Diagnosis and Treatment of Cardiac Sarcoidosis
Article ID: CJ-22-0671
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Article ID: CJ-22-0671
About 5% of sarcoidosis patients develop clinically manifest cardiac features. Cardiac sarcoidosis (CS) typically presents with conduction abnormalities, ventricular arrhythmias and heart failure. Its diagnosis is challenging and requires a substantial degree of clinical suspicion as well as expertise in advanced cardiac imaging. Adverse events, particularly malignant arrhythmias and development of heart failure, are common among CS patients. A timely diagnosis is paramount to ameliorating outcomes for these patients. Despite weak evidence, immunosuppression (primarily with corticosteroids) is generally recommended in the presence of active inflammation in the myocardium. The burden of malignant arrhythmias remains important regardless of treatment, thus leading to the recommended use of an implantable cardioverter defibrillator in most patients with clinically manifest CS.
Sarcoidosis is a systemic inflammatory condition, characterized by the formation of noncaseating granulomas. Despite it being over 100 years from its original description, the etiopathology is still uncertain. Previous observations suggest that genetically susceptible individuals may mount a dysfunctional immunological reaction to undefined external agents. Infectious and occupational factors may also play a role in the development of specific forms of sarcoidosis.1–3 Grouping of macrophages, epithelioid cells, lymphocytes, fibroblasts, and collagen results in the formation of granulomas.1,4 The clinical course is highly variable because granulomas may resolve spontaneously or progress, leading to scarring, fibrosis, and organ failure.5
Sarcoidosis affects the middle-aged population, distributing similarly among both sexes.6 It is a global condition, although higher rates are reported among Northern European and African American individuals. Prevalence varies accordingly between 4.7 and 64 in 100,000.6
Lung involvement is predominant, followed by eyes and skin manifestations; however, sarcoidosis may potentially affect all organs of the body, including the heart. Cardiac sarcoidosis (CS) occurs in up to 25% of patients, although clinically manifest CS is less common, occurring in perhaps 5% of all patients.1,6–8 CS may appear in the context of disseminated disease, but may also present without extracardiac symptoms. The diagnosis of CS is challenging, requiring an elevated level of clinical suspicion. Data from a large prospective registry indicate an average delay of 22±52 months from symptom onset to diagnosis.9 During the past few years, reports have suggested that the incidence of CS is increasing,6,7 which is probably explained by improved clinical awareness and technological advances, particularly in the field of cardiac imaging. However, changing epidemiology of the disease cannot be excluded.
CS may lead to severe, potentially fatal outcomes, so prompt diagnosis is paramount to improving patients’ prognosis. The scope of this review is to summarize the features of this condition, bringing together the latest scientific progress from the field.
CS is often diagnosed in the context of overt cardiologic symptoms, but may sometimes represent an incidental finding in an otherwise asymptomatic patient.6 Conduction abnormalities, ventricular arrhythmias (VAs), including sudden cardiac death (SCD), and heart failure (HF), are the presenting features of clinically manifest CS (Table 1).7,8,10–13 SCD may be the first manifestation of CS.10,14 In a recent investigation of 351 CS patients, 54 of 84 deaths recorded (64%) were unexpected SCD in which CS was diagnosed only postmortem.14
| Publication | Country | Year | Sample | High-degree AVB |
VAs | HF | SCD |
|---|---|---|---|---|---|---|---|
| Kandolin et al7 | Finland | 2015 | 110 | 48 (44%) | 36 (33%) | 20 (18%) | 2 (2%) |
| Bobbio et al10 | Sweden | 2022 | 71 | 17 (24%) | 15 (21%) | 22 (31%) | 5 (7%) |
| Chow et al8 | New Zealand | 2022 | 45 | 18 (40%) | 3 (7%) | 13 (29%) | n/a |
| Cacoub et al11 | France | 2020 | 157 | 15 (10%) | 27 (17%) | 18 (11%) | n/a |
| Fussner et al12 | US | 2018 | 91 | 31 (34%) | 22 (24%) | 47 (51%) | n/a |
| Sato et al13 | Japan | 2022 | 49 | 27 (55%) | 15 (31%) | 25 (51%) | 3 (6%) |
AVB, atrioventricular block; HF, heart failure; SCD, sudden cardiac death and aborted sudden cardiac death; VA, ventricular arrhythmia.
