Executable Network Models of Integrated Multiomics Data.

Multiomics profiling provides a holistic picture of a condition being examined and captures the complexity of signaling events, beginning from the original cause (environmental or genetic), to downstream functional changes at multiple molecular layers. Pathway enrichment analysis has been used with multiomics data sets to characterize signaling mechanisms. However, technical and biological variability between these layered data limit an integrative computational analyses. We present a Boolean network-based method, multiomics Boolean Omics Network Invariant-Time Analysis (mBONITA), to integrate omics data sets that quantify multiple molecular layers. mBONITA utilizes prior knowledge networks to perform topology-based pathway analysis. In addition, mBONITA identifies genes that are consistently modulated across molecular measurements by combining observed fold-changes and variance, with a measure of node (i.e., gene or protein) influence over signaling, and a measure of the strength of evidence for that gene across data sets. We used mBONITA to integrate multiomics data sets from RAMOS B cells treated with the immunosuppressant drug cyclosporine A under varying O2 tensions to identify pathways involved in hypoxia-mediated chemotaxis. We compare mBONITA's performance with 6 other pathway analysis methods designed for multiomics data and show that mBONITA identifies a set of pathways with evidence of modulation across all omics layers. mBONITA is freely available at https://github.com/Thakar-Lab/mBONITA.

Determinants of pacemaker dependency after coronary and/or mitral or aortic valve surgery with long-term follow-up.

The aim of the present study was to investigate potential preoperative, operative, and postoperative predictors of pacemaker (PM) dependency after coronary, mitral valve, and aortic valve surgery. One hundred two patients (mean age 68 +/- 11 years; 62% men) who had received a permanent PM after cardiac surgery were included. The presence of any pacing activity in VVI mode with a lower rate of 30 beats/min was defined as PM dependency. Median time to PM implantation was 10 days after the index surgery. Pacemaker indications were atrioventricular block (AVB), sinus node dysfunction, and slow atrial fibrillation in 70%, 20%, and 11% of patients, respectively. At baseline, PM dependency rates were 0%, 9%, and 15% for patients with sinus node dysfunction, slow atrial fibrillation, and AVB, respectively (p = 0.158). Corresponding values at last follow-up were 15%, 9%, and 41% (p = 0.02). During long-term follow-up, new PM dependency developed in 21 patients (23%). Most patients had AVB as the PM indication (18 of 21 patients; 86%). Cumulative probabilities of freedom from PM dependency in patients with AVB were 63% and 30% at 5 and 10 years, respectively. Of several demographic, preoperative clinical, electrocardiographic, operative, and postoperative characteristics of patients, preoperative history of syncope (odds ratio [OR] 6.58, 95% confidence interval [CI] 1.11 to 38.87), body mass index >or=28.5 kg/m2 (OR 2.88, 95% CI 1.08 to 7.67), bypass time >or=105 minutes (OR 4.81, 95% CI 1.54 to 15.02), and AVB as PM indication (OR 5.14, 95% CI 1.51 to 17.44) were independent predictors of long-term PM dependency in multivariate logistic regression analysis. In conclusion, the long-term PM dependency rate was relatively high in patients with postoperative AVB requiring permanent PM implantation. A preoperative history of syncope, body mass index >or=28.5 kg/m2, bypass time of 105 minutes, and AVB as PM indication were independent predictors of long-term PM dependency after cardiac surgery.

Meta-analysis of magnesium therapy for the acute management of rapid atrial fibrillation.

