Giant Cell Myocarditis

Giant Cell Myocarditis 

Giant cell myocarditis (GCM) is a rare but frequently fatal inflammatory disorder that affects the myocardium characterized by widespread infiltration in the myocardial tissue of multinucleated giant cells.

The myocardiocyte necrosis present is not secondary to ischemic events or cardiac rejection in the setting of transplantation. Giant cells are abnormal masses produced by the fusion of inflammatory cells called macrophages.

Patients may develop acute or fulminant deterioration in left ventricular systolic function despite standard heart failure treatment, ventricular arrhythmias, and heart block. Many individuals with GCM eventually require a heart transplant.

Synonyms

• GCM
• Idiopathic myocarditis
• Isolated myocarditis

Incidence

Overall the incidence of GCM is low, and it varies depending on the population being studied and the method of diagnosis being used. Larger autopsy series report an incidence of GCM ranging from 0.007% to 0.051%. Approximately 20% of patients who develop GCM have history of an autoimmune disorder, including ulcerative colitis or Crohn disease, hyperthyroidism, and post-thymoma resection.

Predominant Gender and Age

In a large multicenter registry of GCM cases (n = 63), patients ranged in age from 16 to 69 yr at time of symptom onset, with an average patient age of 42.6 yr at onset of symptoms. GCM affects males and females in equal numbers.

Risk Factors

Approximately 20% of patients who develop GCM have a history of an autoimmune disorder, including ulcerative colitis or Crohn disease and hyperthyroidism.

Genetics

Gene expression analysis of GCM shows that altered expression of T-cell activation genes (immune response genes), such as chemokine receptor 4; chemokine ligans 5, 9, 13, and 19; interleukin-1 receptor alpha to interleukin-10 receptor alpha; and beta-2 integrin, may play a role in its pathogenesis. Additional studies are required to further elucidate potential therapeutic targets for GCM.

Physical Findings & Clinical Presentation

• •Approximately 75% of patients present with congestive heart failure (CHF)
• •Increased jugular venous pressure, an S3 murmur, hepatomegaly, and peripheral edema may present in worsening heart failure, specifically right ventricular failure
• •Signs of inadequate perfusion with acute progression of heart failure leading to cardiogenic shock, including hypotension, low pulse pressure, cool extremities, persistent tachycardia, and mental status changes
• •Ventricular arrhythmia (14%): Ventricular tachycardia with possible deterioration to ventricular fibrillation or sudden cardiac death (SCD)
• •Heart block (5%): Ranging from first-degree to complete atrioventricular block
• •Initial symptoms resembling an acute myocardial infarction, such as chest pain, present in up to 6% of patients with GCM
• •Syncope/presyncope, dizziness, palpitations, or lightheadedness secondary to heart block or ventricular arrhythmia

Etiology

• •The etiology of GCM is insufficiently known but commonly attributed to immune dysregulation mediated by T lymphocytes.
• •The strong association of GCM with autoimmune disorders, as well as tumors of immune cells (e.g., thymoma and lymphoma), would also suggest the presence of an impaired immune response.
• •Recent gene expression profiling of patients with GCM has revealed upregulation of genes involved in the T-cell immune response.
• •Other conditions reported to be associated with the development of GCM, although rare, include drug hypersensitivity reaction and infection such as parvovirus B19 (diagnosed via DNA polymerase chain reaction [PCR]) or coxsackie B2 virus (diagnosed via serology and cardiac immunoblotting). However, electron microscopic studies to date have not identified viral particles in GCM, and no microbiologic agent has been directly identified in cardiac tissue by microscopy, tissue culture, or inoculation in experimental animals.

Differential Diagnosis

• •Ischemic or nonischemic cardiomyopathy
• •Acute coronary syndrome
• •Other infiltrative diseases of the myocardium, such as sarcoidosis, lymphocytic, and hypersensitivity myocarditis

Workup

• •Medical history to determine various etiologies of myocarditis, specifically history of autoimmune disorders.
• •Diagnostic workup includes chest x-ray, ECG, laboratory evaluation, echocardiogram, cardiac catheterization, cardiac MRI with late gadolinium enhancement, and endomyocardial biopsy.

Laboratory Tests

• •N-terminal brain natriuretic propeptide (NT-pro BNP) is recommended if heart failure symptoms are present.
• •Increased levels of CKMB, troponin I or T, lactate dehydrogenase, and aspartate aminotransferase are present in the setting of myocardial necrosis.
• •Elevated plasma concentrations of troponin T and NT-pro BNP have been shown to be associated with higher incidence of arrhythmias.