CS should be considered as a differential diagnosis in the presence of the following findings:
• Unexplained persistent Mobitz II or 3rd-degree atrioventricular block (AVB) <60 years
• Idiopathic monomorphic VT or aborted SCD, in the absence of obstructive coronary artery disease or other cardiomyopathy
• Nonischemic cardiomyopathy.
Conduction AbnormalitiesHigh-degree AVB occurs due to granulomatous inflammation infiltrating the interventricular septum.15 High-degree AVB is often the presenting manifestation of CS, potentially preceding VT or HF by several years.6,7,16 In a prospective series of 32 patients aged <60 years with unexplained high-degree AV block, CS was diagnosed in 11 (32%).17 Similarly, in a Finnish study investigating 72 individuals <55 years old with significant conduction abnormalities requiring pacemaker implantation, biopsy-verified CS was found in 14 patients (19%), with an additional 4 patients (6%) diagnosed with “probable” CS.16
Screening for CS, by means of chest computed tomography (CT), cardiac magnetic resonance (CMR) or 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is recommended in individuals aged <60 years with significant conduction system disease.18,19
VAsVAs usually arise from areas of granulomatous scarring. Often macro-reentrant in nature, these arrhythmias can be found both in the context of active inflammation, and in scarred areas, after successful immunosuppressive treatment. Their occurrence can be life-threatening, as they often appear in clusters. A recent publication describing 24-h Holter monitoring of 164 CS patients from 25 centers showed that nonsustained VT and premature ventricular complex >5% were the most common findings and were documented in 34% and 22% of patients, respectively.20
HFSarcoid infiltration may lead to scarring, regional wall motion abnormalities and can induce severe geometric distortion and dysfunction of the ventricles. These patients are at risk of developing overt HF.
CS manifesting with HF may mimic other cardiomyopathies (e.g., arrhythmogenic cardiomyopathy, hypertrophic cardiomyopathy, pace-induced cardiomyopathy) and may therefore be difficult to distinguish, particularly in the absence of AVB or VT. Hence the importance of proactive investigation to avoid missing the diagnosis. For example, in a study that examined 130 explanted nonischemic cardiomyopathy hearts after orthotopic transplantation, histological proof of noncaseating granulomas was found in 8 (6.2%) patients with previously undiagnosed CS.21
Clinically Isolated CSThe prevalence of isolated CS varies according to the definition used. It is very important to distinguish between the following subcategories: clinically isolated and imaging not isolated; and clinically isolated and imaging isolated.
The former is likely quite common and the latter much rarer. We and others believe that the best way to exclude extracardiac disease is by means of a negative whole-body FDG-PET (except for myocardial uptake), and no evidence of either skin or eye involvement.22 Using this definition, the prevalence of clinically and imaging isolated CS has been described as between 3.2% and 9.2%.22,23 It is also controversial whether truly isolated CS exists, as sarcoidosis is, by definition and biology, a systemic disease.24,25 Current data suggest there is a small subset of patients who, at the moment of FDG-PET imaging, only have detectable inflammation in their heart. However, it also follows that additional (e.g., bronchial biopsy) or interval investigation will likely reveal extracardiac disease.24 The debate is highly clinically relevant because overdiagnosis of ‘imaging isolated CS’, without endomyocardial biopsy (EMB) confirmation, may lead to unnecessary potentially harmful treatment and/or missed alternative diagnosis. Very importantly and for the first time, the updated JCS guidelines propose diagnostic criteria for isolated CS.13,26
Recent data suggest that clinically isolated CS may be more aggressive, with nearly double the rate (67% vs. 38%) of adverse outcomes than in CS with symptoms in other organs.13,27 However, it must be appreciated that these results may reflect significant selection bias, because many patients diagnosed with systemic CS are often asymptomatic and identified by screening. Clinically isolated CS, on the other hand, implies typical cardiac presentations/symptoms.
Screening of Patients With Extracardiac Sarcoidosis for Cardiac InvolvementThere is a clear rationale for screening patients with sarcoidosis for cardiac involvement, but modest evidence to inform physicians as to the most effective screening test(s). Available literature shows that the use of advanced cardiac imaging, especially with CMR, has higher sensitivity and specificity than any other conventional screening tool, including ECG and echocardiography (Figure 1).28–30 Nevertheless, the limited availability and cost of CMR and FDG-PET studies hampers their use in screening programs.
