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Review
Diagnosis and treatment of cardiac sarcoidosis
  1. Kengo F Kusano1,
  2. Kazuhiro Satomi1,2
  1. 1Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan
  2. 2Department of Cardiology, Tokyo Medical University Hachioji Medical Center, Hachioji, Japan
  1. Correspondence to Dr Kengo F Kusano, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, 5-7-1 Fujishiro-dai, Suita 5658565, Japan; kusanokengo{at}hotmail.com

Abstract

Sarcoidosis is a systemic granulomatous disease of unknown aetiology. The frequency of cardiac involvement (cardiac sarcoidosis (CS)) varies in the different geographical regions, but it has been reported that it is an absolutely important prognostic factor in this disease. Complete atrioventricular block is the most common, and ventricular tachycardia/ventricular fibrillation the second most common arrhythmia in this disease, both of which are associated with cardiac sudden death. Diagnosing CS is sometimes difficult because of the non-specific ECG and echocardiographic findings, and CS is sometimes misdiagnosed as dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy or an idiopathic ventricular aneurysm, and therefore, endomyocardial biopsy is important, but has a low sensitivity. Another problem is the recognition of isolated types of CS. Recently, MRI and 18F-fluorodeoxyglucose positron emission tomography have been demonstrated to be useful tools for the non-invasive diagnosis of CS as well as therapeutic evaluation tools, but are still unsatisfactory. Treatment of CS is usually done by corticosteroid therapy to control inflammation, prevent fibrosis and protect from any deterioration of the cardiac function, but the long-term outcome is still in debate. Despite the advancement of non-pharmacological approaches for CS (pacing, defibrillators and catheter ablation) to improve the prognosis, there are still many issues remaining to resolve diagnosing and managing CS. Here, we attempt a review of the clinical evidence, with special focus on the current understanding of this disease and showing the current strategies and remaining problems of diagnosing and managing CS.

https://doi.org/10.1136/heartjnl-2015-307877

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    Epidemiology

    Sarcoidosis is a systemic non-caseating granulomatous disease of unknown aetiology. Typically, the patients have pulmonary involvement, characterised by bilateral hilar lymphadenopathy on chest X-ray and may also have a variety of lesions in other organs such as the eyes, heart, skin, muscle and nerves. Among them, cardiac involvement (cardiac sarcoidosis (CS)) has been reported to be observed clinically in 5% of patients with systemic sarcoidosis, but an autopsy study has revealed that subclinical CS is observed in about 20% of Caucasians and black Americans and as high as about 70–80% of Japanese patients,1 ,2 indicating that the frequency of CS varies in the different countries and races (figure 1). Sarcoidosis itself may be a benign disease in general because a spontaneous remission is often observed in extracardiac cases such as skin sarcoidosis. However, when cardiac involvement exists, the prognosis is not unfavourable. Yazaki et al3 reported that CS presented a worse outcome compared with dilated cardiomyopathy (DCM) (figure 2). Another report suggested that CS is responsible for as much as 85% of deaths from sarcoidosis.4

    Figure 1
    Figure 1

    Frequency of organ involvement in the different races determined (A) by the clinical evaluation and (B) by the autopsy study. Compared with the clinical evaluation, the results of the autopsy study demonstrated that cardiac involvement (cardiac sarcoidosis) was the most common involved organ as well as the lungs in Japanese patients. Modified according to refs. 1 and 2.

    Figure 2
    Figure 2

    Survival after the diagnosis in those with cardiac sarcoidosis (CS) and dilated cardiomyopathy (DCM). The fractional shortening (FS) was the same level at the time of diagnosis; however, CS had a worse outcome compared with DCM. Modified according to ref. 3.

    In patients with CS, various arrhythmias have been reported including atrial and ventricular ones. Among them, atrioventricular (AV) block is the most common and ventricular tachyarrhythmias (VT)/ventricular fibrillation (VF) are the second most common initial arrhythmia.5 ,6 AV block results from involvement of the basal intraventricular septum due to sarcoid granuloma or scar tissue. Interestingly, it has been reported that high-degree AV block occurs frequently in Japanese women aged 40–69 years old, indicating that CS should be carefully considered in middle-aged or elderly women who exhibit high-degree AV block.7 Other reports have suggested that AV block recovers after corticosteroid therapy,8 ,9 indicating that AV block in CS develops mainly during the active phase of this disease. On the other hand, VT/VF in CS mainly occurs as a re-entrant mechanism related to the damaged myocardial tissue. These arrhythmias are sometimes fatal and account for the worse prognosis of sudden cardiac death in CS. Roberts et al10 reported that sudden death due to VT/VF or AV block accounts for 30–65% of deaths. Therefore, detecting cardiac involvement and an early diagnosis and treatment of CS is the most important issue in this disease.

