, regurgitation, pressures, effusion and tamponade. Hypokinesia may be global or regional and does not necessarily follow a coronary territory; repeated examinations identify deterioration, recovery or changes in loading conditions and are essential when the patient is unstable.

CCTA or coronary angiography is selected according to age, risk, ECG and urgency to exclude coronary disease, without considering normal coronary arteries sufficient proof of the diagnosis. Takotsubo syndrome, ischemic MINOCA, pulmonary embolism, acute valvular regurgitation, sepsis and tachycardia-induced cardiomyopathy remain alternatives; early performed CMR helps distinguish them through function, edema, T1/T2 mapping, ECV and LGE.

The updated Lake Louise criteria support acute inflammation when at least one T2-based marker of edema and one T1-based marker of non-ischemic injury coexist; pericardial enhancement or effusion completes characterization of the mixed process. A subepicardial or intramural distribution separates the injury from infarction, but CMR does not reliably identify histologic subtype and loses sensitivity when performed after edema has regressed.

Endomyocardial biopsy is a priority in shock, rapidly progressive dysfunction, sustained arrhythmias, advanced block, significant eosinophilia, lack of response or suspected giant-cell myocarditis, sarcoidosis or checkpoint inhibitor toxicity. Multiple samples are allocated to histology, immunohistochemistry and molecular testing with appropriate preservation; an etiologic biopsy is useful only if sample quality and specialist interpretation allow the finding to be linked to a therapeutic decision.

Investigation of the cause includes blood cultures when sepsis is present, testing for Borrelia or Trypanosoma with compatible exposures, autoimmune investigations in the presence of systemic signs, and PET or extracardiac biopsy when granulomatous disease is suspected. Because routine viral serology does not demonstrate myocardial infection, Holter monitoring and exercise testing are used after stabilization to define electrical risk and safety of return to physical activity.

Coronary catheterization or CT angiography is selected when age, risk factors, ECG distribution or pain do not allow an ischemic event to be safely excluded. Angiography without stenosis does not complete the diagnostic pathway, because dissection, vasospasm, embolism and other causes of MINOCA may require dedicated methods. CMR integrates the diagnosis by showing the distribution of injury, but should be interpreted after time-dependent questions affecting revascularization have been addressed.

Treatment and Prognosis

Initial treatment depends on stability, and new dysfunction generally makes hospitalization appropriate; shock, major arrhythmias or advanced block require an intensive care unit with access to urgent biopsy, electrophysiology, advanced heart failure care and mechanical support. Oxygenation, ventilation, electrolytes, congestion and perfusion are managed according to the biventricular profile, with early transfer when the required resources are not available.

Diuretics control congestion and vasodilators are used if blood pressure permits. In stable patients with reduced ejection fraction, heart failure therapy is introduced, whereas beta-blockers and other negative inotropic agents are delayed until shock and severe congestion have resolved. Titration continues during recovery because remodeling does not end when troponin normalizes.

The pericardial component may require analgesia and anti-inflammatory therapy, but the presence of dysfunction changes the benefit-risk balance. NSAIDs may promote fluid retention, raise blood pressure and worsen renal function in symptomatic heart failure and are not used to treat myocarditis itself. Colchicine may be considered for a documented pericarditic component, adjusted for renal and hepatic function and drug interactions, without replacing treatment of the myocardial phenotype.

Unstable arrhythmias require cardioversion or defibrillation, and symptomatic block may require temporary pacing; amiodarone is frequently used when pharmacological therapy is needed in the presence of structural heart disease, but selection takes QT interval, organ function and interactions into account. A wearable cardioverter-defibrillator, ICD and ablation are evaluated according to arrhythmia, scar, etiology and probability of recovery.

Immunosuppression is not empiric and is applied promptly to giant-cell myocarditis, necrotizing eosinophilic myocarditis, active sarcoidosis, checkpoint inhibitor-associated myocarditis and other selected autoimmune causes; in stable lymphocytic disease, it instead requires tissue and virologic characterization. Antimicrobials are reserved for proven or strongly suspected agents, and antiviral treatment is not a universal standard.

Heart failure treatment is introduced according to the hemodynamic profile and tolerance, recognizing that the first hours are not the appropriate time to force all prognostic drug classes in a hypotensive or hypoperfused patient. After stabilization, therapy is completed and titrated as in ventricular dysfunction of other causes. Rapid recovery does not justify unsupervised withdrawal because inflammation, scar and underlying predisposition may persist beyond normalization of ejection fraction.

