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Recently, a consensus document on the diagnosis and management of cardiac sarcoidosis (CS) was published.1 This consensus statement was written by experts representing the Heart Rhythm Society, European Heart Rhythm Association, World Association for Sarcoidosis and other Granulomatous Disorders (WASOG), American College of Chest Physicians, American Heart Association the American College of Cardiology and the Asia Pacific Heart Rhythm Society.
The statement was a worldwide effort to address the clinical questions faced by physicians looking after patients with CS in the absence of conclusive clinical data. Although we consider that the recommendations will help in the care of these patients, it is perhaps only a foundation point for comprehending this poorly understood disease. Developing guidelines for uncommon conditions requires adapting the usual methodology for preparing these documents. Most obviously, there are limited randomised and/or blinded studies in the field. Therefore, all recommendations are level of evidence C (ie, expert opinions). The key recommendations are reviewed below.
Sarcoidosis is a disease of unknown aetiology with non-caseating granulomas being the key pathological finding. The lungs are the most commonly affected organ but the disease may also variably occur in the heart, skin, liver, spleen, eye, peripheral lymph nodes and other organs. Recent data suggests that the disease is due to an unidentified antigenic trigger provoking an abnormal immunological response in genetically susceptible individuals. Sarcoidosis occurs worldwide, with the highest rates reported in African–American and Northern Europeans, particularly in women. The overall disease prevalence varies between about 4.7 and 64 in 100 000.
Clinically manifest cardiac involvement is reported in approximately 5% of patients with sarcoidosis. Features of CS are dependent on the activity, extent and location of the disease. The three main manifestations are (1) conduction abnormalities, (2) ventricular arrhythmias including unheralded sudden cardiac death and (3) heart failure. Also, it is estimated that about 25% of patients with systemic sarcoidosis have cardiac involvement without symptoms (clinically silent disease).
The consensus recommendations for the diagnosis of CS are shown in box 1. These diagnostic criteria are aligned with the WASOG tool.2 There is a histological pathway and a clinical pathway to a diagnosis of CS. In patients with extracardiac sarcoidosis, non-cardiac tissue is typically first targeted for biopsy due to the higher diagnostic yield and lower procedural risk. In cases of negative extracardiac biopsy or isolated CS, endomyocardial biopsy (EMB) may be necessary to make the diagnosis. However, due to the patchy nature of the disease, EMB has low sensitivity with a diagnostic biopsy in less than a quarter of patients with CS. To increase the positive biopsy rate, positron emission tomography (PET) or cardiac magnetic resonance (CMR) image-guided or electroanatomic-mapping-guided biopsy procedures are recommended.1 ,3
Expert Consensus Recommendations on Criteria for Diagnosis of Cardiac Sarcoidosis (modified from ref1)
There are two pathways to a diagnosis of CS:
1. Histological diagnosis from myocardial tissue
CS is diagnosed in the presence of non-caseating granuloma on 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
1. Steroid±immunosuppressant responsive cardiomyopathy or heart block
2. Unexplained reduced LVEF (<40%)
3. Unexplained sustained (spontaneous or induced) VT
4. Mobitz type II second-degree heart block or third-degree heart block
5. Patchy uptake on dedicated cardiac PET (in a pattern consistent with CS)
6. Late Gadolinium enhancement on CMR (in a pattern consistent with CS)
7. Positive gallium uptake (in 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.
CMR, cardiac magnetic resonance; CS, cardiac sarcoidosis; LVEF, left ventricular ejection fraction; PET, positron emission tomography; VT, ventricular tachycardia.
Screening for CS
There is limited evidence about the specificity and sensitivity of screening tests/algorithms for CS in patients with sarcoidosis in other organs. Mehta et al4 reported on 62 patients and found that the presence of one abnormal screening test (ECG, Holter monitoring or echocardiography) and/or significant cardiac symptoms had a specificity of 87% and sensitivity of 100% for diagnosing CS.4 These data are limited by the use of a single imaging test to ‘diagnose’ CS, small sample size and possible referral bias. However, this study is the most detailed published and hence on the basis of these findings and the opinions of the expert group, we made the screening recommendations in table 1.
