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Learning objectives
To improve knowledge of the epidemiology and clinical presentation of cardiac sarcoidosis.
To understand the diagnostic approach in patients with suspected cardiac sarcoidosis and how to exclude important differential diagnoses which can mimic the condition.
To understand the basic principles in the management of cardiac sarcoidosis.
Introduction
Sarcoidosis is a systemic inflammatory disease characterised histologically by the formation of non-caseating granuloma in multiple organs.1 The cause of the disease remains unknown. It is hypothesised that exposure to an antigen in patients with a genetic predisposition results in an exaggerated immune response leading to granuloma formation. Clinicians face several challenges including achieving a confident diagnosis and providing patients with a long-term management plan. These challenges largely relate to the heterogeneity of the original presentation, disease evolution and outcome. Sarcoidosis may be diagnosed incidentally in patients who have no symptoms, those with non-specific respiratory symptoms such as a persistent cough or those with prominent systemic features (fever, weight loss and fatigue). Moreover, in many patients, the condition will remit spontaneously, whereas in others long-term immunomodulation is required to prevent disease progression.
While the lungs and intrathoracic lymph nodes are involved in 90%–95% of cases, the exact prevalence of cardiac sarcoidosis (CS) remains largely unknown.2 Clinically overt CS has been reported in 5%–10% of cases with systemic sarcoidosis.2 However, the true prevalence is likely to be higher based on postmortem analyses and registries using advanced imaging modalities.3–12 Patients with CS may present with arrhythmias (such as advanced atrioventricular block or ventricular tachycardia) and/or unexplained new onset heart failure without a history of systemic sarcoidosis.13 14 The initial investigation of such cases should focus on identifying extracardiac disease to improve the certainty of the diagnosis. Histologically confirmed isolated CS has also been reported.7 Therefore, the true burden of CS remains unknown with a significant number of patients being undiagnosed who may experience adverse cardiac adverse events in the future.
Even when a confident diagnosis of CS is made, the treatment options are often based on individual patient characteristics rather than uniform clinical guidelines. This is in view of the paucity of randomised controlled studies due to the disease being relatively rare. A multidisciplinary team approach provides a more robust model for diagnosing the condition and providing a treatment plan for patients (table 1). Patients with CS may require implantation of a cardiac defibrillator (ICD) as a primary or secondary preventative strategy or catheter ablation for the management of arrhythmias. In the presence of active myocardial inflammation, immunosuppression may be required to prevent the development of irreversible changes in cardiac structure and function. This review summarises our current knowledge of the epidemiology and clinical manifestations of CS, highlights the importance of non-invasive cardiac imaging in the diagnosis of the condition and describes the basic principles of management from the respiratory and cardiac perspective.
Epidemiology of cardiac sarcoidosis
The prevalence of systemic sarcoidosis ranges between 5 and 64 per 100 000 of the population.15 16 A higher prevalence has been reported in Northern Europeans and African Americans, with an approximate fourfold greater risk in the African American population as compared with Caucasians.15 16 The average age of disease presentation is 30–50 years for both genders, with women having a second peak in incidence between the age of 50 and 60 years.16 The average age of patients with CS is slightly higher than the general sarcoidosis population suggesting either a delayed diagnosis or later development of the disease.
