Cardiac Sarcoidosis

Etiology

Cardiac sarcoidosis is likely the result of various environmental, genetic, and immune dysregulation factors. It has been postulated that sarcoidosis may result from an exaggerated immune response to microorganisms and tissue antigens, resulting in chronic granulomatous inflammation, even without an infectious agent.[6] 

Approximately 5% to 16% of patients with sarcoidosis have a family history of the disease; a correlation between monozygotic twins suggests a genetic component.[7] Certain genes have also been associated with sarcoidosis, including class II MHC HLA-DR3.[2]  

Environmental factors and the resultant immune response are considered pathogenic mechanisms for CS. Certain environmental and occupational exposures may predispose to sarcoidosis, such as agricultural workers, firefighters, and those exposed to insecticides and microbial bioaerosols in mold. Sarcoidosis may also be more common following exposure to infectious microorganisms such as Chlamydophila pneumoniae, Propionibacterium, and mycobacteria.[8][9] One such study of 25 patients with sarcoidosis and 25 controls demonstrated mycobacteria in 60% of the sarcoid specimens but none of the controls.[2]

Cardiac sarcoidosis is also known to recur in the transplanted organs of patients with sarcoidosis who undergo a heart-lung transplant. Evidence exists of sarcoidosis in a nonsarcoid recipient of a heart transplant from a donor with sarcoidosis; this finding supports the hypothesis that the disease is secondary to an immunological or infectious process.[7][10]

Epidemiology

The prevalence of CS in the United States and Europe is 10 to 40 persons per 100,000. The prevalence of CS is higher in Black patients (35.5 per 100,000) than in White patients (10.9 per 100,000). The clinical diagnosis of CS is made in only 5% of patients with sarcoidosis. However, autopsy studies reveal cardiac involvement in at least 25% of patients with extracardiac sarcoidosis. Additionally, cardiac magnetic resonance imaging (CMR) and autopsy studies of patients with sarcoidosis have detected evidence of CS in up to 26% of patients who remained asymptomatic.[11] 

In the United States, the mean age of diagnosis of CS is 53 years, with a slight preponderance in women (58%).[12] The incidence of sarcoidosis and its associated mortality rate is exceptionally high in Black women; a single study reported a prevalence of 2% in this patient population.[5]

The clinical presentation of sarcoidosis seems to differ among ethnic groups. Lupus pernio is more common in Puerto Rican and Black patients, while erythema nodosum is more prevalent in patients of European descent.[2] Although the rates of sarcoidosis are low in Japan, when sarcoidosis is present, CS is a common manifestation. Autopsy and imaging studies in Japan reveal a prevalence of CS approaching 50%.[13] Patients with sarcoidosis from Japan also have a higher incidence of cardiac death than similar patients from other countries.[13]

Pathophysiology

The natural course of sarcoidosis and CS is unpredictable. Patients demonstrate variable inflammatory responses. Some patients respond with minimal local inflammation, while others respond with extensive inflammation and fibrosis. Sarcoidosis is characterized by significant activation of macrophages and CD4+ T cells. This activation increases the production of tumor necrosis factor-alpha (TNF-α), interferon-gamma (IFN-γ), and the expression of the amyloid A protein.[2] The signature lesions of CS are noncaseating granulomas, particularly within the interventricular septum and inferior left ventricle. While granulomas can be found in epicardial, myocardial, and endocardial tissue, the subepicardium and myocardium are most commonly involved, while the endocardium is typically spared.[5][14] 

Granulomatous involvement of the interventricular septum explains the propensity for conduction system abnormalities. These dysrhythmias include varying degrees of AV block, bundle branch blocks, ventricular arrhythmias, and supraventricular arrhythmias, of which atrial fibrillation is most common. Sarcoid granulomas may involve the left ventricle and cause dilated cardiomyopathy, mitral valve dysfunction, papillary muscle involvement, and left ventricular aneurysms.[2] 

