Management and prognosis of cardiac sarcoidosis

INTRODUCTION — 

The clinical presentation of cardiac sarcoidosis (CS) ranges from an incidentally discovered condition to heart failure (HF), brady- and tachyarrhythmias, and sudden cardiac death (SCD). The diagnosis of CS is challenging and is frequently missed or delayed. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

Patients who have CS are at risk for adverse cardiovascular outcomes, including death and ventricular tachycardia. However, data regarding how various therapies might mitigate this increased risk are limited.

This topic will provide an overview of clinical and imaging variables used to determine the prognosis of patients with definite or probable CS and a discussion of management of CS. The clinical manifestations and diagnosis of CS are discussed separately. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

APPROACH TO MANAGEMENT — 

The management of CS often requires multidisciplinary care teams, especially when other organ involvement is present or when additional expertise regarding the use of potent antiinflammatory therapies (eg, biologic therapy) is required. In such cases, cardiologists (especially electrophysiologists and HF specialists), rheumatologists, imaging experts, and other specialists often work together to provide optimal patient management.

There are several challenges related to the management of patients with CS. First, data regarding the benefit of treatment are limited to small observational studies. Second, most of the treatments that are used (eg, immunosuppressive therapies and implantable cardioverter-defibrillators [ICDs]) have a high likelihood of adverse effects. Third, many patients may have probable (but not definitive) CS, and thus clinicians often have to decide whether or not to use various therapies in cases with an uncertain diagnosis.

The first step in managing patients with suspected CS is determining the probability of CS, as described separately. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

The main goals of patient management include preventing disease progression, avoiding the development of worsening of left ventricular (LV) dysfunction, managing atrioventricular (AV) block, and managing arrhythmias and risk of sudden death. The following approach applies to patients with definite or probable CS (table 1):

●Monitoring – Patients should receive periodic clinical evaluation to detect new or worsening symptoms and assess for adverse effects (eg, diabetes) of any treatment (eg, glucocorticoids). At least yearly evaluation is suggested for asymptomatic patients with CS, with more frequent evaluation in patients receiving immunosuppressive therapy or with HF.

In patients with CS and new evidence of clinical disease activity (eg, symptoms, arrhythmias), we typically obtain echocardiography and either cardiovascular magnetic resonance (CMR) imaging or ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) for further assessment. In such cases, FDG-PET is most helpful if there is a question regarding the need to reinitiate or intensify immunosuppression. CMR is most helpful to identify any changes in scar or ejection fraction. In addition to these tests, or if these tests are not available, echocardiography may be useful if there is concern for a decrease in left or right ventricular (RV) function or valvular function.

●Management of cardiovascular risk factors – Patients with CS may have an increased risk of coronary artery disease (CAD), and primary prevention of CAD should be pursued in a manner similar to the general population [1]. (See "Overview of primary prevention of cardiovascular disease in adults" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

●Heart failure therapies – Patients with HF (HF with reduced ejection fraction, HF with preserved ejection fraction, or HF with mid-range ejection fraction) should receive standard therapy for these conditions, as discussed separately. (See "Treatment and prognosis of heart failure with preserved ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Treatment and prognosis of heart failure with mildly reduced ejection fraction".)

Despite case reports of reactivation of sarcoidosis following orthotopic heart transplantation, the presence of cardiac or systemic sarcoidosis should not preclude cardiac transplantation if otherwise indicated [2]. (See "Heart transplantation in adults: Indications and contraindications", section on 'Considerations for hypertrophic or restrictive cardiomyopathy'.)

●Treatment of asymptomatic LV systolic dysfunction – Patients with LV ejection fraction (LVEF) ≤40 percent who do not have HF should receive standard treatment for asymptomatic LV systolic dysfunction, as discussed separately. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction".)

●Immunosuppressive therapies – Indications for immunosuppressive therapy in patients with definite or probable CS who have evidence of active myocardial inflammation are discussed below. (See 'Indications for immunosuppression' below.)

●Management of conduction abnormalities – Patients with CS with AV block are treated with immunosuppressive therapy and may require a permanent pacemaker. (See 'Indications for immunosuppression' below.)

●Management of ventricular arrhythmias and risk of SCD – Management includes risk stratification to determine when ICD implantation is appropriate. (See 'Arrhythmias and conduction system disease' below.)

