text: DSpace Community: http://hdl.handle.net/2381/10 2018-03-19T08:49:56Z Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study http://hdl.handle.net/2381/41336 Title: Determinants and clinical outcome of uptitration of ACE-inhibitors and beta-blockers in patients with heart failure: a prospective European study Authors: Ouwerkerk, W; Voors, AA; Anker, SD; Cleland, JG; Dickstein, K; Filippatos, G; van der Harst, P; Hillege, HL; Lang, CC; ter Maaten, JM; Ng, Leong; Ponikowski, P; Samani, NJ; van Veldhuisen, DJ; Zannad, F; Metra, M; Zwinderman, AH Abstract: Introduction: Despite clear guidelines recommendations, most patients with heart failure and reduced ejectionfraction (HFrEF) do not attain guideline-recommended target doses. We aimed to investigate characteristics and for treatment-indication-bias corrected clinical outcome of patients with HFrEF that did not reach recommended treatment doses of ACE-inhibitors/Angiotensin receptor blockers (ARBs) and/or beta-blockers. Methods: BIOSTAT-CHF was specifically designed to study uptitration of ACE-inhibitors/ARBs and/or beta-blockers in 2516 heart failure patients from 69 centers in 11 European countries who were selected if they were suboptimally treated while initiation or uptitration was anticipated and encouraged. Patients who died during the uptitration period (n=151) and patients with a LVEF>40% (n=242) were excluded. Median follow up was 21 months. Results: We studied 2100 HFrEF patients (76% male; mean age 68 ±12), of which 22% achieved the recommended treatment dose for ACE-inhibitor/ARB and 12% of beta-blocker. There were marked differences between European countries. Reaching <50% of the recommended ACE-inhibitor/ARB and beta-blocker dose was associated with an increased risk of death and/or heart failure hospitalization. Patients reaching 50-99% of the recommended ACE-inhibitor/ARB and/or beta-blocker dose had comparable risk of death and/or heart failure hospitalization to those reaching ≥100%. Patients not reaching recommended dose because of symptoms, side effects and non-cardiac organ dysfunction had the highest mortality rate (for ACE-inhibitor/ARB: HR 1.72; 95% CI 1.43-2.01; for beta-blocker: HR 1.70; 95% CI 1.36-2.05) Conclusion: Patients with HFrEF who were treated with less than 50% of recommended dose of ACE-inhibitors/ARBs and beta-blockers seemed to have a greater risk of death and/or heart failure hospitalization compared with patients reaching ≥100%. 2018-03-16T12:07:10Z Effects of cerebral near-infrared spectroscopy on the outcome of patients undergoing cardiac surgery: a systematic review of randomised trials http://hdl.handle.net/2381/41330 Title: Effects of cerebral near-infrared spectroscopy on the outcome of patients undergoing cardiac surgery: a systematic review of randomised trials Authors: Serraino, Giuseppe Filiberto; Murphy, Gavin J. Abstract: Objectives Goal-directed optimisation of cerebral oxygenation using near-infrared spectroscopy (NIRS) during cardiopulmonary bypass is widely used. We tested the hypotheses that the use of NIRS cerebral oximetry results in reductions in cerebral injury (neurocognitive function, serum biomarkers), injury to other organs including the heart and brain, transfusion rates, mortality and resource use. Design Systematic review and meta-analysis. Setting Tertiary cardiac surgery centres in North America, Europe and Asia. Participants A search of Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Medline, Embase, and the Cumulative Index to Nursing and Allied Health Literature Plus from inception to November 2016 identified 10 randomised trials, enrolling a total of 1466 patients, all in adult cardiac surgery. Interventions NIRS-based algorithms designed to optimise cerebral oxygenation versus standard care (non-NIRS-based) protocols in cardiac surgery patients during cardiopulmonary bypass. Outcome measures Mortality, organ injury affecting the brain, heart and kidneys, red cell transfusion and resource use. Results Two of the 10 trials identified in the literature search were considered at low risk of bias. Random-effects meta-analysis demonstrated similar mortality (risk ratio (RR) 0.76, 95% CI 0.30 to 1.96), major morbidity including stroke (RR 1. 08, 95% CI 0.40 to 2.91), red cell transfusion and resource use in NIRS-treated patients and controls, with little or no heterogeneity. Grades of Recommendation, Assessment, Development and Evaluation of the quality of the evidence was low or very low for all of the outcomes assessed. Conclusions The results of this systematic review did not support the hypotheses that cerebral NIRS-based algorithms have clinical benefits in cardiac surgery. 2018-03-15T14:35:35Z Importance of anticoagulation and postablation silent cerebral lesions: Subanalyses of REVOLUTION and reMARQable studies http://hdl.handle.net/2381/41315 Title: Importance of anticoagulation and postablation silent cerebral lesions: Subanalyses of REVOLUTION and reMARQable studies Authors: Ng, Ghulam A. Abstract: BACKGROUND: Silent cerebral lesions (SCLs) are a potential complication of left atrial radiofrequency ablation (RFA) procedures for paroxysmal atrial fibrillation (PAF). We aimed to compare the incidence of SCLs in patients treated with irrigated RFA multielectrode catheters (nMARQ® Catheter group) and irrigated focal RFA catheters (NAVISTAR® THERMOCOOL® Catheter; TC group) after PAF ablation from subpopulation neurological assessment (SNA) cohorts of the REVOLUTION and reMARQable studies. METHODS: Data from SNA cohorts in the prospective, nonrandomized REVOLUTION study (March 2011 to September 2013) and the prospective, randomized, controlled reMARQable study (October 2013 to November 2015) were included. The incidence of SCLs was assessed pre- and post-ablation using magnetic resonance imaging. Neurological deficits were assessed using the National Institutes of Health Stroke Scale, modified Rankin Scale, and Montreal Cognitive Assessment. RESULTS: A total of 37 patients from REVOLUTION and 76 patients from reMARQable were included in the SNA cohort of each study. In the REVOLUTION SNA cohort, the incidence of SCLs was 21.1% (4/19) in the nMARQ® Catheter group and 5.9% (1/17) in the TC group. Findings from REVOLUTION helped inform the reMARQable study protocol's stringent anticoagulation regimen. SCL incidence was subsequently reduced in both groups (nMARQ® Catheter, 7.9%; TC, 3.3%). No permanent neurological deficits were observed. CONCLUSION: Adherence to a stringent anticoagulation regimen prior to and during ablation procedures appears to be an important factor in minimizing the risk of SCL. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-03-14T15:39:04Z Penumbra and re-canalization acute computed tomography in ischemic stroke evaluation: PRACTISE study protocol http://hdl.handle.net/2381/41246 Title: Penumbra and re-canalization acute computed tomography in ischemic stroke evaluation: PRACTISE study protocol Authors: El-Tawil, Salwa; Wardlaw, Joanna; Ford, Ian; Mair, Grant; Robinson, Tom; Kalra, Lalit; Muir, Keith W. Abstract: Rationale: Multimodal imaging, including computed tomography angiography and computed tomography perfusion imaging, yields additional information on intracranial vessels and brain perfusion and can differentiate between ischemic core and penumbra which may affect patient selection for intravenous thrombolysis. Hypothesis: The use of multimodal imaging will increase the number of patients receiving intravenous thrombolysis and lead to better treatment outcomes. Sample size: 400 patients. Methods and design: PRACTISE is a prospective, multicenter, randomized, controlled trial in which patients presenting within 4.5 h of symptom onset are randomized to either the current evidence-based imaging (NCCT alone) or additional multimodal computed tomography imaging (NCCT + computed tomography angiography + computed tomography perfusion). Clinical decisions on intravenous recombinant tissue plasminogen activator are documented. Total imaging time in both arms and time to initiation of treatment delivery in those treated with intravenous recombinant tissue plasminogen activator, is recorded. Follow-up will include brain imaging at 24 h to document infarct size, the presence of edema and the presence of intra-cerebral hemorrhage. Clinical evaluations include NIHSS score at baseline, 24 h and day 7 ± 2, and mRS at day 90 to define functional outcomes. Study outcomes: The primary outcome is the proportion of patients receiving intravenous recombinant tissue plasminogen activator. Secondary end-points evaluate times to decision-making, comparison of different image processing software and clinical outcomes at three months. Discussion: Multimodal computed tomography is a widely available tool for patient selection for revascularization therapy, but it is currently unknown whether the use of additional imaging in all stroke patients is beneficial. The study opened for recruitment in March 2015 and will provide data on the value of multimodal imaging in treatment decisions for acute stroke. 2018-02-26T15:18:06Z Frequency, determinants, and effects of early seizures after thrombolysis for acute ischemic stroke: The ENCHANTED trial http://hdl.handle.net/2381/41245 Title: Frequency, determinants, and effects of early seizures after thrombolysis for acute ischemic stroke: The ENCHANTED trial Authors: Xu, Ying; Hackett, Maree L.; Chalmers, John; Lindley, Richard I.; Wang, Xia; Li, Qiang; Robinson, Thompson; Arima, Hisatomi; Lavados, Pablo M.; Anderson, Craig S. Abstract: Background: Seizures after ischemic stroke have not been well-studied. We aim to determine the frequency, determinants, and significance of early seizures after thrombolysis for acute ischemic stroke. Methods: Data are from the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), an international, multicenter, randomized controlled trial where patients with acute ischemic stroke were randomized to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) IV alteplase. The protocol prespecified prospective data collection on in-hospital seizures over 7 days postrandomization. Logistic regression models were used to determine variables associated with seizures and their significance on poor outcomes of death or disability (modified Rankin scale scores 3-6), symptomatic intracerebral hemorrhage (sICH), and European Quality of Life 5-Dimensions questionnaire [EQ-5D] over 90 days. Results: Data were available for 3,139 acute ischemic stroke participants, of whom 42 (1.3%) had seizures at a median 22.7 hours after the onset of symptoms. Baseline variables associated with seizures were male sex (odds ratio [OR] 2.19, 95% confidence interval [CI] 1.07-4.50), severe neurologic impairment (NIH Stroke Scale score ≥10; OR 2.16, 95% CI 1.06-4.40), and fever (OR 4.55, 95% CI 2.37-8.71). Seizures independently predicted poor recovery: death or major disability (OR 2.88, 95% CI 1.28-6.47), unfavorable ordinal shift of mRS scores (OR 1.94, 95% CI 1.10-3.39), and lower than median EQ-5D health utility index score (OR 3.50, 95% CI 1.37-8.91). There was no association of seizures with sICH in adjusted analysis. Conclusions: In thrombolysis-treated patients with acute ischemic stroke, seizures are uncommon, occur early, and predict poor recovery. 2018-02-26T15:07:21Z Influence of Renal Impairment on Outcome for Thrombolysis-Treated Acute Ischemic Stroke: ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) Post Hoc Analysis http://hdl.handle.net/2381/41244 Title: Influence of Renal Impairment on Outcome for Thrombolysis-Treated Acute Ischemic Stroke: ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study) Post Hoc Analysis Authors: Carr, Susan J.; Wang, Xia; Olavarria, Veronica V.; Lavados, Pablo M.; Rodriguez, Jorge A.; Kim, Jong S.; Lee, Tsong-Hai; Lindley, Richard I.; Pontes-Neto, Octavio M.; Ricci, Stefano; Sato, Shoichiro; Sharma, Vijay K.; Woodward, Mark; Chalmers, John; Anderson, Craig S.; Robinson, Thompson G. Abstract: BACKGROUND AND PURPOSE: Renal dysfunction (RD) is associated with poor prognosis after stroke. We assessed the effects of RD on outcomes and interaction with low- versus standard-dose alteplase in a post hoc subgroup analysis of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS: A total of 3220 thrombolysis-eligible patients with acute ischemic stroke (mean age, 66.5 years; 37.8% women) were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset. Six hundred and fifty-nine (19.8%) patients had moderate-to-severe RD (estimated glomerular filtration rate, <60 mL/min per 1.73 m(2)) at baseline. The impact of RD on death or disability (modified Rankin Scale scores, 2-6) at 90 days, and symptomatic intracerebral hemorrhage, was assessed in logistic regression models. RESULTS: Compared with patients with normal renal function (>90 mL/min per 1.73 m(2)), those with severe RD (<30 mL/min per 1.73 m(2)) had increased mortality (adjusted odds ratio, 2.07; 95% confidence interval, 0.89-4.82; P=0.04 for trend); every 10 mL/min per 1.73 m(2) lower estimated glomerular filtration rate was associated with an adjusted 9% increased odds of death from thrombolysis-treated acute ischemic stroke. There was no significant association with modified Rankin Scale scores 2 to 6 (adjusted odds ratio, 1.03; 95% confidence interval, 0.62-1.70; P=0.81 for trend), modified Rankin Scale 3 to 6 (adjusted odds ratio, 1.20; 95% confidence interval, 0.72-2.01; P=0.44 for trend), or symptomatic intracerebral hemorrhage, or any heterogeneity in comparative treatment effects between low-dose and standard-dose alteplase by RD grades. CONCLUSIONS: RD is associated with increased mortality but not disability or symptomatic intracerebral hemorrhage in thrombolysis-eligible and treated acute ischemic stroke patients. Uncertainty persists as to whether low-dose alteplase confers benefits over standard-dose alteplase in acute ischemic stroke patients with RD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616. 2018-02-26T14:56:05Z Managing high blood pressure during acute ischemic stroke and intracerebral hemorrhage. http://hdl.handle.net/2381/41243 Title: Managing high blood pressure during acute ischemic stroke and intracerebral hemorrhage. Authors: Appiah, Karen O.; Minhas, Jatinder S.; Robinson, Thompson G. Abstract: PURPOSE OF REVIEW: Blood pressure (BP) elevations above premorbid levels are observed in at least 60% of acute ischemic and hemorrhagic stroke patients, within the first 24 h of symptom onset. A number of potential causes have been hypothesized, and high BP may be associated with poor stroke outcome. This review discusses management strategies of high BP in acute stroke, in the context of current guidelines. RECENT FINDINGS: Excessive BP elevation can impact acute stroke therapeutic strategies, particularly in modifying intervention safety and efficacy. Currently, guidance on BP management in acute ischemic stroke and intracerebral hemorrhage (ICH) exists in a limited number of specific clinical presentations, including spontaneous ICH and continuing versus stopping preexisting antihypertensive therapy. However, ongoing clinical trials will further investigate the safety and efficacy of urgent BP-lowering therapy for other indications. SUMMARY: There are clear national and international guidelines on BP lowering for specific indications, as well as ongoing clinical trials aiming to address common clinical scenarios in which the evidence-base is lacking and uncertain. This is specifically in important stroke subgroups previously excluded from trials, patients requiring mechanical thrombectomy and nonvitamin K antagonist-associated ICH reversal. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-02-26T14:31:39Z Positive impact of the participation in the ENCHANTED trial in reducing Door-to-Needle Time http://hdl.handle.net/2381/41242 Title: Positive impact of the participation in the ENCHANTED trial in reducing Door-to-Needle Time Authors: Yang, Jie; Wang, Xia; Yu, Jian Ping; Hang, Jing; Lavados, Pablo; Robinson, Thompson; Arima, Hisatomi; Lindley, Richard I.; Anderson, Craig S.; Chalmers, John Abstract: Door-to-needle time (DNT) is a key performance indicator for efficient use of intravenous thrombolysis in acute ischemic stroke (AIS). We aimed to determine whether DNT improved over time in the Enhanced Control of Hypertension and Acute Stroke Study (ENCHANTED) and the clinical predictors of DNT. Temporal trends in DNT were assessed across fourths of time since activation of study centers using generalized linear model. Predictors of long DNT (>60 min) were determined in logistic regression models. Overall mean DNT (min) was 71.8 (95% confidence interval [CI] 70.4-73.2), but decreased significantly over time (fourths): 77.9 (74.9-80.9), 69.3 (66.7-72.0), 69.1 (66.5-71.8) and 71.4 (68.7-74.2) (P for trend, 0.003). The reduction in DNT was particularly marked in China (P for trend, 0.001), but was not significant across the other participating countries (P for trend, 0.065). Independent predictors of long DNT were recruitment from China, short onset-to-door time, lower numbers of patients treated per center, higher diastolic blood pressure, off-hour admission, and absence of proximal clot occlusion. DNT in ENCHANTED declined progressively during the trial, especially in China. However, DNT in China is still longer than the key performance parameter of ≤60 minutes recommended in guidelines. Effective national programs are needed to improve DNT in China. 2018-02-26T13:24:14Z Characteristics, management and response to alteplase in China versus non-China participants of the ENCHANTED trial http://hdl.handle.net/2381/41241 Title: Characteristics, management and response to alteplase in China versus non-China participants of the ENCHANTED trial Authors: Song, Lily; Wang, Xia; Robinson, Thompson; Lindley, Richard I.; Arima, Hisatomi; Lavados, Pablo M.; Chen, Xiaoying; Chalmers, John; Anderson, Craig S. Abstract: BACKGROUND: The characteristics of patients with acute ischaemic stroke (AIS) and their management vary across regions, which may influence outcomes. We examined for differential patterns of outcome between China and non-China participants of the ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED), which tested different alteplase doses in AIS. METHODS: ENCHANTED was an international, multicentre, open, blinded-endpoint trial of the effects of low-dose (0.6 mg/kg) versus standard-dose (0.9 mg/kg) intravenous alteplase on 90-day disability outcomes and symptomatic intracerebral haemorrhage (sICH) in 3310 patients with AIS. RESULTS: Participants (n=1419, 48%) in China were younger, and more often male, hypertensive and with