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Background The National Institute for Health and Care Excellence (NICE) updated their guidance for the management of patients with stable chest pain and recommended that all patients undergo computed tomography coronary angiography (CTCA). This update has sparked a great deal of debate, and was followed by upgrade of CTCA into a Class I indication in the recent ESC guidelines. The cost-effectiveness of using CTCA as first line investigation is still unclear. Purpose To describe the current clinical pathway of patients with stable chest pain presented to outpatient clinics, assess the compliance with the updated NICE guideline, and explore the costs and health outcomes of different non-invasive diagnostic tests in real-world clinical setting. Methods We used data of 4,297 patients who attended chest pain clinics in Oxford between 1 January 2014 and 31 July 2018. Data included clinical presentation (e.g. age and previous cardiovascular conditions), diagnostic tests, outpatient visits, hospitalization, and hospital mortality and was compared between 6 alternative first-line diagnostic tests. Multinomial regressions were performed to estimate the probability of receiving each alternative and the associated cost after adjusting for clinical presentation. A decision tree was developed to describe the clinical pathway for each alternative first-line diagnostic in terms of subsequent diagnostic tests and treatments and to estimate the associated costs and life days. Results The proportion of patients who received CTCA as first line diagnostic test increased from 1% in 2014 to 17% in 2018, while the publication of the updated NICE guidelines in 2016 led to a threefold increase in this proportion. CTCA is less likely to be provided as a first-line diagnostic to patients who are younger age, males, smokers, and have angina, PVD, or diabetes. The standardised rate of hospital admission was the lowest in the exercise ECG cohort (0.35 admissions per 1,000 life-days) followed by the CTCA cohort (0.40 admissions per 1,000 life-days) while the latter cohort had the lowest standardised rate of cardiovascular treatment (2.74% per 1,000 life days). Stress echocardiography and MPS were associated with higher costs compared with CTCA, other ECG, and exercise ECG after adjusting for clinical presentation and days of follow-up. CTCA is the pathway most likely to be cost-effective, even compared to exercise ECG, while the other diagnostic alternatives are dominated (i.e. they cost more for less life-days). Conclusions Currently, the updated NICE guidelines for stable chest pain are implemented only to a fifth of the cases in England. Our findings support existing evidence that CTCA is the most-cost effective first-line diagnostic test for this population. Hopefully, this will inform the debate around the implementation of the guidelines and help commissioning and clinical decision processes worldwide. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Institute of Health Research Oxford Biomedical Research Centre

Background Recent clinical trials have demonstrated a role for sodium glucose cotransporter 2 (SGLT2) inhibitors in improving cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We investigated the direct effects of canagliflozin, a non-selective SGLT1/SGLT2 inhibitor on myocardial redox signalling in humans. Methods Study 1 included 364 patients undergoing cardiac surgery. Human right atrial appendage biopsies, obtained during surgery, were used to quantify the sources of superoxide (O2.-) and the gene expression of inflammation, fibrosis and myocardial stretch markers. In Study 2, myocardial biopsies from 51 patients were used ex vivo to study the direct effects of canagliflozin on O2.- generation and understand its role in controlling the activity of NADPH-oxidases and uncoupled nitric oxide synthase (NOS). Finally, we used differentiated H9C2 and human primary cardiomyocytes (hCM) to further characterise the key regulatory mechanisms (Study 3). Results SGLT1 was abundantly expressed in the human myocardial biopsies and hCM whilst SGLT2 was barely detectable. SGLT1 expression levels were positively correlated with basal O2.- production and the expression of natriuretic peptides, proinflammatory cytokines and pro-fibrotic markers in human myocardial biopsies from study 1. Incubation of human myocardium with canagliflozin significantly reduced basal and NADPH-oxidase-derived O2.- via AMP kinase (AMPK)-mediated suppression of GTP-activation and consequent reduction of membrane translocation of Rac1, an NADPH-oxidase subunit. This resulted in reduced oxidation and increased bioavailability of tetrahydrobiopterin, the nitric oxide synthase (NOS) co-factor essential for enzymatic coupling, leading to improved NOS coupling. These findings were replicated in hCM, where canagliflozin was shown to regulate AMP/ATP ratio, which could be upstream of AMPK activation. The effects of canagliflozin were significantly attenuated by knocking-down SGLT1 in hCM. Transcriptional profiling of hCM treated with canagliflozin revealed that canagliflozin had striking effects on myocardial redox signalling, causing suppression of apoptotic and inflammatory pathways in the human heart. Conclusions We demonstrate for the first time in humans that canagliflozin suppresses myocardial NADPH-oxidase activity and improves NOS coupling through an SGLT1/AMPK/Rac1-mediated pathway, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings provide a mechanistic basis for the beneficial effects of SGLT1/2 inhibitors in patients with heart failure. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): 1. British Heart Foundation (FS/16/15/32047 and PG/13/56/30383 to CA, CH/16/1/32013 to KC, and Centre of Research Excellence award RG/13/1/30181), 2. The Japanese Heart Rhythm Society-European Heart Rhythm Association fellowship grant sponsored by Biotronik.