IMMUNOSUPPRESSIVE THERAPIES

Goals of therapy — The main rationale for immunosuppressive therapies is to reduce the burden of inflammation, thus preventing fibrosis and preventing deterioration of cardiac structure and function. Immunosuppressive therapy may also decrease the burden of ventricular and supraventricular arrhythmias and of HF symptoms. There are no reliable studies that address quality of life.

Indications for immunosuppression — The indications for immunosuppression are dependent on the certainty of the diagnosis and the effect on the heart and other organs:

Definite or probable cardiac sarcoidosis — The following recommendations apply to patients with definite or probable CS by Heart Rhythm Society criteria:

●Symptomatic patients with signs of cardiac involvement – For patients who have clinical manifestations of cardiac involvement (HF, LV systolic dysfunction, heart block, or ventricular arrhythmias) and evidence of active myocardial inflammation (by FDG-PET or myocardial histology), we suggest immunosuppressive therapy rather than no such therapy.

●Asymptomatic patients – For asymptomatic patients with normal LVEF and RV ejection fraction (RVEF) and no history of arrhythmias, we suggest an individualized assessment of the potential risks and benefits of treatment. Such assessment may include evaluation of the burden of inflammation in the heart, as well as the burden of inflammation that may be present in other organs, as determined by a limited whole-body FDG-PET study. Patients with CS who are asymptomatic and have a preserved LVEF generally have a low event rate; data are lacking on immunosuppressive therapy in this population. Thus, this recommendation is based upon indirect observational evidence on immunosuppressive therapy in patients with CS and depressed LVEF.

Suspected cardiac sarcoidosis — In patients with suspected CS, we do not administer immunosuppression; further testing is required to ensure that there is probable or definite CS as well as active inflammation.

The role of glucocorticoids in treating extracardiac disease is discussed separately. (See "Treatment of pulmonary sarcoidosis: Initial approach" and "Neurologic sarcoidosis" and "Kidney disease in sarcoidosis" and "Hypercalcemia in granulomatous diseases".)

Identification of inflammation — Evidence of inflammation should generally be evaluated by the use of cardiac imaging tests or myocardial histology, as blood markers of inflammation convey the presence of systemic inflammation and are not specific to the heart.

The most robust data on the presence and severity of myocardial inflammation are provided by cardiac FDG-PET; it is recommended that this test be performed whenever immunosuppressive therapies are considered in order to determine the amount and severity of myocardial inflammation and obtain a baseline measure of disease activity for the purpose of future comparison. However, FDG uptake by the heart is not specific to CS and has been described in other conditions [2]. The presence of a resting perfusion defect on single-photon emission computed tomography (SPECT) or FDG-PET imaging can be used to increase diagnostic certainty, as described separately. Cardiac FDG-PET is not a test that is routinely available at most centers and often requires referral to a center that has PET availability, as well as expertise in the acquisition and interpretation of this examination. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'FDG-PET' and "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Differential diagnosis'.)

Alternatively, CMR imaging may identify the presence of edema via T2-weighted imaging or T2 mapping techniques [3,4]. However, while identification of increased T2 signal by CMR may have an adequate positive predictive value, the negative predictive value is low, and thus the absence of edema on CMR cannot be used to rule out myocardial inflammation or to determine that immunosuppressive therapy is not required. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Cardiovascular magnetic resonance' and 'CMR studies' below.)

Agents — Immunosuppressive regimens for treatment of CS are not well established. Further study is needed to better define the role of immunosuppressive therapies, including the ideal regimen, dose, and duration of therapy, as well as whether glucocorticoid-sparing agents can be used as first-line therapy, thus avoiding glucocorticoids. However, given that CS remains relatively infrequent, and since there is a wide variability in severity of disease and clinical symptoms upon presentation, such studies are difficult to conduct and require multicenter collaborations.

Glucocorticoid — Glucocorticoid therapy is the most commonly used immunosuppressive agent in this setting, but there is lack of consensus on glucocorticoid dosing, duration of therapy, or when to use additional immunosuppressive agents in CS [5]. The optimal dose of glucocorticoid therapy for CS is not known, and choosing a dose requires balancing the risk of side effects with the likelihood of response [6,7]. It is unknown whether glucocorticoid dose should be adjusted for body surface area or whether the effective dose varies among patient populations.

