Value of 3D mapping-guided endomyocardial biopsy in cardiac sarcoidosis: Case series and narrative review on the value of electro-anatomic mapping-guided endomyocardial biopsies.

AIM: Integration of endomyocardial biopsy (EMB) in the diagnostic workup of cardiac sarcoidosis (CS) is under-recognized in current clinical practice, since capturing focal granulomas is challenging. Our aim was to describe our experience with electro-anatomic mapping (EAM)-guided EMB and provide a comprehensive review of the literature. METHODS AND RESULTS: Five patients (age 49.4 ± 11.4) with suspected CS underwent EAM-guided EMB in Isala Heart Center (Zwolle, the Netherlands) between 2017 and 2019. In all patients, a 3D bipolar voltage map (<0.5-1.5 mV) and unipolar voltage map (LV < 8.3 mV, RV < 5.5 mV) was created using a high-density mapping catheter. The bioptome was connected to the mapping system to guide targeted EMB. Biopsy samples (2-9 samples) were taken from both LV and RV sites, guided by EAM and areas with abnormal electrograms, without complications. CS diagnosis was based on EMB in 2/5 patients. A granuloma was captured in one patient at the LV basal septum with normal bipolar and abnormal unipolar voltage. All patients with delayed enhancement on cardiac magnetic resonance, revealed fibrosis in the biopsy sample. In one patient with suspected isolated cardiac sarcoidosis, diagnosis could not be confirmed by histopathology analysis, while unipolar voltage mapping was abnormal and diastolic potentials were present. Literature search revealed 7 reports (18 patients) describing EAM-guided EMB in CS patients, with 100% of the EMB taken form the RV. CONCLUSION: Unipolar voltage mapping may be superior to target active inflamed tissue and should be evaluated in future research regarding EAM-guided EMB in CS.

Electrophysiologic testing for diagnostic evaluation and risk stratification in patients with suspected cardiac sarcoidosis with preserved left and right ventricular systolic function.

INTRODUCTION: While cardiac sarcoidosis (CS) carries a risk of ventricular arrhythmias (VAs) and sudden cardiac death (SCD), risk stratification of patients with CS and preserved left ventricular/right ventricular (LV/RV) systolic function remains challenging. We sought to evaluate the role of electrophysiologic testing and programmed electrical stimulation of the ventricle (EPS) in patients with suspected CS with preserved ventricular function. METHODS: One hundred twenty consecutive patients with biopsy-proven extracardiac sarcoidosis and preserved LV/RV systolic function underwent EPS. All patients had either probable CS defined by an abnormal cardiac positron emission tomography or cardiac magnetic resonance imaging, or possible CS with normal advanced imaging but abnormal echocardiogram (ECG), SAECG, Holter, or clinical factors. Patients were followed for 4.5 ± 2.6 years for SCD and VAs. RESULTS: Seven of 120 patients (6%) had inducible ventricular tachycardia (VT) with EPS and received an implantable cardioverter defibrillator (ICD). Three patients (43%) with positive EPS later had ICD therapies for VAs. Kaplan-Meier analysis stratified by EPS demonstrated a significant difference in freedom from VAs and SCD (P = 0.009), though this finding was driven entirely by patients within the cohort with probable CS (P = 0.018, n = 69). One patient with possible CS and negative EPS had unrecognized progression of the disease and unexplained death with evidence of CS at autopsy. CONCLUSIONS: EPS is useful in the risk stratification of patients with probable CS with preserved LV and RV function. A positive EPS was associated with VAs. While a negative EPS appeared to confer low risk, close follow-up is needed as EPS cannot predict fatal VAs related to new cardiac involvement or disease progression.

Characterization of the Electroanatomic Substrate in Cardiac Sarcoidosis: Correlation With Imaging Findings of Scar and Inflammation.