Background Coronary computed tomography angiography (CCTA) provides useful information regarding cardiovascular risk assessment. Key aspects of coronary biology induce changes in perivascular adipose tissue composition, detectable by the pericoronary Fat Radiomic Profile (FRP) index. Purpose We assessed the ability of FRP to further stratify cardiac risk in patients with Coronary Artery Calcium (CAC) scoring below 100 following routine CCTA. Methods The study population consisted of 1,575 participants from the CCTA arm of the SCOT-HEART trial (NCT01149590) with images available and eligible for analysis. Pericoronary FRP mapping was performed in perivascular adipose tissue segmentations around the proximal sites of the right and left coronary arteries, as previously validated. The prognostic potential of FRP was initially tested in a sub-cohort, consisting of patients with Coronary Artery Calcium (CAC) score lower than 100. Further analysis was performed after sub-grouping based on the absence of high risk plaque (HRP) features and obstructive coronary artery disease (CAD). The association with future incidence of major adverse cardiac events (MACE: cardiac mortality or non-fatal myocardial infarction) or a composite endpoint of MACE ± late revascularization (MACE-ReVasc) was assessed using adjusted Cox regression models [adjusted for age, sex, systolic blood pressure (SBP), diabetes mellitus (DM), body mass index (BMI), smoking, CAD (≥50% stenosis), total cholesterol, high-density lipoprotein (HDL), and HRP features]. Results Two-thirds (66%) of the study population were at low-risk according to the CAC score (CAC Conclusion The Fat Radiomic Profile biormarker significantly improves risk prediction for adverse clinical events beyond the current state-of-the-art in individuals with low CAC scores. Non-invasive profiling of pericoronary adipose tissue using CCTA-derived FRP captures irreversible changes in perivascular adipose tissue composition associated with chronic vascular inflammation and atherosclerotic disease, and can improve risk stratification and clinical decision making in low-risk populations. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation, National Institute of Health Research, Oxford Biomedical Research Centre

Background Adipose tissue regulates energy balance and glucose homeostasis via the secretion of circulating molecules, termed adipokines, such as leptin and adiponectin. Excess adiposity and adipose tissue dysfunction have been involved in the pathogenesis of dyslipidemias. Positron emission tomography/computed tomography (PET/CT) with F-18-Fluorodeoxyglycose (FDG) has been used for the assessment of adiposity. Purpose To compare abdominal adipose tissue function assessed by FDG uptake with serum indices, such as plasma adipokines' levels in individuals with different subtypes of dyslipidemia and normolipidemics. Methods Seventy individuals (mean age 44±13 years, range 21–75, 43 men) with a clinical diagnosis of either heterozygous familial hypercholesterolemia (heFH) (n=38) or familial combined hyperlipidemia (FCH) (n=32), not under statins for at least one year, and 20 age and sex matched controls, were enrolled. Visceral (VAT) and subcutaneous adipose tissue metabolic activity (SAT) was assessed with FDG-PET/CT imaging and was quantified by calculating the target-to-background ratios (TBR) in consecutive axial fat images between the proximal (cephalic) end of the L1 and distal (caudal) end of the L3 vertebrae by dividing the average of the mean standard uptake value (SUV) to the mean SUV of the vena cava. Leptin and adiponectin were measured in all the subjects. Results There was no significant difference of plasma leptin values between FCH, heFH and non dyslipidemics subjects (p=0.204). FCH had reduced adiponectin values compared to heFH patients and controls [median 5.7 IQR (3.9–7.6) vs. 13.1 (9.2–23.3) vs. 10.9 (6.1–19.1) μg/mL, respectively, p Conclusions Visceral adipose tissue FDG uptake is reduced in patients with FCH compared to those with heFH and normolipidemics. In addition, serum adiponectin levels are lower in patients with FCH. These findings highlight the different pathophysiological role of visceral fat function in the two most common types of familial dyslipidemia and suggest that visceral fat could be an attractive target for the treatment of FCH.

Background The adipose tissue is now established as a major regulator of cardiovascular status, mediated by the secretion of several bioactive molecules, including adipocytokines. Individuals with genetic dyslipidaemias of either familial combined hyperlipidemia (FCH) or heterozygous familial hypercholesterolemia (heFH) subtype are characterized by accelerated atherosclerosis. Nonetheless, limited data exists on the relationship between adiposity and arterial inflammation, a marker of cardiovascular risk, in this setting. Purpose To investigate the relationship between adiposity indices and arterial inflammation evaluated by 18F fluorodeoxyglycose positron emission tomography (PET/CT) in patients with hereditary lipid metabolism disorders. Methods Consecutive patients with either FCH or heFH, free of statin therapy, and normolipidaemic individuals underwent PET/CT imaging. Arterial FDG uptake was estimated as the average value of target-to-background ratio (TBR) within aortic and carotid wall. Volumes of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) were measured from CT images between the proximal (cephalic) end of the L1 and distal (caudal) end of the L3 vertebrae by selecting all voxels with attenuation between −190 and −30 Hounsfield Units (HU). Serum adiponectin and leptin levels were measured with ELISA by available commercial kits. For comparisons with arterial TBR, adiponectin and leptin concentrations above and below the 25th percentile, were stratified as high and low, respectively. Results In total, 60 individuals (20 FCH, 20 heFH and 20 controls) were included. A modest but significant correlation between SAT volume and arterial TBR (R=0.386, p=0.004) was detected. This relationship did not remain significant after controlling for VAT volume (p=0.303). A strong correlation between VAT volume and arterial TBR (R=0.621, p=0.001) was observed. This relationship remained significant after controlling for SAT volume (R=0.541, p Conclusions Abdominal adipose tissue imaging markers and serum adipocytokines correlate with arterial inflammation as assessed by PET/CT in patients with familial dyslipidaemias highlighting the role of abdominal adipose tissue for atherosclerosis progression in this population.

Background NADPH oxidase activity is a major source of superoxide anions (O2·−) in the human myocardium, linked with adverse short-term clinical outcomes after cardiac surgery, but its prognostic value for the long-term clinical outcome of these patients is unknown. Purpose To explore the association between NADPH oxidase activity in the human myocardium and the clinical outcome of patients undergoing cardiac surgery. Methods A total of 216 patients from the Oxford Heart Vessels and Fat (OxHVF) cohort were enrolled. Myocardial tissue samples were collected during cardiac surgery and used for RNA isolation and myocardial O2·− quantification using lucigenin-enhanced chemiluminescence (5μmol/L). The specific contribution of NADPH oxidase activity to myocardial O2·− production was quantified as the Vas287021 (40 μmol/L)-inhibitable signal following NADPH (100μmol/L) stimulation (Vas2870 is a NADPH oxidases inhibitor). Malonyldialdehyde and hsCRP levels were measured in plasma isolated from peripheral blood collected pre-operatively. Patients were followed-up for a mean of 2.9±1.4 years for the primary endpoint of cardiovascular mortality. Results Myocardial NADPH oxidase activity was not correlated with systemic oxidative stress (evidenced by malonyldialdehyde, panel A) or systemic inflammation (reflected by hsCRP levels, panel B). NADPH oxidase activity was significantly higher in the cardiovascular death group (panel C) and was associated with cardiovascular (HR [95% CI]: 1.53 [1.10–2.13], p=0.01 per SD increase) but not all-cause mortality (HR [95% CI]: 1.32 [0.96–1.80], p=0.08 per SD increase). This association remained significant after adjustment for EuroscoreII (HR [95% CI]: 1.80 [1.14–2.82], p=0.01 per SD increase). For an optimal cut-off value of 7,920 RLU/sec/mg tissue, patient survival was significantly poorer in the high vs. low NADPH oxidase activity subgroup (panel D). Adding NADPH oxidase activity to the baseline clinical model significantly improved model's performance (panel E). Interestingly, myocardial NOX gene expression levels didn't show any significance in mortality prediction, highlighting the fact that NADPH oxidase activity, rather than enzyme levels, is the key outcomes regulator. Conclusion Increased NADPH oxidase activity in the human myocardium independently predicts high cardiovascular mortality in patients with advanced coronary atherosclerosis. Targeting NADPH oxidase in the human heart may be a rational therapeutic approach. Acknowledgement/Funding BHF, EPSRC

