Continuing Education Activity

Cardiac sarcoidosis (CS) is infiltrative cardiomyopathy that results from granulomatous inflammation affecting the heart. It is a rare condition with a poor prognosis. Given the high morbidity and mortality associated with this condition, it would help to diagnose and treat patients diagnosed with the same promptly. This activity reviews the evaluation and management of CS and highlights the need for an inter-professional team to evaluate and manage patients with this condition.

Objectives:

• Outline the clinical manifestations of cardiac sarcoidosis.
• Describe the diagnostic criteria, typical histopathological and imaging findings for cardiac sarcoidosis.
• Summarize the management strategies for cardiac sarcoidosis.
• Explain the need for an interprofessional team’s approach for managing patients with cardiac sarcoidosis.

Introduction

Sarcoidosis is a multisystem granulomatous disorder usually involving the lungs, and cardiac sarcoidosis (CS) is the presentation of sarcoidosis involving the heart. It is thought to be a rare form of sarcoidosis reported in less than 10% of patients with sarcoidosis. The granulomatous inflammation affects the heart to cause infiltrative cardiomyopathy either in isolation or as part of systemic sarcoidosis.[1] 

The most common clinical manifestations are conduction system disorders and heart failure.[2] Sudden cardiac death is also a known manifestation of the disease.[3] CS largely occurs with evidence of extra-cardiac manifestations and has been associated with ocular, neurological, and cutaneous sarcoid.[4] However, about one-third of patients can have isolated CS.[5]

The most common manifestations of cardiac sarcoidosis are in the form of atrioventricular (AV) block and ventricular tachyarrhythmia (VT).[6][7] AV block as the first manifestation of CS has been found in greater than 30% of patients.[8] VT is the second most common conduction abnormality due to reentrant activity and increased automaticity associated with granuloma scars.[9] Sudden cardiac death from CS is also thought to be from conduction system disease either from high-grade AV block or VT.

Etiology

Although certain associations have been observed, there is no clearly defined etiology for sarcoidosis. Studies suggest that sarcoidosis may be more common in agricultural workers and firefighters, in those with occupational exposure to insecticides and microbial bioaerosols in mold, and following exposure to Chlamydia pneumoniae.[10][11] 

Cigarette smoking was found to be less commonly associated with sarcoidosis when compared to controls.[10] Studies show familial clustering of sarcoidosis and increased incidence in monozygotic twins, suggesting a possible genetic preponderance.[12] 

For cardiac sarcoidosis specifically, there have been reports of recurrence of cardiac sarcoid following heart-lung transplant and evidence of sarcoidosis in a non-sarcoid recipient of a heart transplant from a donor with sarcoidosis.[13] It is hypothesized that this may mean sarcoidosis is secondary to an immunological or infectious process.[12]

Epidemiology

Cardiac sarcoidosis has been reported in less than 10% of patients diagnosed with sarcoidosis. However, in patients with extracardiac sarcoidosis, cardiac magnetic resonance imaging (CMR) and autopsy studies have detected evidence of cardiac involvement in up to 26% of patients that remained asymptomatic.[14] In the United States, the mean age of CS is 53 years, and it is more common in females (58%).[15] 

The prevalence of CS is higher in African Americans (35.5 per 100,000) than whites (10.9 per 100,000). Cardiac sarcoidosis is more common in Japan, with autopsy studies showing a higher prevalence of myocardial sarcoidosis and a higher incidence of death from myocardial sarcoidosis in Japanese patients than whites and African Americans.[16]

Pathophysiology

Cardiac sarcoidosis can involve pericardial, myocardial, and endocardial tissue, although it most commonly involves the myocardium.[17] Sarcoid granulomas tend to involve the base of the interventricular septum, which explains the predilection for conduction system disease. 