OBJECTIVES: This study sought to characterize the electroanatomic (EAM) substrate in patients with cardiac sarcoidosis (CS) and ventricular tachycardia and its relationship to imaging findings of inflammation and fibrosis. BACKGROUND: CS is characterized by coexistence of active inflammation and replacement fibrosis. METHODS: A total of 42 patients with CS based on established criteria and ventricular tachycardia underwent high-density EAM mapping. Abnormal electrograms (EGM) were collected and independently classified as multicomponent fractionated, isolated, late, and split according to standard criteria and regardless of the peak-to-peak bipolar/unipolar voltage. A total of 29 patients (69%) underwent pre-procedural cardiac magnetic resonance (CMR) and positron emission tomography (PET)/computed tomography (CT). The distribution of EAM substrate was correlated with regions of late gadolinium enhancement (LGE) on CMR and increased 18F-fluorodeoxyglucose uptake on PET/CT. RESULTS: Of 21,451 bipolar and unipolar EGM, 4,073 (19%) were classified as abnormal with a predominant distribution in the basal perivalvular segments and interventricular septum. Using the standard bipolar (<1.5 mV) and unipolar (<8.3 mV for left ventricle <5.5 mV for the right) voltage cutoff values, 40% and 22% of the abnormal EGM were located outside the EAM low-voltage areas, respectively. LGE was present in 26 of 29 patients (90%), whereas abnormal 18F-fluorodeoxyglucose uptake in 14 of 29 patients (48%) with imaging. Segments with abnormal EGM had more LGE-evident scar transmurality [median: 24% (interquartile range [IQR]: 4% to 40%) vs. median: 5% (IQR: 0% to 15%); p < 0.001] and lower metabolic activity (median: 20 g glucose [IQR: 14 g to 30 g] vs. median: 29 g glucose [IQR: 18 g to 39 g]; p < 0.001). Overall, the agreement between the presence of abnormal EGM was higher with the presence of LGE (κ = 0.51; p < 0.001) than with the presence of active inflammation (κ = -0.12; p = 0.003). CONCLUSIONS: In patients with CS and ventricular tachycardia, pre-procedural imaging with CMR and PET/CT can be useful in detecting EAM abnormalities that are potential targets for substrate ablation. Abnormal EGM were more likely located in segments with more scar transmurality (LGE) at CMR and a lower degree of inflammation on PET.

Right ventricular scar-related ventricular tachycardia in nonischemic cardiomyopathy: Electrophysiological characteristics, mapping, and ablation of underlying heart disease.

BACKGROUND: Right ventricular (RV)-scar related ventricular tachycardia (VT) is often due to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) or cardiac sarcoidosis (CS), but some patients whose clinical course has not been described do not fulfill diagnostic criteria for these diseases. We sought to characterize the electrophysiologic substrate and catheter ablation outcomes of such patients, termed RV cardiomyopathy of unknown source (RCUS). METHODS AND RESULTS: Data of 100 consecutive patients who presented with RV cardiomyopathy and/or RV-related VT for ablation were reviewed (51 ARVC/D, 22 CS; 27 RCUS). Compared to ARVC/D, RCUS patients were older (P = 0.001), less commonly had RV dilatation (P = 0.001) or dysfunction (P = 0.01) and fragmented QRS, parietal block, and T-wave inversion. Compared to CS, R-CUS patients had less severe LV dysfunction. Extent and distribution of endocardial/epicardial scar and inducible VTs in RCUS patients were comparable with ARVC/D and CS patients. At a median follow-up of 23 months, RCUS patients had more favorable VT-free survival (RCUS 71%, ARVC/D 60%, CS 41%, P = 0.03) and survival free of death or cardiac transplant (RCUS 92%, ARVC/D 92%, CS 62%, P = 0.01). No RCUS patients developed new criteria for ARVC/D or CS in follow-up. CONCLUSIONS: Up to one-third of patients with RV scar-related VT are not classifiable as ARVC/D or CS. These patients had a somewhat better prognosis than ARVC/D or sarcoid and did not develop evidence of these diseases during the initial 2 years of follow-up. The extent to which this population comprises mild ARVC/D, CS, or other diseases is not clear.

Effects of Inspiratory Muscle Training in Subjects With Sarcoidosis: A Randomized Controlled Clinical Trial.

BACKGROUND: Respiratory muscle weakness occurs in sarcoidosis and is related to decreased exercise capacity, greater fatigue, dyspnea, and lower quality of life in sarcoidosis patients. The effects of inspiratory muscle training in this population have not been comprehensively investigated so far. This study was planned to investigate the effects of inspiratory muscle training on exercise capacity, respiratory and peripheral muscle strength, pulmonary function and diffusing capacity, fatigue, dyspnea, depression, and quality of life in subjects with sarcoidosis. METHODS: This was a prospective, randomized, controlled, and double blind study. Fifteen sarcoidosis subjects (treatment group) received inspiratory muscle training at 40% of maximal inspiratory pressure (P(Imax)), and 15 subjects (control group) received sham therapy (5% of P(Imax)) for 6 weeks. Functional and maximal exercise capacity, respiratory and peripheral muscle strength, pulmonary function and diffusing capacity, fatigue, dyspnea, depression, and quality of life were evaluated. RESULTS: Functional (P < .001) and maximal exercise capacity (P = .038), respiratory muscle strength (P(Imax) [P < .001] and P(Emax) [P = .001]), severe fatigue (P = .002), and dyspnea perception (P = .02) were statistically significantly improved in the treatment group compared with controls; no significant improvements were observed in pulmonary function and diffusing capacity, peripheral muscle strength, fatigue, depression, and quality of life between groups after inspiratory muscle training. CONCLUSIONS: Inspiratory muscle training improves functional and maximal exercise capacity and respiratory muscle strength and decreases severe fatigue and dyspnea perception in subjects with early stages of sarcoidosis. Inspiratory muscle training can be safely and effectively included in rehabilitation programs. (ClinicalTrials.gov registration NCT02270333.).