For a patient with CS with an indication for immunosuppressive therapy, we suggest generally starting with a dose of 30 mg/day of prednisone and gradually reducing this dose to a maintenance level of 10 to 15 mg/day over one year. Higher doses may be considered when there is evidence of extensive inflammation (by cardiac PET) as well as significant clinical manifestations of myocardial inflammation. However, doses of 40 to 60 mg of prednisone daily are associated with greater side effects and it is unclear if there is greater efficacy from using higher doses. Prednisone may be combined with a glucocorticoid-sparing agent, such as methotrexate, mycophenolate mofetil, azathioprine, or leflunomide [6]. The details on adding such agents are discussed below. (See 'Second-line treatment' below and 'Third-line treatment' below.)

Patients who have complete resolution of inflammation are at risk for recurrence of disease activity. Therefore, we suggest continuing low-dose glucocorticoid therapy (eg, prednisone 5 mg) for at least one year, especially if low-dose glucocorticoid therapy is well tolerated. Thus, glucocorticoid treatment should be continued for at least one to two years. In patients with significant inflammation, FDG-PET imaging at approximately six months of therapy may be reasonable to assess treatment response. If serial evaluations reveal that the disease is stable or dormant, glucocorticoids may be tapered and eventually discontinued. However, vigilance must continue for the rest of the patient's life, as relapses are common after tapering of glucocorticoid therapy. Any evidence of recurrence may be handled by reinstituting or increasing prednisone to 30 mg/day or adding a glucocorticoid-sparing agent as described below.

There are no data from randomized trials regarding the efficacy of glucocorticoid therapy, and observational studies have generally lacked adjustment for potential prognostic differences in treated and untreated patients. With this caveat, retrospective studies suggest that glucocorticoid therapy can improve AV block. In addition, there are limited data suggesting that glucocorticoid therapy may prevent LV dysfunction, particularly if treatment is initiated before the onset of moderate or severe systolic dysfunction. A means to predict who may or may not be glucocorticoid-responsive remains unknown. The effect of glucocorticoid therapy on ventricular arrhythmias is even less certain [8,9].

A systematic review of 34 retrospective studies included 1125 patients treated with glucocorticoids, 235 that received additional or other immunosuppressant therapy, and 97 patients that received no therapy [10]. There were 178 patients treated for AV conduction disease, and 43 percent improved with glucocorticoid therapy. In contrast, among the 21 patients who were not treated with immunosuppressive therapy, there was no improvement. Therapy was associated with the prevention of deterioration in LV function. The data quality was too limited to draw conclusions for the impact of therapy on ventricular arrhythmia burden (eight studies) or mortality (19 studies).

Second-line treatment — Due to the harmful side effects of glucocorticoids, the use of glucocorticoid-sparing agents is becoming increasingly common, either in addition to glucocorticoids or instead of glucocorticoids. The addition of a glucocorticoid-sparing agent to glucocorticoid therapy is often helpful to minimize glucocorticoid-related toxicities [5,11-13]. Limited data and clinical experience support selective use of methotrexate as an add-on agent to glucocorticoid therapy, enabling discontinuation or tapering of glucocorticoid to low doses [13-15]. An observational study of patients treated with glucocorticoid plus methotrexate and/or adalimumab is discussed below. (See 'Third-line treatment' below.)

There is substantial variability among experts in the use of glucocorticoid-sparing agents for initial treatment of CS. With no prospective comparative studies available, we recommend using an approach that minimizes drug toxicity. One approach is to initiate therapy with prednisone 30 mg/day and a glucocorticoid-sparing agent, generally methotrexate or mycophenolate. Another approach is to start prednisone therapy and to add on a glucocorticoid-sparing agent while tapering the dose of prednisone (a decision which can be guided by a favorable response to therapy by FDG-PET imaging). Glucocorticoid-sparing agents may be especially preferred in patients who are more likely to experience adverse events from glucocorticoids, such as those with diabetes.

Third-line treatment — For patients who do not respond to therapy with glucocorticoid and/or a glucocorticoid-sparing agent or who cannot tolerate the side effects of such therapy, options include azathioprine, leflunomide, mycophenolate mofetil, or a tumor necrosis factor (TNF) antagonist (eg, infliximab or adalimumab). Data regarding these agents remain limited but suggest effectiveness in selected cases. Their use depends on clinical features including the severity of the disease and the experience of the clinician. The role of these agents in treating extracardiac disease is discussed separately. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

Limited data are available on mycophenolate use in this setting [16,17]. In a case series including 73 patients with criteria for CS, mycophenolate use was associated with a survival benefit on a univariate analysis, but this did not persist in a multivariable model [16].

There is an increasing role for TNF antagonists in patients with CS [18], although these agents may worsen HF and thus should be used with great caution in patients who have volume overload or other signs or symptoms of HF. Given the increased toxicities (including risk of infection) and cost associated with anti-TNF agents, these should be used as third-line options in patients who have an inadequate response to or intolerance of other agents [18,19].