The most common manifestations include AV blocks followed by ventricular arrhythmias, bundle branch blocks, and supraventricular arrhythmias, of which atrial fibrillation is most common. Besides the intraventricular septum, sarcoid granulomas can involve the left ventricle and cause dilated cardiomyopathy, mitral valve dysfunction, papillary muscle involvement, and left ventricular aneurysm. Extensive involvement of the myocardium usually results in restrictive cardiomyopathy leading to left ventricular dysfunction in up to 80% of cases. Still, clinical heart failure is seen in less than 30% of cases. 

Right ventricular involvement in sarcoidosis is usually a consequence of pulmonary fibrosis, pulmonary hypertension, or left ventricular dysfunction causing right heart failure but can also be from granulomatous infiltration of the right ventricle.[18][19]

Histopathology

On pathological examination of autopsy specimens of cardiac sarcoidosis patients, gross findings include patchy fibrosis of myocardial tissue not consistent with ischemia from coronary artery disease.[17] 

The main histopathological finding that favors a diagnosis of CS on endomyocardial biopsy is noncaseating granulomas. Sarcoid granulomas measure in the range of a few millimeters and have well-defined margins. They are composed of macrophages, epithelial cells, and T lymphocytes.[19]

Other microscopic findings that have been noted include micro-granulomas, confluent fibrosis, and fatty infiltration.[20]

History and Physical

The most common presenting symptoms for cardiac sarcoidosis include palpitations, pre-syncope, and syncope. Palpitations could be due to a number of conduction disorders, including AV blocks, atrial fibrillation, or other supraventricular tachycardias.[19] Pre-syncope and syncope could indicate either high-grade AV block or VT, which can also lead to sudden cardiac death.[21] 

An autopsy study in Finland showed that sudden cardiac death was the first manifestation of CS in 14% of patients and that undiagnosed CS made up for 64% of sudden cardiac deaths. AV blocks can also lead to more chronic symptoms of fatigue, exertional dyspnea, and chest discomfort.[22] Patients with right ventricular dysfunction due to either left ventricular dysfunction or pulmonary hypertension from pulmonary sarcoid can have dyspnea and lower extremity edema as the main symptoms.

Physical examination findings can include bradycardia, and irregular rhythm can suggest AV block and atrial fibrillation. In addition, a third or fourth heart sound can indicate left ventricular dysfunction, systolic or diastolic murmurs at the apex can be found in mitral valve involvement, and a loud second heart sound can occur in pulmonary hypertension.[23]

Sarcoidosis involving other organ systems, typically cutaneous, ocular, and neurological disease, or family history of sarcoidosis can help diagnose CS in patients with concerning symptoms. Other organ involvement from sarcoidosis can include skin findings like erythema nodosum or lupus pernio, ocular findings like uveitis, neurological findings like cranial nerve palsies or seizures, and/or pulmonary findings like hilar lymphadenopathy or parenchymal lung disease.[24]

Evaluation

The evaluation of cardiac sarcoidosis is two-pronged: histological and clinical. According to the 2014 Heart Rhythm Society (HRS) expert consensus statement, histological diagnosis can be made by the presence of non-caseating granulomas in the myocardium following endomyocardial biopsy. However, it is important to note that endomyocardial biopsy has a low sensitivity (25 to 36%) due to patchy involvement of the myocardium. The diagnostic sensitivity can be increased to about 50% using electrophysiology study, FDG-PET, or CMR-guided endomyocardial biopsy.[19]

As a result, the consensus statement developed criteria for the probable diagnosis of CS, which can be made with a combination of histological identification of sarcoid from an extracardiac organ, exclusion of other diagnoses, and presence of at least one of the following:[25]

1. Left ventricular systolic dysfunction (ejection fraction less than 40%), not explained by any other etiology.
2. Sustained VT, not explained by any other etiology
3. Mobitz Type II second-degree AV block or complete heart block
4. Fluorodeoxyglucose-positron emission tomography (FDG-PET) (dedicated sarcoid protocol) showing patchy uptake consistent with CS.
5. CMR showing late gadolinium enhancement (LGE) consistent with CS.
6. Gallium scintigraphy showing positive gallium uptake consistent with CS