prior stroke and coronary artery disease, but less likely to have atrial fibrillation and use antihypertensive, antithrombotic and lipid-lowering agents, compared with non-China patients with AIS. Although China participants had more AIS due to large artery occlusion, were treated later and had differing ancillary management, there was no significant difference in 90-day modified Rankin scale scores 2-6 (55.6% vs 47.8%; OR, adjusted for baseline and management factors 0.87 (95% CI 0.71 to 1.07; p=0.20)) and risk of sICH (Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria: 1.4% vs 1.8%; p=0.12) compared with non-China participants. There was no heterogeneity in the treatment effects of low-dose versus standard-dose alteplase between China and non-China participants. CONCLUSION: Patients with AIS recruited to the ENCHANTED trial in China had similar outcomes in response to thrombolysis treatment despite significantly differing demographic, clinical and management factors to patients with AIS in other regions. 2018-02-26T13:04:33Z Reporting individual surgeon outcomes does not lead to risk aversion in abdominal aortic aneurysm surgery http://hdl.handle.net/2381/41236 Title: Reporting individual surgeon outcomes does not lead to risk aversion in abdominal aortic aneurysm surgery Authors: Saratzis, Athanasios; Thatcher, A.; Bath, M. F.; Sidloff, David A.; Bown, Matthew J.; Shakespeare, J.; Sayers, Robert D.; Imray, C. Abstract: INTRODUCTION: Reporting surgeons' outcomes has recently been introduced in the UK. This has the potential to result in surgeons becoming risk averse. The aim of this study was to investigate whether reporting outcomes for abdominal aortic aneurysm (AAA) surgery impacts on the number and risk profile (level of fitness) of patients offered elective treatment. METHODS: Publically available National Vascular Registry data were used to compare the number of AAAs treated in those centres across the UK that reported outcomes for the periods 2008-2012, 2009-2013 and 2010-2014. Furthermore, the number and characteristics of patients referred for consideration of elective AAA repair at a single tertiary unit were analysed yearly between 2010 and 2014. Clinic, casualty and theatre event codes were searched to obtain all AAAs treated. The results of cardiopulmonary exercise testing (CPET) were assessed. RESULTS: For the 85 centres that reported outcomes in all three five-year periods, the median number of AAAs treated per unit increased between the periods 2008-2012 and 2010-2014 from 192 to 214 per year (p=0.006). In the single centre cohort study, the proportion of patients offered elective AAA repair increased from 74% in 2009-2010 to 81% in 2013-2014, with a maximum of 84% in 2012-2013. The age, aneurysm size and CPET results (anaerobic threshold levels) for those eventually offered elective treatment did not differ significantly between 2010 and 2014. CONCLUSIONS: The results do not support the assumption that reporting individual surgeon outcomes is associated with a risk averse strategy regarding patient selection in aneurysm surgery at present. 2018-02-23T12:19:47Z National initiatives to improve outcomes from out-of-hospital cardiac arrest in England. http://hdl.handle.net/2381/41232 Title: National initiatives to improve outcomes from out-of-hospital cardiac arrest in England. Authors: Perkins, Gavin D.; Lockey, Andrew S.; de Belder, Mark A.; Moore, Fionna; Weissberg, Peter; Gray, Huon; Community Resuscitation Group Abstract: NHS England report that the ambulance services attempt to resuscitate approximately 28 000 people from out-of-hospital cardiac arrest each year (approximately 1 per 2000 inhabitants per year).1 The rate of initial success (return of spontaneous circulation) was 25%, with less than half of those who are successfully resuscitated initially surviving to go home from hospital (survival to discharge 7%–8%, 2011–2014).1 (see figure 1). The survival rates contrast sharply with those observed in the best-performing emergency medical services systems, which have survival rates of 20%–25%.2–4 In 2013, the government's Cardiovascular Disease Outcomes Strategy for England set the ambitious, but achievable target of increasing survival from out-of-hospital cardiac arrest by 50%, leading to an additional 1000 lives saved each year. 2018-02-21T14:16:13Z Relative Survival After Transcatheter Aortic Valve Implantation: How Do Patients Undergoing Transcatheter Aortic Valve Implantation Fare Relative to the General Population? http://hdl.handle.net/2381/41231 Title: Relative Survival After Transcatheter Aortic Valve Implantation: How Do Patients Undergoing Transcatheter Aortic Valve