    Diagnosis

    Various guidelines for systemic sarcoidosis have been proposed, but the mainstay of the diagnosis is obtained from the histology results (figure 3A). Recently, the World Association of Sarcoidosis and Other Granulomatous Diseases has proposed a new organ assessment instrument, which is fulfilled with two criteria.11 One is the histological evidence of granulomatous inflammation of an unknown cause in an organ that was not being assessed, and the other is that the clinical manifestation being addressed requires that alternative causes other than sarcoidosis be reasonably excluded. These clinical manifestations were assessed as (a) highly probable, (b) probable and (c) possible. However, this instrument has some limitations; it does not assess the disease activity or severity and does not suggest an algorithm to detect any specific sarcoidosis organ involvement.11 Another diagnosis was proposed by the Japanese Society of Sarcoidosis and Other Granulomatous disease (JSSOG) in 1993 and was modified in 2006, which is accepted as the standard guideline.12 ,13 Importantly, this diagnosis does not necessarily require a histological confirmation but requires clinical confirmation of at least two different organs (box 1). Recently, an expert consensus statement for the diagnosis of CS has been published by the Heart Rhythm Society (box 2),14 and this statement requires a positive biopsy of any organ for the diagnosis of CS and recommends an electrophysiological or image-guided endomyocardial biopsy to increase the sensitivity for CS.

    Box 1

    Diagnostic guidelines for cardiac manifestations of cardiac sarcoidosis (2006)12

    Patient group diagnosed based on histological findings

    Histopathological findings include non-necrotising epithelioid granuloma in the myocardium, and patients are found to exhibit histopathological changes in organs other than the heart or clinical signs.

    Patient group diagnosed based on clinical signs

    Histopathological findings do not include non-necrotising epithelioid granuloma in the myocardium. Patients are diagnosed with cardiac sarcoidosis when they have histopathological changes in organs other than the heart or clinical signs, together with the following conditions and one or more of six primary diagnostic criteria.

    • Two or more major criteria

    • One major and two or more minor criteria

    1. Major criteria

      • (A) Severe atrioventricular block

      • (B) Ventricular septal thinning localised to the basal portion

      • (C) Abnormal uptake of gallium-67 (67Ga) in the heart on 67Ga scintigraphy

      • (D) Left ventricular contraction failure (left ventricular ejection fraction <50%)

    2. Minor criteria

      • (A) Abnormal ECG: ventricular arrhythmia (ventricular tachycardia, multiorigin or frequent ventricular premature beats), right bundle branch block, axis deviation or abnormal Q waves

      • (B) Echocardiography: localised abnormal left ventricular wall motion or morphological abnormalities (ventricular aneurysm and/or ventricular wall thickening)

      • (C) Nuclear medicine techniques: abnormal blood flow on myocardial perfusion scintigraphy (thallium-201 chloride, technetium-99m methoxyisobutylisonitrile or technetium-99m tetrofosmin)

      • (D) Abnormal imaging on delayed gadolinium-enhanced cardiac MRI

      • (E) Endomyocardial biopsy: moderate or more severe myocardial interstitial fibrosis and mononuclear cell infiltrates

    Primary diagnostic criteria in tests:

    1. Bilateral hilar lymphadenopathy

    2. Elevated serum ACE

    3. Negative tuberculin reaction

    4. Abnormal uptake of 67Ga in any organ on scintigraphy

    5. An increased lymphocyte count and elevated CD4/CD8 ratio in bronchoalveolar lavage fluid

    6. Elevated serum or urinary calcium level

    Diagnostic exclusion: giant cell myocarditis must be excluded.

    Additional information:

    1. Perform coronary angiography to differentiate from ischaemic heart diseases.

    2. Cardiac manifestations of sarcoidosis occasionally appearing a few years after sarcoidosis in organs other than the heart have been diagnosed. The patient must, therefore, be followed with an ECG and echocardiography on a regular basis.

    3. Abnormal uptake of 18F-fluorodeoxyglucose positron emission tomography in the heart is a useful diagnostic clue in cardiac sarcoidosis.