The profile of electrophysiologic effects of magnesium on the heart suggests that magnesium might be effective in the treatment of atrial fibrillation (AF) in terms of rhythm and rate control. We aimed to investigate the efficacy of magnesium administration in the acute treatment of rapid AF. Randomized controlled trials comparing intravenous magnesium versus placebo or antiarrhythmic agents for the acute management of rapid AF were included. Nine electronic databases were searched for relevant trials from the earliest possible dates through June 2005, as were abstract books from 8 cardiovascular meetings held in the past 10 years. We analyzed all outcomes using a fixed-effect model because of the low number of trials in each comparison. The results were expressed as relative risks (RRs) or odds ratios (ORs) for dichotomous outcomes and weighted mean differences for continuous outcomes, along with their 95% confidence intervals (CIs). Data were pooled for 4 trials (n=303) and 8 trials (n=476), respectively, for rate control (<100 beats/min) and rhythm control. Magnesium was effective in achieving rate control (OR 1.96, 95% CI 1.24 to 3.08) or rhythm control (OR, 1.60, 95% CI 1.07 to 2.39). An overall response was achieved in 86% and 56% of patients in the magnesium and control groups, respectively (OR 4.61 95% CI 2.67 to 7.96). Time to response (in hours) was significantly shorter in the magnesium group (weighted mean difference, -6.98; 95% CI -9.27 to -4.68). The risk of having a major adverse effect in the magnesium group was similar to that in the placebo group (RR 0.85, 95% CI 0.44 to 1.61). In conclusion, the present meta-analysis of published data suggests that intravenous magnesium administration is an effective and safe strategy for the acute management of rapid AF.

Multifactorial QT Interval Prolongation and Takotsubo Cardiomyopathy.

A 71-year-old woman collapsed while working as a grocery store cashier. CPR was performed and an AED revealed torsades de pointes (TdP). She was subsequently defibrillated resulting in restoration of sinus rhythm with a QTc interval of 544 msec. Further evaluation revealed a diagnosis of Takotsubo Cardiomyopathy (TCM) contributing to the development of a multifactorial acquired long QT syndrome (LQTS). The case highlights the role of TCM as a cause of LQTS in the setting of multiple risk factors including old age, female gender, hypokalemia, and treatment with QT prolonging medications. It also highlights the multifactorial nature of acquired LQTS and lends support to growing evidence of an association with TCM.

Remote magnetic navigation for catheter ablation of atrioventricular nodal reentrant tachycardia: a systematic review and meta-analysis.

Catheter ablation has become a well-established, first-line therapy for atrioventricular nodal reentrant tachycardia (AVNRT), the most common reentry supraventricular tachycardia in humans. Robotic systems are becoming increasingly common in both complex and simple ablation procedures with presumed potential improvements in procedural efficacy and safety. The authors of this article conducted a systematic review and meta-analysis on the effectiveness and safety of the magnetic navigation system (MNS) in comparison with conventional catheter navigation for AVNRT ablation. An electronic search was performed using Cochrane Central database, Medline, Embase and Web of Knowledge between 2002 and 2012. References were searched manually. Outcomes of interest were: acute and long-term success, complications, total procedure, ablation and fluoroscopic times. Continuous variables were reported as standardized difference in means (SDM); odds ratios (OR) were reported for dichotomous variables. Thirteen studies (seven of which were nonrandomized controlled, four were case series and two were randomized controlled studies) involving 679 adult patients were identified. Twelve studies were based on a single center and one study was multicentral. MNS was deployed in 339 patients. The follow-up period ranged between 75 and 180 days. Acute success and long-term freedom from arrhythmia were not significantly different between MNS and control groups (98 vs 98%, OR: 0.94 [95% CI: 0.21-4.1] and 97 vs 96%, OR: 1.18 [95% CI: 0.35-4.0], respectively). A shorter fluoroscopic time was achieved with MNS; however, this did not reach statistical significance (15 vs 19 min, SDM: -0.26 [95% CI: -0.64-0.12]). Longer total procedure but similar ablation times were noted with MNS (160 vs 148 min, SDM: 3.48 [95% CI: 0.75-6.21] and 4 vs 6 min, SDM: -0.83 [95% CI: -2.19-0.53], respectively). The overall complication rate was similar between both groups (2.7 vs 1.0%, OR: 1.28 [95% CI: 0.33-4.96]). Our data suggest that the usage of MNS results in similar rates of success and complications when compared with conventional manual catheter ablation for AVNRT. MNS had a trend for reduced fluoroscopic time. Longer total procedure time was observed with MNS while the actual ablation time remained similar. Prospective randomized trials will be needed to better evaluate the relative role of MNS for catheter ablation of AVNRT.