A multicenter randomized controlled trial indicates that paclitaxel-coated balloons provide no benefit for arteriovenous fistulas.

The role of paclitaxel-coated balloons has been established in the coronary and peripheral arterial circulations with recent interest in the use of paclitaxel-coated balloons to improve patency rates following angioplasty of arteriovenous fistulas. To assess the efficacy of paclitaxel-coated angioplasty balloons to prolong the survival time of target lesion primary patency in arteriovenous fistulas, we designed an investigator-led multi-center randomized controlled trial with follow up time variable for a minimum of one year. Patients with an arteriovenous fistula who were undergoing an angioplasty for a clinical indication were included but patients with one or more lesions outside the treatment segment were excluded. Following successful treatment with a high-pressure balloon, 212 patients were randomized. In the intervention arm, the second component was insertion of a paclitaxel-coated balloon. In the control arm, an identical procedure was followed, but using a standard balloon. The primary endpoint was time to loss of clinically driven target lesion primary patency. Primary analysis showed no significant evidence for a difference in time to end of target lesion primary patency between groups: hazard ratio 1.18 with a 95% confidence interval of 0.78 to 1.79. There were no significant differences for any secondary outcomes, including patency outcomes and adverse events. Thus, our study demonstrated no evidence that paclitaxel-coated balloons provide benefit, following standard care high-pressure balloon angioplasty, in the treatment of arteriovenous fistulas. Hence, in view of the benefit suggested by other trials, the role of paclitaxel-coated angioplasty balloons remains uncertain.

A phase 2 randomised controlled trial of serelaxin to lower portal pressure in cirrhosis (STOPP).

BACKGROUND: In preclinical models, recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure. METHODS: In a phase 2, double-blind, randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically significant PH (CSPH; hepatic venous pressure gradient (HVPG) > 10 mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 3:1 ratio. The placebo was matched to serelaxin on appearance and administration protocol to create and maintain blinding. The primary endpoint was the change from baseline in fasting HVPG after 2 h of peripheral i.v. serelaxin infusion (80 µg/kg/day for 60 min followed by 30 µg/kg/day for at least 60 min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin were assessed. RESULTS: A total of 17 participants were screened, 15 were randomised and 11 completed the study (n = 9 serelaxin, n = 2 placebo). Reasons for withdrawal were baseline HVPG < 10 mmHg (n = 2) and technical failure (n = 2). The trial ended early due to manufacturer discontinuation of the study drug. The median age was 56 (range 43-69) years and 73% of participants were male. Alcohol was the commonest cirrhosis aetiology (n = 10). Participants had a median Model for End-Stage Liver Disease score of 10 (range 6-14). The mean baseline HVPG was 16.3 (range 10.3-21.7) mmHg. Individual responses were variable, but overall there was no statistically significant change in HVPG after 2 h of i.v. serelaxin (arithmetic mean of difference ± SD was 0.4 ± 3.5 mmHg (95% CI -2.3, 3.1; p = 0.76)). There were also no substantial changes from baseline in hepatic or systemic haemodynamics. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events. CONCLUSION: In a small randomised, phase 2, proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02669875. Registered on 1 February 2016.

Substantial Metabolic Activity of Human Brown Adipose Tissue during Warm Conditions and Cold-Induced Lipolysis of Local Triglycerides.

Current understanding of in vivo human brown adipose tissue (BAT) physiology is limited by a reliance on positron emission tomography (PET)/computed tomography (CT) scanning, which has measured exogenous glucose and fatty acid uptake but not quantified endogenous substrate utilization by BAT. Six lean, healthy men underwent 18fluorodeoxyglucose-PET/CT scanning to localize BAT so microdialysis catheters could be inserted in supraclavicular BAT under CT guidance and in abdominal subcutaneous white adipose tissue (WAT). Arterial and dialysate samples were collected during warm (∼25°C) and cold exposure (∼17°C), and blood flow was measured by 133xenon washout. During warm conditions, there was increased glucose uptake and lactate release and decreased glycerol release by BAT compared with WAT. Cold exposure increased blood flow, glycerol release, and glucose and glutamate uptake only by BAT. This novel use of microdialysis reveals that human BAT is metabolically active during warm conditions. BAT activation substantially increases local lipolysis but also utilization of other substrates such as glutamate.

18F-Sodium Fluoride Uptake in Abdominal Aortic Aneurysms: The SoFIA3 Study.

BACKGROUND: Fluorine-18-sodium fluoride (18F-NaF) uptake is a marker of active vascular calcification associated with high-risk atherosclerotic plaque. OBJECTIVES: In patients with abdominal aortic aneurysm (AAA), the authors assessed whether 18F-NaF positron emission tomography (PET) and computed tomography (CT) predicts AAA growth and clinical outcomes. METHODS: In prospective case-control (n = 20 per group) and longitudinal cohort (n = 72) studies, patients with AAA (aortic diameter >40 mm) and control subjects (aortic diameter <30 mm) underwent abdominal ultrasound, 18F-NaF PET-CT, CT angiography, and calcium scoring. Clinical endpoints were aneurysm expansion and the composite of AAA repair or rupture. RESULTS: Fluorine-18-NaF uptake was increased in AAA compared with nonaneurysmal regions within the same aorta (p = 0.004) and aortas of control subjects (p = 0.023). Histology and micro-PET-CT demonstrated that 18F-NaF uptake localized to areas of aneurysm disease and active calcification. In 72 patients within the longitudinal cohort study (mean age 73 ± 7 years, 85% men, baseline aneurysm diameter 48.8 ± 7.7 mm), there were 19 aneurysm repairs (26.4%) and 3 ruptures (4.2%) after 510 ± 196 days. Aneurysms in the highest tertile of 18F-NaF uptake expanded 2.5× more rapidly than those in the lowest tertile (3.10 [interquartile range (IQR): 2.34 to 5.92 mm/year] vs. 1.24 [IQR: 0.52 to 2.92 mm/year]; p = 0.008) and were nearly 3× as likely to experience AAA repair or rupture (15.3% vs. 5.6%; log-rank p = 0.043). CONCLUSIONS: Fluorine-18-NaF PET-CT is a novel and promising approach to the identification of disease activity in patients with AAA and is an additive predictor of aneurysm growth and future clinical events. (Sodium Fluoride Imaging of Abdominal Aortic Aneurysms [SoFIA3]; NCT02229006; Magnetic Resonance Imaging [MRI] for Abdominal Aortic Aneurysms to Predict Rupture or Surgery: The MA3RS Trial; ISRCTN76413758).

Elution characteristics of doxorubicin-loaded microspheres differ by drug-loading method and microsphere size.

PURPOSE: To examine the loading and elution behavior of doxorubicin and superabsorbent polymer microspheres (SAP-MS) as they relate to particle size and loading techniques. MATERIALS AND METHODS: SAP-MS, 30-60 µm and 50-100 µm, were subject to loading 50 mg of doxorubicin from a dry lyophilized state. Doxorubicin loading was performed after prehydration of SAP-MS (one-step method) or serially in two divided administrations (two-step method). Loading rate and elution characteristics were determined after doxorubicin analysis using a high-pressure liquid chromatography (HPLC) assay. All experiments were performed in triplicate. RESULTS: All systems showed the ability to load and elute doxorubicin effectively in the specified time frame (loading 15 minutes to 2 hours and elution 1 hour to 14 days). For the two loading methods, 30-60 µm SAP-MS showed no statistically significant difference in loading rate but a statistically significant difference in cumulative elution at 14 days (19.13 mg vs 17.83 mg, one-step vs two-step; P = .02). For the two loading methods, 50-100 µm SAP-MS showed no statistically significant difference in loading rate and no statistically significant difference in cumulative elution at 14 days (14.87 mg vs 12.77 mg, one-step vs two-step; P = .20). CONCLUSIONS: SAP-MS exhibit the ability to load and release doxorubicin. In comparing particle size and loading methods, higher cumulative elution rates were associated with smaller (30-60 µm) particle size and one-step loading. Higher elution from the one-step loading method may be due to release of unbound doxorubicin. Differences in the loading and elution of doxorubicin may depend on the increased surface area of smaller SAP-MS resulting in alterations of behavior of doxorubicin and its interactions with the polymer microspheres.

Carotid artery stenting: relationship between experience and complication rate.

To investigate the evidence for the relationship between volume and outcome for carotid artery stenting. We performed a systematic review of the literature to examine the influence of experience and/or volume on outcome for carotid artery stenting. The primary search strategy was to identify studies presenting year-on-year data. The Pubmed, Embase, Medline and the Cochrane Collaboration databases were searched. Studies with over 100 interventions were included. The main outcome measure compared across studies was all stroke/death. Where possible, comparable data were pooled and analysed using meta-regression techniques. It was not possible to perform a standard systematic review and meta-analysis because of the lack of data from randomised studies. When redundant studies were excluded, four sizeable case series and one registry met the inclusion criteria. When the case series results were pooled, the χ²-test for trend demonstrated a significant reduction in the combined stroke and death rate over time. Meta-regression analysis of case series data allowed the setting of thresholds for 'acceptable' stroke/death rates. Where year-on-year data are available, published stroke and death rates for carotid artery stenting show improvements over time. While advances in technology and pharmacology may in part be responsible, temporal improvement in outcomes demonstrated in both early and contemporary time-frames together with the consistency of the results suggests the presence of a learning curve. In active carotid artery stenting units, it may take almost 2-years before the stroke/death rates fall below an arbitrary 5% threshold.