Sensitivity and specificity of various tests for the diagnosis of cardiac involvement in 2 different sarcoidosis cohorts.28,29 Values are provided with 95% confidence intervals. Cardiac Sx, cardiac symptoms; CMR, cardiac magnetic resonance; ECG, electrocardiography; TTE, transthoracic echocardiography. Reproduced with permission from Judson MA.30
Larger, prospective studies are required to determine the best screening modality and to assess whether a screening program affects prognosis for patients with extracardiac sarcoidosis. Multiple prospective studies, including the CHASM Registry (NCT01477359), PAPLAND (NCT03902223), and CASPA (NCT03599414), as well as data from the Cardiac Sarcoidosis Consortium are expected to provide insight on these issues.9 The HRS consensus document suggests that all patients diagnosed with extracardiac sarcoidosis should undergo cardiac history, ECG and echocardiography at baseline.18 In contrast, the latest guidelines from the American Thoracic Society recommend baseline ECG in all asymptomatic sarcoidosis patients and echocardiography or Holter ECG to be considered on a case-by-case basis.31
Perihilar lymphadenopathy is the most common extracardiac feature of sarcoidosis. However, cardiac lymphatics are connected to the mediastinal lymph nodes, which are not typically seen on chest X-ray. Data from our group reported a sensitivity of 35% and specificity of 85% for chest X-ray whereas chest CT attained a sensitivity of 94% and sensitivity of 86%.32 Chest CT may therefore be a reasonable initial screening test, in resource and/or logistic constrained healthcare systems, for patients with certain cardiac presentations (most importantly, unexplained significant conduction disease in younger adults), particularly in centers without access to advanced cardiac imaging.18,26,32 Nevertheless, it must be kept in mind that extracardiac disease may be modest, as previously discussed, and supplemental imaging with CMR and/or FDG-PET is warranted in many cases.
EchocardiographyThe sensitivity and specificity for CS are poor, particularly in the early stages of the disease.6,18 The most suggestive finding is thinning of the basal interventricular septum. Other nonspecific findings include septal hypertrophy, and regional wall motion abnormalities, often in a noncoronary distribution.18,26 Newer echo modalities, as well as deep learning AI algorithms, are being investigated but none are ready for clinical use.33,34 For example, speckle tracking echocardiography is a promising technique that may facilitate CS diagnosis, particularly in the early stages. Additionally, some data support the hypothesis that impaired left and/or right ventricular strain may predict adverse outcomes.34
Cardiac Magnetic ResonanceCMR offers detailed review of cardiac morphology and function, additionally providing tissue characterization. Native T1 mapping and late gadolinium enhancement (LGE) may reveal focal fibrosis. T2-weighted sequences may identify focal edema and suggest active inflammation, although this latter feature is rarely used in clinical practice to guide treatment decisions. Although no CMR findings are pathognomonic for sarcoid, patchy LGE uptake in a noncoronary distribution, often with sparing of the endocardium, is suggestive of CS. LGE can be found anywhere in the myocardium, but basal segments of the septum, the lateral wall and the right ventricle (RV) are predilection sites for sarcoid infiltration.6,15,18,32,35 CMR has excellent sensitivity for diagnosing CS.18,32,35 A meta-analysis pooled the results of 8 studies for a total of 649 patients. Considering only studies performed after 2011, the authors found a sensitivity of 0.95 (95% confidence interval (CI) 0.88–0.98) and a specificity of 0.92 (95% CI 0.49–0.99).35
FDG-PETFDG-PET is a nuclear medicine technique that uses a radioactive glucose tracer (FDG) to identify areas with high metabolic activity. Neoplastic or inflammatory lesions, such as those seen in sarcoidosis, are avid for this tracer and display focal uptake. Whole-body FDG-PET scans allow not only identification of active myocardial inflammation but can also facilitate targeting biopsy of extracardiac disease. Myocardial rest-perfusion scans may be performed additionally to locate areas of resolved inflammation/scar. FDG-PET imaging has considerably improved the diagnostic process of CS; this technique is also well suited to monitoring the treatment response after systemic immunosuppression. An important limitation for FDG as a tracer is its physiological uptake in the myocardium, requiring optimal preparation (fat-rich, low-carbohydrate diet followed by a 12-h fasting prior to the scan, blood sugar <10 mmol/L, preprocedural 50 IU/kg heparin IV), to avoid false-positive results. It is therefore recommended that FDG-PET scans for sarcoid workup are performed and interpreted at institutions with experience in CS imaging.18 In experienced hands FDG-PET shows good diagnostic accuracy for CS; a meta-analysis of 17 studies with a total of 891 patients reported a pooled sensitivity of 84% and specificity of 83%.36 Novel radioactive tracers such as 3’-deoxy-3’-(18F)-fluorothymidine or 68Ga-DOTANOC seem to be less affected by physiological myocardial uptake and are currently being investigated as alternatives to FDG.37,38