The prevalence of CS among patients with systemic sarcoidosis has increased considerably partly due to an increased awareness of the condition as well as due to the wider use of advanced imaging modalities. Cardiac magnetic resonance imaging (CMR) and cardiac fluoro-deoxy-glucose positron emission tomography (FDG-PET) have detected a significant number of patients with myocardial involvement of sarcoidosis with limited or no cardiac symptoms.4–12
Traditionally, the 2006 Japanese Cardiology Society (JCS) diagnostic criteria were used.17 They focused on detecting clinically overt cardiac involvement and included major arrhythmias and/or structural changes as major criteria. As a result, the reported prevalence was estimated at 5%–10% of the general sarcoidosis population.2 4 Studies using CMR and FDG-PET in the suspected or general sarcoidosis population have highlighted the superiority compared with JCS criteria in detecting myocardial damage and/or inflammation as well as predicting major adverse events during follow-up .4–6 9–12 This resulted in their inclusion as major diagnostic criteria in the latest Heart Rhythm Society (HRS) expert consensus statement as well as in the updated JCS diagnostic guidelines.18 19 In these studies, the prevalence increased to 20%–50%, which is similar to postmortem data.3
CS is the most common cause of death in the Japanese sarcoidosis population, suggesting a genetic predisposition.19 Certain HLA subtypes may be associated with cardiac involvement, but the studies are small and lack genome-wide significance.20
Clinical presentation of cardiac sarcoidosis
The clinical presentation of CS is dependent on the location and extent of myocardial damage as well as the degree of myocardial inflammatory activity. Cardiac manifestations may precede systemic disease or can develop subsequently. Cardiac symptoms often do not correlate with the severity of the disease as determined by advanced cardiac imaging.
The most common symptoms of CS are palpitations followed by presyncope and syncope, whereas chest pains are much less frequent. Breathlessness disproportionate to the extent of pulmonary disease may be due to cardiac involvement of sarcoidosis and should be investigated. However, in 15% of patients, sudden cardiac death is the first presentation of the disease, and approximately 20%–25% of patients are asymptomatic, which highlights the importance of screening at risk individuals.21
Abnormalities of the ECG, such as Q waves, ventricular ectopics and axis deviation, can be a useful as a screening tool for CS, although with a low specificity.18 19 CS can lead to conduction system disease due to involvement of the basal septum resulting in atrioventricular block, left or right bundle branch block or left anterior hemiblock. Ventricular tachycardia can occur due to a re-entry phenomenon in areas of myocardial inflammation and/or granulomatous fibrotic tissue. Atrial arrhythmias tend to be associated with systemic inflammation, comorbidities or the development of heart failure rather than granulomatous involvement of the atrial myocardium, although this is still unclear.22
Diagnosis of cardiac sarcoidosis
Despite significant advances in the field, there are no validated clinical guidelines for the diagnosis of CS. As for most organs involved in sarcoidosis, histological confirmation of non-caseating granuloma within the myocardium would establish a definitive diagnosis of CS.18 19 However, the sensitivity of endomyocardial biopsies remains low due to patchy nature of the disease despite improvements in sampling techniques.3 Therefore, the diagnosis in the majority of cases is based on the patient’s clinical presentation integrated with findings from advanced cardiac imaging modalities.
There are practically two diagnostic criteria sets which are currently used and are broadly similar in content (table 2).18 19 The HRS 2014 expert consensus statement for the diagnosis of CS is the most widely used. The criteria require evidence of extracardiac biopsy proven sarcoidosis, abnormalities of cardiac rhythm or structure, as well as characteristic features from advanced cardiac imaging modalities.18 This expert consensus statement was published with the acknowledgement of significant advances in non-invasive cardiovascular imaging within the last 10 years. The World Association of Granulomatous diseases (WASOG) organ assessment instrument published in 2014 was based on the HRS consensus statement,23 while the updated JCS criteria set in 2019 included CMR and cardiac FDG-PET abnormalities in the major diagnostic criteria set.19 The division between major and minor criteria set in the JCS guidelines can be difficult to interpret.
A clinical diagnosis can have different levels of confidence due to the wide range of abnormalities included in the diagnostic criteria sets. This was well recognised by WASOG, which defined define different categories of the likelihood of organ involvement (highly probable, probable and possible).23 Advanced imaging modalities have several weaknesses (outlined below) and cannot be viewed as reference standard in isolation. Therefore, a multidisciplinary team approach in the diagnosis of CS has been proposed as a more accurate and holistic approach, although this remains to be validated.24 This involves the integration of four domains: (a) clinical information about extracardiac sarcoidosis (confidence of diagnosis and disease behaviour), symptoms at presentation and available biomarkers, (b) type of rhythm abnormalities (if any) and association with presentation, (c) type of structural abnormalities and association with presentation and (d) type of tissue damage (fibrosis and/or inflammation) detected on advanced imaging modalities (figure 1). This model allows for the categorisation of the level of confidence of the diagnosis, with potential differential diagnoses being excluded where this is reasonable and appropriate. CS can mimic other conditions, such as arrhythmogenic cardiomyopathy, and therefore a comprehensive assessment is mandatory.