Most patients with CS have a reduced ejection fraction, but clinical heart failure is uncommon. In patients with known CS, the 10-year incidence of clinically evident heart failure is 3%; this is twice that of the general population.[5] Right ventricular dysfunction in patients with sarcoidosis is usually a consequence of pulmonary fibrosis, pulmonary hypertension, or left ventricular dysfunction causing right heart failure; granulomatous infiltration of the right ventricle does occur.[2][15]

Isolated Cardiac Sarcoidosis Versus Systemic Sarcoidosis With Cardiac Manifestations

There is evidence that isolated CS, defined as cardiac involvement without systemic signs of sarcoidosis, may confer a different clinical picture and prognosis than systemic sarcoidosis with cardiac involvement. Autopsy and imaging studies estimate that 25% of patients with evidence of CS have isolated CS. Many studies have shown that patients with isolated CS have worse prognoses than patients with systemic sarcoidosis and cardiac involvement. Patients with isolated CS typically present with worse left ventricular function and higher rates of ventricular arrhythmia. However, it is unclear whether these findings relate to the disease process or delayed diagnosis due to a lack of systemic manifestations.[1]

Histopathology

The heart is the third-most common site of involvement in systemic sarcoidosis following the lungs and lymph nodes. The gross pathological examination of autopsy specimens of patients with CS typically reveals patchy myocardial fibrosis inconsistent with a specific coronary artery distribution.[14] Cardiac granulomas grossly appear as tan, yellow, or brown nodular masses, measure a few millimeters in greatest diameter, and have well-defined margins. Pericardial and endocardial granulomas appear to be an extension of myocardial involvement.

Noncaseating granulomas are the characteristic histopathological finding of endomyocardial CS. Sarcoid granulomas can be differentiated from other granulomas due to their compact appearance, epithelioid cell abundance, confluent fibrosis, and fatty infiltration.[16][17] The granulomas comprise macrophages, epithelial cells, and T lymphocytes.[2] Multinucleated giant cells cluster peripherally in a linear fashion and may have cytoplasmic inclusions such as Schaumann or asteroid bodies.[17]

History and Physical

History

The most common presenting symptoms of CS include palpitations, presyncope, and syncope related to various arrhythmias, including AV blocks, atrial fibrillation, or other supraventricular and ventricular tachycardia.[2][18][19][2] Presyncope and syncope may be indicative of underlying life-threatening arrhythmias, such as high-grade AV block or ventricular tachycardia, which can precipitate sudden cardiac death.[5][20] One small study found AV block as the first manifestation of CS in more than 40% of patients; the second-most common presenting symptom in this study of patients with CS was ventricular tachycardia (28%).[21] Alternatively, arrhythmias can lead to more subtle, chronic symptoms of fatigue, exertional dyspnea, and chest discomfort.[22] The predominant symptomatology of patients with right ventricular dysfunction due to left ventricular dysfunction or pulmonary hypertension from pulmonary sarcoidosis may be dyspnea and lower extremity edema.

Patients may present with heart failure symptoms such as exertional dyspnea, orthopnea, or paroxysmal nocturnal dyspnea due to dilated or restrictive cardiomyopathy. Patients can also present with respiratory symptoms due to concomitant pulmonary sarcoidosis. Sarcoidosis can also cause coronary vasculitis, and patients may present with symptoms of myocardial ischemia. 

Physical Examination

The physical examination of a patient may reveal tachycardia, bradycardia, an irregular pulse, pedal edema, or jugular venous distention. A loud second heart sound may indicate pulmonary hypertension. A third or fourth heart sound can indicate left ventricular dysfunction. Systolic or diastolic murmurs at the apex are common in mitral valve involvement.[23]

Sarcoidosis usually involves multiple organ systems. Pulmonary symptoms are present in 90% of patients; cutaneous, ocular, and neurological manifestations are also common. Erythema nodosum, lupus pernio, uveitis, cranial nerve palsies, or seizures may be indicative of systemic sarcoidosis.[24]

