How often should we monitor for reliable detection of atrial fibrillation recurrence? Efficiency considerations and implications for study design

OBJECTIVE: Although atrial fibrillation (AF) recurrence is unpredictable in terms of onset and duration, current intermittent rhythm monitoring (IRM) diagnostic modalities are short-termed and discontinuous. The aim of the present study was to investigate the necessary IRM frequency required to reliably detect recurrence of various AF recurrence patterns. METHODS: The rhythm histories of 647 patients (mean AF burden: 12±22% of monitored time; 687 patient-years) with implantable continuous monitoring devices were reconstructed and analyzed. With the use of computationally intensive simulation, we evaluated the necessary IRM frequency to reliably detect AF recurrence of various AF phenotypes using IRM of various durations. RESULTS: The IRM frequency required for reliable AF detection depends on the amount and temporal aggregation of the AF recurrence (p<0.0001) as well as the duration of the IRM (p<0.001). Reliable detection (>95% sensitivity) of AF recurrence required higher IRM frequencies (>12 24-hour; >6 7-day; >4 14-day; >3 30-day IRM per year; p<0.0001) than currently recommended. Lower IRM frequencies will under-detect AF recurrence and introduce significant bias in the evaluation of therapeutic interventions. More frequent but of shorter duration, IRMs (24-hour) are significantly more time effective (sensitivity per monitored time) than a fewer number of longer IRM durations (p<0.0001). CONCLUSIONS: Reliable AF recurrence detection requires higher IRM frequencies than currently recommended. Current IRM frequency recommendations will fail to diagnose a significant proportion of patients. Shorter duration but more frequent IRM strategies are significantly more efficient than longer IRM durations. CLINICAL TRIAL REGISTRATION URL: Unique identifier: NCT00806689

The Outcome of the Axillofemoral Bypass: A Retrospective Analysis of 45 Patients

Purpose This study was designed to retrospectively analyze outcomes of axillofemoral bypass (AxFB) operations performed in patients with severe comorbidities. Methods All patients (n = 45) who received an AxFB between 1990 and 2005 for aortoiliac occlusive disease (AIOD, n = 35) or infectious aortic disease (IAD, n = 10) were included. Information on patency of the bypass and mortality was retrieved from patient records. A Kaplan-Meier survival analysis was performed to illustrate survival rates, limb salvage, and primary and secondary patency. Results Included patients had several comorbidities and a high operative risk. In this group, a 30-day mortality rate of 20% was found: 17% for the AIOD group, and 30% for the IAD group. During 5-year follow-up 20 patients died, of which 15 during the first year after operation. Survival rates were at 64 and 41% at 1 and 5 years and limb salvage rates were 84% for both these years. Primary patency rates at 1 and 5 years were 72 and 58%, respectively, and secondary patency rates were 86% at both time points. Conclusions High mortality rates were found in AIOD or IAD patients who received an AxFB. However, for high-risk patients with an already reduced life expectancy, the AxFB remains an alternative with acceptable patency rate

The Efficacy of Generating Three Independent Anti-HIV-1 siRNAs from a Single U6 RNA Pol III-Expressed Long Hairpin RNA

RNA Interference (RNAi) effectors have been used to inhibit rogue RNAs in mammalian cells. However, rapidly evolving sequences such as the human immunodeficiency virus type 1 (HIV-1) require multiple targeting approaches to prevent the emergence of escape variants. Expressed long hairpin RNAs (lhRNAs) have recently been used as a strategy to produce multiple short interfering RNAs (siRNAs) targeted to highly variant sequences. We aimed to characterize the ability of expressed lhRNAs to generate independent siRNAs that silence three non-contiguous HIV-1 sites by designing lhRNAs comprising different combinations of siRNA-encoding sequences. All lhRNAs were capable of silencing individual target sequences. However, silencing efficiency together with concentrations of individual lhRNA-derived siRNAs diminished from the stem base (first position) towards the loop side of the hairpin. Silencing efficacy against HIV-1 was primarily mediated by siRNA sequences located at the base of the stem. Improvements could be made to first and second position siRNAs by adjusting spacing arrangements at their junction, but silencing of third position siRNAs remained largely ineffective. Although lhRNAs offer advantages for combinatorial RNAi, we show that good silencing efficacy across the span of the lhRNA duplex is difficult to achieve with sequences that encode more than two adjacent independent siRNAs