Imaging Studies

• •Chest x-ray: Enlargement of the cardiac silhouette with or without pulmonary congestion.
• •ECG: Sinus tachycardia with nonspecific ST-T wave changes, intraventricular conduction defects, and bundle branch blocks are common manifestations in idiopathic GCM. Ventricular arrhythmias or heart blocks may also be present.
• •Echocardiogram: Acute severe myocarditis is associated with global systolic dysfunction and decreased left ventricular ejection fraction. The left ventricle may be dilated or hypokinetic. Abnormal tissue Doppler signal can provide additional evidence for the presence of myocarditis.
• •Cardiac catheterization and angiography: Used to rule out coronary artery disease and valvular disease.
• •Cardiac MRI can be used to detect myocardial edema and myocyte injury in myocarditis. It has the sensitivity and specificity of approximately 80% for diagnosing acute myocarditis. Late gadolinium enhancement (LGE) demonstrates myocardial damage from inflammation or fibrosis. Combining T2 imaging with LGE can help distinguish acute inflammation from chronic injury.
• •Fluorine-18-fluorodeoxyglucose (18F-FDG) combined with positron emission tomography (-PET) can assess the severity of myocardial inflammation, as well as likelihood of disease progression to fibrosis, dilated cardiomyopathy, and heart failure. Ideally this scan should be used in conjunction with endomyocardial biopsy (EMB).
• •EMB is considered the gold standard for diagnosis. The sensitivity of right ventricular EMB for GCM is 80% to 85%; it is 93% with repeated biopsy, or with combined right and left ventricular biopsies. Histopathology reveals the presence of giant cells, the character of inflammation (lymphocytes, eosinophils, macrophages), the presence of myocyte hypertrophy and interstitial fibrosis, and, less frequently, granulomas.
• •It is important to distinguish between various types of inflammatory myocarditis because survival among patients in whom GCM is diagnosed on the basis of endomyocardial biopsy or apical wedge sampling is worse than patients with either cardiac sarcoid or lymphocytic myocarditis.
• •GCM usually has diffuse or multifocal involvement of the endocardium; therefore EMB tends to have a higher diagnostic sensitivity in GCM than in cardiac sarcoidosis (35%) or lymphocytic myocarditis (25%).

Features of Select Causes of Inflammatory Myocarditis

From Kadkhodayan A et al: Imaging of inflammation in unexplained cardiomyopathy, JACC Cardiovasc Imaging 9(5):603-617, 2016.

Inflammatory Disorder	Histologic Features	Common Presentations	Diagnosis	Treatment Monitoring
CS	Granulomas, in the absence of infection. Eosinophils and necrosis rare or absent.	Heart block, ventricular arrhythmias, more indolent cardiomyopathy.	Clinical, electrocardiographic, and advanced imaging with18F-FDG PET or CMR. EMB sensitivity increased by ventricular voltage mapping. Basal septal aneurysm is rare but specific.	Clinical status, arrhythmia monitoring, natriuretic peptides, LV function, and possibly serial PET imaging.
Idiopathic GCM	Necrotizing inflammation with lymphocytes, eosinophils, histiocytes, and multinucleated giant cells often near the region of myocyte damage. No well-formed granulomas.	Ventricular tachycardia in the setting of acute or fulminant systolic heart failure with/without heart block. Progressive course over weeks to months, requiring inotropic and/or mechanical circulatory support.	EMB	Clinical status, assessment of ventricular function, repeat EMB indicated for suspected recurrent disease.
Eosinophilic myocarditis	Endocardial or perivascular forms. Extensive myocyte damage suggests necrotizing eosinophilic myocarditis or very early GCM.	Heart failure related to valvular involvement. Thrombi with peripheral emboli are common.	CMR. Disease may be isolated to the LV, decreasing the diagnostic use of right ventricular EMB.	Clinical status, assessment of ventricular function, CMR for tissue characterization, peripheral eosinophil count if initially elevated.
Lymphocytic myocarditis	Lymphocyte predominant, nonischemic infiltrate with or without myocyte necrosis (borderline if no myocyte damage).	Heart failure with a dilated LV. Fulminant disease associated with a smaller ventricular size and thicker walls.	CMR	Clinical status, natriuretic peptides, assessment of ventricular function.

CMR, Cardiac magnetic resonance; CS, cardiac sarcoidosis; EMB, endomyocardial biopsy; 18 F-FDG, Fluorine- 18-fluorodeoxyglucose; GCM, giant cell myocarditis; LV, left ventricle; PET, positron emission tomography.