Background Sodium glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic drugs that control plasma glucose levels by inhibiting reabsorption of glucose in kidney. Recent clinical trials have suggested a class effect of SGLT2 inhibitors in preventing hospitalization due to heart failure. However, the underlying mechanism has not been fully elucidated. Purpose We investigated the direct effect of the SGLT2 inhibitor, Canagliflozin (Cana), on myocardial redox state in humans. Methods The study included 48 patients undergoing cardiac surgery. Fresh myocardial tissues were incubated ex vivo with or without Cana and then used for superoxide quantification and Western immunoblotting. NADPH-oxidases activity was evaluated with NADPH 100μM stimulation, while nitric oxide synthase (NOS) coupling was assessed by using N(ω)-nitro-L-arginine methyl ester (L-NAME, a NOS inhibitor). A human cardiomyocyte (HCM) cell line was also used for in vitro validation of the effects of Cana on myocardium. Results Ex vivo incubation of myocardium with Cana significantly reduced baseline (A) and NADPH-oxidase-derived O2·− (B) and improved NOS coupling reflected by positive L-NAME delta O2·− values (C). Regulation of NADPH-oxidases activity by Cana was found to result from reduced GTP-activation (D) and consequent membrane translocation (E) of Rac1, a key subunit of NADPH-oxidases. Cana also reduced tetrahydrobiopterin (BH4) oxidation, increasing its bioavailability (F), which is a key mechanism to improve NOS coupling. Incubation with Cana enhanced phosphorylation of AMPK, and the downstream signalling, ACC (not shown). Additional Compound C, which is inhibitor of AMPK, significantly reversed these effects of Cana (A, B, C, D, E, F). These findings were replicated in HCM (not shown). In line with these, Cana increased the ADP/ATP ratio of cytoplasm in HCM, which could provide an upstream mechanism for AMPK activation. Conclusions We demonstrate for the first time in humans, that Cana suppresses myocardial NADPH-oxidases activity and improves NOS coupling through an AMPK-mediated pathway. This could be an underlying mechanism for the cardioprotective effects of SGLT2 inhibitors.

Background Diabetic cardiomyopathy is characterised by metabolic remodelling, impaired glucose and high-energy phosphate metabolism. Transgenic mice overexpressing the creatine transporter in the heart (CrT-OE) have high intracellular creatine and elevated glucose, suggesting changes in substrate utilisation. Objective We aimed at investigating the unexplored glucose-creatine link, in addition to the involvement of shared molecules in glucose and creatine metabolism. Methods and results The correlation between myocardial creatine and glucose (r2=0.67; p=0.002) is accompanied by increased Glucose transporter 4 (Glut4) (p To test if modulating creatine in vivo alters glucose uptake, we measured 3H-2-deoxyglucose incorporation in isolated cardiomyocytes from CrT-OE and WT hearts. In WT, insulin caused a 2-fold increase (p 0.05) and responded to creatine (p In a cohort of samples taken during coronary artery by-pass surgery from diabetic and non-diabetic patients (n=8 each; blood glucose 90±7.1 and 138±16.5, respectively), there was a negative correlation between CrT and Glut4 transcript (r2=−0.5; p=0.028) further supporting the glucose-creatine relationship in the clinical setting. Conclusion Our observations suggest that changing myocardial creatine can regulate glucose uptake. Further studies will explore the potential use of creatine as a biochemical ‘switch’ to correct impaired glucose uptake and potentially insulin resistance.

BACKGROUND: Familial dyslipidemias of either heterozygous (heFH) or combined (FCH) type lead to accelerated atherogenesis and increased cardiovascular risk. OBJECTIVE: The aim of this study was to investigate in statin-naïve adult patients with familial dyslipidemias whether inflammatory activation and liver, spleen and bone marrow metabolic activity differ compared with normolipidemic subjects and between dyslipidemic groups. METHODS: Fourteen patients with FCH, 14 with heFH, and 14 normolipidemic individuals were enrolled. Serum lipids, high-sensitivity C-reactive protein, and fibrinogen levels were measured, followed by 18F-fluorodeoxyglucose positron-emission tomography/computed tomography imaging. Radiotracer uptake in the aortic wall, spleen, bone marrow, and liver was quantified as tissue-to-background ratio (TBR). RESULTS: Patients with heFH had significantly higher low-density lipoprotein levels compared with those with FCH and controls (P CONCLUSIONS: Systemic, as well as vascular inflammation and spleen, bone marrow, and hepatic metabolic activity are increased in patients with FCH despite lower levels of low-density lipoprotein.