The Management of Sarcoidosis: A Primary Care Approach.

Sarcoidosis is an idiopathic inflammatory disorder characterized by noncaseating granulomas, which can affect any organ system. The lungs are most commonly affected but extrapulmonary sites may cause the initial and/or sole symptoms. In this review, the disease manifestations and treatment are described, with particular emphasis on the management of each affected organ system. Diagnosis and management can be difficult and greatly affect quality of life, but despite these challenges, it is possible to successfully manage patients with sarcoidosis in the primary care setting.

Feasibility of combined unipolar and bipolar voltage maps to improve sensitivity of endomyocardial biopsy.

BACKGROUND: Endomyocardial biopsy (EMB) has a low sensitivity. Electroanatomic voltage mapping (EVM) is effective in guiding EMB thanks to its ability in identifying and locating low-voltage regions. The analysis of unipolar EVM can correlate with epicardial pathological involvement. We evaluated the unipolar EVM in EMB areas to determine whether it can increase EMB sensitivity in diagnosing epicardial diseases. METHODS AND RESULTS: We performed endocardial bipolar EVM-guided EMBs in 29 patients and we analyzed unipolar EVM at withdrawal sites. Eighty myocardial samples were collected (mean, 2.8±0.9; median, 3 fragments per patient) and 60 were suitable for histological analysis. Ten specimens (17%) were collected from an area with discordant normal bipolar/low-voltage unipolar EVM and they were diagnostic or suggestive for arrhythmogenic right ventricular dysplasia/cardiomyopathy in 6 patients, for myocarditis and sarcoidosis in 1 patient each. Six samples (10%) were collected from an area with discordant low-voltage bipolar/normal unipolar EVM and they showed nonspecific features. The sensitivity of unipolar EVMs for a diagnostic biopsy finding EMB was significantly higher compared with bipolar EVMs analyzed according to samples (P<0.01) and patients (P=0.008). The specificity of unipolar EMB was better than bipolar EMB when analyzed for all samples (P=0.0014) but the difference did not reach statistical significance when analyzed by patient (P=0.083). The diagnostic yield was 63.3% for the bipolar and 83.3% for the unipolar EVM. CONCLUSIONS: These findings suggest that use of a combined bipolar/unipolar map may be able to improve the diagnostic yield of endomyocardial ventricular biopsy.

Bone density is normal and does not change over 2 years in sarcoidosis.

SUMMARY: Small studies have previously suggested that sarcoidosis may be associated with low bone mineral density. In this observational study of 64 patients with sarcoidosis, bone mineral density was within the normal range at baseline, and there was no evidence of accelerated bone loss over 1-2 years. INTRODUCTION: Several small studies have suggested that sarcoidosis may be associated with low bone mineral density (BMD). METHODS: We undertook a cross-sectional study of BMD in 64 patients with sarcoidosis. Of these, 27 with 25-hydroxyvitamin D<50 nmol/L entered a 1-year intervention study of vitamin D supplements, and 37 entered a 2-year longitudinal study of BMD, with the primary endpoint of the change in lumbar spine BMD. RESULTS: The mean age of participants was 58 years, 68% were female, and 8% were currently using oral glucocorticoids. At baseline, BMD for the entire cohort was greater than the expected values for the population at the lumbar spine (mean Z-score 0.7, P<0.001) and total body (0.5, P<0.001) and similar to expected values at the femoral neck (0.2, P=0.14) and total hip (0.2, P=0.14). BMD did not change at any of these four sites (P>0.19) over 2 years in the longitudinal study. In the intervention study, vitamin D supplements had no effect on BMD, and therefore we pooled the data from all participants. BMD did not change over 1 year at the spine, total hip, or femoral neck (P>0.3), but decreased by 0.7% (95% confidence interval 0.3-1.1) at the total body (P=0.019). CONCLUSIONS: BMD was normal at baseline, and there was no consistent evidence of accelerated bone loss over 1-2 years, regardless of baseline vitamin D status. Patients with sarcoidosis not using oral glucocorticoids do not need routine monitoring of BMD.

