Novel mechanisms in the pathogenesis of atrial fibrillation: practical applications

Intensive research over the last few decades has seen significant advances in our understanding of the complex mechanisms underlying atrial fibrillation (AF). The epidemic of AF and related hospitalizations has been described as a 'rising tide' with estimates of the global AF burden showing no sign of retreat. There is urgency for effective translational programs in this field to facilitate more individualized and targeted therapy to modify the abnormal atrial substrate responsible for the perpetuation of this arrhythmia. In this review, we chose to focus on several novel aspects of AF pathogenesis whereby practical applications in clinical practice are currently available or potentially not too far away. Specifically, we explored the contribution of atrial fibrosis, epicardial adipose tissue, autonomic nervous system, hyper-coagulability, and focal drivers to adverse atrial remodelling and AF persistence. We also highlighted the potential practical means of monitoring and targeting these factors to achieve better outcomes in patients suffering from this debilitating illness. Emerging data also support a new paradigm for targeting AF substrate with aggressive risk factor management. Finally, multi-disciplinary integrated care approach has shown great promise in improving cardiovascular outcomes of patients with AF along with potential cost savings.Dennis H. Lau, Ulrich Schotten, Rajiv Mahajan, Nicholas A. Antic, Stephane N. Hatem, Rajeev K. Pathak, Jeroen M. L. Hendriks, Jonathan M. Kalman and Prashanthan Sander

Nocturnal Hypoxemia and Severe Obstructive Sleep Apnea are Associated with Incident Type 2 Diabetes in a Population Cohort of Men

Freely available online at PubMed Central Study Objectives Studies examining the longitudinal association of untreated obstructive sleep apnea (OSA) with diabetes in population samples are limited. This study therefore examined the relationship between previously undiagnosed OSA with incident type 2 diabetes in community-dwelling men aged ≥ 40 y. Methods The Men Androgen Inflammation Lifestyle Environment and Stress (MAILES) Study is a longitudinal population-based cohort in Adelaide, South Australia. Clinic assessments at baseline and follow-up identified diabetes (self-reported doctor diagnosed, fasting plasma glucose ≥ 7.0 mmol/L, glycated hemoglobin ≥ 6.5% or diabetes medication use) and included anthropometry. At cohort follow-up (2010–2012), n = 837 underwent full in-home unattended polysomnography (PSG, Embletta X100, Broomfield, CO). Results Of 736 men free of diabetes at baseline, incident diabetes occurred in 66 (9.0%) over a mean follow-up time of 56 mo (standard deviation = 5, range: 48–74 mo). Incident diabetes was associated with current oxygen desaturation index (3%) ≥ 16 events/h (odds ratio [OR]: 1.85 [1.06–3.21]), and severe OSA [OR: 2.6 (1.1–6.1)], in adjusted models including age, percentage total body fat, and weight gain (> 5 cm waist circumference). An age-adjusted association of incident diabetes with percentage of total sleep time with oxygen saturation < 90% did not persist after adjustment for percentage of body fat. No modification of these relationships by excessive daytime sleepiness was observed. Conclusions Severe undiagnosed OSA and nocturnal hypoxemia were independently associated with the development of diabetes. A reduction in the burden of undiagnosed OSA and undiagnosed diabetes is likely to occur if patients presenting with one disorder are assessed for the other

Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL

Chronic lymphocytic leukemia (CLL) is characterized by the existence of subsets of patients with (quasi)identical, stereotyped B cell receptor immunoglobulins (BcR IG). Patients in certain major stereotyped subsets often display remarkably consistent clinicobiological profiles, suggesting that the study of BcR IG stereotypy in CLL has important implications for understanding disease pathophysiology and refining clinical decision-making. Nevertheless, several issues remain open, especially pertaining to the actual frequency of BcR IG stereotypy and major subsets, as well as the existence of higher-order connections between individual subsets. In order to address these issues, we investigated clonotypic IGHV-IGHD-IGHJ gene rearrangements in a series of 29,856 patients with CLL, by far the largest series worldwide. We report that the stereotyped fraction of CLL peaks at 41% of the entire cohort and that all 19 previously identified major subsets retained their relative size and ranking, while 10 new ones emerged; overall, major stereotyped subsets had a cumulative frequency of 13.5%. Higher-level relationships were evident between subsets, particularly for major stereotyped subsets with unmutated IGHV genes (U-CLL), for which close relations with other subsets, termed 'satellites', were identified. Satellite subsets accounted for 3% of the entire cohort. These results confirm our previous notion that major subsets can be robustly identified and are consistent in relative size, hence representing distinct disease variants amenable to compartmentalized research with the potential of overcoming the pronounced heterogeneity of CLL. Furthermore, the existence of satellite subsets reveals a novel aspect of repertoire restriction with implications for refined molecular classification of CLL

Comprehensive molecular characterization of urothelial bladder carcinoma

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomasto provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalitiesclose27