1. Definition and Prevalence

Sarcoidosis is a multisystemic non-caseating granulomatous disease of uncertain etiology, most frequently involving lung (>90%). Sarcoidosis is a chronic progressive disorder, although acute presentation can occur in rare cases. The prevalence of sarcoidosis is about 4.7 to 64 in 100,000, and it usually occurs in patients between 25 and 60 years of age. Clinically apparent cardiac sarcoidosis occurs in approximately 5~10% of patients with systemic sarcoidosis. The prevalence of clinically silent cardiac involvement, on the basis of autopsy studies, is estimated to be at least 25% of patients with systemic sarcoidosis. Recent studies suggest that the prevalence of cardiac sarcoidosis is increasing over time, probably due to the improvements in imaging and diagnosis.

2. Diagnosis of Cardiac Sarcoidosis

2.1. Biopsy

Cardiac sarcoidosis can be diagnosed directly by demonstrating non-caseating granuloma on endomyocardial biopsy (Figure 1). However, due to the focal nature of disease, the diagnostic yield of endomyocardial biopsy has been reported to be less than 25% in patients with cardiac sarcoidosis. Thus, in patients with extra-cardiac sarcoidosis, biopsy of lymph node or lung is typically targeted first, which has virtues of lower procedural risk as well as higher diagnostic yield. On the other hand, imaging-guided or electro-anatomic mapping-guided biopsy procedures are increasingly recommended based on recent studies demonstrating that these techniques have improved diagnostic yield to up to 50%.

Figure 1. Histology showing non-caseating granulomas, which is the pathological hallmark of cardiac sarcoidosis.

2.2. Electrocardiogram

Patients with clinically apparent cardiac sarcoidosis often have abnormal findings on electrocardiogram (ECG). Although many ECG findings are non-specific, we should pay attention to the presence of various degrees of conduction abnormalities, including atrio-ventricular block, bundle branch block, and fascicular block (Figure 2). Patients with cardiac sarcoidosis may also experience ventricular arrhythmias. Contrary to clinically apparent cardiac sarcoidosis, abnormal ECG findings are presented in only a small portion of patients with clinically silent cardiac sarcoidosis (between 3.2% and 8.6%). Screening for cardiac sarcoidosis with a Holter monitoring can be useful to detect heart rhythm abnormalities which are not apparent with standard ECG.

Figure 2. ECG demonstrating trifascicular block consisting of right bundle branch, left anterior fascicular block, and first degree atrioventricular block. Trifascicular block, usually heralding complete atrioventricular block, is an important electrocardiographic finding that should raise the suspicion of cardiac sarcoidosis, on the basis of clinical impression.

2.3. Echocardiography

Similar to ECG, patients with clinically apparent cardiac sarcoidosis often have abnormal findings on echocardiography, while those with clinically silent disease usually have normal echocardiographic findings. Although echocardiographic abnormalities are frequently nonspecific, the classic feature of cardiac sarcoidosis is multiple regional wall motion abnormalities (RWMAs) which are not corresponding to the coronary artery territories. In rare cases, there may be an increase in left ventricular (LV) wall thickness mimicking hypertrophic cardiomyopathy or a predominantly right ventricular (RV) involvement masquerading arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Other abnormalities include basal inter-ventricular thinning (Figure 3), systolic and diastolic dysfunction of LV and/or RV, and aneurysmal changes in the myocardium.

Figure 3. Echocardiography revealing a marked thinning of basal inter-ventricular septum in a patient diagnosed with cardiac sarcoidosis.