Electrophysiologic manifestations of cardiac sarcoidosis.

PURPOSE OF REVIEW: Cardiac involvement in sarcoidosis patients is frequently unrecognized with ventricular arrhythmias and sudden cardiac death (SCD) sometimes occurring as its initial presentation. Early involvement of an electrophysiologist as part of a multidisciplinary team is essential to screening, risk stratification, and management of cardiac sarcoidosis patients. This review outlines potential manifestations of cardiac sarcoidosis, as well as diagnostic and treatment strategies. RECENT FINDINGS: Recent retrospective analyses have shown that the incidence of atrioventricular block, atrial tachyarrhythmias, and ventricular tachyarrhythmias in these patients is substantial. In addition to advanced cardiac imaging, there is a role for ECG, signal-averaged ECG, ambulatory telemetry monitoring, and electrophysiologic testing in the initial evaluation of a patient with suspected cardiac sarcoidosis. There have been recent investigations into the role of implantable cardioverter-defibrillators (ICDs) for SCD prevention with a high rate of appropriate therapies observed. Immunosuppressive therapy, antiarrhythmic drugs, and catheter ablation each also have a role in the reduction of overall arrhythmic burden. SUMMARY: The electrophysiologist's approach to a patient with cardiac sarcoidosis can aid in diagnosis, risk stratification, and management with antiarrhythmic therapy, catheter ablation, and ICD implantation for the prevention of SCD.

Coexisting primary hyperparathyroidism and sarcoidosis cause increased angiotensin-converting enzyme and decreased parathyroid hormone and phosphate levels.

CONTEXT: Primary hyperparathyroidism (PHPT) and sarcoidosis may separately contribute to abnormal calcium and phosphate metabolism via different mechanisms, and their coexistence is infrequently reported. OBJECTIVE: We sought to characterize a group of 50 patients with coexisting PHPT and sarcoidosis in our institution to evaluate their clinical and laboratory characteristics. DESIGN AND SETTING: This was a retrospective observational study of patients with both disorders at our institution between January 1980 and December 2011. OUTCOME: A cohort of 50 patients was identified, with mean ± SD age 59.6 ± 13.9 years and 86% women. Serum calcium in the cohort was 11.1 ± 1.1 mg/dL, phosphate was 3.3 ± 0.6 mg/dL, and PTH was 76 ± 42 pg/mL. Serum 25-hydroxyvitamin D was 25 ± 9 ng/mL, and serum 1,25-dihydroxyvitamin D was 51 ± 20 pg/mL; 24-hour urine calcium was 275 ± 211 mg. In subjects with sarcoidosis, serum angiotensin-converting enzyme (ACE) was 47.2 ± 37.4 U/L. Sarcoidosis was diagnosed first in 50% of patients, PHPT was diagnosed first in 16% of patients, and sarcoidosis and PHPT were both diagnosed within 6 months of each other in 30% of patients. The interval between the 2 diagnoses when sarcoidosis was diagnosed first was 15.5 ± 12.4 years and was 5.5 ± 6.0 years when PHPT was diagnosed first. Patients with PHPT who had active sarcoidosis had higher serum ACE levels (60.9 ± 38.1 vs 20.2 ± 14.0 U/L, P <.0001), lower PTH levels (60 ± 24 vs 96 ± 41 pg/mL, P = .01), and lower phosphate levels (2.7 ± 0.6 vs 3.2 ± 0.5 mg/dL, P = .02). CONCLUSIONS: Fifty patients with coexisting PHPT and sarcoidosis are described, with patients with PHPT coexisting with clinically active sarcoidosis having increased serum ACE levels and decreased serum PTH and phosphate levels compared with those with inactive sarcoidosis.

Hypothalamo-pituitary sarcoidosis: a multicenter study of 24 patients.