Larger studies are required to assess the diagnostic yield (and cost effectiveness) of various screening algorithms/tests. This research should critically evaluate the screening strategy advised in the statement.1 Finally, the writing group agreed not to make a formal recommendation on rescreening of patients with baseline normal screening, as there are no studies addressing this key clinical question. However, physicians should consider retesting if the patient develops new cardiac symptoms or signs. The document also highlighted the importance of considering CS in the differential diagnosis in certain cardiac presentations in patients not known to have sarcoidosis; most importantly in idiopathic advanced conduction system disease in younger patients (age <60), as this can be the first presentation of sarcoidosis anywhere. Also physicians should be aware that CS and arrhythmogenic right ventricular cardiomyopathy may have overlapping clinical features.
Role of immunosuppression
Despite a paucity of data, immunosuppression (primarily with corticosteroids) has been advocated as the cornerstone of treatment for CS. However, the optimal doses of corticosteroids, and how best to assess response to therapy, is not known. Also it is unknown whether corticosteroid therapy should be recommended for all patients with CS or only for those with clinically manifest disease. Fluorodeoxyglucose (FDG) is a glucose analogue that can diagnose active inflammatory lesions as activated macrophages have a greater glucose usage. Hence, FDG-PET imaging can identify ongoing inflammation and might be useful as a disease activity marker to guide CS therapy. However, the exact role of FDG-PET remains to be defined, and more research is needed. It should be noted that FDG-PET testing should be performed at a centre with expertise in CS imaging protocols.1
Management of conduction abnormalities
Clinically manifest CS can often present with heart block due to scar tissue or granulomas in the basal septum. Furthermore, it can be the initial presentation of sarcoidosis anywhere in the body. Importantly, up to one-third of younger patients (aged <60) presenting with significant conduction system disease have undiagnosed sarcoidosis. Thus, the writing group recommends investigating this group for undiagnosed sarcoidosis as the underlying aetiology. The writing group reached consensus on three additional recommendations (see table 1).
Management of ventricular arrhythmias
The most frequent mechanism of ventricular arrhythmia is macro-reentrant arrhythmias around segments of granulomatous scar. Active inflammation may initiate/maintain monomorphic ventricular tachycardia (VT), either by triggering it with ectopy, or by further slowing conduction within granulomatous scar. Despite limited evidence, steroids are often used in patients with CS and VT. Antiarrhythmic drug therapy and ablation for ventricular arrhythmias have shown modest results. Hence, the expert consensus recommends a stepwise approach with initial therapy with steroids (if evidence of active inflammation) followed by antiarrhythmic therapy. Ablation is a final option for drug-resistant patients (see table 1 for specific recommendations).
Risk stratification for sudden death and indications for implantable cardioveter defibrillator implantation
There are few data to help with sudden death risk stratification (see figure 1). Our consensus document suggests that evidence from the major implantable cardioveter defibrillator (ICD) randomised trials is applicable. Also we suggest that in the primary prevention group, the left ventricular ejection fraction (LVEF) should be reassessed after heart failure medication optimisation and immunosuppression if indicated. Clearly, there is no research to inform the timing of LVEF reassessment, and we suggest that this should be individualised and probably should occur at least 3 months after the intervention.
CS, likely due to the active inflammation, and perhaps because of the frequent involvement of both ventricles may behave differently to other forms of non-ischemic cardiomyopathy with respect to LVEF, ventricular arrhythmias and sudden death risk. In support of this, cohorts of patients with CS have more frequent therapies from their ICDs than other groups. Even patients with mild left ventricular dysfunction have a higher than expected risk of ventricular arrhythmias. Hence, we state that in patients with LVEF, 36%–49% and/or right ventricular ejection fraction <40%, ICD implantation may be considered. Also, we recommend that in patients with an indication for permanent pacemaker implantation, an ICD can be useful.
Patients with sarcoidosis with cardiac involvement have a worse prognosis than patients without it; death is due to sudden cardiac death or heart failure. The most important predictor of survival in patients with clinically manifest CS appears to be left ventricular function, with good 10-year outcomes in patients with preserved function.5 There is considerable controversy in the literature as to the prognosis of clinically silent CS. This is a key clinical question with very important relevance to large numbers of patients and further research is needed.
Conclusions and future directions
In the consensus statement, we attempted to summarise the current knowledge of CS, and given the marked limitations, to make the best possible recommendations.1 Perhaps as importantly, the document reviews the key unanswered clinical questions and needed research. Much remains to be understood about how to optimally diagnose and treat patients with CS. These clinical questions can best be answered by multicentre prospective research and such studies are ongoing (CS Multicenter Cohort Study, NCT: 01477359 and the CS Consortium).
Contributors DB wrote the manuscript. WS and MJ reviewed and commented.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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