Finally, hybrid PET/CMR scanners are now available and may combine the strengths of each modality in a single study. Recent publications have investigated their use in CS, with promising results.39
A definite CS diagnosis requires findings of noncaseating granulomas on EMB.6,26 However, due to the patchy nature of sarcoid infiltration, unguided EMB yields poor sensitivity, reported to be as low as 20%.6,26,40 Imaging guidance, for instance with electroanatomic mapping, can improve EMB accuracy, but its sensitivity is likely to remain modest at best.41
Clinical criteria, such as those from the Heart Rhythm Society (HRS), the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) or from the Japanese Circulation Society (JCS), were developed to guide clinicians towards a “probable” CS diagnosis (Table 2).18,26,42 Comparison of the 3 sets found good concordance between the HRS and WASOG criteria but poor concordance between the HRS/WASOG and the JCS criteria.43 This discrepancy is caused by the much-debated issue of whether CS can be diagnosed without a positive extracardiac biopsy.
| Organization | Year | Criteria |
|---|---|---|
| HRS criteria18 | 2014 | a) Histological diagnosis of extracardiac sarcoidosis |
| b) One of the following is present: | ||
| - Immunosuppressant-responsive cardiomyopathy or heart block | ||
| - Unexplained LVEF <40% | ||
| - Unexplained sustained VA or high-degree AVB | ||
| - Patchy FDG uptake on a dedicated cardiac PET scan | ||
| - LGE on CMR in a pattern consistent with CS | ||
| - Positive 67Ga uptake in a pattern consistent with CS | ||
| c) Other causes have been reasonably excluded | ||
| JCS criteria26 | 2016 | Two or more of the five major criteria are satisfied |
| OR | ||
| One in five major and two or more minor criteria are satisfied | ||
| Major criteria: | ||
| - High-degree AVB or fatal VA | ||
| - Basal thinning of the ventricular septum or abnormal ventricular wall anatomy | ||
| - Left ventricular contractile dysfunction (LVEF <50%) or focal wall motion asynergy | ||
| - 67Ga or FDG-PET scan reveals abnormally high level of tracer in the heart | ||
| - CMR reveals LGE of the myocardium | ||
| Minor criteria: | ||
| - Abnormal ECG findings (nonsustained VAs, PVC), conduction abnormalities, abnormal Q waves | ||
| - Perfusion defects on SPECT | ||
| - Monocyte infiltration or moderate myocardial fibrosis on EMB | ||
| AND | ||
| Granulomas are found in other organs than the heart or the patient shows clinical findings strongly suggestive of pulmonary or ophthalmic sarcoidosis and at least 2 of 5 characteristic laboratory findings of sarcoidosis: |
||
| a) Bilateral hilar lymphadenopathy | ||
| b) Elevated serum angiotensin-converting enzyme or lysozyme levels | ||
| c) Elevated serum soluble interleukin-2 receptor levels | ||
| d) Significant tracer accumulation on 67Ga scintigraphy or FDG-PET scan | ||
| e) High percentage of lymphocytes in BAL fluid with CD4/CD8 ratio >3.5 | ||
| WASOG criteria42 | 2014 | a) Granulomatous inflammation demonstrated in another organ and one of the following: |
| - Treatment responsive cardiomyopathy and AVB | ||
| - Reduced LVEF in absence of other risk factors | ||
| - Spontaneous or inducible sustained VA with no risk factors | ||
| - High-degree AVB | ||
| - Patchy uptake on a dedicated cardiac PET scan | ||
| - LGE on CMR | ||
| - Positive 67Ga uptake | ||
| - Defect on perfusion scintigraphy or SPECT scan | ||
| - T2 prolongation on CMR | ||
| b) Alternative causes have been reasonably excluded |
AVB, atrioventricular block; BAL, bronchoalveolar lavage; CMR, cardiac magnetic resonance; CS, cardiac sarcoidosis; ECG, electrocardiogram; EMB, endomyocardial biopsy; FDG, fluorodeoxyglucose; LGE, late gadolinium enhancement; LVEF, left ventricular ejection fraction; PET, positron emission tomography; PVC, premature ventricular complex; SPECT, single photon emission cardiac tomography; VA, ventricular arrhythmia. (Modified from references 18, 26, 42.)
