Anaesthesia Choice for Creation of Arteriovenous Fistula (ACCess) study protocol : a randomised controlled trial comparing primary unassisted patency at 1 year of primary arteriovenous fistulae created under regional compared to local anaesthesia.

INTRODUCTION: Arteriovenous fistulae (AVF) are the 'gold standard' vascular access for haemodialysis. Universal usage is limited, however, by a high early failure rate. Several small, single-centre studies have demonstrated better early patency rates for AVF created under regional anaesthesia (RA) compared with local anaesthesia (LA). The mechanistic hypothesis is that the sympathetic blockade associated with RA causes vasodilatation and increased blood flow through the new AVF. Despite this, considerable variation in practice exists in the UK. A high-quality, adequately powered, multicentre randomised controlled trial (RCT) is required to definitively inform practice. METHODS AND ANALYSIS: The Anaesthesia Choice for Creation of Arteriovenous Fistula (ACCess) study is a multicentre, observer-blinded RCT comparing primary radiocephalic/brachiocephalic AVF created under regional versus LA. The primary outcome is primary unassisted AVF patency at 1 year. Access-specific (eg, stenosis/thrombosis), patient-specific (including health-related quality of life) and safety secondary outcomes will be evaluated. Health economic analysis will also be undertaken. ETHICS AND DISSEMINATION: The ACCess study has been approved by the West of Scotland Research and ethics committee number 3 (20/WS/0178). Results will be published in open-access peer-reviewed journals within 12 months of completion of the trial. We will also present our findings at key national and international renal and anaesthetic meetings, and support dissemination of trial outcomes via renal patient groups. TRIAL REGISTRATION NUMBER: ISRCTN14153938. SPONSOR: NHS Greater Glasgow and Clyde GN19RE456, Protocol V.1.3 (8 May 2021), REC/IRAS ID: 290482.

Ferumoxytol magnetic resonance angiography: a dose-finding study in patients with chronic kidney disease.

OBJECTIVES: Ferumoxytol is an alternative to gadolinium-based compounds as a vascular contrast agent for magnetic resonance angiography (MRA), particularly for patients with chronic kidney disease (CKD). However, dose-related efficacy data are lacking. We aimed to determine the optimal (minimum effective) dose of ferumoxytol for MRA in patients with CKD. METHODS: Ferumoxytol-enhanced MRA (FeMRA) was performed at 3.0 T in patients with CKD after dose increments up to a total of 4 mg/kg. Image quality was assessed by contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) in the abdominal aorta and inferior vena cava. Quadratic regression analyses were performed to estimate the effects of dose increments on CNR and SNR. RESULTS: Twenty-three patients underwent FeMRA (mean age 60 [SD 13] years, 87% men, 48% had diabetic nephropathy) with cumulative doses of 0, 1, 2, 3 and 4 mg/kg of ferumoxytol. On regression analyses, a parabolic relationship was observed between ferumoxytol dose and signal with progressive signal loss using doses exceeding 4 mg/kg. A dose of 3 mg/kg achieved ≥ 75% of predicted peak CNR and SNR and images were deemed of excellent diagnostic quality. CONCLUSIONS: In patients with CKD undergoing FeMRA, a dose of 3 mg/kg provides excellent arterial and venous enhancement. The benefits of increasing the dose to a theoretically optimal value of 4 mg/kg appear to be negligible and likely of minimal, if any, diagnostic value. KEY POINTS: • Ferumoxytol is used off-label as an MRI contrast agent but dose-related data are lacking. • In patients with CKD requiring MR angiography, a dose of 3 mg/kg provides excellent vascular enhancement.

Disease Activity in Mitral Annular Calcification.

