It is crucial for clinicians to screen for CS in all patients with extra cardiac sarcoidosis. Patients suspected of isolated CS without known sarcoidosis are less frequent; diagnosis in this case requires a high level of suspicion and exclusion of common diagnoses (mainly ischemic heart disease). The screening starts with a detailed history and physical examination and electrocardiogram (ECG) (Dubrey and Falk, 2010; Mantini et al., 2012). Patients with symptoms, an abnormal ECG, or cardiomegaly on chest x-ray without known risk factors should be referred for further testing. Transthoracic echocardiogram and 24h-holter monitoring may add additional information before the patient proceeds with subsequent advanced imaging (Kim et al., 2009). All patients with a pathologic ECG should be further investigated for CS, particularly those who experience clinical symptoms including palpitations, pre-syncope and syncope (From et al., 2011). Mehta et al. showed that the presence of cardiac symptoms (significant palpitations, syncope, or presyncope) and/or an abnormal cardiac test in known sarcoidosis patients had a sensitivity of 100% and a specificity of 87% for CS diagnosis (Mehta et al., 2008). Despite this, the absence of cardiac related symptoms does not exclude the diagnosis of CS, and data on whether and when patients with a negative initial work-up should be rescreened, are lacking (Birnie et al., 2014). Male sex, cardiac-related symptoms, ECG changes, serum NT-proBNP level, multiorgan involvement, and radiological pulmonary progression have been suggested as potential risk factors for cardiac sarcoidosis development (Darlington et al., 2014; Youssef et al., 2011).

The electrocardiogram (ECG) result is usually abnormal in patients with clinically evident disease and mostly normal in clinically silent CS. Abnormalities include various degrees of conduction block, such as isolated bundle branch block and fascicular block. Furthermore, QRS complex fragmentation, pathological Q waves (pseudo infarct pattern), ST changes and (rarely) epsilon waves can occur. These ECG findings in patients with extra cardiac sarcoidosis warrant further imaging studies to rule out cardiac sarcoidosis, with which they have shown significant association (Martusewicz-Boros et al., 2016b). Some patients are diagnosed with abnormal ECG features years after the onset of non-cardiac sarcoidosis; thus, ECG is essential for long-term follow-up. Other possible signals might be baseline heart rate and PR interval. Signal averaged ECG and Holter monitoring revealing late potentials might predict cardiac involvement in sarcoidosis (Yodogawa et al., 2018). Most studies show that Holter monitoring can be a predictor of cardiac involvement with sensitivity of 89% and specificity of 21% (Freeman et al., 2013). Holter is also useful to monitor response to treatment with immune-suppressives in conductive abnormalities in serial fashion (Padala et al., 2017). The exact place of Holter monitoring in the screening for CS is not clearly defined; however, it is certainly a comfortable, out-patient assessment follow-up tool in patients suspected of or diagnosed with CS.

Similar to ECG, the trans-thoracic echocardiogram (TTE) result is oftenabnormal in manifested disease and normal in clinically silent CS (Kim et al., 2009). Though not pathognomonic, some findings are accepted as major and minor criteria in various diagnostic guidelines (Birnie et al., 2014; Hiraga et al., 1993; Judson et al., 2014; Patel et al., 2009; Terasaki et al., 2019). Echocardiography is not useful in screening for CS, due to its low sensitivity, around 25% in most studies (Kouranos et al., 2017). The most characteristic abnormality is basal interventricular thinning, and less often myocardial wall thickness, isolated wall motion abnormalities, LV and/or RV diastolic and systolic dysfunction and aneurysms are detected (Agarwal et al., 2014; Skold et al., 2002; Burstow et al., 1989; Sun et al., 2011). Newer techniques, including strain rate, might improve echocardiography sensitivity in CS diagnosis (Joyce et al., 2015; Murtagh et al., 2016).

Most biomarkers such as angiotensin-converting enzyme, neopterin and troponin are elevated in patients with sarcoidosis; however, they lack sensitivity and specificity and may be affected by concomitant drugs administered (d’Alessandro et al., 2020; Kandolin et al., 2015; Vorselaars et al., 2015). Hypercalciuria, increased serum chitotriosidase and BAL biomarkers (elevated CD4${}^{+}$/CD8${}^{+}$ ratio and KL-6, decreased Natural Killer and CD103${}^{+}$CD4${}^{+}$cells) indicate sarcoidosis diagnosis and disease activity (Cameli et al., 2020; d’Alessandro et al., 2020). Exhaled nitric oxide has failed to prove useful in pulmonary sarcoidosis (Cameli et al., 2016).