Treatment of CS aims at: (1) Preventing fibrosis formation in the myocardium, (2) preventing SCD, and (3) managing cardiac complications, primarily arrhythmias and HF.
ImmunosuppressionSystemic immunosuppression, especially with corticosteroids, has long been used in the treatment of sarcoidosis to suppress inflammation and prevent complications. A recent meta-analysis included 34 studies investigating immunosuppressive therapy for CS: only 2 studies were of good quality and there were no randomized trials.44 In summary, limited data support that conduction disease may improve and that deterioration in left ventricular ejection fraction (LVEF) may be prevented with systemic immunosuppression. No conclusions could be drawn for death or VAs, as the data quality was too poor.44 Historically, CS is believed to carry a poorer prognosis than other forms of sarcoidosis, thus leading experts to advocate for CS treatment despite the paucity of evidence. Current guidelines support the treatment of clinically manifest CS (strong recommendation, low quality of evidence).4,6,45
Systemic immunosuppression is usually started with oral prednisone at a dose of 0.5–1 mg/kg (maximum 60 mg) daily for 2–3 months followed by slow tapering. We use a maximum dose of 30 mg daily. Many centers, including ours, monitor disease activity by serial FDG-PET scans after the treatment to document improvement/resolution of inflammation.36,37
Other immunosuppressive medications, methotrexate, azathioprine, mycophenolate, infliximab, and rituximab among others, may be used as second-line agents in patients refractory or intolerant to corticosteroids. Evidence to support second-line agents is even scarcer and arises mostly from small case series. A treatment algorithm, as suggested by the European Respiratory Society, is presented in Figure 2. Little is known about the optimal duration of immunosuppressive treatment. In a small study of 28 CS patients, 19 received uninterrupted immunosuppression and 9 discontinued therapy after an average of 32±9 months. The authors showed that a radiological relapse (documented by FDG-PET) occurred more commonly among those who discontinued immunosuppression (88.9% vs. 15.8%).46 These findings are supported by the low relapse rate among heart transplant recipients on life-long immunosuppression.47 On the other hand, long-term immunosuppression is associated with an important burden of side effects, and many patients may experience worse quality of life (QOL) during the treatment itself.48 We continue immunosuppression for a minimum of 12 months.
Clinical practice guideline from the European Respiratory Society suggesting a treatment algorithm to clinically manifest CS. Reproduced with permission from Baughman RP, et al.45
Clearly, more evidence is needed to guide immunosuppressive treatment in CS. Several randomized trials are currently in the recruiting phase. The Cardiac Sarcoidosis Multicenter Randomized Trial (CHASM CS-RCT; NCT03593759) allocates patients with clinically manifest CS to either prednisone 0.5 mg/kg/day alone for 6 months or to rapidly tapered prednisone (20 mg daily for 1 month, 10 mg daily for 1 month, 5 mg daily for 1 month) and methotrexate 15–20 mg weekly for 6 months. The primary endpoint will be the summed perfusion rest score, a marker of myocardial damage, on the 6-month PET scan.49 The study is expected to report in about 3 years.
The Japanese antibacterial Drug Management for CS (J-ACNES) is a randomized multicenter trial comparing corticosteroid therapy alone or in combination with antibiotics (clarithromycin and doxycycline), using change in the total cardiac FDG uptake as the primary endpoint.50 Study recruitment is completed and results are due soon (Personal communication from Dr. Kengo Kusano).