BACKGROUND: Mitral annular calcification (MAC) is associated with cardiovascular events and mitral valve dysfunction. However, the underlying pathophysiology remains incompletely understood. In this prospective longitudinal study, we used a multimodality approach including positron emission tomography, computed tomography, and echocardiography to investigate the pathophysiology of MAC and assess factors associated with disease activity and progression. METHODS: A total of 104 patients (age 72±8 years, 30% women) with calcific aortic valve disease, therefore predisposed to MAC, underwent 18F-sodium fluoride (calcification activity) and 18F-Fluorodeoxyglucose (inflammation activity) positron emission tomography, computed tomography calcium scoring, and echocardiography. Sixty patients underwent repeat computed tomography and echocardiography after 2 years. RESULTS: MAC (mitral annular calcium score >0) was present in 35 (33.7%) patients who had increased 18F-fluoride (tissue-to-background ratio, 2.32 [95% CI, 1.81-3.27] versus 1.30 [1.22-1.49]; P<0.001) and 18F-Fluorodeoxyglucose activity (tissue-to-background ratio, 1.44 [1.37-1.58] versus 1.17 [1.12-1.24]; P<0.001) compared with patients without MAC. MAC activity (18F-fluoride uptake) was closely associated with the local calcium score and 18F-Fluorodeoxyglucose uptake, as well as female sex and renal function. Similarly, MAC progression was closely associated with local factors, in particular, baseline MAC. Traditional cardiovascular risk factors and calcification activity in bone or remote atherosclerotic areas were not associated with disease activity nor progression. CONCLUSIONS: MAC is characterized by increased local calcification activity and inflammation. Baseline MAC burden was associated with disease activity and the rate of subsequent progression. This suggests a self-perpetuating cycle of calcification and inflammation that may be the target of future therapeutic interventions.

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).

End stage renal disease-induced hypercalcemia may promote aortic valve calcification via Annexin VI enrichment of valve interstitial cell derived-matrix vesicles.

Patients with end-stage renal disease (ESRD) have elevated circulating calcium (Ca) and phosphate (Pi), and exhibit accelerated progression of calcific aortic valve disease (CAVD). We hypothesized that matrix vesicles (MVs) initiate the calcification process in CAVD. Ca induced rat valve interstitial cells (VICs) calcification at 4.5 mM (16.4-fold; p < 0.05) whereas Pi treatment alone had no effect. Ca (2.7 mM) and Pi (2.5 mM) synergistically induced calcium deposition (10.8-fold; p < 0.001) in VICs. Ca treatment increased the mRNA of the osteogenic markers Msx2, Runx2, and Alpl (p < 0.01). MVs were harvested by ultracentrifugation from VICs cultured with control or calcification media (containing 2.7 mM Ca and 2.5 mM Pi) for 16 hr. Proteomics analysis revealed the marked enrichment of exosomal proteins, including CD9, CD63, LAMP-1, and LAMP-2 and a concomitant up-regulation of the Annexin family of calcium-binding proteins. Of particular note Annexin VI was shown to be enriched in calcifying VIC-derived MVs (51.9-fold; p < 0.05). Through bioinformatic analysis using Ingenuity Pathway Analysis (IPA), the up-regulation of canonical signaling pathways relevant to cardiovascular function were identified in calcifying VIC-derived MVs, including aldosterone, Rho kinase, and metal binding. Further studies using human calcified valve tissue revealed the co-localization of Annexin VI with areas of MVs in the extracellular matrix by transmission electron microscopy (TEM). Together these findings highlight a critical role for VIC-derived MVs in CAVD. Furthermore, we identify calcium as a key driver of aortic valve calcification, which may directly underpin the increased susceptibility of ESRD patients to accelerated development of CAVD.

Cardiac αVß3 integrin expression following acute myocardial infarction in humans.

OBJECTIVE: Maladaptive repair contributes towards the development of heart failure following myocardial infarction (MI). The αvß3 integrin receptor is a key mediator and determinant of cardiac repair. We aimed to establish whether αvß3 integrin expression determines myocardial recovery following MI. METHODS: 18F-Fluciclatide (a novel αvß3-selective radiotracer) positron emission tomography (PET) and CT imaging and gadolinium-enhanced MRI (CMR) were performed in 21 patients 2 weeks after ST-segment elevation MI (anterior, n=16; lateral, n=4; inferior, n=1). CMR was repeated 9 months after MI. 7 stable patients with chronic total occlusion (CTO) of a major coronary vessel and nine healthy volunteers underwent a single PET/CT and CMR. RESULTS: 18F-Fluciclatide uptake was increased at sites of acute infarction compared with remote myocardium (tissue-to-background ratio (TBRmean) 1.34±0.22 vs 0.85±0.17; p<0.001) and myocardium of healthy volunteers (TBRmean 1.34±0.22 vs 0.70±0.03; p<0.001). There was no 18F-fluciclatide uptake at sites of established prior infarction in patients with CTO, with activity similar to the myocardium of healthy volunteers (TBRmean 0.71±0.06 vs 0.70±0.03, p=0.83). 18F-Fluciclatide uptake occurred at sites of regional wall hypokinesia (wall motion index≥1 vs 0; TBRmean 0.93±0.31 vs 0.80±0.26 respectively, p<0.001) and subendocardial infarction. Importantly, although there was no correlation with infarct size (r=0.03, p=0.90) or inflammation (C reactive protein, r=-0.20, p=0.38), 18F-fluciclatide uptake was increased in segments displaying functional recovery (TBRmean 0.95±0.33 vs 0.81±0.27, p=0.002) and associated with increase in probability of regional recovery. CONCLUSION: 18F-Fluciclatide uptake is increased at sites of recent MI acting as a biomarker of cardiac repair and predicting regions of recovery. TRIAL REGISTRATION NUMBER: NCT01813045; Post-results.