Evaluation

The diagnosis of CS can be histological or clinical. A definite diagnosis of CS can be made with histological evidence of myocardial noncaseating granulomas in tissue obtained via endomyocardial biopsy in the absence of another identified noncaseating granulomatous disease. However, endomyocardial biopsy has a 25% to 36% sensitivity for CS due to patchy involvement of the myocardium. The diagnostic sensitivity of endomyocardial biopsy can be increased to approximately 50% using electrophysiologic mapping.[2]

Electrocardiography

Electrocardiography (ECG) can identify rhythm abnormalities. However, when patients present with palpitations as the only symptoms, ambulatory rhythm monitoring is superior at identifying transient AV blocks and ventricular tachycardia. The diagnostic yield can be low; less than 10% of patients with asymptomatic CS have an abnormal ECG.[2][25]

Echocardiography 

Echocardiography in patients with CS may reveal thinning of the basal septum, akinetic and dyskinetic regional wall motion abnormalities not in a coronary artery distribution, left ventricular systolic dysfunction, and left ventricular dilation with or without aneurysm.[26] However, echocardiography is an insensitive tool to detect the early stages of the disease, and patients with cardiac sarcoidosis can have a normal echocardiogram. 

Cardiac Magnetic Resonance Imaging

Cardiac magnetic resonance imaging (CMR) provides valuable information about structural cardiac abnormalities. Wall thinning, aneurysms, and chamber dilation are commonly seen in patients with CS.[2] Barring contraindications, gadolinium administration is recommended. Late gadolinium enhancement is a critical diagnostic tool in patients with CS that usually indicates myocardial fibrosis but can also indicate edema. Enhancement is primarily seen in the midseptum and left ventricular subepicardium and myocardium, but not the endocardium. Late gadolinium enhancement is an especially poor prognostic indicator.[2] The sensitivity of CMR for detecting CS is 75% to 100%, and the specificity is 76% to 100%.[27]

Fluorodeoxyglucose F 18 Positron Emission Tomography

Fluorodeoxyglucose F 18 positron emission tomography (FDG-PET) is a functional study employing labeled FDG as a surrogate for glucose. Inflammatory cells have a very high metabolic rate; a positive FDG-PET correlates with inflammation. However, myocardial glucose uptake must be suppressed to highlight the inflammatory cells.[28] Suppression is achieved by fasting before the test, consuming a low-carbohydrate and high-fat diet the day before the fast, avoiding exercise during the fast, an altered insulin regimen for people with diabetes the day before the test, and avoiding peritoneal dialysis the day before the test.[29] 

FDG-PET is staged with cardiac and whole-body imaging and may identify high-yield biopsy sites with active inflammation. FDG uptake in CS can be focal, diffuse, or patchy, and with or without perfusion abnormalities, depending on whether there is inflammation or scar formation. FDG uptake can be decreased in coronary artery disease or ischemia. The sensitivity of FDG-PET is estimated at 89% and specificity at 78%.[28] 

FDG-PET and CMR are often used in combination to add valuable information about active inflammation, extracardiac involvement, and cardiac structural details.[30] These tests can be used individually or together to assess the effectiveness of therapeutic interventions.

Endomyocardial Biopsy

Biopsy showing noncaseating granulomas is the only definitive way to diagnose CS, but the diagnostic yield is low at 25% to 36% due to the patchy and focal nature of the disease. In patients with extracardiac manifestations of sarcoidosis, an extracardiac biopsy site is preferred due to a higher diagnostic yield and lower rate of complications. If an endomyocardial biopsy is required, FDG-PET or CMR may identify a suitable biopsy site; patients undergoing an electrophysiologic study should be mapped to increase the diagnostic yield of an endomyocardial biopsy. In cases of isolated CS or when an extracardiac biopsy site is nondiagnostic, endomyocardial biopsy may be required to confirm a diagnosis of CS.[2]

Treatment / Management

The management of CS aims to slow disease progression, reduce the risk of sudden cardiac death, treat heart failure, and manage arrhythmias. 