A retrospective observational study of 28 CS patients, most of whom received an initial course of high-dose prednisone (>30 mg/day), followed by a taper, evaluated the response of maintenance with methotrexate with or without low doses (<10 mg/day) of prednisone [13]. The use of methotrexate resulted in initial reduction of FDG uptake in 88 percent of patients and elimination in 60 percent of patients. Adalimumab was added in 19 patients with persistently active CS or those intolerant to methotrexate and was associated with FDG uptake improvement in 84 percent and resolution in 63 percent. While nonrandomized and nonblinded, these findings support an important role for these add-on or alternative agents.

Monitoring treatment effects — When immunosuppressive therapy is implemented, the response rate, as assessed by cardiac PET, can be highly variable [20,21]. Factors that may be associated with improved treatment response include higher baseline (ie, pretreatment) disease activity and use of moderate- to high-intensity glucocorticoid dose. Because of the variable response rate and the need to minimize exposure to high doses of antiinflammatory therapies, repeat FDG-PET imaging to assess treatment response is reasonable to perform four to six months after treatment initiation, especially if such information will impact the intensity or duration of treatment.

ARRHYTHMIAS AND CONDUCTION SYSTEM DISEASE — 

Among patients with CS, sudden death is estimated to account for nearly two-thirds of all fatalities [22], and, in 14 percent of patients, fatal or aborted SCD accounts for the presenting manifestation of CS. In addition, there is a high rate of recurrence of ventricular tachycardia (VT) or sudden death with antiarrhythmic drug therapy, even when guided by electrophysiologic (EP) testing [9]. These observations constitute the rationale for the use of pacemakers and ICDs.

Management of conduction abnormalities — A permanent pacemaker is indicated when there is complete AV block or other high-grade conduction system disease is present, even if the high-grade conduction disease reverses transiently [23]. Glucocorticoids or other forms of antiinflammatory therapy should be continued on an individual basis (as tolerated and as needed clinically) in patients who have pacemakers. (See "Permanent cardiac pacing: Overview of devices and indications".)

Approach to ventricular arrhythmias — The management of ventricular arrhythmias and risk of SCD in patients with CS includes the following components (in addition to treatment of HF or asymptomatic LV systolic dysfunction) [24]:

●Immunosuppressive therapy (although there is limited evidence of efficacy for this purpose). (See 'Immunosuppressive therapies' above.)

●Antiarrhythmic drug therapy as for other patients with structural heart disease and VT, although evidence in patients with CS is limited [25]. (See "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management", section on 'Treatment of patients with structurally normal hearts' and "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.)

●Catheter ablation is an option if arrhythmias are refractory to medical therapy, although results have been mixed [26-28]. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation' and "Nonsustained ventricular tachycardia: Clinical manifestations, evaluation, and management".)

●Risk stratification and ICD therapy as indicated. (See 'Implantable cardioverter-defibrillator' below.)

Implantable cardioverter-defibrillator

Indications — The following recommendations for ICD therapy for patients with definite or probable CS are consistent with the 2017 American College of Cardiology/American Heart Association/Heart Rhythm Society (AHA/ACC/HRS) guideline for management of ventricular arrhythmias and the prevention of sudden death, which includes specific recommendations for patients with CS [29,30]. As for ICD therapy generally, these indications are limited to patients with expected meaningful survival of greater than one year. (See "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Indications'.)

●ICD therapy is appropriate for secondary prevention for patients with structural heart disease (including CS) who have survived sustained VT or sudden cardiac arrest (SCA), as discussed separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Evidence for use of ICD therapy'.)

●For patients with CS with one or more of the following features, we suggest ICD therapy for primary prevention:

•LVEF ≤35 percent

•Abrupt-onset syncope

•Imaging evidence of scar (significant late gadolinium enhancement [LGE] on CMR or perfusion/metabolism mismatch on FDG-PET)

One study found that certain LGE patterns (termed "pathology frequent LGE," as these patterns were based on typical findings observed on pathology specimens) may be associated with a higher risk of events: LV subepicardial, LV multifocal, septal, or RV free wall involvement. Importantly, these features added additional prognostic value beyond LGE extent greater than 5.7 percent [31]. Thus, beyond just the presence or amount of LGE, the pattern of LGE may also contribute to risk assessment. Our experience, and that of others, is similar in that multifocal LGE is more likely to be associated with increased risk, while some LGE findings (eg, single small focus of patchy LGE along the RV insertion point) are less likely to be associated with high risk.