Objective/Background Biomarker(s) for prediction of the future progression rate of abdominal aortic aneurysms (AAA) may be useful to stratify the management of individual patients. AAAs are associated with features of systemic inflammation and endothelial dysfunction. Flow mediated dilatation (FMD) of the brachial artery is a recognised non-invasive measurement for endothelial function. We hypothesised that FMD is a potential biomarker of AAA progression and reflects the temporal changes of endothelial function during AAA progression. Methods In a prospectively recruited cohort of patients with AAAs (Oxford Abdominal Aortic Aneurysm Study), AAA size was recorded by antero-posterior diameter (APD) (outer to outer) on ultrasound. Annual AAA progression was calculated by (ΔAPD/APD at baseline)/(number of days lapsed/365 days). FMD was assessed at the same time as AAA size measurement. Analyses of data were performed in the overall cohort, and further in subgroups of AAA by size (small: 30–39 mm; moderate: 40–55 mm; large: > 55 mm). Results FMD is inversely correlated with the diameter of AAAs in all patients (n = 162, Spearman's r = −.28, p < .001). FMD is inversely correlated with AAA diameter progression in the future 12 months (Spearman's r = −.35, p = .001), particularly in the moderate size group. Furthermore, FMD deteriorates during the course of AAA surveillance (from a median of 2.0% at baseline to 1.2% at follow-up; p = .004), while surgical repair of AAAs (n = 50 [open repair n = 22, endovascular repair n = 28)] leads to an improvement in FMD (from 1.1% pre-operatively to 3.8% post-operatively; p < .001), irrespective of the type of surgery. Conclusion FMD is inversely correlated with future AAA progression in humans. FMD deteriorates during the natural history of AAA, and is improved by surgery. The utility of FMD as a potential biomarker in the context of AAA warrants further investigation.

BACKGROUND: Exercise improves the clinical outcome of patients with coronary artery disease (CAD); however, the ideal exercise duration for each patient remains unclear. OBJECTIVE: To investigate the effects of exercise duration on arterial elastic properties and antioxidant/pro-oxidant mechanisms in patients with CAD. DESIGN, SETTING, PATIENTS, INTERVENTIONS: Sixty male patients with CAD were randomised into two groups, and underwent exercise for 30 min or 60 min in a crossover design with 2 weeks' wash-out period. In all participants aortic and radial blood pressures (BP) and arterial elastic properties (augmentation index (AIx)/pulse wave velocity (PWV)) were determined at baseline and 24 h after exercise. Plasma malonyldialdehyde (MDA) and superoxide dismutase (SOD)1 and SOD2 levels were also measured. RESULTS: Exercise had no effect on aortic and radial BP (p=NS for all). Walking for 30 min improved AIx (from 33.79 ± 0.91% to 31.73 ± 0.86%, p

OBJECTIVE: To investigate the effects of short term atorvastatin treatment on forearm vasodilatory response to reactive hyperaemia (RH%) and on components of the thrombosis-fibrinolysis system (antithrombin III, proteins and S, factors V and VII, von Willebrand factor, tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI-1)) in patients with heart failure. PATIENTS AND METHODS: 35 patients with heart failure were enrolled in this study; 17 patients received atorvastatin 10 mg/day and 18 patients received no statin for four weeks. Forearm blood flow (FBF) was measured by venous occlusion strain gauge plethysmography. RH% and forearm vasodilatory response to nitrate were defined as the percentage change of FBF from rest to the maximum flow during reactive hyperaemia and after nitrate administration, respectively. Plasma concentrations of antithrombin III, protein C, protein S, factor V, factor VII, von Willebrand factor, tPA, and PAI-1 were determined before and after treatment. RESULTS: Maximum hyperaemic FBF remained unchanged in both groups. Baseline FBF was slightly but not significantly decreased in the atorvastatin treated group. RH% was significantly increased only in the atorvastatin treated group, from mean (SD) 42.44 (18.9)% to 83.7 (36.1)% (p < 0.01). Plasma concentrations of antithrombin III (from mean (SD) 81.7 (11.37)% to 73.5 (13.8)%), protein C (from mean (SD) 88.3 (26.9)% to 63.9 (25.0)%), factor V (from mean (SD) 126.2 (33.4)% to 94.9 (29.8)%), tPA (from median (25th-75th percentile) 11.68 (8.60-20.95) ng/ml to 10.30 (8.65-15.12) ng/ml), and PAI-1 (from median (25th-75th percentile) 3.10 (2.15-4.40) IU/l to 1.90 (0.75-3.0) IU/l) were significantly decreased in the atorvastatin treated group (p < 0.05) but not in the control group. Plasma concentrations of von Willebrand factor, factor VII, and protein S remained unaffected in both groups. CONCLUSION: Atorvastatin did not change the maximum hyperaemic flow, although it decreased plasma concentrations of antithrombin III, protein C, factor V, tPA, and PAI-1 in patients with heart failure. Therefore, short term treatment with atorvastatin may affect the expression of both endothelium and liver derived components of the thrombosis-fibrinolysis system in patients with heart failure.