Recent studies have focused on the diagnostic and prognostic value of advanced cardiac imaging, trying to overcome the limitations of the aforementioned exams, in order to achieve an earlier diagnosis, at less advanced stages of the disease (Cheong et al., 2009; Kim et al., 2009; Patel et al., 2009). CMR showing late gadolinium enhancement (LGE) is regarded as the study of choice for diagnosing cardiac involvement in sarcoidosis (Smedema et al., 2005). Apart from LGE, CMR may detect morphologic abnormalities (such as wall thinning and aneurysms) and functional parameters of cardiac chambers (LV and RV). LGE most commonly represents scar tissue, although inflammation may sometimes lead to extracellular expansion leading to LGE. In a study of 321 biopsy-proven sarcoidosis patients, CMR allowed the diagnosis of 44 patients with normal echocardiograms, as well as 15 asymptomatic patients. LGE may independently predict future adverse events, such as atrioventricular block (AVB), ventricular tachycardia (VT), sudden cardiac death (SCD) and heart failure (Nadel et al., 2015). Association of LGE on CMR with adverse cardiac outcomes is shown in other studies as well (Ichinose et al., 2008; Nagai et al., 2014). There is often a multifocal distribution, although a pattern of enhancement is not pathognomonic for CS (Cummings et al., 2009). LGE is mostly seen in basal segments, particularly of the septum and lateral wall, and usually in the midmyocardium and sub-epicardium (non-infarct pattern) as opposed to sub-endocardial scarring in the event of myocardial infarction. Few studies have focused on right ventricular involvement, suggesting that the RV free wall may also be involved in predicting adverse outcomes, particularly ventricular tachyarrhythmias (Crawford et al., 2014; Patel et al., 2011). The presence of LGE in patients with normal or near-normal LVEF greatly increases the likelihood of adverse events (Agoston-Coldea et al., 2016; Coleman et al., 2017; Ekström et al., 2016; Ise et al., 2014; Murtagh et al., 2016; Shafee et al., 2012; Yasuda et al., 2016). Remarkably, CMR identifies small regions of myocardial damage in subjects with preserved LV systolic function, allowing detection of “silent” CS (Pizarro et al., 2016). Interestingly, involvement of the RV in addition to the LV increases the risk of worse outcomes and all-cause mortality (Smedema et al., 2017). CMR with LGE is less sensitive regarding active myocardial inflammation; consequently, it may not properly guide immunosuppressive therapy. Moreover, CMR is not useful for extra-cardiac sarcoidosis compared to CT and PET-CT. Novel CMR techniques utilizing T1 and T2 mapping may allow detection of myocardial inflammation, suggesting a role in monitoring response to treatment (Crouser et al., 2014; Puntmann et al., 2017). The main value of CMR in the diagnostic algorithm of CS is its high negative predictive value, which exceeds 90% (Cheong et al., 2009). Representative CMR images of cardiac sarcoidosis are shown in Fig. 2.

Fig. 2.

Cardiac magnetic resonance images in a 54-year-old male with cardiac sarcoidosis, showing late gadolinium enhancement in the posterior-lateral left ventricle wall sub-epicardially (B, yellow arrows).

Neither CMR nor PET alone are positive in all CS cases. This is why when CMR is found normal – or is not available – further investigation with PET is warranted. Fluorodeoxyglucose (FDG) is a glucose analog that is useful in differentiating between normal and active inflammatory lesions (Pellegrino et al., 2005). In contrast to CMR which detects scar tissue, PET recognizes myocardial inflammation. FDG-PET testing should be performed at experienced centers (Birnie et al., 2014). Its use in assessing cardiac involvement in sarcoidosis requires extensive pre-imaging preparation to suppress physiologic glucose uptake by normal myocardium (Osborne et al., 2017). Although there are no specific imaging findings pathognomonic for CS diagnosis, focal or focal-on diffuse FDG uptake patterns suggest active CS (Ishimaru et al., 2005; Youssef et al., 2012). PET alone compared to Japanese guidelines showed 89% sensitivity and 78% specificity in diagnosing CS (Ishimaru et al., 2005). The presence of FDG uptake and perfusion defects on PET is associated with higher risk of VT or death. RV involvement on PET scan may be a marker of severe disease, a finding observed in CMR studies as well. FDG uptake serves as an excellent tool for early diagnosis and guiding therapy with a follow up approximately every 6 months (Blankstein et al., 2014). Abnormal tracer accumulation, initially considered a minor criterion for diagnosis, is now upgraded as a major criterion for diagnosis in recently published Japanese guidelines (Chareonthaitawee et al., 2017; Kumita et al., 2019; Terasaki and Yoshinaga, 2017; Wicks et al., 2018).

Given the high negative predictive value of CMR and the likelihood of 10-20% of false negatives with PET, CMR is given priority as initial diagnostic modality when CS is suspected in patients without contraindications for CMR testing. In a position statement, Slart et al. recommend the addition of FDG-PET to increase the diagnostic accuracy of CMR when disease is highly suspected (Slart et al., 2017). CMR and PET are therefore rather complementary, enabling imaging of the 2 different stages of the disease (i.e., fibrosis and inflammation); combination of the data is encouraged, especially if one of the tests yields inconclusive results (White et al., 2013). It should be noted that when CMR and/or PET reveal regional myocardial anomalies that may be due to sarcoidosis or atherosclerotic coronary artery disease, coronary angiography may be necessary to exclude significant coronary artery defects.

Three major guidelines exist for the diagnosis of CS. The first is the WASOG organ assessment tool published in 2014 and updated in the recent American Thoracic Society guidelines for sarcoidosis diagnosis (Crouser et al., 2020; Judson et al., 2014). The second is the HRS expert consensus statement in 2014 (Birnie et al., 2014) that suggested two diagnostic pathways: (a) histological diagnosis with the presence of noncaseating granulomas in myocardial tissue or (b) clinical diagnosis, as in histological diagnosis of extra cardiac sarcoidosis and one or more of the following clinical/imaging criteria: (1) cardiomyopathy and/or heart block, (2) unexplained sustained ventricular tachycardia, below 40%, (3) unexplained reduced left ventricular ejection fraction (4) Mobitz type II second-degree AV block or third-degree AV block, (5) late gadolinium enhancement on CMR in a pattern consistent with cardiac sarcoidosis, (6) patchy uptake of cardiac FDG-PET in a pattern consistent with cardiac sarcoidosis, or (7) positive gallium uptake in a pattern consistent with cardiac sarcoidosis.

All of these criteria, as well as immunomodulatory treatment responsive cardiomyopathy and/or AV block are considered features probable of sarcoidosis and in particular cardiac involvement in ATS guidelines (Crouser et al., 2020). When these criteria are present in a patient with known extra cardiac sarcoidosis, cardiac sarcoidosis is probable ($>$ 50% probability). When present in a patient without sarcoidosis diagnosis, these clinical features-criteria constitute compatible with sarcoidosis disease and necessitate histological confirmation (not necessarily from the heart) according to standard diagnostic criteria. Using the HRS criteria, isolated CS can thus only be diagnosed with myocardial tissue, making this challenging diagnosis difficult to confirm (Birnie et al., 2014). No firm criteria on how to manage suspected isolated CS exist.

The third major guideline is the Japanese Ministry of Health and Welfare guidelines, initially described in 1993 and updated in 2017 with the following significant changes: (1) allowing diagnosis of isolated CS without a positive endomyocardial biopsy, (2) adding ventricular arrhythmia to the major criteria along with high-grade atrioventricular block and (3) moving abnormal ventricular wall anatomy, elevated myocardial uptake with FDG-PET and late gadolinium-enhanced CMR imaging to major criteria (Hiraga et al., 1993; Terasaki et al., 2019). Most recently, the Japanese Society of Nuclear Cardiology updated the recommendations regarding the 18FDG PET/CT use in diagnosis of CS (Ishimaru et al., 2005). The Japanese criteria may reflect the increased incidence of CS and its implications in Japan.

The latest ATS sarcoidosis guidelines recommend screening for cardiac sarcoidosis based solely on symptoms or signs and ECG, considering TTE and 24-hour Holter monitoring only in selected cases (conditional recommendation with low quality evidence). Patients with suspected cardiac involvement should undergo initial investigation with cardiac magnetic resonance imaging, and/or PET when CMR is not available, to obtain diagnostic and prognostic information (Crouser et al., 2020). Major recommendations and guidelines are displayed in Tables 1 and 2.

When cardiac sarcoidosis is diagnosed or suspected without systemic sarcoidosis diagnosis, the term isolated cardiac sarcoidosis is used (ICS). Since established criteria for diagnosing CS require either extra-cardiac biopsy confirmation or EMB confirmation (a method of limited sensitivity as already shown), the diagnosis of ICS represents a true clinical challenge. Previous reports describe ICS as responsible for 25-65% of total CS (Kandolin et al., 2015; Okada et al., 2018). More recent data using FDG-PET report a more modest prevalence for ICS (9% of total) (Giudicatti et al., 2020). Scarce data indicate that ICS presents with lower LVEF, more frequent VTs, and necessitate ICDs more frequently than CS with systemic sarcoidosis (Kron et al., 2015; Okada et al., 2018).

ICS is rarely diagnosed compared to other causes of arrhythmogenic cardiomyopathy (ACM), often in cardiac explants post-transplant (Chang et al., 2012). Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease caused by mutations in desmosome encoding genes. Although HRS 2019 guidelines have established criteria for ARVC diagnosis (inverted T and epsilon waves on ECG, myocardial biopsy with decreased myocytes, VT‘s of LBBB, CMR features and family history, among others), confusion with ICS still occurs (Towbin et al., 2019). Electrophysiology studies have shown that reduced LVEF, a significantly wider QRS, right-sided apical VT, and more inducible forms of monomorphic VT are mainly encountered in ICS (Dechering et al., 2013). Differential diagnosis between ICS and ARVC may only partly be aided by modern diagnostic modalities, as shown in small cohorts (Steckman et al., 2012). Left ventricle scar on CMR points to ICS, while solely RV fibrosis points to ARVC, although both of these clues are not pathognomonic (Macias et al., 2014). The FDG-PET CT scan may test positive in ARVC as well as in ICS, as shown by Protonotarios et al (Protonotarios et al., 2019). Hoogendoorn et al. applied electroanatomical voltage mapping in order to characterize RV scar characteristics and distribution in ICS and ARVC. The authors validated their results in a separate CS population with excellent sensitivity and specificity (Hoogendoorn et al., 2020). Undiagnosed ICS may warrant ICD placement or transplant, as in other causes of ACM. An algorithm including CMR, FDG-PET, electroanatomic mapping (and guided-EMB) in experienced centers may facilitate the diagnosis of ICS in the near future (Muser et al., 2018).

Corticosteroids have been used for decades as first line treatment of cardiac sarcoidosis (Aryal and Nathan, 2019; Grutters and van den Bosch, 2006). Steroid-sparing immunomodulators have been used or tested as second line treatment for refractory disease. A large international multicenter registry found that 26.4% of CS patients were on steroids alone, 22.6% were on steroids and a steroid-sparing agent, and 9.7% were on steroid-sparing agent alone, with methotrexate being the first steroid-sparing choice (Kron et al., 2017). Retrospective studies have shown that corticosteroid treatment led to a reduction in VT, reversal of atrioventricular block, improvement in left ventricular ejection fraction and survival benefit (Banba et al., 2007; Furushima et al., 2004; Hulten et al., 2016; Kusano, 2013; Stees et al., 2011). Corticosteroid therapy in cardiac sarcoidosis is mainly responsible for an improvement in ejection fraction in patients with mild to moderate LV dysfunction, or in patients with severe dysfunction and LVEF 35% as shown elsewhere (Sadek et al., 2013).

Long-term use of high doses of corticosteroids adversely affects patients’ quality of life and has been associated with life-threatening side effects (Baughman et al., 2006; Cox et al., 2004; Nagai et al., 2014; Uthman et al., 2007). A prednisone dose of 40mg daily appears to be as effective and less toxic than higher doses administered in the past. A commonly used initial dose for those receiving prednisone only is 40mg daily, while for those patients receiving an additional immunosuppressive agent, the initial dose is often $\le$ 20 mg daily. Based on response to treatment after 1 to 3 months, prednisone should be tapered to 5 to 15 mg/day for an additional 9 to 12 months, while follow up should comprise at least 3 years in case of disease relapse (Fussner et al., 2018) Silent CS patients are difficult to handle, since a clear benefit on survival lacks. Hence, as mentioned above, the balancing between suppression of the disease and side effects can be challenging, while optimal dosage and duration of therapy remain unclear (Hamzeh et al., 2012; Chapelon-Abric et al., 2004; Chiu et al., 2005; Sperry et al., 2018). Regarding asymptomatic cardiac sarcoidosis, some centers will assess and monitor, while others will initiate therapy with a dose of 30-40 mg prednisolone (Beegle et al., 2013). The effect of corticosteroids is variable, depending on whether the mechanism is related to myocardial scar formation or active inflammation (Schutt et al., 2010). Methotrexate is often used as a second-line agent, with a study showing that 80% of physicians consider it as a first-choice second-line treatment (Nagai et al., 2014). The usual dose of methotrexate is 10-25 mg once weekly with a 5 mg folic acid supplement (Nagai et al., 2014). Other second line therapies include mycophenolate mofetil, azathioprine, cyclophosphamide and lately infliximab (Demeter, 1988; Müller-Quernheim et al., 1999). Methotrexate and/or adalimumab have shown efficacy in maintaining radiographic disease quiescence after a tapering-off of prednisone, although patients who discontinue immunosuppression have increased risk of radiologic recurrence and recurrent VT (Rosenthal et al., 2019). Furthermore, immunosuppression with prednisone and methotrexate showed lower risk for recurrence, lower steroid dose and less side effects compared to treatment solely with prednisone (Ballul et al., 2019). The use of immunosuppression to prevent disease reactivation is prolonged, and close follow up with PET scans is useful when treatment is stopped (Fig. 3) (Bremer et al., 2018; Mankad et al., 2019). Studies on cardiac sarcoidosis treatment are shown in Table 3.

Fig. 3.

FDG-PET of a 63-year-old female on methotrexate for cardiac sarcoidosis before (a) and during (b) therapy with methotrexate for 2 years, exhibiting a significant decrease in FDG uptake in the heart suggesting adequate response to therapy. The scan continues to show FDG uptake in mediastinal lymph nodes (Bremer et al., 2018)

Corticosteroids and antiarrhythmic drugs are initiated together for VTs when active inflammation is evident (Jefic et al., 2009), while catheter ablation and cardioverter defibrillator implantation are suggested if VT cannot be controlled (Naruse et al., 2014; Segawa et al., 2016). Amiodarone and sotalol are classic choices, although VTs are frequently resistant. The potential side effects of amiodarone include pneumonitis and pulmonary fibrosis, so a long-term treatment is not indicated for young patients (Birnie et al., 2014). Ablation therapy can be an option in VTs refractory to medical therapy. Despite a successful ablation, the recurrence rate remains high, although the total arrythmia burden may be reduced in up to 88% of cases with few major procedure related complications (Muser et al., 2016; Okada et al., 2018; Papageorgiou et al., 2018). CMR and PET findings could help in selecting more suitable patients for ablation therapy (Sohn et al., 2018). Yalagudri et al. stratified sarcoidosis patients with unexplained VT by FDG-PET results. They found that patients with increased myocardial FDG uptake were treated with immunosuppression, antiarrhythmics, and received ICD placement. If they had recurrence and had increased myocardial FDG uptake on their repeat FDG-PET CT scan, their immunosuppression was intensified. Patients without myocardial FDG uptake on initial PET CT scan were treated with antiarrhythmics and ICD without immunosuppression; if they lacked good clinical response, they later underwent catheter ablation. 13/14 patients in the inflammation cohort remained free of VT at their last follow-up visit (mean 38.2 months). All 4 patients in the scar cohort, despite the use of ICD and antiarrhythmics, experienced VT recurrence and underwent catheter ablation (Yalagudri et al., 2017). This study illustrates the fact that myocardial disease is more responsive to immunosuppressive treatment while arrythmias, though also partially responsive, will need risk assessment and electrophysiology study for ICD placement. In a large series, all patients with atrioventricular block at presentation underwent device placement (Fussner et al., 2018). According to HRS statement, implantable cardioverter defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-Ds) are the preferred options compared to conventional pacemakers for cardiac sarcoidosis patients presenting with heart block (Birnie et al., 2014). Heart transplantation is seldom indicated, but may be of use in young refractory cases with non-responsive ventricular tachycardia or severe heart failure (Fussner et al., 2018).