Electrocardiograms can help identify rhythm abnormalities, and when patients present with palpitations as the only symptoms, ambulatory rhythm monitoring can help identify transient AV blocks and nonsustained VT.[26] Similarly, echocardiography does not show findings sensitive or specific for CS.[27] On echocardiography, there can be thinning of the basal septum, regional wall motion abnormalities that are often not in a coronary distribution, left ventricular systolic dysfunction and left ventricular dilation with or without aneurysm.[28]

Currently, CMR is recommended as the first-line imaging study to diagnose CS, given that it has a high negative predictive value; however, recent studies recommend the addition of FDG-PET to assist in the diagnosis of CS. The pattern that favors a diagnosis of CS on CMR is usually patchy LGE in a distribution not consistent with infarct from coronary distribution. There is also a tendency for LGE to preferentially affect the basal septal wall and cause thinning of the septum and spare the endocardial border, with transmural scar being very uncommon.[29] 

Another finding very suggestive of CS on CMR is the hook sign where LGE of the anterior and inferior septum can involve right ventricular insertion points.[30] T2 mapping on CMR can sometimes show evidence of edema in this distribution even before there is evidence of LGE. The sensitivity of CMR for detecting CS is in the range of 75 to 100%, and the specificity is 76 to 100%.[31] 

FDG-PET can add valuable information in the diagnosis of CS, such as evidence of active inflammation and extracardiac involvement.[32] FDG uptake in CS can be focal, diffuse, or patchy with or without perfusion abnormalities, depending on whether there is inflammation with or without scar formation.[33]

The sensitivity of FDG-PET is estimated at 89%, and the specificity is 78%. FDG-PET diagnosis of sarcoid requires suppressing myocardial glucose uptake to promote uptake of FDG by inflammatory cells.[33][34] This is achieved by measures including fasting before the test, low carbohydrate and high-fat diet the day prior to the fast, avoiding exercise during the fast, altered insulin regimen for people with diabetes the day before the test, avoidance of peritoneal dialysis a few days prior to the test and administration of heparin before FDG.

Treatment / Management

First-line management of cardiac sarcoidosis is immunosuppression with corticosteroids with the goal of reducing inflammation and fibrosis, thereby preventing disease progression.[27] Steroids have been reported to reduce the burden of VT, reverse AV block, and improve left ventricular ejection fraction.[35] 

A Finnish nationwide study on 110 patients, of whom 93% received immunosuppressive therapy, showed that cardiac transplant-free survival at 1, 5, and 10 years was 97%, 90%, and 83%, respectively.[36]

FDG-PET is used to follow response to immunosuppression after three months of starting therapy. If patients show reduced uptake on FDG-PET after three months, they can be put on a steroid taper to complete a total of 12 months. If there is evidence of active disease after the initial three months of steroids, second-line agents can be tried, including methotrexate, mycophenolate mofetil, cyclophosphamide, azathioprine, infliximab, and adalimumab. FDG-PET should be repeated three months after stopping therapy to determine if steroids need to be resumed for relapse. In the absence of evidence of relapse on FDG-PET after three months of steroids, patients should undergo surveillance echocardiogram and electrocardiogram every six months to follow left ventricular ejection fraction and conduction system disease, respectively.

The HRS consensus statement recommends using antiarrhythmic medications and catheter ablation for VT that does not respond to immunosuppression. First-line management for VT storm in CS is a combination of steroids and amiodarone, with catheter ablation reserved for patients refractory to medical therapy. 