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.

OBJECTIVE: To assess the effects of intravenous vitamin C administration on the vasomotor responses to intracoronary L-arginine infusion in epicardial coronary arteries. METHODS: 28 patients with coronary artery disease and stable angina were enrolled in the study. Eight patients received intracoronary infusions of 150 micromol/min L-arginine before and after intravenous infusion of vitamin C, 10 patients received intracoronary infusions of 150 micromol/min L-arginine before and after intravenous infusion of normal saline, and 10 patients received intracoronary normal saline before and after intravenous infusion of vitamin C. The diameter of proximal and distal coronary artery segments was measured by quantitative angiography. RESULTS: Infusion of L-arginine caused significant dilatation of both proximal (4.87 (0.96)%, p < 0.01 v normal saline) and distal (6.33 (1.38)%, p < 0.01 v normal saline) coronary segments. Co-infusion of vitamin C and L-arginine dilated proximal coronary segments by 8.68 (1.40)% (p < 0.01 v normal saline, p < 0.01 v L-arginine) and distal segments by 13.07 (2.15)% (p < 0.01 v normal saline, p < 0.01 v L-arginine). Intravenous infusion of vitamin C caused a borderline increase in proximal and distal coronary segment diameters (1.93 (0.76)% and 2.09 (1.28)%, respectively, not significant). CONCLUSIONS: L-arginine dependent coronary segment vasodilatation was augmented by the antioxidant vitamin C in patients with coronary artery disease. Thus, vitamin C may have beneficial effects on nitric oxide bioavailability induced by L-arginine.

Coronary artery disease (CAD) is the leading cause of mortality in Western Societies and several developing countries. Recent evidence suggests that most detrimental clinical manifestations of CAD, such as acute coronary syndromes (ACS), are the outcome of inflammatory processes that lead to plaque formation and rupture and eventually to ischemia and potentially myocardial necrosis. Neither of the traditionally used biomarkers is thought to be the gold standard in detection of myocardial ischemia or necrosis. A biomarker that could detect quite early the ischemic myocardium as well as define the risk of a future event with high sensitivity and specificity is still lacking. Several biomarkers, implicated in the pathogenesis and clinical evolution of atherosclerosis, have emerged as potent biomarkers for early detection of myocardial ischemia. In the current review, we summarize recent evidence of the most promising biomarkers and discuss their potential role in clinical practice in patients suffering from ACSs.

OBJECTIVE: To investigate the effects of atorvastatin on endothelial function and low-grade systemic inflammation in subjects with successful surgery for aortic coarctation repair (SCR). DESIGN: Open-label study. SETTING: Outpatients visiting the adult congenital heart disease department of our hospital. PATIENTS: 34 young people with SCR. INTERVENTIONS: Patients with SCR received atorvastatin 10 mg/day (n=17) or no treatment (n=17) for 4 weeks. At baseline and at 4 weeks, endothelial function was assessed by flow-mediated dilatation (FMD) of the right brachial artery, and blood samples were obtained. Serum levels of interleukin (IL) 1b, IL-6 and soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined by ELISA. MAIN OUTCOME MEASURES: Effects of treatment on FMD and serum levels of IL-1b, IL-6 and sVCAM-1. RESULTS: FMD in the atorvastatin group was significantly improved after 4 weeks (from 6.46±0.95% to 11.24±1.38%, p

Background The use of telehealth technologies to remotely monitor patients suffering chronic diseases may enable preemptive treatment of worsening health conditions before a significant deterioration in the subject's health status occurs, requiring hospital admission. Objective The objective of this study was to develop and validate a classification algorithm for the early identification of patients, with a background of chronic obstructive pulmonary disease (COPD), who appear to be at high risk of an imminent exacerbation event. The algorithm attempts to predict the patient's condition one day in advance, based on a comparison of their current physiological measurements against the distribution of their measurements over the previous month. Method The proposed algorithm, which uses a classification and regression tree (CART), has been validated using telehealth measurement data recorded from patients with moderate/severe COPD living at home. The data were collected from February 2007 to January 2008, using a telehealth home monitoring unit. Results The CART algorithm can classify home telehealth measurement data into either a ‘low risk' or ‘high risk' category with 71.8% accuracy, 80.4% specificity and 61.1% sensitivity. The algorithm was able to detect a ‘high risk' condition one day prior to patients actually being observed as having a worsening in their COPD condition, as defined by symptom and medication records. Conclusion The CART analyses have shown that features extracted from three types of physiological measurements; forced expiratory volume in 1s (FEV 1 ), arterial oxygen saturation (SPO 2 ) and weight have the most predictive power in stratifying the patients condition. This CART algorithm for early detection could trigger the initiation of timely treatment, thereby potentially reducing exacerbation severity and recovery time and improving the patient's health. This study highlights the potential usefulness of automated analysis of home telehealth data in the early detection of exacerbation events among COPD patients.