2.4. Cardiac Magnetic Resonance Imaging

The two most useful cardiac magnetic resonance imaging (CMR) techniques are cine-CMR and late-gadolinium enhancement (LGE)-CMR. Cine-CMR is a powerful method for assessing regional wall motion with high imaging quality, enabling detection of subtle abnormalities that could be missed by other imaging modalities, such as echocardiography. LGE-CMR can provide scar tissue characterization of myocardium; non-ischemic pattern of LGE is useful for the diagnosis of cardiac sarcoidosis (Figure X). Importantly, LGE can be observed in myocardial segments with no evidence of RWMAs or systolic dysfunction, suggesting the advantage of LGE-CMR in terms of sensitivity compared to echocardiography which is insensitive for detecting early stages of cardiac sarcoidosis. Hence, CMR is increasingly used for the diagnosis of clinically silent cardiac sarcoidosis, in view of its ability to detect small amount of myocardial involvement. However, although the pattern of LGE is usually patchy and multifocal, with endocardial sparing (Figure 4), no specific LGE pattern is diagnostic for cardiac sarcoidosis. For example, LGE is seen most frequently in basal septal and lateral segments, but it can be observed in the RV free wall in some cases. Furthermore, transmural LGE may occur in patients with cardiac sarcoidosis, although the involvement of epi- and mid-myocardium, the so-called endocardial sparing pattern is a common CMR finding in this population.

Figure 4. LGE-CMR depicting epicardial and mid-myocardial enhancement of the inter-ventricular septum and anterior wall.

Other CMR techniques have gained growing attention as a useful tool to assess cardiac sarcoidosis over the past few years. Specifically, T2-weighted images and T1 mapping may allow identification of active inflammation/myocardial edema and quantification myocardial fibrosis, respectively, but poses several technical challenges. Concurrent imaging of the 2 phages of cardiac sarcoidosis, consisting of inflammation and fibrosis, can be obtained by positron emission tomography (PET)/CMR fusion images.

2.5. 18Fluoro-2-deoxyglucose positron emission tomography (FDG-PET)

18F-Fluorodeoxyglucose (FDG) is a glucose analogue that is useful for differentiating normal from diseased myocardium having abnormal glucose utilization, such as inflammatory, ischemic, or neoplastic conditions. Given that FDG-PET can identify the lesions infiltrated by activated macrophages having a higher glucose utilization rate, the presence of multiple patchy uptakes of FDG suggests multifocal myocarditis, particularly when alternative diagnosis, such as multiple areas of ischemia or multiple metastatic tumors, can be excluded. Three patterns of FDG-PET uptake, including diffuse, focal, and focal on diffuse uptakes, are regarded as typical for cardiac sarcoidosis. However, the major hurdles for the clinical application of PET for cardiac sarcoidosis is the difficulties in obtaining optimal FDE-PET images with adequate suppression of physiologic FDG uptake in normal myocardium. For the purpose of suppressing physiologic myocardial glucose uptake, 3 approaches are currently used: 1) prolonged fasting, shifting substrate use from glucose to free fatty acids (FFA), 2) low-carbohydrate/high-fat diets, and 3) heparin loading, producing a milieu of high level of FFA.

Figure 5. FDG-PET showing the focal on diffuse uptake pattern, which can support the diagnosis of cardiac sarcoidosis.

FDG-PET offers another important advantage; it enables the detection of reversible stages of cardiac sarcoidosis and thus the assessment of the response to steroids. However, the effect of steroid on false-positive FDG-PET scans should be considered in the interpretation of the results, because steroid can affect glucose metabolism by increasing the rate of hepatic formation of glucose and glycogen.

3. Treatment

3.1. Immunosuppression

Despite the paucity of data, steroid is recommended as the mainstay in the treatment of cardiac sarcoidosis. According to one systemic review of steroid in the treatment of cardiac sarcoidosis, the quality of all publications was poor to fair and there were no randomized trials. The best quality data were those on AV conduction recovery; steroid appeared to have beneficial effects on this complication in cardiac sarcoidosis. However, it is not possible to draw any conclusion regarding the benefits of steroid treatment on other outcomes of cardiac sarcoidosis, such as LV function, ventricular arrhythmia, and mortality, due to the limited quality of data.
The optimal dosage of steroid for cardiac sarcoidosis is still unclear. High-dose prednisolone treatment (1 mg/kg daily) has been advocated as an initial therapy for cardiac sarcoidosis for the sake of minimizing the treatment failure. However, one study suggests that a high initial dose of steroid might not be essential for the treatment of cardiac sarcoidosis, by showing no significant difference in the overall survival of patients treated with a high initial dose of prednisone (>40 mg daily) compared with those treated with a low initial dose (<30 mg daily). In this regard, most experts recommend an initial dose of 30 to 40 mg/day, followed by a maintenance treatment with the same dose for 2-3 months. Thereafter, response to prednisolone should be assessed, and if there is a therapeutic response, the dose should be tapered to 5 to 15 mg per day, with treatment planned for an additional 9-12 months. Follow-up of at least 3 years after discontinuing treatment is considered necessary to assess for relapse of cardiac sarcoidosis.
Second-line agents can be used in cases of refractory cardiac sarcoidosis or significant steroid side effects. There are some data on the effect of second-line agents on cardiac sarcoidosis, such as methotrexate, cyclophosphamide, azathioprine, and infliximab.