Implantable cardioverter-defibrillator is recommended for CS patients with a history of sustained VT or inducible sustained VT on electrophysiology study, cardiac arrest, left ventricular ejection fraction less than 35% despite immunosuppression, history of syncope thought to be from CS, and/or right ventricular ejection fraction less than 40% with evidence of active inflammation. In addition, if patients meet indications for permanent pacemaker implantation, the HRS recommends implantation of an implantable cardioverter-defibrillator instead.[25]

Differential Diagnosis

Myocarditis can be hard to distinguish from cardiac sarcoidosis due to similar clinical presentation, including ventricular arrhythmias, heart failure, presence of LGE 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.[37] Endomyocardial biopsy may be needed to distinguish these from sarcoidosis.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is another condition that can present with findings very similar to CS.[38] Ventricular arrhythmias are common in both conditions; however, AV block and heart failure symptoms are more common in CS.[38][39] 

LGE in the ventricular septum is usually absent in ARVC, and intramyocardial fat infiltration is more likely in ARVC.[40] Extracardiac manifestations consistent with sarcoidosis are also more likely to favor CS.

The presence of LGE on CMR can be found in a multitude of other conditions, including prior myocardial infarction, cardiac amyloidosis, hypertrophic cardiomyopathy, Fabry disease, and hereditary hemochromatosis. A pattern of distribution of LGE that appears to correlate with coronary artery supply can help distinguish scar from prior myocardial infarction and CS. Similarly, hereditary hemochromatosis can present with arrhythmias and heart failure but is associated with skin hyperpigmentation and diabetes, and there is evidence of reduced T2* times on CMR.[41]

Histologically, granulomas seen on endomyocardial biopsy can also be seen in tuberculosis, fungal infections, systemic vasculitis, and immunodeficiencies.[42] However, these conditions have significantly different clinical presentations and imaging findings, which is where taking a detailed clinical history would help rule out these conditions.

Prognosis

Cardiac sarcoidosis carries a poor prognosis compared to other forms of sarcoidosis.[6] It is unclear whether silent CS without cardiac manifestations has a better prognosis than clinically manifest CS. Heart failure as a clinical manifestation and reduced left ventricular ejection fraction on cardiac imaging carry the worst prognosis with a reported 10-year survival of 19 to 53% in the absence of cardiac transplant.[43] 

cardiac sarcoidosis patients with evidence of LGE on CMR also have an increased risk of VT and cardiovascular death.[44] Similarly, abnormal uptake and perfusion defects on FDG-PET are associated with an increased risk of VT and death.

Complications

If untreated, cardiac sarcoidosis usually leads to dilated cardiomyopathy and an increased risk of ventricular arrhythmias. In addition, untreated or refractory pulmonary sarcoidosis that progresses to pulmonary fibrosis can lead to right heart failure.[18][19]

Sudden cardiac death is the most feared complication of CS, which is why patients at high risk for the same should undergo evaluation for an implantable cardioverter-defibrillator.[21]

Deterrence and Patient Education

Cardiac sarcoidosis carries a poor prognosis and is associated with a significant risk of sudden cardiac death. Patients with a diagnosis of sarcoidosis should be made aware of the possibility of cardiac involvement and symptoms that should prompt evaluation for the same. Patients with this condition need to initiate immunosuppression promptly to decrease the progression of the disease process in the heart.

Enhancing Healthcare Team Outcomes

Cardiac sarcoidosis can be best dealt with using an interprofessional approach to enhance the chances of diagnosing CS and help recognize the coexistence of extra-cardiac manifestations. Cardiac sarcoidosis can be a frequently missed diagnosis given its rarity and the high index of suspicion needed to make the diagnosis. Even amongst specialists, the combined effort of advanced imaging specialists, electrophysiologists, and interventional cardiologists is often required to arrive at the diagnosis of CS. 

Early diagnosis and initiation of immunosuppression hold a clear benefit in reducing disease progression.[35] This is why managing CS should be holistic, with care coordination between primary care clinicians, cardiologists, pulmonologists, and immunologists to oversee immunosuppressive therapy. Electrophysiology support early on can help risk-stratify patients who would need device implantation to prevent sudden cardiac death. It would also enhance patient care to involve advanced heart failure specialists for CS patients with heart failure and identify those who may benefit from referral for advanced heart failure therapies, given its poor prognosis.[36]