Other differential diagnoses include myocarditis, non-ischaemic dilated cardiomyopathy and, less commonly, hypertrophic cardiomyopathy.
We outline below the diagnostic role of available imaging modalities describing their strengths and weaknesses (table 3). The available imaging modalities differ significantly with respect to the type of histopathological features they detect. Based on experience from managing patients with systemic sarcoidosis, granulomatous inflammation may persist, resolve or progress to the development of fibrotic tissue.25 In figures 2 and 3, we present a proposed diagnostic algorithm to detect CS based on the HRS consensus statement for (a) patients with known systemic sarcoidosis and (b) patients that present with unexplained cardiac manifestations including advanced atrioventricular block, ventricular tachycardia and new onset cardiomyopathy.
Non-invasive imaging for the diagnosis of cardiac sarcoidosis
Echocardiography
Transthoracic echocardiography may be considered as the first-line conventional imaging modality for patents with suspected CS. Echocardiography has a low specificity and sensitivity in detecting CS primarily due to the fact that left ventricular impairment is the only diagnostic criterion detected by this modality.18 19 Nonetheless, such findings do not usually affect the left ventricular systolic function, until the latter stages of the natural history of the condition. Regional wall motion abnormalities associated with wall thinning or thickening, especially in the absence of coronary artery disease in patients with extracardiac sarcoidosis, have been strongly associated with CS and should be investigated.26 Pericardial and valvular involvement have only rarely been reported.
Modern echocardiographic techniques have emerged to detect subtle changes in cardiac structure by evaluating myocardial deformation. Longitudinal speckle tracking imaging can detect subclinical myocardial dysfunction, even when wall motion and ejection fraction are normal.27 Global longitudinal strain (GLS) has been found to have a sensitivity and specificity in detecting CS that ranges between 67%–94% and 60%–94%, respectively.27 Nonetheless, the recommended normal range of GLS in CS is yet to be validated.
CMR
CMR provides a high-resolution assessment of cardiac structure with the ability for tissue characterisation. Cine sequences offer an accurate morphological evaluation including measurement of ventricular function and detection of regional wall motion abnormalities, focal wall thickening and ventricular wall aneurysms.4–9
T2-weighted short-tau inversion recovery (T2-STIR) imaging is used for the detection of myocardial oedema, a surrogate marker of the active inflammatory phase of CS. Novel markers of quantitative tissue characterisation imaging (T1 and T2 mapping) may detect active myocardial inflammation even at an early stage of the disease.28 By far, the most important diagnostic finding on CMR is the identification of late gadolinium enhancement (LGE), which signifies the detection of macroscopic interstitial fibrosis occurring in both acute and chronic phases of CS. The extent of LGE may increase when there is coexisting oedema due to vasodilatation during the inflammatory phase.
While a range of different patterns of LGE have been described in patients with CS, a non-ischaemic distribution with subepicardial and mid-wall involvement of the basal septum and/or inferolateral wall are most frequently reported. Involvement of the basal anteroseptum and inferoseptum with contiguous extension into the right ventricle is almost pathognomonic of CS even in the absence of extracardiac biopsy evidence (figure 4).29
Nonetheless, in a recent study evaluating the diagnostic accuracy of advanced imaging in CS only one out of four highly probable CS cases and none of the probable ones were confirmed histologically postcardiac transplantation.30 Therefore, careful review of the CMR appearances with a multidisciplinary team approach is recommended before making a firm conclusion of the diagnosis.