AIM: To assess clinical features, treatment and outcome of Hypothalamo-pituitary (HP) sarcoidosis and to determine whether HP is associated with a particular clinical phenotype of sarcoidosis. DESIGN: Multicentric retrospective study. METHODS: Retrospective chart review. Each patient was matched with two controls. RESULTS: Twenty-four patients were identified (10 women, 14 men). Their median age at the sarcoidosis diagnosis was 31.5 years (range: 8-69 years). HP involvement occurred in the course of a previously known sarcoidosis in 11 cases (46%), whereas it preceded the diagnosis in 13 patients (54%). All but two patients had anterior pituitary dysfunction, 12 patients presented with diabetes insipidus. The most common hormonal features were gonadotropin deficiency (n=21), TSH deficiency (n=15) and hyperprolactinemia (n=12). Magnetic Resonance Imaging (MRI) revealed infundibulum involvement (n=8), pituitary stalk thickness (n=12) and involvement of the pituitary gland (n=14). All but two patients received prednisone. After a mean follow-up of 4 years, only two patients recovered from hormonal deficiencies. MRI abnormalities improved or disappeared in 12 cases under corticosteroid. There was no correlation between the hormonal dysfunctions and the radiologic outcomes. Patients with HP sarcoidosis had significantly more frequent sinonasal localizations and neurosarcoidosis and required a systemic treatment more frequently than controls. CONCLUSION: Although HP sarcoidosis is unusual, physicians should be aware that such specific localization could be the first manifestation of sarcoidosis. HP involvement is associated with general severity of sarcoidosis. MRI abnormalities can improve or disappear under corticosteroid treatment, but most endocrine defects are irreversible.

Quercetin reduces markers of oxidative stress and inflammation in sarcoidosis.

BACKGROUND & AIMS: Oxidative stress and low antioxidant levels are implicated in the aetiology of sarcoidosis, an inflammatory disease. Quercetin is a potent dietary antioxidant that also displays anti-inflammatory activities. Consequently, the aim is to examine the effect of quercetin supplementation on markers of oxidative stress and inflammation in sarcoidosis. METHODS: A double-blind intervention study has been conducted with two groups of non-smoking, un-treated sarcoidosis patients, matched for age and gender. One group was given 4x500 mg quercetin (n = 12) orally within 24 h, the other one placebo (n = 6). Plasma malondialdehyde levels were used as marker of oxidative damage, plasma ratios of TNFα/IL-10 and IL-8/IL-10 as pro-inflammatory markers. RESULTS: Quercetin supplementation improved the antioxidant defence, indicated by the increased total plasma antioxidant capacity. Moreover, quercetin supplementation also reduced markers of oxidative stress and inflammation in the blood of sarcoidosis patients. The effects of quercetin supplementation appeared to be more pronounced when the levels of the oxidative stress and inflammation markers were higher at baseline. CONCLUSIONS: Sarcoidosis patients might benefit from the use of antioxidants, such as quercetin, to reduce the occurring oxidative stress as well as inflammation. The effects of long-term use of antioxidant supplementation in sarcoidosis, using e.g. quercetin, on improvement of lung function remain to be investigated. (www.clinicaltrials.gov; NCT-00402623).

Primary prevention of sudden cardiac death in silent cardiac sarcoidosis: role of programmed ventricular stimulation.

BACKGROUND: Cardiac involvement in sarcoidosis is often silent and may lead to sudden death. This study was designed to assess the value of programmed electric stimulation of the ventricle (PES) for risk stratification in patients with sarcoidosis and evidence of preclinical cardiac involvement on imaging studies. METHODS AND RESULTS: Patients with biopsy-proven systemic sarcoidosis but without cardiac symptoms who had evidence of cardiac sarcoidosis on positron emission tomography (PET) or cardiac MRI (CMR) were included. All patients underwent baseline evaluation, echocardiographic assessment of left ventricular function, and programmed electric stimulation of the ventricle. Patients were followed for survival and arrhythmic events. Seventy-six patients underwent PES of the ventricle. Eight (11%) were inducible for sustained ventricular arrhythmias and received an implantable defibrillator. None of the noninducible patients received a defibrillator. Left ventricular ejection fraction was lower in patients with inducible ventricular arrhythmia (36.4±4.2% versus 55.8±1.5%, P<0.05). Over a median follow-up of 5 years, 6 of 8 patients in the group with inducible ventricular arrhythmias had ventricular arrhythmia or died, compared with 1 death in the negative group (P<0.0001). CONCLUSIONS: In patients with biopsy-proven sarcoidosis and evidence of cardiac involvement on PET or CMR alone, positive PES may help to identify patients at risk for ventricular arrhythmia. More importantly, patients in this cohort with a negative PES appear to have a benign course within the first several years following diagnosis. PES may help to guide the use of implantable cardioverter defibrillators in this population.