In shock, inotropes and vasopressors are used as a bridge to decision-making and are not prolonged while lactate and organ function worsen. VA-ECMO, a microaxial flow pump or ventricular assist device is selected according to right and left ventricular function, oxygenation and the need for unloading; escalation before multiorgan failure increases the probability that support will function as a bridge to recovery.

Follow-up includes early echocardiography, clinical and biochemical reassessment, CMR in appropriate profiles and rhythm monitoring; return to sports requires remission, recovered or stabilized function and absence of significant arrhythmias on Holter monitoring and exercise testing. A favorable prognosis and possible recovery do not eliminate the need to monitor persistent LGE, right ventricular dysfunction, arrhythmias and recurrences.

Long-term reassessment separates four dimensions that do not always recover together: symptoms, biomarkers, mechanical function and electrical stability. Echocardiography, CMR and Holter monitoring are selected according to initial risk and persistence of abnormalities, whereas exercise testing is performed only after the active phase. Septal or extensive LGE, residual dysfunction and arrhythmias prevent a patient from being considered recovered on the basis of perceived well-being alone.

Complications

Acute heart failure results from contractile depression, stiffness and edema and may involve one or both ventricles; pulmonary and systemic congestion cause hypoxemia, renal and hepatic injury and reduce tolerance to medications. Part of the dysfunction is reversible, but rapid progression requires monitoring because the useful window for support may be short.

Cardiogenic shock combines insufficient output, vasoconstriction or vasoplegia, acidosis and organ injury; catecholamines and acidosis increase arrhythmic susceptibility and oxygen consumption, establishing a cycle of deterioration. Late escalation exposes the patient to multiorgan failure, neurologic injury and loss of transplant candidacy.

Ventricular arrhythmias may result from acute edema or reentry within scar and lead to cardiac arrest and sudden death. Risk may persist after functional recovery, especially with septal or extensive LGE and an arrhythmogenic genotype; atrioventricular block and sinus node dysfunction may resolve with edema or become permanent because of necrosis of the conduction system.

Pericardial effusion may increase to tamponade and superimpose impaired filling on pump dysfunction; echocardiography distinguishes a collection without hemodynamic significance from right-sided chamber collapse and guides drainage. Pericarditic recurrence may prolong pain even after myocardial recovery and requires separate assessment of activity in the two compartments.

Akinesia, dilation, low output and atrial fibrillation promote intracardiac thrombi and systemic embolism; CMR or contrast echocardiography improves detection when the apex is poorly visualized. Anticoagulation is decided on the basis of demonstrated thrombus or standard indications and must be coordinated with biopsy and the risk of hemopericardium.

Residual scar may support late arrhythmias and reduce contractile reserve, while myocyte loss and neurohormonal activation may produce dilation and functional mitral regurgitation. Transition to inflammatory cardiomyopathy occurs when chronic myocarditis lasting more than three months is associated with cardiac dysfunction and ventricular remodeling and may progress even after the inflammatory infiltrate decreases.

Recurrences may be related to autoimmunity, drugs, infections, sarcoidosis or genetic hot phases and add new fibrosis to a pre-existing substrate; a new episode requires renewed coronary and etiologic assessment, not automatic repetition of the previous treatment. The most serious diagnostic complication remains failure to identify an aggressive histologic subtype or coronary syndrome requiring time-dependent treatment.

A proportion of patients progress to inflammatory cardiomyopathy with dilation, functional mitral regurgitation and chronic reduction in reserve; progression may continue even after edema decreases, sustained by fibrosis, wall stress and neurohormonal activation. Failure of functional recovery during follow-up requires reconsideration of immune activity, a persistent agent, genotype and alternative diagnoses rather than empirically prolonging the same anti-inflammatory therapy.

Simultaneous involvement of the pericardium and myocardium may generate complex physiology in which transient constriction, right ventricular dysfunction and increased filling pressures are additive. Echocardiographic signs of ventricular interdependence and pericardial imaging help distinguish this condition from isolated pump failure. Defining the mechanism avoids indiscriminate escalation of diuretics and identifies the rare patients in whom the pericardial component requires dedicated treatment.