CMR has certain key advantages, although with limitations, as compared with other imaging modalities (table 3). Above and beyond its safety profile and accuracy in the assessment of the cardiac structure, CMR is extremely sensitive in detecting subclinical manifestations of the disease. As would be expected, myocardial fibrosis is more commonly found than myocardial oedema. As a result, CMR is more sensitive in detecting CS as compared with nuclear medicine imaging modalities. When compared with the JCS criteria, the sensitivity and specificity of LGE are 92%–100% and 78%–100%, respectively.4–9 In addition, the identification of LGE plays a crucial role in the risk stratification of patients. The presence of LGE is an independent predictor of major adverse events in both suspected patients with CS as well as the general sarcoidosis population.4–6 8 In a meta-analysis of 7 studies with a total of 694 patients, LGE-positive patients carried an approximate 11-fold higher risk of cardiovascular mortality and 20-fold higher risk of ventricular arrhythmias when compared with LGE negative ones.31 In patients with CS, the extent of LGE is associated with worse outcome.8 Limited in extent LGE (<6%) and subclinical disease (asymptomatic population with LGE) seem to have a better outcome compared with extensive LGE (>20%).8 Future studies are warranted to develop an accurate risk stratification model in cases where patients do not meet the conventional criteria for an implantable cardiac defibrillator but may be at high risk of ventricular arrhythmias due to the pattern and extent of LGE.
Cardiac FDG-PET in diagnosis of cardiac sarcoidosis
Gallium scintigraphy (67Ga) has been used for the diagnosis of CS but in the last decade FDG-PET has emerged as a superior technique with improved sensitivity and spatial resolution.32 Cardiac FDG-PET is a radionuclide imaging technique combined with CT for attenuation correction and anatomical localisation using a glucose analogue (FDG) that is densely present in inflammatory cells such as neutrophils and macrophages. Strict adherence to specific fasting protocols is required to ensure normal myocardial glucose uptake has been suppressed to allow the accurate detection of myocardial inflammatory activity.32 FDG-PET is usually performed along with a resting myocardial perfusion scan. Myocardial perfusion helps in excluding coexistent coronary artery disease. The perfusion defects may be due to either active inflammation or myocardial fibrosis, with abnormal FDG uptake representing inflammation. A mismatch pattern of perfusion defects and myocardial inflammation is considered characteristic of CS. The perfusion and FDG uptake patterns can be used to define different stages of the disease process29 33 (figure 5). Scans which show diffuse global uptake of FDG within the left ventricle should be considered non-diagnostic, most likely due to inadequate dietary preparation. Cardiac FDG-PET provides a half-body scan allowing for the identification of potential sites for extracardiac biopsy which may enhance the level of confidence in diagnosing the disease.
Similar to CMR, cardiac FDG-PET is superior to JCS diagnostic criteria in detecting CS.10–12 CMR and cardiac FDG-PET should be considered complementary imaging modalities. CMR is the imaging modality of choice for the evaluation of patients with suspected CS due to its accuracy in the assessment of cardiac structure and tissue characterisation.34 35 On the other hand, cardiac FDG-PET is the gold standard test for identifying inflammation and monitoring treatment response in CS. Our experience has shown the superiority of cardiac FDG-PET in detecting myocardial inflammation as compared with CMR using T2-STIR sequences. The frequency of follow-up scans has not been clearly defined, but in our practice cardiac FDG-PET is usually repeated 6–9 months after the introduction of immunosuppressive treatment to evaluate treatment response (figure 6).
Management of cardiac sarcoidosis
A multidisciplinary team approach for the management of CS is required in order to address the complex clinical issues that patients often face. Deciding on whether device implantation is indicated, the optimisation of heart failure therapy for patients with left ventricular systolic impairment, arrhythmia management and the titration of immunosuppressive drugs requires members of the team to have expertise in the relevant areas.
Sarcoidosis specific therapies
It should be acknowledged from the outset that there is a paucity of randomised controlled trial data and, as a result, recommendations are primarily based on accumulated experience in expert centres.
In active CS, early treatment should be definitive. Historically, very high doses of oral corticosteroid therapy were introduced, reducing to a maintenance phase of moderately high oral doses. The use of parenteral corticosteroid therapy in active CS is now increasingly widespread. This is based on the rapidity of action of intravenous steroids which allows the subsequent reduction in oral steroid dosage, with a concomitant decrease in potential side effects from long-term steroid therapy. After evaluating the efficacy of corticosteroid treatment, the early introduction of a steroid-sparing agent should be considered.