Myocardial Fibrosis and Cardiac Decompensation in Aortic Stenosis.

OBJECTIVES: Cardiac magnetic resonance (CMR) was used to investigate the extracellular compartment and myocardial fibrosis in patients with aortic stenosis, as well as their association with other measures of left ventricular decompensation and mortality. BACKGROUND: Progressive myocardial fibrosis drives the transition from hypertrophy to heart failure in aortic stenosis. Diffuse fibrosis is associated with extracellular volume expansion that is detectable by T1 mapping, whereas late gadolinium enhancement (LGE) detects replacement fibrosis. METHODS: In a prospective observational cohort study, 203 subjects (166 with aortic stenosis [69 years; 69% male]; 37 healthy volunteers [68 years; 65% male]) underwent comprehensive phenotypic characterization with clinical imaging and biomarker evaluation. On CMR, we quantified the total extracellular volume of the myocardium indexed to body surface area (iECV). The iECV upper limit of normal from the control group (22.5 ml/m2) was used to define extracellular compartment expansion. Areas of replacement mid-wall LGE were also identified. All-cause mortality was determined during 2.9 ± 0.8 years of follow up. RESULTS: iECV demonstrated a good correlation with diffuse histological fibrosis on myocardial biopsies (r = 0.87; p < 0.001; n = 11) and was increased in patients with aortic stenosis (23.6 ± 7.2 ml/m2 vs. 16.1 ± 3.2 ml/m2 in control subjects; p < 0.001). iECV was used together with LGE to categorize patients with normal myocardium (iECV <22.5 ml/m2; 51% of patients), extracellular expansion (iECV ≥22.5 ml/m2; 22%), and replacement fibrosis (presence of mid-wall LGE, 27%). There was evidence of increasing hypertrophy, myocardial injury, diastolic dysfunction, and longitudinal systolic dysfunction consistent with progressive left ventricular decompensation (all p < 0.05) across these groups. Moreover, this categorization was of prognostic value with stepwise increases in unadjusted all-cause mortality (8 deaths/1,000 patient-years vs. 36 deaths/1,000 patient-years vs. 71 deaths/1,000 patient-years, respectively; p = 0.009). CONCLUSIONS: CMR detects ventricular decompensation in aortic stenosis through the identification of myocardial extracellular expansion and replacement fibrosis. This holds major promise in tracking myocardial health in valve disease and for optimizing the timing of valve replacement. (The Role of Myocardial Fibrosis in Patients With Aortic Stenosis; NCT01755936).

MRI using ultrasmall superparamagnetic particles of iron oxide in patients under surveillance for abdominal aortic aneurysms to predict rupture or surgical repair: MRI for abdominal aortic aneurysms to predict rupture or surgery-the MA(3)RS study.