Finally, the Interleukin-1 Blockade for Treatment of CS (MAGIC-ART, NCT04017936) is a randomized trial comparing the addition of an IL-1 blocker (anakinra 100 mg daily) to standard of care vs. standard of care alone. The surrogate primary endpoint for this pilot trial will be changes in C-reactive protein in the 2 groups at 28 days.51
HF ManagementPatients with CS and ventricular dysfunction should be treated with all relevant medications and devices available for the general HF population.6 Cardiac resynchronization therapy (CRT) should be considered on the same grounds as for other cardiomyopathies, although recent data suggest poorer response in CS patients, perhaps due to the high degree of scarring. A recent investigation of 55 CS patients who underwent CRT implantation (94.5% CRT-D) showed no significant improvement in LVEF at 6 months post-implantation.52 After a follow-up of 4.1±3.7 years and despite CRT and optimal medical management, 34.5% of patients either died or underwent advanced HF therapies.52 Females CRT recipients with CS may have fewer adverse events than their male counterparts.53
Heart transplantation and ventricular assist device should be considered in CS patients with endstage HF despite medical and interventional therapies. Recurrence of sarcoidosis in the transplanted heart has been described and may occur in up to 5% of patients.47 Long-term outcomes, however, are excellent and appear to be similar or better than in the non-CS population.47,54
Management of Arrhythmias and Risk StratificationCS is an arrhythmogenic condition. Some patients experience an important burden of arrhythmias, especially VT, with implications for QOL. Studies of VT ablation in CS patients report that patients usually have multiple inducible VT morphologies (consistently more, on average, than with other cardiomyopathies).55,56 This is probably because of the patchy nature of sarcoid infiltration and the overlap between inflammation and scarring that can occur in the ventricular myocardium. Clinically manifest CS patients remain at considerable risk for arrhythmias regardless of immunosuppressive treatment and disease activity.20 Although β-blockers and Class III agents are commonly administered, Class I agents are generally avoided. Catheter ablation can be useful to reduce VT burden in selected CS patients. A review analyzed outcomes after VT ablation in a CS population. After an average follow-up of 2 years, 38/83 (45.7%) patients were free from recurrent VT and 61/83 (88.4%) patients experienced clinical improvement.57 In another meta-analysis, VT recurrence was 55% after 1 procedure and 37% after multiple procedures.55 Nevertheless, it appears that CS patients requiring VT ablation have a higher recurrence rate than in patients with other cardiomyopathies.55–57
Implantable cardioverter defibrillators (ICD) are recommended in patients with a previous episode of sustained VA and aborted SCD and/or a LVEF <35%, and in CS patients with a concomitant indication for pacing (high-degree AVB).18 However, due to the considerable incidence of VAs, ICD implantation can be considered also for those with LVEF between 35% and 49%, and for those with normal LVEF but with signs of extensive myocardial scar by CMR or PET scan.18 Moreover, recent evidence also suggests that the extent or location of LGE (particularly in the RV) may also be important for the risk of VAs.58,59 A recent analysis of 398 CS patients from Finland found a cumulative 5-year incidence of either SCD or VT in 24% of the total cohort and of 12% in those patients without a Class I or IIa ICD indication. In the latter group the cumulative 5-year incidence of SCD was 4.8%, suggesting that current guidelines fail to identify the low-risk population and that most (85–100%) CS patients may benefit from an ICD.60
Guidelines for risk prognostication and ICD implantation, as suggested by the HRS consensus statement, are presented in Figure 3. In the 2017 AHA/ACC/HRS document, a largely similar guideline was produced for the use of ICDs in CS patients.61 These recommendations have been validated in American and Japanese cohorts, with consistent results.62,63
Risk stratification and ICD indications as suggested by the 2014 HRS consensus document. CMR, cardiac magnetic resonance; FDG, fluorodeoxyglucose; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; PET, positron emission tomography; RV, right ventricular; VF, ventricular fibrillation; VT, ventricular tachycardia. Reproduced with permission from Birnie DH, et al.18
The key difference between the 2 documents pertains to patients without significant LV dysfunction (i.e., LVEF >35%). The 2017 document suggested ICD implantation (Class IIa recommendation) in patients with evidence of extensive myocardial scar by CMR or PET scan. However, there are a number of issues with the current body of data including: most studies being single center and/or retrospective, very wide CIs around the odds ratios, and little data on how many of the cardiovascular deaths were SCD.64
Hence there is a clear need for more and higher quality data to better inform shared decision making regarding ICD implantation in patients with CS.