Furthermore, when there is the likelihood of major reversible disease, a steroid-sparing agent may be commenced at the outset of immunosuppressive treatment. In the era of advanced imaging modalities, the early identification of active myocardial inflammation is key to enabling the prompt commencement of immunosuppressive therapy.36 The aim is to prevent potentially irreversible myocardial fibrosis and adverse LV remodelling that can lead to intractable arrhythmias and heart failure.
A systematic review of the use of corticosteroids for the treatment of CS has shown an approximate 50% improvement in conduction system abnormalities with immunosuppression, whereas no improvement was noted in the treatment naïve population.37
In another study, a total of 7 out of 35 patients presenting with third-degree atrioventricular block recovered AV conduction after initiation of steroids.7 Therefore, immunosuppression in the context of conduction abnormalities seems to be beneficial, which has been highlighted in the HRS consensus statement.18
Data regarding the use of immunosuppression for the treatment of ventricular tachycardias in patients with CS are less clear, but overall treatment in the context of active myocardial inflammation is highly recommended. In a study with 31 patients with CS presenting with frequent premature ventricular ectopics (PVCs) and treated with steroids, there were no differences in the number of PVCs and in the prevalence of non-sustained VT (NSVT) before and after steroid therapy. However, patients with LVEF ≥35% (n=17) were found to have a significant reduction in the number of PVCs (p=0.048) and in the prevalence of NSVT (p=0.039) with steroid treatment.38 In a small case series of patients (n=18) presenting with ventricular tachycardia in the context of CS, more than half of the patients with evidence of active myocardial inflammation on PET (64%) did not require long-term treatment with antiarrhythmic drugs after successful treatment with a combination of prednisolone and methotrexate.39
The data on the effect of immunosuppression in the context of heart failure are also unclear.38 40 The response according to cardiac FDG PET scan appearances has been associated with an improvement in LVEF which would support the targeted treatment of patients with active myocardial inflammation.41 In a systematic review, steroid treatment was beneficial in patients with normal or mild to moderate LV systolic impairment but failed to provide significant benefit in those with severe LV systolic impairment.37 This is probably due to irreversible structural changes within the myocardium in the latter cohort due to the presence of scar tissue.
The combination of steroids with steroid sparing agents can be equally effective and may potentially reduce steroid related side effects. One prospective open-label study compared outcomes in patients with CS receiving a combination of low-dose steroids and weekly Methotrexate vs steroids alone. The study found that at 3 years LVEF, cardiothoracic ratio and NT-proBNP levels were stable in the combination therapy group, but not in cohort who received steroids alone.42 Furthermore, the duration of immunosuppressive treatment that should be prescribed is largely unknown. In a study with 61 consecutive patients with CS, steroids were discontinued in 12 patients after clinical improvement was reported. Cardiac death was reported in 5/12 patients after steroid cessation, which was probably associated with a lower LVEF.43
The role of immunosuppression and the population that would benefit from that would require further investigation especially since tumour necrosis factor alpha inhibitors were found to have beneficial effect in previously considered refractory disease.44 A multicentre randomised control study has been recently designed and will provide insight to this question.45
Heart failure treatment in cardiac sarcoidosis
The most important clinical predictor of mortality among patients with CS is the LVEF. Patients who have CS and heart failure should be treated using standard medical and device therapies, including cardiac transplantation, as per established current clinical guidelines.46
Antiarrhythmic medication and catheter ablation
Limited data are available regarding the use of antiarrhythmic medications in the context of CS. Sotalol and Amiodarone may be effective for the management of ventricular tachycardia in this patient cohort, although the latter should be prescribed with caution given the common involvement of the lungs and potentially also the liver, in sarcoidosis. Class I antiarrhythmics are usually avoided in view of the presence of myocardial fibrosis and a degree of cardiac dysfunction.18 Electrophysiological studies and catheter ablation should be considered in selected cases, particularly where antiarrhythmic therapy has been ineffective.47 A multidisciplinary team approach is advisable, and any significant active myocardial inflammation should be suppressed, prior to embarking on ablation therapies.