Background Methotrexate has been recognised as one of the main therapeutic agents used in rheumatoid arthritis (RA). However some of the adverse effects of low-dose methotrexate therapy and in particular pancytopenia have caused major concern. Objectives The aim was to describe our experience of long-term follow up of patients with RA treated with low-dose methotrexate, in particular in reference to the appearance of pancytopenia. Methods During the last 14 years 528 RA patients were treated with methotrexate 7.5–15 mg/week by the Rheumatology Department. These patients were followed up by the Rheumatology Department and they had a complete laboratory evaluation and clinical examination in regular intervals. Results In 528 RA patients treated with low-dose methotrexate therapy over a period of 14 years 4 cases of aplastic anaemia were diagnosed (0.76%). In these patients the white cell count, platelet count, haemoglobin and haematocrit values decreased. In all 4 cases liver function tests were slightly elevated. Folinic calcium was administered and white cell and platelet counts improved, while haematocrit remained stable. The increase in white cell count after the administration of folinic calcium was satisfactory and the addition of growth factors to aid haemopoiesis was not considered necessary. In a female patient a very marked decrease in white cell count was observed and the patient died from sepsis, despite the administration of antibiotics. Conclusion Low-dose methotrexate therapy in long term follow-up appears to be a safe and effective form of therapy for RA patients. Therapy appears to be well tolerated by the patients. Pancytopenia appears to be one of the most significant and dangerous complications of this form of therapy, being observed even in the absence of other recognised risk factors. Pancytopenia may occur abruptly in patients with RA on low-dose methotrexate therapy. Regular laboratory investigations are essential for the early detection of this complication. The administration of supplement folate in patients with RA on low-dose methotrexate therapy may reduce the incidence of pancytopenia.

Background: Internal mammary artery (IMA) is used as a graft in bypass surgery (CABG), but it is unclear whether it should be harvested with or without its perivascular adipose tissue (PVAT). Given that PVAT produces the antiatherogenic adipokine adiponectin (AdN), we examined the role of AdN as a signalling molecule between PVAT and IMA grafts. Methods: In Study 1, IMA segments were obtained from 364 patients undergoing CABG and used to determine NADPH-oxidase activity by lucigenin chemiluminescence (+/-NADPH 100μM). Mesothoracic (Mt-AT), subcutaneous (Sc-AT) and PVAT were obtained for gene expression studies. In Study 2, IMA segments from 17 patients were exposed ex vivo to AdN (10 μg/ml) for 6 hours ± wortmannin (a PI3K/Akt inhibitor); changes to NADPH-stimulated and Vas2870 (specific NADPH-oxidase inhibitor)-inhibitable O2- as well as the activation and membrane translocation of Rac1 (NADPH-oxidase subunit responsible for its activation) were determined. Results: Elevated circulating AdN was related with reduced NADPH-stimulated O2- (A). Increased expression of ADIPOQ in Mt- and Sc-AT was related with reduced NADPH-oxidase activity, however in PVAT it was associated with increased NADPH-stimulated O2-(B). AdN directly suppressed NADPH-stimulated (C) and Vas2870-inihibitable (D) O2- in the IMA. This was due to reduced activation (E)/membrane translocation (F) of Rac1, which was reversed by wortmannin. ![Figure][1] Conclusions: We demonstrate for the first time in humans, that AdN directly suppresses NADPH-oxidase through an Akt-mediated reduction of Rac1 activation and translocation to the membrane. The observed increase of AdN expression in PVAT in the presence of high oxidative stress may represent a novel, local defence mechanism of IMA against oxidative stress, that warrants further investigation. [1]: pending:yes