An electrophysiological study (EPS) may help select truly low-risk patients. In a meta-analysis of 8 papers, the EPS attained a sensitivity of 0.70 (95% CI 0.51–0.85) but a specificity of 0.93 (95% CI 0.85–0.97) in predicting adverse outcomes.65
It should be appreciated that CS patients experience higher rates of ICD therapies: in a recent study of 105 patients with an ICD, 32.4% received appropriate ICD therapies with a median of 4.0 therapies per patient distributed over a median follow-up of 2.8 years.58
Heart transplantation may be considered, as a last resort, in those CS patients with refractory VT and an unacceptable amount of ICD therapies.
Follow-upPatients undergoing systemic immunosuppression should be followed regularly to assess clinical and radiological response, as well as to evaluate tolerability of treatment. We use serial FDG-PET as the modality of choice to monitor disease activity (Figures 4,5).66,67 Biomarkers, such as soluble IL-2 receptor, angiotensin-converting enzyme, and C-reactive protein, have been proposed as surrogates to evaluate disease activity, but none has proven to be of clinical use.
Serial FDG-PET imaging before and after immunosuppressive treatment. FDG, fluorodeoxyglucose; PET, positron emission tomography. Reproduced with permission from Birnie DH, et al.66
Treatment algorithm for patients with clinically manifest CS practiced at the University of Ottawa Heart Institute. FDG, fluorodeoxyglucose; LVEF, left ventricular ejection fraction; PET, positron emission tomography. Reproduced with permission from Birnie DH.67
Although historical literature associated CS with a poor prognosis, contemporary data show significant improvement, likely due to modern HF management as well as increased clinical awareness and increasing use of ICDs.7,11,32,68,69 A Finnish nationwide study of biopsy-verified CS patients found a 92.5% transplant-free 10-year survival.7 Recent registry data including 1,638 CS patients implanted with ICD showed that the mortality rate at 2 years was not different (9.0% and 9.3%) to that in a propensity matched cohort with non-ischemic cardiomyopathy.68 Furthermore, it should be noted that among studies reporting the cause of death, noncardiovascular death was significant.7,11,69 LVEF <40% and RV dysfunction at presentation have been consistently reported as negative prognostic factors.7,8,11,12,68,70
Finally, QOL is expected to be affected in CS. Side effects of treatment, frequent ICD therapies and hospitalizations are among the factors that may disrupt patients’ lives regardless of their overall survival.48,70 A previous survey directed at a general sarcoidosis population (n=1,842) showed that QOL was the highest ranked outcome by patients, outperforming survival and improvement of imaging studies.71 Currently, no data are available on QOL for clinically manifest CS patients: we believe that future trials should include this important outcome in their analyses.
Clinically manifest CS occurs in ≈5% of sarcoidosis patients. High-degree AVB, VT and HF are typical presentations: clinicians should consider CS among their differential diagnosis when evaluating these findings in patients (especially in those aged <60 years). Cardiac imaging is paramount for the diagnostic workup of CS, particularly CMR and FDG-PET. Immunosuppression is recommended in clinically manifest CS, to try to prevent fibrosis formation and preserve ventricular function. Most clinically manifest CS patients require an implantable cardiac device (mostly ICDs) due to the significant risk of VAs that may occur regardless of immunosuppressive treatment. Fatal outcome is rare with modern HF management, but QOL may be significantly impaired. Good quality, multicenter, prospective data are needed to improve our understanding of this disease and improve the care for CS patients.
A. De B. is supported by restricted grants provided by the Caroline Musæus Aarsvolds Fund, Tom Wilhelmsen’s Foundation, Gidske and Peter Jacob Sørensens Fund and by Vestfold Hospital Trust. D.H.B. discloses being on the advisory board for Star Therapeutics and Kinevant/Roivant Sciences Inc. No conflict of interest is pertinent to this work.