    4. Some cases of cardiac sarcoidosis are manifested only by complete atrioventricular block without any other minor criteria as listed.

    5. Cardiac sarcoidosis may initially manifest itself as pericarditis (as shown by ST segment elevation or a pericardial effusion on the ECG).

    6. Cases of a non-necrotising epithelioid granuloma are not observed frequently on the endomyocardial biopsy.

    Adapted from ref. 31

    Box 2

    Expert consensus recommendations on the criteria for the diagnosis of cardiac sarcoidosis (CS)14

    There are two pathways to achieve a diagnosis of CS:

    1. Histological diagnosis from myocardial tissue

    (A) CS is diagnosed in the presence of non-caseating granuloma on the histological examination of myocardial tissue with no alternative cause identified (including negative organismal stains if applicable).

    2. Clinical diagnosis from invasive and non-invasive studies

    It is probable* that there is CS if

    • (A) There is a histological diagnosis of extracardiac sarcoidosis

    • (B) One or more of following is present

      • Steroid±immunosuppressant responsive cardiomyopathy or heart block

      • Unexplained reduced left ventricular ejection fraction (<40%)

      • Unexplained sustained (spontaneous or induced) ventricular tachycardia

      • Mobitz type II second-degree heart block or third-degree heart block

      • Patchy uptake on dedicated cardiac positron emission tomography (with a pattern consistent with CS)

      • Late gadolinium enhancement on cardiac MRI (with a pattern consistent with CS)

      • Positive gallium uptake (with a pattern consistent with CS)

    • (C) Other causes for the cardiac manifestation(s) have been reasonably excluded

    *In general, ‘probable involvement’ is considered adequate to establish a clinical diagnosis of CS.

    Figure 3
    Figure 3

    (A) Typical histology of cardiac sarcoidosis (CS) in endomyocardial biopsy. A non-caseating epithelioid granuloma with giant cells was observed. Bar 100 μm, H&E stain (B) Upper: typical cardiac MRI in CS. Basal septal thinning, which is typical of sarcoidosis was confirmed (black arrow). Bottom: late gadolinium enhancement corresponded with this wall thinning. (C) Typical positron emission tomography in CS. From the top, each image is an 18F--fluorodeoxyglucose (FDG) scan image from anterior to inferior, septal to lateral, and apex to base, respectively. The scans show the basal septum and lateral FDG uptake (heterogeneous pattern) in those regions suggestive of myocardial inflammation.

    The diagnosis of CS is sometimes difficult because of non-specific ECG and echocardiographic findings, and thus CS is sometimes misdiagnosed as DCM, arrhythmogenic right ventricular cardiomyopathy or an idiopathic ventricular aneurysm, and therefore, endomyocardial biopsy is important but the sensitivity is low (<25%). Because sarcoid lesions in the myocardium are thought to have a patchy pattern and sarcoid lesions are more frequently observed in the left ventricular free wall or basal septum, the usual right ventricular biopsy may result in a sampling error.

    Therefore, there is a compelling need for a specific non-invasive marker for making a CS diagnosis and evaluating the disease activity. Recently, new imaging modalities such as cardiac MRI and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) have been shown to be challenging but useful tools for evaluating CS, and JSSOG is planning to put these new imaging results into the next guidelines.

    Magnetic resonance imaging

    Cardiac MRI is a non-invasive diagnostic tool for detecting subclinical CS. T2-weighted imaging enables the detection of acute inflammation and late gadolinium enhancement (LGE) imaging enables the detection of fibrosis or scar. It has been reported that MRI imaging can reveal the efficacy of corticosteroid therapy and can also predict the prognosis of CS.15 Greulich reported that patients with an LGE on cardiac MRI had an >30-fold increased risk of death, aborted sudden death or appropriate implantable cardioverter defibrillator (ICD) discharges during a mean follow-up period of 2.6 years.

    18F-Fluorodeoxyglucose positron emission tomography

    FDG-PET is a glucose analogue that has been reported to be a useful tool for detecting active inflammatory lesions. It is more sensitive than gallium (67Ga)-scintigraphy, thallium-201 or technicium-99m single photon emission CT. FDG-PET can also predict the prognosis of CS. Blankstein et al reported that 26% of adverse events (27 VT and 8 deaths) occur in patients with a positive FDG-PET uptake in the heart during a mean follow-up period of 1.5 years. They also reported that an extracardiac FDG uptake was not associated with adverse events.16 However, the physiological accumulation of FDG is sometimes observed in the entire myocardium, which is associated with a low specificity of a CS diagnosis using FDG-PET. Thus, a low-carbohydrate and high-fat diet prolongs the fasting diet and an intravenous heparin injection has been proposed to increase the specificity. Recently, Tahara et al17 reported that the FDG uptake pattern was distinctly heterogeneous in CS compared with DCM or control subjects. Further evaluation is required, but this would be an interesting and valuable observation.