ICD implantation
The HRS expert consensus statement recommends an ICD for patients with a LVEF <35% or sustained VT/cardiac arrest, as is the case for the non-CS population (Class I indication).18 47 A Class IIa indication is proposed for patients with unexplained syncope or inducible VT at an electrophysiological study. There is less clarity for patients who have less severe LV systolic impairment (LVEF 35%–50%) and for those with extensive myocardial fibrosis in the setting of preserved LV systolic function. The more recent ACC/AHA/HRS guidelines published in 2017 have been controversial in that they propose a Class IIa indication for patients with a LVEF >35% and myocardial scar detected by CMR or PET, as they do not quantify the amount of scar tissue.47 If this guideline were to be applied, then most patients who have a diagnosis of CS based on advanced imaging modalities would also fulfil the criteria for an ICD implant. Prospective multicentre studies will be required to address this issue. The risks associated with device implantation should always be considered in patients with CS especially due to frequent concomitant treatment with immunosuppression. In a study of 235 patients with CS who underwent ICD implantation, there were inappropriate therapies in 24% of patients and adverse events in 17% of patients including device-related infections and lead dislodgements or fractures.48
In our practice, if a patient requires a pacemaker due to a brady-arrhythmia indication, then a dual chamber ICD is implanted. This is to protect the patient from potential ventricular arrhythmias and to avoid an upgrade procedure in the future with its inherent risks. This practice is in keeping with HRS guidance.
Future directions
CS is increasingly being recognised by clinicians worldwide, yet the exact pathophysiological mechanisms remain unknown. Retrospective studies have demonstrated that CS has a much more diverse clinical presentation than initially appreciated, especially in view of subclinical disease being identified with advanced cardiac imaging. Further research is needed to help guide clinical decision-making and the development of novel screening strategies as even asymptomatic CS may not be a benign phenomenon. A validated risk stratification strategy for those at risk of mortality and major adverse cardiac events is essential. Large-scale multicentre randomised controlled trials are being designed to obtain more robust evidence for the optimal immunosuppressive therapy regimen as well as identifying patients who may benefit from device implantation.
Key messages
The precise aetiology of cardiac sarcoidosis (CS) and systemic sarcoidosis remains unclear. Exposure to an environmental antigen in patients with a genetic predisposition, which leads to an exaggerated immune response, may be a plausible explanation.
The prevalence of CS is likely to be grossly underestimated because a significant proportion of patients have subclinical disease and different criteria set have been used over the years.
A multidisciplinary approach with the integration of clinical findings and advanced cardiac imaging modalities is recommended for the diagnosis and management of CS.
Cardiac magnetic resonance (CMR) imaging provides accurate functional information as well as tissue characterisation of the myocardium. It is an invaluable tool for confirming the diagnosis and differentiating it from other myocardial diseases.
Late gadolinium enhancement on CMR imaging, associated with the presence of myocardial fibrosis, may be the result of myocardial inflammation in the active phase of the disease.
Cardiac fluoro-deoxy-glucose positron emission tomography is at present the most sensitive tool for identifying myocardial inflammatory activity, which is the target for immunosuppressive treatment.
The aim of immunosuppressive treatment should be to eliminate active myocardial inflammation.
Key members of the CS multidisciplinary team are a respiratory physician with expertise in sarcoidosis, a cardiologist with experience in arrhythmia and heart failure management and advanced cardiac imaging specialists.
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Acknowledgments
We would like to acknowledge the contribution of the whole cardiac sarcoidosis multidisciplinary team at Royal Brompton hospital including Professor Athol Wells, Dr Rajdeep Khattar, Dr John Baksi and Dr Kshama Wechalekar. All of them have contributed to the development and validation of multidisciplinary approach in the diagnosis and management of cardiac sarcoidosis. Dr John Baksi provided us with the CMR imaging in the figures and Dr Kshama Wechalekar provided us with the FDG-PET/resting myocardial perfusion imaging in the figures.
References
Footnotes
Contributors Both VK and RS have reviewed the literature and wrote the manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Commissioned; externally peer reviewed.
Author note References which include a * are considered to be key references.