INTRODUCTION: Population screening for abdominal aortic aneurysms (AAA) halves the associated mortality and has led to the establishment of national screening programmes. Prediction of aneurysm growth and rupture is challenging and currently relies on serial diameter measurements with ultrasound. Recently, a novel MRI-based technique using ultrasmall superparamagnetic particles of iron oxide (USPIO) has demonstrated considerable promise as a method of identifying aneurysm inflammation and expansion. METHODS AND ANALYSIS: The MA(3)RS study is a prospective observational multicentre cohort study of 350 patients with AAA in three centres across Scotland. All participants will undergo MRI with USPIO and aneurysm expansion will be measured over 2 years with CT in addition to standard clinical ultrasound surveillance. The relationship between mural USPIO uptake and subsequent clinical outcomes, including expansion, rupture and repair, will be evaluated and used to determine whether the technique augments standard risk prediction markers. To ensure adequate sensitivity to answer the primary question, we need to observe 130 events (composite of rupture or repair) with an estimated event rate of 41% over 2 years of follow-up. The MA(3)RS study is currently recruiting and expects to report in 2017. DISCUSSION: This is the first study to evaluate the use of USPIO-enhanced MRI to provide additional information to aid risk prediction models in patients with AAA. If successful, this study will lay the foundation for a large randomised controlled trial targeted at applying this technique to determine clinical management. TRIAL REGISTRATION NUMBER: Current Controlled Trials: ISRCTN76413758.

Salt in the wound: (18)F-fluoride positron emission tomography for identification of vulnerable coronary plaques.

Ischaemic vascular events occur in relation to an underlying vulnerable plaque. The pathological hallmarks of high-risk plaques are well described and include inflammation and microcalcification. To date, non-invasive imaging modalities have lacked the spatial resolution to detect these processes with the necessary precision to facilitate clinical utility. Positron emission tomography (PET) using targeted radiopharmaceuticals affords a highly sensitive tool for identifying features of interest and has been in use for several decades in oncological practice. Recent developments have created hybrid scanning platforms which add the detailed spatial resolution of computed tomography (CT) and, for the first time, made imaging of individual coronary plaques feasible. In this study we compared the utility of PET-CT using (18)F-fluoride and (18)F-fluorodeoxglucose ((18)F-FDG) to detect high-risk or ruptured atherosclerotic plaques in vivo. (18)F-fluoride localized to culprit and vulnerable plaques as determined by a combination of invasive imaging and histological tissue examination. In contradistinction, (18)F-FDG analysis was compromised by non-specific myocardial uptake that obscured the coronary arteries. We discuss the findings of this study, the limitations of the current approach of vulnerable plaque assessment and some on-going developments in cardiovascular imaging with (18)F-fluoride.

What evidence is there for the use of workplace-based assessment in surgical training?

BACKGROUND: Recent years have seen broad changes in postgraduate training with a move toward structured formative and summative evaluation of trainees' competencies using workplace-based assessment (WBA) tools. The fitness for purpose of these instruments in surgery has been much debated. The aim of this study is to explore the evidence underlying the introduction and ongoing use of WBAs in surgical training. METHODS: A critical literature review was conducted to identify studies evaluating the use of WBAs in postgraduate surgical training. The search was conducted using the electronic databases PubMed for full-text articles in English. Additional critical evaluations of the curriculum relating to WBAs were included. The articles were synthesized in a narrative review. RESULTS: The implementation of WBA requirements in surgical training has occurred despite a relative dearth of direct evidence of their efficacy and benefit. Studies and critical reviews are being regularly undertaken to ensure that supporting evidence is accrued and the drive for improvement and refinement is maintained. It is emerging that WBAs are (contrary to their current nomenclature) formative tools for feedback and hence learning. They can facilitate the progression toward expert practice at the center of the zone of proximal development and the higher levels of Miller's pyramid, but fall short--owing to their focus on competence--of guiding surgical trainees to the higher levels of Maslow's hierarchy. CONCLUSIONS: Limited evidence has potentially undermined the introduction of WBAs in surgical training to date. There are misunderstandings regarding their use as either summative or formative educational tools. These shortcomings are an opportunity for further work in examining WBAs in their current or modified form.

18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis.

BACKGROUND: 18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression. METHODS AND RESULTS: Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/ BACKGROUND: =0.65; P=0.04) and osteocalcin (r=0.68; P=0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining (r=-0.43; P=0.22). After 1 year, aortic valve calcification increased from 314 (193-540) to 365 (207-934) AU (P<0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score (r=0.66; P<0.01), and this improved further (r=0.75; P<0.01) when 18F-NaF uptake overlying computed tomography-defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score (r=-0.11; P=0.66). CONCLUSIONS: 18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.