    Serum markers

    No specific biomarkers are known. It has been reported that the serum ACE activity is elevated in about 60% of systemic sarcoidosis patients, but Japanese data indicate that only a small number of patients with CS had an elevated ACE activity (normal range <21.4 IU/L).18 Recently, the usefulness of a soluble form of a interleukin-2 receptor measurement has been reported,19 but there is not sufficient data for CS.

    Others

    Most ECG and echocardiographic findings were non-specific. However, Kato tried to check the septal diameters at the thinnest position. He reported that a finding of <4 mm can separate those with CS from the controls, and he also checked the ratio of the adjacent part, and a ratio of <0.6 increases the sensitivity (figure 4).20 Nagano et al21 recently demonstrated that this basal thinning is associated with an adverse long-term outcome in patients with CS.

    Figure 4
    Figure 4

    Septal diameters at the thinnest position. (A) Part measured. (B) Distribution of the thickness A. (C) Distribution of the ratio of thickness A/B. Compared with the control, a finding of a thickness of <4 mm at position A could differentiate cardiac sarcoidosis from the control. The ratio of the adjacent part (A/B<0.6) increased the sensitivity. Modified according to ref. 20.

    Isolated CS

    Another problem is the existence of an isolated type of CS (isolated CS). This type of CS has been proposed22 ,23 and generally accepted now. It might contain some diagnostic limitations such as clinically undetectable inflammation in other organs or cardiac regions may arise as just the first manifestation, but Takaya et al18 recently reported that this type of sarcoidosis (they called it ‘probable CS’) has a worse outcome compared with definite CS (systemic sarcoidosis with cardiac involvement). Therefore, the early diagnosis of isolated CS is an important issue in the clinical setting. Isobe et al recently proposed, but has not been widely accepted, a suggested algorithm in patients without extracardiac sarcoidosis (figure 5). In that algorithm, the most important problem is the low positivity of the histological examination of cardiac specimens and a repeated endomyocardial biopsy is sometimes required. The Heart Rhythm Society expert consensus statement14 recommends an electrophysiological or image-guided endomyocardial biopsy in high probable cases of patients with CS. Further examination should be performed concerning this issue.

    Figure 5
    Figure 5

    Proposed algorithm for isolated CS according to ref. 23. Initially, suspicion of CS from cardiac manifestations relatively specific to CS, such as AV block, ventricular arrhythmias, septal thinning or LV aneurysms without coronary artery disease, is important. Then ruling out extracardiac granulomas of systemic organs is important to diagnose isolated CS. AV, atrioventricular; CMR, cardiac MRI; CS, cardiac sarcoidosis; Ga, gallium; FDG, fluorodeoxyglucose; LGE; late gadolinium enhancement; LV, left ventricular; PET, positron emission tomography; PVC, premature ventricular contraction; sIL-2R, soluble form of the interleukin-2 receptor; VT, ventricular tachycardia.

    Treatment

    Treatment for CS is usually done by administering corticosteroids to control the inflammation, prevent fibrosis and protect from any deterioration of the cardiac function. There are also conflicting data on the efficacy of steroids for the long-term disease outcomes. However, Kandolin et al24 recently reported the long-term effects of an immunosuppressive therapy (mainly corticosteroid) in Finnish CS, and the 1-year, 5-year and 10-year transplantation-free survival was 97%, 90% and 83%, respectively, during a mean follow-up period of 6.6 years. They also reported that the presence of heart failure and the cardiac function before the corticosteroid treatment is the most important factor for estimating their prognosis, indicating that the early initiation of corticosteroids is important. Nagai et al25 also reported the beneficial effects of corticosteroids (mean maintenance doses of 7.3 mg daily) in patients with CS. Daily doses of 60–80 mg of corticosteroids and tapered to around 10 mg are generally used, but a study from Japan indicated that the effects of an initial high dose (>40 mg daily) did not differ from those of a low dose (<30 mg daily),3 and thus, a dose adjustment for each patient with CS should be performed. AV block sometimes recovers after the corticosteroids, but the effect of the corticosteroids on VT/VF is not consistent. Several studies have suggested a beneficial effect of corticosteroids on VT/VF,26 while others have failed to show a benefit27 and have shown the prognosis may sometimes worsen28 after corticosteroids. It was also reported that corticosteroids have been linked to an aneurysm formation, indicating that corticosteroids may be effective for ventricular arrhythmia cases during the early phase and preserved left ventricular phases, but less effective in the later disease phase, probably due to a wide and spreading fibrosis.

