Atrioventricular block as the initial manifestation of cardiac sarcoidosis in middle-aged adults.

INTRODUCTION: Atrioventricular block (AVB) can be caused by several conditions, including cardiac sarcoidosis (CS). The prevalence of CS causing this presentation in a North American population has not been investigated and was the purpose of this study. METHODS: We prospectively evaluated patients aged 18-60 years presenting with unexplained 2nd or 3rd degree AVB and no previous history of sarcoidosis in any organ. All patients had fluorodeoxyglucose-positron emission tomography (FDG-PET) scans for the evaluation of CS. Japanese Ministry of Health Welfare (JMHW) criteria and biopsy results were used to confirm the diagnosis of CS. Subjects with advanced imaging suggestive of CS were investigated for extracardiac involvement. Patients were followed for major adverse cardiac events. RESULTS: Thirty-two patients presenting with unexplained AVB underwent cardiac and whole body FDG-PET for the investigation of CS from February 2010 to June 2013. Mean age was 52.8 ± 6.2 years, and 20 were male. CS was diagnosed in 11/32 (34%) subjects and 11/11 were subsequently diagnosed with extra-CS. Average follow-up was 21 ± 9 months. Adverse events were observed in 3 subjects with CS but none in subjects with idiopathic AVB. All 3 patients presented with heart failure, 2 also had recurrent VT resulting in ICD shocks. CONCLUSIONS: In this prospective study of consecutive patients aged ≤60 years presenting with unexplained AVB, we found that 11/32 (34%) had previously undiagnosed CS. Among patients with CS, 3/11 had adverse clinical outcomes compared with 0/21 (P = 0.011). Our data suggest that all patients aged ≤60 years with unexplained AVB should be investigated for CS. Moreover, patients diagnosed with CS should be closely followed.

Prevalence of cardiac sarcoidosis in patients presenting with monomorphic ventricular tachycardia.

INTRODUCTION: Sarcoidosis is a granulomatous disease of unknown etiology, which involves the heart in 5-25% of cases. Although ventricular tachycardia (VT) has been reported as the first presentation of sarcoidosis, its prevalence has not previously been investigated. In this prospective study, we sought to systematically investigate the prevalence of cardiac sarcoidosis (CS) in patients presenting with monomorphic VT (MMVT) and no previous history of sarcoidosis. METHODS: Consecutive patients presenting with MMVT to a tertiary care center were screened for inclusion. Patients with idiopathic VT, VT secondary to coronary artery disease, or prior diagnosis of sarcoidosis were excluded. Included patients underwent F-18-fluorodeoxyglucose positron emission tomography (PET) scan. In subjects with PET scanning suggestive of active myocardial inflammation, histological diagnosis was confirmed through extracardiac or endomyocardial biopsy (EMB). RESULTS: A total of 182 patients presented to our institution with VT between February 2010 and September 2012 and 14 subjects met inclusion criteria. Within this group, six of 14 (42%) patients had abnormal PET scans suggesting active myocardial inflammation. Four of the six patients had tissue biopsies that were diagnostic of sarcoidosis; the remaining two patients had guided EMB indicating nonspecific myocarditis. Atrioventricular block was observed in three of four (75%) patients with CS and none in 10 of the others (P = 0.022). Three of the four patients had pulmonary sarcoidosis and one patient had isolated CS. All four patients were treated with corticosteroids. CONCLUSION: In this prospective study, four of 14 (28%) patients presenting with MMVT (without idiopathic VT, ischemic VT, or known sarcoidosis) had CS as the underlying etiology. Clinicians should consider screening for CS in patients with unexplained MMVT.

Stat3 and c-Myc genome-wide promoter occupancy in embryonic stem cells.

Embryonic stem (ES) cell pluripotency is regulated in part by transcription factor (TF) pathways that maintain self-renewal and inhibit differentiation. Stat3 and c-Myc TFs are essential for maintaining mouse ES cell self-renewal. c-Myc, together with Oct4, Sox2, and Klf4, is a reprogramming factor. While previous studies have investigated core transcriptional circuitry in ES cells, other TF pathways that promote ES cell pluripotency have yet to be investigated. Therefore, to further understand ES cell transcriptional networks, we used genome-wide chromatin immunoprecipitation and microarray analysis (ChIP-chip) to map Stat3 and c-Myc binding targets in ES cells. Our results show that Stat3 and c-Myc occupy a significant number of genes whose expression is highly enriched in ES cells. By comparing Stat3 and c-Myc target genes with gene expression data from undifferentiated ES cells and embryoid bodies (EBs), we found that Stat3 binds active and inactive genes in ES cells, while c-Myc binds predominantly active genes. Moreover, the transcriptional states of Stat3 and c-Myc targets are correlated with co-occupancy of pluripotency-related TFs, polycomb group proteins, and active and repressive histone modifications. We also provide evidence that Stat3 targets are differentially expressed in ES cells following removal of LIF, where culture of ES cells in the absence of LIF resulted in downregulation of Stat3 target genes enriched in ES cells, and upregulation of lineage specific Stat3 target genes. Altogether, we reveal transcriptional targets of two key pluripotency-related genes in ES cells--Stat3 and c-Myc, thus providing further insight into the ES cell transcriptional network.