Sudden cardiac death (SCD) is considered responsible for the majority of deaths in cardiac sarcoidosis (Roberts et al., 1977). HRS 2014 guidelines highlight that in CS with conduction abnormalities, device implantation and an implantable cardioverter-defibrillator are useful, along with immunosuppression when 2${}^{nd}$ or 3${}^{rd}$ degree AV block are present (Birnie et al., 2014). Atrial arrythmias require anti-coagulation, electrophysiological study (EPS) in cases other than atrial fibrillation and avoidance of class I anti-arrhythmic drugs (propafenone, flecainide, procainamide). On the other hand, ventricular arrythmias may require ablation and anti-arrhythmics in addition to systemic treatment. EPS is recommended in CS in cases of LVEF $>$ 35% despite immunosuppression.

ICD is recommended in case of 1) spontaneous sustained ventricular arrhythmias and 2) in cases of LVEF 35% despite optimal immunosuppression treatment. ICD may be useful in cases of inducible ventricular arrythmias, unexplained syncope, when a pacemaker placement is indicated, and in cases of LVEF between 36-49%. ICD is not recommended when EF is normal, without syncope history, with normal CMR and EPS study, or with no indication for pacemaker use (Birnie et al., 2014).

Identifying patients at risk for SCD is difficult (Ekstrom et al., 2016; Mehta et al., 2011; Vignaux et al., 2002). CS patients who have had sustained VT/ VF or LVEF 35% have a high risk of recurrent events, SCD, and a class I indication/recommendation for ICD (Betensky et al., 2012; Kron et al., 2013; Schuller et al., 2012). In general ICD is used in CS with low LVEF, as shown in a multicenter study of 235 CS patients, where patients who received ICD therapy had a lower mean LVEF compared with those who did not receive such therapy (38.1% versus 48.5%) (Kron et al., 2013).

CS patients with AV block and preserved LV function are shown to carry a 9% risk of SCD and 24% risk of SCD/VT at 5 years (Nordenswan et al., 2018). This is in line with the above suggestion to implant an ICD when a pacemaker is recommended, even with preserved LVEF (Birnie et al., 2014). The 2018 ACC/AHA/HRS Guideline agreed with the recommendation for ICD implantation in cardiac sarcoidosis patients with an indication for pacing (Kusumoto et al., 2019). This recommendation includes patients with second- or third-degree AV block who are on antiarrhythmic or beta blocker therapy and immunosuppression.

EPS is recommended in relatively preserved LVEF. This is because it has not shown more predictive value than LVEF, whereas the inducibility of sustained ventricular arrhythmias is inversely correlated with LVEF (Aizer et al., 2005). We have already discussed the prognostic significance of CMR and PET on VAs, VTs, and SCD (Yasuda et al., 2016; Youssef et al., 2012).

A recent study showed that adverse cardiovascular events in cardiac sarcoidosis (VA, SCD, and heart transplantation) occur even if LVEF is moderately affected (Rosenthal et al., 2020). This is in accordance with other studies showing that Electro-physiology study had good predictive value for future VA as well in patients with LVEF $>$ 35% that don’t meet primary indication for ICD therapy; this subgroup is mainly indicated for EPS to guide management (Freeman et al., 2013; Hamzeh et al., 2015; Okada et al., 2019; Suzuki et al., 1994). A suggested management algorithm of cardiac sarcoidosis is proposed in Fig. 4.

Fig. 4.

Suggested management algorithm for patients with probable cardiac sarcoidosis. ATS, American thoracic society criteria, biopsy of extra cardiac site; ECG, electrocardiogram; CMR, cardiac magnetic resonance, PET, positron emission tomography; VA, ventricular arrythmias; LVEF, left ventricle ejection fraction; EPS, electrophysiologic study; ICD, implantable cardioverter defibrillator.