Expression and Function of Osteopontin in Vascular Adventitial Fibroblasts and Pathological Vascular Remodeling

Osteopontin is known to play important roles in various diseases including vascular disorders. However, little is known about its expression and function in vascular adventitial fibroblasts. Adventitial fibroblasts have been shown to play a key role in pathological vascular remodeling associating with various vascular disorders. In this study, we measured activation of Osteopontin and its biological functions in cultured adventitial fibroblasts and injured rat carotid injury arteries induced by balloon angioplasty. Our results showed that angiotensin II and aldosterone increased Osteopontin expression in adventitial fibroblasts in a time- and concentration-dependent manner. MAPKs and AP-1 pathways were involved in Osteopontin upregulation. In addition, Adventitial fibroblast migration stimulated by Angiotensin II and aldosterone required OPN expression. Perivascular delivery of antisense oligonucleotide for Osteopontin suppressed neointimal formation post-injury. We concluded that upregulation of Osteopontin expression in adventitial fibroblasts might be important in the pathogenesis of vascular remodeling after arterial injury

Post-operative atrial fibrillation: a maze of mechanisms

Post-operative atrial fibrillation (POAF) is one of the most frequent complications of cardiac surgery and an important predictor of patient morbidity as well as of prolonged hospitalization. It significantly increases costs for hospitalization. Insights into the pathophysiological factors causing POAF have been provided by both experimental and clinical investigations and show that POAF is ‘multi-factorial’. Facilitating factors in the mechanism of the arrhythmia can be classified as acute factors caused by the surgical intervention and chronic factors related to structural heart disease and ageing of the heart. Furthermore, some proarrhythmic mechanisms specifically occur in the setting of POAF. For example, inflammation and beta-adrenergic activation have been shown to play a prominent role in POAF, while these mechanisms are less important in non-surgical AF. More recently, it has been shown that atrial fibrosis and the presence of an electrophysiological substrate capable of maintaining AF also promote the arrhythmia, indicating that POAF has some proarrhythmic mechanisms in common with other forms of AF. The clinical setting of POAF offers numerous opportunities to study its mechanisms. During cardiac surgery, biopsies can be taken and detailed electrophysiological measurements can be performed. Furthermore, the specific time course of POAF, with the delayed onset and the transient character of the arrhythmia, also provides important insight into its mechanisms

Pathway-Consensus Approach to Metabolic Network Reconstruction for Pseudomonas putida KT2440 by Systematic Comparison of Published Models

Over 100 genome-scale metabolic networks (GSMNs) have been published in recent years and widely used for phenotype prediction and pathway design. However, GSMNs for a specific organism reconstructed by different research groups usually produce inconsistent simulation results, which makes it difficult to use the GSMNs for precise optimal pathway design. Therefore, it is necessary to compare and identify the discrepancies among networks and build a consensus metabolic network for an organism. Here we proposed a process for systematic comparison of metabolic networks at pathway level. We compared four published GSMNs of Pseudomonas putida KT2440 and identified the discrepancies leading to inconsistent pathway calculation results. The mistakes in the models were corrected based on information from literature so that all the calculated synthesis and uptake pathways were the same. Subsequently we built a pathway-consensus model and then further updated it with the latest genome annotation information to obtain modelPpuQY1140 for P. putida KT2440, which includes 1140 genes, 1171 reactions and 1104 metabolites. We found that even small errors in a GSMN could have great impacts on the calculated optimal pathways and thus may lead to incorrect pathway design strategies. Careful investigation of the calculated pathways during the metabolic network reconstruction process is essential for building proper GSMNs for pathway design