●For patients with CS requiring pacemaker placement for high-grade AV block, we suggest implanting a system with pacemaker and ICD functions rather than a pacemaker system alone. (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Acquired AV block'.)

●Most patients with definite or probable CS will have one of the above indications for ICD implantation. For patients with CS without one of the above indications for an ICD, referral to an electrophysiologist for EP study is reasonable. For patients with inducible sustained VT on EP study, we suggest ICD implantation. (See 'Role of electrophysiologic study' below and "Invasive diagnostic cardiac electrophysiology studies".)

Risk stratification — Patients at highest risk of ventricular arrhythmias and SCD are those most likely to benefit from ICD therapy. Thus, prognostic information is useful to aid shared decision-making on ICD implantation based upon an individualized assessment of potential benefits and risks, particularly for patients who do not have a general indication for an ICD for secondary or primary prevention of SCA (such as those with normal or only mildly impaired LV systolic function). The above recommendations are based upon studies showing adverse prognosis among patients with CS with the following risk factors: prior VT/ventricular fibrillation (VF), severity of HF, history of syncope, severity of LV dysfunction, and extent of cardiac involvement on CMR or FDG-PET [9,32-35]. (See 'Indications' above.)

Of note, some CS patients with normal EF and no HF symptoms have a high event rate, especially when extensive LGE is identified on CMR or abnormal myocardial FDG uptake and resting perfusion defects are identified on cardiac FDG-PET imaging. Therefore, the decision on whether to proceed with ICD therapy should not be based solely upon LVEF. Some patients with CS who do not have prior sustained VT, SCA, or LVEF ≤35 percent have higher risk of death and VT than generally seen in primary and secondary SCD prevention cohorts. In fact, once accounting for abnormal findings based on FDG-PET or CMR, the association between EF and subsequent events is no longer significant. Supporting this, a single-center study evaluating 205 patients with extracardiac sarcoidosis with preserved LVEF found that the presence of LGE on CMR was associated with increased risk of death/VT [36]. Similarly, two studies evaluating the prognostic values of cardiac FDG-PET found that abnormalities on these tests offered incremental prognostic data after accounting for all clinical variables and LVEF [37,38]. (See 'Advanced cardiac imaging' below.)

A study of 290 patients with biopsy-proven sarcoidosis with known or suspected CS examined the relationship between various ICD criteria from the 2018 ACC/AHA/HRS guidelines and patient outcomes at a median follow-up of three years [39]. The endpoint was a composite of SCD, resuscitated cardiac arrest with documented VT, significant ventricular arrhythmia including sustained VT, and appropriate ICD therapy.

The following annualized event rates were observed (from highest to lowest) for the following indications:

●Prior history of sustained VT or SCA – 81.7 percent.

●LVEF >35 percent with need for permanent pacemaker – 19.6 percent.

●LVEF ≤35 percent – 19.4 percent.

●LVEF >35 percent with syncope – 2.7 percent.

●LVEF >35 percent with any LGE – 2.1 percent (LVEF >35 percent with >5.7 percent LGE – 12.0 percent). (See 'CMR studies' below.)

●LVEF >35 percent with inducible VT – 0 percent, but there was only one patient in this group. The role of invasive EP study is discussed below. (See 'Role of electrophysiologic study' below.)

Sustained ventricular tachycardia — Patients who have a prior history of sustained VT [39] or who have an ICD appear to have the highest rate of adverse events, and patients with CS with ICDs have high rates (approximately one-third of patients over two years) of appropriate therapies [6,40,41]. Although this may be in part be due to bias, as having an ICD likely results in an increased rate of detection and treatment of arrhythmic events, evidence suggests that patients with prior ventricular arrhythmias or with an indication for an ICD have a more arrhythmogenic substrate.

Advanced cardiac imaging — Several studies have demonstrated that advanced cardiac imaging with CMR or FDG-PET has predictive value for adverse cardiovascular events including death [37,42-44]. In fact, once accounting for abnormal findings based on FDG-PET or CMR, the association between LVEF and subsequent events is no longer significant.