Immunosuppressive Therapy

Immunosuppressive therapy is recommended for patients with CS with evidence of cardiac involvement, such as heart block, ventricular arrhythmias, or heart failure, and evidence of active inflammation on histological examination or FDG-PET. The initial therapeutic intervention for CS is immunosuppression with corticosteroids to reduce inflammation and fibrosis; randomized control trials investigating the efficacy of corticosteroids have not been performed.[25] Corticosteroids have been reported to reduce the burden of ventricular tachycardia, reverse AV block, and improve LVEF.[31] The goal of corticosteroid immunosuppression is early initiation of therapy before the LVEF decreases and to reduce corticosteroid exposure. 

A Finnish study of 110 patients, 93% of whom received immunosuppressive therapy, revealed that cardiac transplant-free survival at 1, 5, and 10 years was 97%, 90%, and 83%, respectively.[32] FDG-PET is employed to assess the response to immunosuppression 3 months after initiating therapy. If FDG-PET performed after 3 months of treatment reveals reduced uptake, the corticosteroids may be tapered to complete a 12-month course of therapy. The Cardiac Sarcoidosis Multi-Center Randomized Controlled Trial (CHASM CS-RCT) is currently being conducted to compare methotrexate with standard- and low-dose prednisone for the initial treatment of CS.(B2)

Corticosteroid-sparing agents are regularly used in conjunction with corticosteroids to minimize steroid exposure. While no consensus guidelines exist, many clinicians use methotrexate or mycophenolate mofetil with steroids or in patients who appear to be steroid-resistant. Other therapeutic agents used include azathioprine, cyclophosphamide, and leflunomide.[5] Immunologic therapies such as infliximab, adalimumab, and rituximab are considered third- or fourth-line agents in treating CS because of potential complications. (B3)

Managing Dysrhythmias in Cardiac Sarcoidosis

When managing conduction abnormalities in patients with CS, it is recommended to follow the 2012 ACCF/AHA/HRS Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities. Pacemaker implantation may be helpful in patients with CS and a reversible conduction block. An implantable cardioverter-defibrillator (ICD) may be an option for those requiring permanent pacing. The guidelines suggest immunosuppression can be useful in patients with CS and Mobitz type II or third-degree AV block.[33](B3)

Anticoagulation is recommended for patients with CS and atrial fibrillation, as guided by the CHA₂DS₂-VASc score. A therapeutic electrophysiology study may be performed in patients with CS and atrial arrhythmias, except for atrial fibrillation. Class I antiarrhythmic medications carry a class III indication in patients with CS and arrhythmias.[33](B3)

The consensus guidelines suggest that an FDG-PET is useful for identifying inflamed myocardium in patients with CS. Furthermore, immunosuppressive therapy can be useful in CS patients with unustained ventricular ectopy or sustained ventricular arrhythmias. Antiarrhythmic medications and catheter ablation are recommended for ventricular tachycardia unresponsive to immunosuppression. The initial therapeutic strategy for patients with CS and ventricular tachycardia is corticosteroids and amiodarone; catheter ablation is reserved for patients refractory to medical therapy.[33] (B3)

An ICD is recommended for patients with CS and a spontaneous sustained ventricular arrhythmia that includes prior cardiac arrest or those with LVEF less than 35% despite medical therapy and immunosuppression. ICD therapy is useful in patients with CS with a pacer indication, unexplained syncope or presyncope of likely arrhythmic etiology, or inducible sustained ventricular arrhythmia. ICD therapy may be considered in patients with LVEF of 36% to 49% and RV ejection fraction less than 40% on optimal medical therapy and immunosuppression. ICD therapy is not recommended in patients with incessant ventricular arrhythmias or New York Heart Association class IV heart failure. Additionally, ICD therapy is not indicated in patients with no history of arrhythmia or syncope, no pacing indication, normal LV/RV function, absent late gadolinium enhancement during CMR, or a negative electrophysiologic study.[33](B3)