3.2. Heart Failure

There are only limited data on the effect of steroid on the recovery of LV function in patients with cardiac sarcoidosis. Several small, single-center observational studies suggests that steroid treatment can lead to the improvement in LV ejection fraction (LVEF) in patients with mild to moderate LV systolic dysfunction as well as the maintenance of LV systolic function in those with normal function at diagnosis. However, it has been reported that steroid therapy cannot improve LVEF in patients with severe LV systolic dysfunction. In contrast, one nationwide study with long-term follow-up over 25 years found opposite results; patients with severely impaired LV systolic function (LVEF <35%) had an improvement in LVEF with steroid treatment, while those with lesser extent of LV dysfunction had no improvement. Thus, the role of steroid therapy on improving or preserving LV systolic function remains to be explored further.
Besides immunosuppressive treatment targeting inflammation, the mainstay of treatment for cardiac sarcoidosis includes all standard medical and device therapies for heart failure. Heart transplantation is also a viable treatment option for patients with end-stage cardiac sarcoidosis.

3.3. Conduction disturbance

Steroid treatment might be effective for improving conduction abnormalities. Several studies reported that steroid therapy could lead to the recovery of the conduction abnormalities in a substantial proportion of patients, suggesting the potential reversibility of conduction disturbance with steroid therapy. However, a recent Heart Rhythm Society consensus statement recommends pacemaker implantation under the same indication as that for non-sarcoid patients, largely because of the unpredictable reversibility of conduction abnormalities with steroid therapy. Thus the effect of immunosuppressive therapy on conduction disturbances is still a challenging issue.

3.4. Ventricular arrhythmia

It is not surprising that the risk of non-sustained or sustained ventricular tachycardia (VT) is high in patients with cardiac sarcoidosis, considering that granulomatous scar and/or active inflammation can play a role in VT-promoting re-entry. Although data on the benefit of immunosuppression in the treatment of VT is limited, steroid therapy is the first suggested step, particularly if evidence of active inflammation is present. Treatment with anti-arrhythmic agents is frequently started at the same time as immunosuppression is started.
Catheter ablation can be a treatment option if patients are refractory to medical therapies. In spite of the advances in ablation technology, the recurrence rates still remain high, often requiring a second procedure. It has been reported that CMR and PET findings are associated with arrhythmia-free survival, which suggests that CMR and PET findings can aid in identifying more suitable candidates for catheter ablation.

3.5. Sudden cardiac death

The risk of sudden cardiac death (SCD) is another challenging issue in cardiac sarcoidosis, along with the difficulty of selecting appropriate patient for ICD insertion. It is generally accepted that patients with cardiac sarcoidosis are at risk of SCD, but few data are available to guide decision-making for ICD insertion. Specifically, there are no reliable data providing an approximation of the true incidence of SCD in patients with cardiac sarcoidosis. It has been reported that SCD occurs with a broad range of incidence (24% to 65%) in the patients whose deaths are associated with cardiac sarcoidosis. More importantly, data on SCD risk stratification are lacking. Several studies suggest a potential role of imaging modalities for identification of patients at risk for SCD, such as 1) the presence of LGE and RV involvement in CMR and 2) perfusion defect and/or abnormal FDG uptake in PET. With regard to echocardiography, a lower LVEF was found to be associated with appropriate ICD therapy in patients with cardiac sarcoidosis, suggesting that echocardiography can improve SCD risk stratification in this population. However, the problem is that patients with mildly reduced LV systolic function may also have a substantial risk of fatal arrhythmia, making it difficult to use LVEF alone to decide who should receive an ICD.