Calcium and vitamin D in sarcoidosis: how to assess and manage.

The synthesis of vitamin D is altered by the granulomatous inflammation of sarcoidosis leading to increased production of 1, 25-dihydroxyvitamin D. Mounting evidence suggests that vitamin D is an immunomodulating hormone that inhibits both antigen presentation by cells of the innate immune system, and the cytokine release and proliferation of Th1 cells. These and other extraskeletal health benefits have led to an increase in vitamin D assessment and pharmacological supplementation in the general population. This review highlights the altered synthesis and general immunomodulating properties of vitamin D with a special emphasis on known interactions with sarcoidosis. In addition, the assessment of vitamin D nutritional status, its pharmacological supplementation, and the management of bone health in patients with sarcoidosis are reviewed.

Role of radiofrequency catheter ablation of ventricular tachycardia in cardiac sarcoidosis: report from a multicenter registry.

BACKGROUND: Management of ventricular tachycardia (VT) is challenging in patients with cardiac sarcoidosis. OBJECTIVE: The purpose of this study was to assess the response of VT in patients with cardiac sarcoidosis to medical therapy and radiofrequency ablation. METHODS: Forty-two patients with a diagnosis of cardiac sarcoidosis based on the Japanese Health Ministry criteria were followed. When VT occurred, a stepwise approach was used: implantable cardioverter-defibrillator placement, immunosuppressive agents, antiarrhythmic medications, then radiofrequency ablation. RESULTS: In nine patients (age 46.7 +/- 8.6 years; ejection fraction 42 +/- 14%), VT was not controlled by medical therapy, and radiofrequency ablation was performed. A total of 44 VTs (mean cycle length 348 +/- 78 ms) were induced. Endocardial radiofrequency ablation was performed in eight patients (right ventricular in 5, left ventricular in 3) and epicardial radiofrequency ablation in one patient. In 4 of 5 patients with right ventricular VTs, a peritricuspid circuit was identified. Critical areas were identified for 21 (48%) of 44 VTs, resulting in elimination of 31 (70%) of 44 VTs. The most frequent VT circuit was reentry in the peritricuspid area. This type of VT was eliminated in all patients. Arrhythmic events decreased from 271 +/- 363 episodes preablation to 4.0 +/- 9.7 postablation. All patients had either a decrease (n = 4) or complete elimination (n = 5) of VT during mean follow-up of 19.8 +/- 19.6 months. CONCLUSION: Catheter ablation of VT in patients with cardiac sarcoidosis refractory to medical therapy is effective in eliminating VT or markedly reducing the VT burden. The disease process in cardiac sarcoidosis often involves a specific area in the basal right ventricle predisposing to peritricuspid reentry.

Antioxidant status associated with inflammation in sarcoidosis: a potential role for antioxidants.

RATIONALE: Enhanced production of reactive oxygen species (ROS), capable of reducing endogenous defense levels and enhancing inflammation, is suggested to play a role in sarcoidosis. Antioxidant supplementation might offer protection against such ROS-mediated damage. A promising candidate for antioxidant supplementation is the flavonoid quercetin. AIM: To determine the antioxidant and inflammatory status in sarcoidosis. Furthermore, the potential of quercetin to mitigate the occurring inflammation will be assessed. METHODS: Non-smoking sarcoidosis patients and healthy controls matched for age, gender and dietary behavior were enrolled (NCT-00512967). Measurements included assessment of total plasma antioxidant capacity, vitamin C, uric acid, glutathione, basal and LPS-induced levels of tumor necrosis factor alpha (TNFalpha), interleukin (IL)-8 and -10 as well as the effect of quercetin on these levels. RESULTS: Compared to their controls, the sarcoidosis patients displayed significantly lower total plasma antioxidant capacity, decreased levels of vitamin C, uric acid and glutathione and increased levels of basal TNFalpha and IL-8. Quercetin significantly decreased ex vivo LPS-induced TNFalpha- and IL-8 production in a concentration-dependent manner in both groups. Interestingly, this quercetin effect was more pronounced in sarcoidosis patients. DISCUSSION: The endogenous antioxidant defense was significantly reduced in sarcoidosis, indicating that oxidative stress underlies the pathology of this disease. Furthermore, the inflammatory status was significantly enhanced in sarcoidosis. Finally, our results regarding the effect of quercetin on cytokine production imply that sarcoidosis patients might benefit from antioxidant supplementation not only by empowering the relatively low protection against ROS but also by reducing inflammation.