    Other immunosuppressive drugs such as methotrexate, azathioprine, leflunomide, mycophenolate mofetil and tumour necrosis factor-α antibody are reported to be effective in systemic sarcoidosis. In CS, there is one report of the combination of low-dose prednisolone (5–15 mg/day) with a weekly dose of methotrexate (6 mg/week), which stabilises the cardiac function of CS,29 but the other immunosuppressive drug effects for CS still lack sufficient data.

    Therapy for arrhythmias (devices)

    AV block is the most common initial arrhythmia in CS, and therefore, pacemaker therapy is often needed in patients with an indication for the general guidelines. Corticosteroids sometimes help AV block recover, but the recent Heart Rhythm consensus statement has shown that pacemaker implantations can be a reasonable therapy even if the AV block reverses transiently.14 VT/VF is the second most common initial arrhythmia, thus an ICD is also needed in patients with VT/VF (for the secondary prevention). The Heart Rhythm consensus statement has suggested that an ICD implantation (for the primary prevention) can be a reasonable therapeutic choice in patients with CS and an indication for a permanent pacemaker implantation.14 However, the current guidelines indicate that ICD therapy for primary prevention is performed in selected patients with heart failure (New York Heart Association 2 or 3) and a decreased cardiac function (left ventricular ejection fraction (LVEF)≤35%). Therefore, additional data are needed to satisfy the efficacy especially in patients with CS with no heart failure and/or an LVEF of >35%. Mehta et al demonstrated that the efficacy of electrophysiological study (EPS)-guided therapy was similar to that for the other structural heart diseases. Thus, we believe an EPS-guided therapy should be considered in patients with CS with a suspected high risk such as a decreased EF (LVEF>35%), non-sustained VT or syncope/presyncope, but further research is required in such cases.

    Therapy for arrhythmias (catheter ablation)

    Catheter ablation of VT is usually considered after an ICD implantation or failure of antiarrhythmic drug therapy (box 2). Because CS is a disease involving both fibrosis and inflammation, mainly related to VT, the mechanism is not well known. Naruse et al30 retrospectively examined 37 patients with CS with sustained VT, including 14 patients that underwent catheter ablation. They concluded that an absence of a 67Ga myocardial uptake at baseline was significantly associated with VT recurrence, indicating that the scar-related re-entrant mechanism due to myocardial fibrosis secondary to inflammation was the most prominent mechanism. Interestingly, they also mentioned that another type of Purkinje-related focal VT (non-re-entry type) was observed in 6 of 37 patients. Thus, a standard mapping and entrainment technique could be applied in patients with CS with VT, but the ablation results are not sufficient (box 2). One reason is that the critical circuit is sometimes observed on the intramural free wall or deep in the septum, where the radiofrequency current from the ablation catheter could not reach, and sometimes in the proximity of the His bundle, which could create AV block. Similar results have been reported,30 thus a new ablation technique such as an epicardial approach, bipolar ablation or needle/chemical ablation would be required. Further study is needed to increase the ablation results.

    Therapy for arrhythmias (drugs)

    Because CS directly causes myocardial damage, class I antiarrhythmic drugs should be avoided because of the proarrhythmic effects. Thus, β-blockers, sotalol and amiodrone should be selected (table 1).

    View this table:
    Table 1

    Ventricular tachycardia ablation in cardiac sarcoidosis

    Summary

    In summary, corticosteroids are the mainstream therapy to slow the disease progression in CS and sometimes are effective in recovering the AV conduction. Brady and Tachy devices are needed to treat lethal arrhythmias. However, even after a device implantation, additional medical treatment for VT/VF is often needed, but the results still remain insufficient.

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    Footnotes

    • Contributors Both authors contributed equally to the article.

    • Competing interests Remuneration for lecture: Boehringer Ingelheim, Bayer, Bristol Myers, Medtronic Inc.

    • Provenance and peer review Commissioned; externally peer reviewed.