Treatment

• •Cyclosporine-based combined immunosuppression may be able to reduce myocardial inflammation and improve clinical outcome. The goal of immunosuppression therapy is to delay heart transplantation and delay transplant. Cessation or sometimes reduction of immunosuppression is associated with GCM recurrence as far as 8 yr after diagnosis. Heart transplantation is frequently inevitable. The rate of death or cardiac transplantation was 89% with a median survival of 5.5 mo from the onset of symptoms to the time of death or transplantation.
• •The prognosis of GCM with no or limited immunosuppressive therapy is poor. Without appropriate immunosuppressive therapy, the median survival from GCM symptom onset to death or transplant is only 3 mo. With appropriate immunosuppressive therapy, the 5-yr survival rate free of transplant ranges from 52% to 72%.

Nonpharmacologic Therapy

Mechanical circulatory support may be required for acute decompensated heart failure. Cardiac transplantation is often required.

Acute General Treatment

• •Immunosuppressive therapy: Usually involves a combination of muromonab-CD3, cyclosporine, azathioprine, and corticosteroids. Mycophenolate mofetil is a potential substitute for azathioprine.
• •Antiarrhythmic drugs (AADs) for ventricular arrhythmias including amiodarone, sotalol, and mexiletine. Sustained arrhythmias should be treated with urgent cardioversion.
• •Treatment for heart failure with reduced ejection fraction includes angiotensin-converting enzyme inhibitor (or angiotensin receptor blocker) and evidence-based beta blocker.
• •Catheter or surgical ablation for VT.
• •Implantable cardiac defibrillator (ICD). Generally deferred in patients with acute myocarditis, although in cases of GCM it may be necessary to implant earlier because of high risk of arrhythmia in recovery phase.
• •Mechanical circulatory support and cardiac transplant: Potential options for patients with refractory heart failure or cardiogenic shock include ventricular assist device (VAD) or extracorporeal membrane oxygenation (ECMO). Cardiac transplant needs to be considered soon after diagnosis. GCM can recur in ∼25% of transplanted hearts.

Disposition

• •GCM has a significantly worse prognosis compared with lymphocytic or presumed viral myocarditis.
• •Immunosuppression must be continued long term because GCM can recur up to 8 yr after diagnosis if immunosuppressive therapy is tapered or terminated.
• •Even with long-term immunosuppression, patients remain at risk for developing ventricular arrhythmias and may require ICD.
• •Rate of death or cardiac transplant was 89% and the median survival from onset of symptoms was 5.5 mo.

Referral

• •Implantation of a cardiac defibrillator should be considered (class IIa indication) in GCM, with this diagnosis as the sole criterion in patients who have reasonable expectation of survival with a good functional status for more than 1 yr. Permanent ICD is not recommended until the resolution of the acute phase and a wearable external defibrillator may be considered during recovery.
• •Endomyocardial biopsy is the gold standard and should be performed when there is clinical suspicion present.
• •Most patients will require heart transplant despite aggressive treatment with immunosuppressive therapy.
• •Catheter or surgical VT ablation may be considered in patients with recurrent ventricular arrhythmias; however, success rate in this population is unknown.
• •Complete heart block and symptomatic bradycardia are indications for pacing during acute phase of GCM.

 Pearls & Considerations

• •Rapid diagnosis is critical, as the management differs from that of other myocardial processes containing giant cells, and early institution of combined cyclosporine-based immunosuppression can dramatically affect the disease course by reducing inflammation and improving transplant-free survival.
• •Owing to advancements in diagnostic and therapeutic options, it is now increasingly diagnosed on the basis of endomyocardial biopsies, explanted hearts, or apical wedge sections removed at the time of ventricular assist device placement.

Suggested Readings

• Cooper L.T., et al.: Idiopathic giant-cell myocarditis—natural history and treatment. N Engl J Med 1997; 336 (26): pp. 1860-1866.
• Cooper L.T., et al.: Usefulness of immunosuppression for giant cell myocarditis. Am J Cardiol 2008; 102 (11): pp. 1535-1539.
• Ekström K., et al.: Incidence, risk factors, and outcome of life-threatening ventricular arrhythmias in giant cell myocarditis. Circ Arrhythm Electrophysiol 2016; 9 (12):
• Kadkhodayan A., et al.: Imaging of inflammation in unexplained cardiomyopathy. JACC Cardiovasc Imaging 2016; 9 (5): pp. 603-617.
• Kandolin R., et al.: Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression. Circ Heart Fail 2013; 6 (1): pp. 15-22.