Cardiac FDG-PET studies — Retrospective studies in patients with known or suspected CS have found that abnormal cardiac FDG-PET findings (abnormal FDG uptake plus a resting perfusion defect) are associated with adverse cardiac events, including sustained VT and death, as illustrated by the following studies:

●The prognostic value of perfusion-metabolism mismatch was demonstrated by a retrospective study of 118 patients with known or suspected CS referred for cardiac FDG-PET [37]. Thirty-one patients (26 percent) had an adverse event (sustained VT or death) at a mean follow-up of 1.5 years. Patients with both abnormal FDG uptake by the myocardium (eg, focal inflammation) and a resting perfusion defect (eg, scar or compression of the microvasculature) had a fourfold increase in the annual rate of VT or death compared with patients with normal imaging. These findings remained significant even after accounting for the Japanese Ministry of Health and Welfare (JMHW) criteria [45] and LVEF. Individuals who had evidence of focal FDG uptake involving the RV had the highest rate of death or VT [37]. Extracardiac FDG uptake was not associated with adverse events, suggesting that this finding is not helpful in determining need for ICD therapy. A similar relationship between abnormal FDG update and adverse effects was observed in a retrospective study of 38 patients with suspected CS [46].

●A role for quantitative analysis of FDG-PET results was suggested by a retrospective study of 203 patients with suspected CS referred for cardiac FDG-PET, which found that 63 patients (31 percent) had an adverse event (ventricular arrhythmia requiring defibrillation, death, or heart transplantation) during mean follow-up of 1.8 years [38]. Events were more common in patients with abnormal cardiac FDG-PET studies. Quantitative measures of the extent and severity of resting perfusion defects in segments that had evidence of inflammation (perfusion-metabolism mismatch) and heterogeneity (coefficient of variation) of FDG uptake were found to have incremental prognostic value after accounting for baseline clinical risk factors including LVEF, history of ventricular arrhythmias, and JMHW criteria.

CMR studies

●Late gadolinium enhancement – Observational studies in patients with suspected CS have suggested that CMR detection of LGE is associated with adverse outcomes. Collectively, these studies found that patients with suspected CS with LGE had significantly higher rates of death or ventricular arrhythmias than those without LGE. In part, this finding may reflect that most patients who do not have LGE do not have CS, but it also suggests that patients with suspected CS who demonstrate LGE should be considered for ICD therapy, particularly if they are symptomatic, if they have a reduced LVEF, or if they have other risk factors for having adverse events.

A systematic review and meta-analysis of patients referred to CMR imaging for known or suspected CS identified seven studies representing 694 subjects with mean follow-up of three years [47]. Overall, 29 percent of the patients had abnormal LGE on CMR, and the mean LVEF was 59 percent. Patients with LGE had a higher annual rate of all-cause mortality (3.1 versus 0.6 percent), cardiovascular mortality (1.9 versus 0.3 percent), and VT (5.9 versus 0 percent). These findings suggest that patients with known or suspected CS who do not have abnormal LGE on CMRs have an extremely low event rate.

Similar results were obtained by a second meta-analysis including 10 studies with a total of 760 patients with known or suspected CS referred for CMR imaging [48]. Patients with LGE had higher odds for all-cause mortality during a mean follow-up of three years (10.5 versus 3.5 percent; odds ratio 3.06). A subsequent series also identified LGE as an independent predictor of adverse cardiac events [49].

The prognostic value of a threshold LGE percentage of LV mass was suggested by the above cited single-center study of 290 patients with biopsy-proven sarcoidosis who underwent CMR for evaluation of known or suspected cardiac involvement [39]. The study examined the relationship between various ICD criteria from the 2018 ACC/AHA/HRS guidelines and patient outcomes. Over a median follow-up of three years, the optimal cutoff of LGE extent for the prediction of adverse events was >5.7 percent. Patients with LVEF >35 percent with any LGE by CMR had an annualized event rate of 2.1 percent while those who had >5.7 percent LGE had an annualized event rate of 12.0 percent. Thus, a cutoff of >5.7 percent LGE may improve specificity when compared with the criteria of any LGE. However, studies have reinforced the notion that the pattern of LGE involvement may be more important than the amount.

●Right ventricular abnormalities – In the above described cohort of 290 patients with sarcoidosis with known or suspected CS, RV dysfunction was present in 12 percent, and, over a median follow-up of 3.2 years, reduced RVEF was independently associated with all-cause death, while the presence of RV LGE (present in 5.5 percent of the cohort) was independently associated with a composite arrhythmic endpoint of SCD or significant ventricular arrhythmia [50].

●Other CMR parameters – While there are emerging data on various CMR quantitative techniques that may aid the detection of CS (eg, T1 and T2 mapping), data are lacking on how these parameters relate to diagnosis or prognosis. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Cardiovascular magnetic resonance'.)

Role of electrophysiologic study — While EP studies are not routinely performed for the diagnosis of CS, selected patients with suspected CS undergo EP studies for risk stratification. For patients with CS with LVEF >35 percent who lack a general or CS-specific indication for ICD therapy, we refer to an electrophysiologist for an individualized assessment and discussion with the patient of the risks/benefits of EP testing. For patients with CS who lack an indication for ICD therapy, the finding of inducible sustained VT would impact the decision to implant an ICD [24]. (See 'Approach to ventricular arrhythmias' above and "Invasive diagnostic cardiac electrophysiology studies".)

Some observational studies suggest that EP testing may help identify patients with CS at risk for ventricular arrhythmias or SCD and that those with spontaneous or inducible arrhythmias should receive an ICD [25,51-53].

●One series included 32 patients with CS with symptoms (palpitations, syncope, presyncope) and/or ventricular arrhythmia (including ventricular premature beats, nonsustained or sustained VT, or ventricular fibrillation [VF]) who underwent programmed ventricular stimulation [51]. All 12 patients with spontaneous (6) or inducible (10; 4 with spontaneous) sustained VT or VF received an ICD. At a mean 32-month follow-up, 9 of the 12 patients who had received an ICD had received an appropriate shock. By contrast, 2 of 20 patients without ICDs experienced SCD or sustained ventricular arrhythmias.

●In a series of 76 patients with CS identified by cardiac FDG-PET or CMR imaging and with no cardiac symptoms, 11 percent had inducible sustained ventricular arrhythmias and received an ICD [52]. LVEF was lower in patients with inducible ventricular arrhythmia (36.4 versus 55.8 percent). Over a median five-year follow-up, six of eight patients in the group with inducible ventricular arrhythmias had appropriate ICD shocks or died, compared with one death in the noninducible group.

●In a series of 25 patients with probable or definite CS with abnormal CMR or FDG-PET who all underwent EP testing, ventricular arrhythmias occurred in 10 (40 percent) patients over a median follow-up of 4.8 years. The presence of inducible arrhythmias on EP testing had a positive predictive value of 100 percent and negative predictive value of 93 percent for future ventricular arrhythmia events [25].

●In a series of 120 patients with probable or possible CS, biopsy-proven extracardiac sarcoidosis, and preserved LV and RV systolic function, seven (6 percent) patients had inducible VT during an EP study, of whom three (43 percent) required ICD therapies during 4.5-year mean follow-up. There was one fatal ventricular arrhythmia in a patient with possible CS and a negative EP study who was later found to have CS on autopsy [53].

However, the added value of EP testing in risk stratification and management remains uncertain, since many patients with inducible ventricular arrhythmias meet criteria for ICD placement for primary prevention in patients with CS (LVEF ≤35 percent, syncope, or imaging evidence of scar) or the indication for primary prevention in patients with nonischemic cardiomyopathy (LVEF ≤35 percent plus HF with New York Heart Association functional class II or III). For example, in the study of 32 patients cited above, the mean LVEF in the inducible VT group was 33 percent, and 40 percent of the inducible group had HF [51]. Thus, many patients with inducible VT may meet criteria for ICD placement regardless of the EP study results or their sarcoidosis diagnosis. (See "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF", section on 'Nonischemic dilated cardiomyopathy' and 'Approach to management' above.)

In patients with symptomatic bradycardia or heart block, an EP study is not required to determine need for pacemaker placement. However, EP studies may be helpful in deciding whether to implant a pacemaker or an ICD if it is unclear if the patient has an indication. (See "Permanent cardiac pacing: Overview of devices and indications".)

PROGNOSIS — 

A combination of clinical features, cardiac imaging findings and selective electrophysiologic (EP) testing is used to assess the risk of future adverse cardiovascular events in patients with CS, although the best means of assessing disease prognosis and choosing therapeutic interventions remains uncertain. There is marked variability in the presentation, progression and severity of CS. While patients with CS face high rates of adverse events, including ventricular arrhythmias, heart block requiring pacemaker implantation, HF, and death, many patients with CS do not have these events [24,43].

The role of identification of depressed LVEF, spontaneous sustained VT, advanced imaging findings (on FDG-PET and CMR), and inducible VT on EP testing in evaluating candidates for ICD placement is described above (see 'Implantable cardioverter-defibrillator' above). Additional clinical features in patients with CS that predict adverse cardiac events include symptoms of HF and depressed RVEF [50,54].