Differential Diagnosis

Cardiac sarcoidosis is a challenging diagnosis. Myocarditis can be especially difficult to distinguish from cardiac sarcoidosis due to similar clinical presentations, including ventricular arrhythmias, heart failure, late gadolinium enhancement on CMR, and abnormal uptake on FDG-PET. Viral myocarditis may or may not be preceded by a viral prodrome, and giant cell myocarditis usually has a more fulminant course.[34] An endomyocardial biopsy may be needed to distinguish these from sarcoidosis.

Cardiomyopathies, particularly arrhythmogenic right ventricular cardiomyopathy (ARVC), is another condition that can present with findings very similar to CS.[35] Ventricular arrhythmias are common in both conditions; AV block and heart failure symptoms are more common in CS.[35][36] Ventricular septal late gadolinium enhancement is usually absent in patients with ARVC, while intramyocardial fat infiltration is more likely.[37] Extracardiac manifestations consistent with sarcoidosis are also more likely to favor CS.

Late gadolinium enhancement on CMR is observed in many pathologic conditions, including myocardial infarction, cardiac amyloidosis, hypertrophic cardiomyopathy, Fabry disease, and hereditary hemochromatosis. An enhancement pattern within the distribution of coronary artery supply can help distinguish CS from scarring secondary to prior myocardial infarction and CS. Hereditary hemochromatosis can present with arrhythmias and heart failure but is associated with skin hyperpigmentation, diabetes, and evidence of reduced T2-weighted times on CMR.[38]

The myocardial granulomas characteristic of CS can also be seen in tuberculosis, fungal infections, systemic vasculitis, and immunodeficiencies.[39] However, these conditions have significantly different clinical presentations, which can be differentiated by historical and physical examination findings in addition to diagnostic testing.

Prognosis

Patients with systemic sarcoidosis and CS have a worse prognosis than patients with extrapulmonary sarcoidosis without cardiac involvement. A history of sustained ventricular tachycardia, an increased left ventricular end-diastolic diameter, and an increased NYHA class are independent predictors of mortality in patients with CS.[32] Heart failure as a clinical manifestation and reduced LVEF carry an especially poor prognosis with a reported 10-year survival of 19 % to 53% in the absence of cardiac transplant.[40]

Cardiac sarcoidosis carries a poor prognosis compared to other forms of sarcoidosis.[18] It is unclear whether silent CS has a better prognosis than CS with clinical manifestations. However, patients with asymptomatic CS and a benign course might initially present with sudden cardiac arrest. Patients with CS and evidence of late gadolinium enhancement on CMR or abnormal uptake and perfusion defects on FDG-PET have an increased risk of VT and cardiovascular death.[41] 

Right ventricular dysfunction and RV late gadolinium enhancement may also have prognostic implications. Among 260 biopsy-proven patients with CS, RV systolic function was independently associated with all-cause mortality. In contrast, right ventricular late gadolinium enhancement was associated with sudden cardiac death and ventricular arrhythmia.[42] 

Complications

If untreated, CS usually leads to dilated cardiomyopathy and an increased risk of ventricular arrhythmias. Untreated or refractory pulmonary sarcoidosis that progresses to pulmonary fibrosis can lead to right heart failure.[15][2] Sudden cardiac death is the most feared complication of CS, warranting risk stratification and evaluation for an ICD.[20]

The following complications are also commonly encountered in patients with CS:

• Left and right heart failure
• Cardiomyopathy with or without heart failure
• Ventricular arrhythmia
• Bradyarrhythmias, such as variable degrees of atrioventricular block, including third-degree heart block
• Sudden cardiac death
• Atrial tachycardia, including atrial fibrillation
• Pulmonary hypertension with subsequent right heart failure
• Coronary vasculitis and myocardial ischemia.