Background Endothelial nitric oxide synthase (eNOS) plays a crucial role in maintenance of vascular homeostasis. However, loss of eNOS co-factor tetrahydrobiopterin (BH4) due to oxidative degradation leads to uncoupling of the enzyme, that is turned into a source of superoxide radicals (O 2 − ) instead of nitric oxide (NO). Adipose tissue has been identified as the source of hormone-like molecules termed adipokines, which can exert endocrine and paracrine effects on the vascular wall. However, little is known about the role of adipokines such as adiponectin (AdN) in the regulation of vascular redox signalling in the human arterial wall or the mechanisms regulating their synthesis in perivascular adipose tissue (PVAT). Methods In Study 1, 677 patients undergoing coronary bypass surgery (CABG) were recruited. Blood samples were obtained preoperatively and internal mammary artery (IMA) segments as well as PVAT surrounding them were harvested during surgery. Serum AdN was quantified ELISA, vascular O 2 − was determined by lucigenin chemiluminescence (+/−LNAME to estimate eNOS coupling) and qRTPCR was performed to determine AdN gene expression in PVAT. In Study 2, IMA segments from 17 patients undergoing CABG were exposed to AdN (10 µg/ml, 6h)±wortmannin (W, a PI3K/Akt inhibitor) ex vivo to determine the effects of AdN on vascular redox state, eNOS phosphorylation status and BH4 content. In addition, PVAT was exposed to 4-hydroxynonenal (4HNE, a peroxidation product released by the vascular wall in the presence of high vascular oxidative stress) ex vivo to determine its effects on AdN gene expression. Results In Study 1, serum AdN was inversely related with resting O 2 − (p 2 − (p ex vivo . This was due to Akt-dependent eNOS phosphorylation at Ser1177 (C&D) and an increase in vascular BH4 (p 2 − triggered the release of 4HNE, while ex vivo exposure of PVAT to 4HNE up-regulated the expression of PPARγ (P Conclusions We describe a novel cross-talk between adipose tissue and the vascular wall in humans. Oxidative stress triggers the release of 4HNE from the vascular wall, which in turn up-regulates the expression of AdN in PVAT; then AdN exerts a paracrine effect on the vascular wall by activating eNOS and improving its BH4-mediated coupling.

31 CD4+CD25HIFOXP3+ T-REGS AND LIVER TRANSPLANTATION FOR END-STAGE HCV-RELATED LIVER DISEASE: A ROLE IN HCV RECURRENCE? S. Ferri, G. Lanzoni, C. Lalanne, M.C. Morelli, M. Bassi, P. Muratori, S. Berardi, M.R. Tame, A. Gianstefani, M. Cescon, G. Ballardini, A.D. Pinna, M. Lenzi, L. Muratori, Region Emilia Romagna-University Research Programme 2007–2009 “Immunological, Virological and Oncological Follow-up of the Liver Recipients”. Dept. Clinical Medicine, Dept. Liver and Multiorgan Transplantation, University of Bologna, Dept. Clinical Pathology, S. Orsola-Malpighi Hospital, Bologna, Dept. Internal Medicine, Hospital of Rimini, Rimini, Italy E-mail: silvia.ferri9@unibo.it

Coronary restenosis, a major unresolved problem for percutaneous coronary revascularization procedures, has thus far been resistant to all therapeutic strategies. In part, ineffective treatment or prevention of coronary restenosis may be due to reliance on a conceptualization of the restenosis process that incompletely reflects the pathophysiologic factors associated with neointimal formation after arterial injury. In a porcine coronary restenosis model, three stages of neointimal growth after arterial injury have been identified: an early thrombotic stage, with platelets, fibrin, and erythrocytes; a cellular recruitment stage, with endothelialization and an infiltration by lymphocytes and monocytes; and a proliferative stage, in which smooth muscle cells migrate into and proliferate within the fibrin-rich degenerating thrombus. Evaluation of basic mechanisms responsible for neointimal formation has been possible with this model. In particular, a direct relationship exists between the depth of arterial injury and subsequent neointimal thickness. This relationship can be used for investigating the efficacy of new therapies. Treatment strategies for restenosis should be directed toward interference with the cellular or humoral events that lead to neointimal formation, with the specific goal of decreasing the neointimal volume. These strategies may include delivery of drugs to the site of arterial injury to limit the amount of early mural thrombus or decreasing subsequent cellular recruitment and proliferation as well as synthesis of extracellular matrix.

The comments from Dr Pfister and Dr Schneider are well founded. Figure 1 does appear to be a diagnostic algorithm for untreated patients suspected of having heart failure. Unfortunately, the legend calls it a ‘flow-chart’ and implies that it represents a diagnostic algorithm that would include clinical examination, ECG, chest X-ray, and echocardiography. We agree that it was unfortunate to include echocardiography in this figure as it does imply that sampling of natriuretic peptides should follow an …