Patients with symptomatic CS and coexisting pulmonary involvement account for approximately 5 percent of all cases of sarcoidosis and experience worse survival than other patients with extracardiac sarcoidosis [54]. In the above cited study demonstrating the prognostic significance of sustained VT, worse New York Heart Association functional class and larger LV end diastolic diameter were additional independent predictors of mortality [6]. In one series of 110 patients with CS diagnosed between 1988 and 2012, the 20 patients presenting with HF had 1-, 5-, and 10-year transplantation-free survival rates of 90, 75 and 52.5 percent; these rates were substantially lower than those for the group as a whole (99.1, 93.5, and 89.3 percent) [54]. Similarly, in a series of 101 patients with pulmonary sarcoidosis, 16 of the 19 patients presenting with cardiac symptoms (predominantly HF) were diagnosed with CS; 4 of these 16 died during a mean follow-up of 1.7 years [55]. By contrast, 0 of 82 patients without a cardiac presentation died or had a cardiovascular complication during the follow-up period.

While patients with asymptomatic CS are thought to generally have a more benign course, sudden death can occur as an initial clinical manifestation of disease [22,56-58]. Thus, optimal detection and management of CS require heightened clinical suspicions of CS and close monitoring of CS disease progression, even for asymptomatic patients. (See 'Approach to management' above.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Myocarditis" and "Society guideline links: Sarcoidosis".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Sarcoidosis (The Basics)")

●Beyond the Basics topics (see "Patient education: Sarcoidosis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Approach to management – Management of patients with definite or probable cardiac sarcoidosis (CS) includes monitoring, management of underlying cardiovascular risk factors, heart failure (HF) therapy, treatment of asymptomatic left ventricular (LV) systolic dysfunction, immunosuppressive therapies, and management of arrhythmias, including device (pacemaker and/or implantable cardioverter-defibrillator [ICD]) therapy. (See 'Approach to management' above.)

•Immunosuppression – For patients with definite or probable CS who have clinical manifestations of cardiac involvement (HF, LV systolic dysfunction, heart block, or ventricular arrhythmias) and definitive evidence of active myocardial inflammation (by ¹⁸F-fluorodeoxyglucose-positron emission tomography [FDG-PET] or myocardial histology), we suggest immunosuppressive therapy (Grade 2C). (See 'Immunosuppressive therapies' above.)

For asymptomatic patients with definite or probable CS with normal LV ejection fraction (LVEF) and right ventricular ejection fraction (RVEF), we suggest an individualized assessment of the potential risks and benefits of immunosuppressive therapy. Such assessment may include evaluation of the burden of inflammation in other organs, as determined by a limited whole-body FDG-PET study.

•Treatments to prevent sudden death – As for ICD therapy generally, the following indications are limited to patients with definite or probable CS with expected meaningful survival of greater than one year (see 'Implantable cardioverter-defibrillator' above and "Implantable cardioverter-defibrillators: Overview of indications, components, and functions", section on 'Indications'):

-Secondary prevention – ICD therapy is appropriate for secondary prevention for patients with structural heart disease (including CS) who have sustained ventricular tachycardia (VT) or ventricular fibrillation or are survivors of sudden cardiac arrest (SCA), as discussed separately. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Evidence for use of ICD therapy'.)

-Primary prevention – For patients with one or more of the following features, we suggest ICD therapy for primary prevention: an LVEF ≤35 percent, abrupt onset-syncope, or imaging evidence of scar (significant late gadolinium enhancement [LGE] on cardiovascular magnetic resonance [CMR] imaging or perfusion/metabolism mismatch on FDG-PET when there is a high probability of CS) (Grade 2C).

For patients requiring pacemaker placement for high-grade atrioventricular (AV) block, we suggest implanting a pacemaker with ICD functionality, rather than a pacemaker system alone (Grade 2C). (See "Permanent cardiac pacing: Overview of devices and indications", section on 'Acquired AV block'.)

Most patients with definite or probable CS will have one of the above indications for ICD implantation. For patients with CS without one of the above indications for an ICD, it is reasonable to refer to an electrophysiologist for electrophysiologic (EP) study. (See 'Role of electrophysiologic study' above and "Invasive diagnostic cardiac electrophysiology studies".)

●Prognosis – Patients with CS face high rates of adverse events, including ventricular arrhythmias, heart block requiring pacemaker implantation, HF, and death. (See 'Prognosis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Talmadge King Jr, MD, who contributed as section editor to an earlier version of this topic review.