Combined metabolomic and proteomic analysis of human atrial fibrillation.

OBJECTIVES: We sought to decipher metabolic processes servicing the increased energy demand during persistent atrial fibrillation (AF) and to ascertain whether metabolic derangements might instigate this arrhythmia. BACKGROUND: Whereas electrical, structural, and contractile remodeling processes are well-recognized contributors to the self-perpetuating nature of AF, the impact of cardiac metabolism upon the persistence/initiation of this resilient arrhythmia has not been explored in detail. METHODS: Human atrial appendage tissues from matched cohorts in sinus rhythm (SR), from those who developed AF post-operatively, and from patients in persistent AF undergoing cardiac surgery were analyzed using a combined metabolomic and proteomic approach. RESULTS: High-resolution proton nuclear magnetic resonance (NMR) spectroscopy of cardiac tissue from patients in persistent AF revealed a rise in beta-hydroxybutyrate, the major substrate in ketone body metabolism, along with an increase in ketogenic amino acids and glycine. These metabolomic findings were substantiated by proteomic experiments demonstrating differential expression of 3-oxoacid transferase, the key enzyme for ketolytic energy production. Notably, compared with the SR cohort, the group susceptible to post-operative AF showed a discordant regulation of energy metabolites. Combined principal component and linear discriminant analyses of metabolic profiles from proton NMR spectroscopy correctly classified more than 80% of patients at risk of AF at the time of coronary artery bypass grafting. CONCLUSIONS: The present study characterized the metabolic adaptation to persistent AF, unraveling a potential role for ketone bodies, and demonstrated that discordant metabolic alterations are evident in individuals susceptible to post-operative AF.

Endothelial progenitor cells are mobilized after cardiac surgery.

BACKGROUND: There is evidence that endothelial progenitor cells (EPCs) are mobilized into the circulation after coronary artery bypass grafting (CABG) with cardiopulmonary bypass. However, there is little known about EPC mobilization after off-pump CABG or valve surgery. We aimed to establish the response of EPCs to various forms of cardiac surgery and examine the role of well-known mobilizing cytokines on EPC levels. METHODS: One hundred and ten patients were studied: 54 elective CABG (30 on-pump, 24 off-pump); 23 urgent CABG; and 33 non-CABG. The EPC functional status was assessed using the colony forming unit assay (EPC-CFU) and plasma levels of granulocyte colony-stimulating factor (G-CSF), stromal cell-derived factor 1-alpha, matrix metalloproteinase, and vascular endothelial growth factor were assessed by enzyme-linked immunosorbent assay. Samples were taken preoperatively and on days 1 and 5 after surgery. RESULTS: Patients requiring urgent CABG and non-CABG patients had significantly higher numbers of EPC-CFU prior to surgery than elective CABG patients. All elective patients showed a significant increase in postoperative EPC-CFU levels: on-pump CABG 10.4 +/- 3.8 to 53.9 +/- 11.9, p = 0.001; off-pump CABG 9.5 +/- 3.5 to 65.7 +/- 17.3, p = 0.006; non-CABG 23.5 +/- 6.8 to 84.6 +/- 27.2, p = 0.05. The postoperative EPC rise in elective patients correlated with plasma G-CSF levels (r = 0.387, p < 0.01). Urgent patients demonstrated a significant increase in G-CSF levels but this was not associated with an increase in EPC-CFU level. CONCLUSIONS: Patients undergoing elective cardiac surgery demonstrated an increase in EPC-CFU postoperatively, which correlated with increased plasma G-CSF level. Urgent patients did not have an increase in EPC-CFU despite a plasma G-CSF rise. Endogenously mobilized EPCs present a potential therapeutic target.

Current strategies in the management of atrial fibrillation.

Treatment of atrial fibrillation (AF) has been undergoing significant changes recently. This is due partly to different mechanisms proposed for persistent and permanent AF and partly due to the introduction of energy-based techniques, providing less invasive procedures. This article aims to review the mechanisms of AF leading to the changes in clinical practice and to review the results of surgery, energy-based, and percutaneous techniques. It is difficult to compare and contrast the results of reported series in the literature due to different definitions of AF; freedom from and recurrence of it. Furthermore, in most series it is difficult to distinguish results of surgery for lone AF and AF associated with valvular heart disease and coronary artery disease.