Implantation Fare Relative to the General Population? Authors: Martin, Glen P.; Sperrin, Matthew; Hulme, William; Ludman, Peter F.; de Belder, Mark A.; Toff, William D.; Alabas, Oras; Moat, Neil E.; Doshi, Sagar N.; Buchan, Iain; Deanfield, John E.; Gale, Chris P.; Mamas, Mamas A.; National Institute of Cardiovascular Outcomes Research (NICOR) Abstract: BACKGROUND: Transcatheter aortic valve implantation (TAVI) is indicated for patients with aortic stenosis who are intermediate-high surgical risk. Although all-cause mortality rates after TAVI are established, survival attributable to the procedure is unclear because of competing causes of mortality. The aim was to report relative survival (RS) after TAVI, which accounts for background mortality risks in a matched general population. METHODS AND RESULTS: National cohort data (n=6420) from the 2007 to 2014 UK TAVI registry were matched by age, sex, and year to mortality rates for England and Wales (population, 57.9 million). The Ederer II method related observed patient survival to that expected from the matched general population. We modelled RS using a flexible parametric approach that modelled the log cumulative hazard using restricted cubic splines. RS of the TAVI cohort was 95.4%, 90.2%, and 83.8% at 30 days, 1 year, and 3 years, respectively. By 1-year follow-up, mortality hazards in the >85 years age group were not significantly different from those of the matched general population; by 3 years, survival rates were comparable. The flexible parametric RS model indicated that increasing age was associated with significantly lower excess hazards after the procedure; for example, by 2 years, a 5-year increase in age was associated with 20% lower excess mortality over the general population. CONCLUSIONS: RS after TAVI was high, and survival rates in those aged >85 years approximated those of a matched general population within 3 years. High rates of RS indicate that patients selected for TAVI tolerate the risks of the procedure well. 2018-02-21T14:10:29Z Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI). http://hdl.handle.net/2381/41225 Title: Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI). Authors: Siddiqi, Nishat; Neil, Christopher; Bruce, Margaret; MacLennan, Graeme; Cotton, Seonaidh; Papadopoulou, Sofia; Feelisch, Martin; Bunce, Nicholas; Lim, Pitt O.; Hildick-Smith, David; Horowitz, John; Madhani, Melanie; Boon, Nicholas; Dawson, Dana; Kaski, Juan Carlos; Frenneaux, Michael; NIAMI investigators Abstract: AIM: Despite prompt revascularization of acute myocardial infarction (AMI), substantial myocardial injury may occur, in part a consequence of ischaemia reperfusion injury (IRI). There has been considerable interest in therapies that may reduce IRI. In experimental models of AMI, sodium nitrite substantially reduces IRI. In this double-blind randomized placebo controlled parallel-group trial, we investigated the effects of sodium nitrite administered immediately prior to reperfusion in patients with acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A total of 229 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of 70 μmol sodium nitrite (n = 118) or matching placebo (n = 111) over 5 min immediately before primary percutaneous intervention (PPCI). Patients underwent cardiac magnetic resonance imaging (CMR) at 6-8 days and at 6 months and serial blood sampling was performed over 72 h for the measurement of plasma creatine kinase (CK) and Troponin I. Myocardial infarct size (extent of late gadolinium enhancement at 6-8 days by CMR-the primary endpoint) did not differ between nitrite and placebo groups after adjustment for area at risk, diabetes status, and centre (effect size -0.7% 95% CI: -2.2%, +0.7%; P = 0.34). There were no significant differences in any of the secondary endpoints, including plasma troponin I and CK area under the curve, left ventricular volumes (LV), and ejection fraction (EF) measured at 6-8 days and at 6 months and final infarct size (FIS) measured at 6 months. CONCLUSIONS: Sodium nitrite administered intravenously immediately prior to reperfusion in patients with acute STEMI does not reduce infarct size. Description: Supplementary material is available at European Heart Journal online. 2018-02-21T12:08:10Z High-intensity physical activity for improving glucose regulation: can science justify IT? http://hdl.handle.net/2381/41223 Title: High-intensity physical activity for improving glucose regulation: can science justify IT? Authors: Jelleyman, Charlotte Lauren Abstract: Background: Interest in high-intensity interval training (HIIT) has recently resurfaced as a way to improve adherence to physical activity by addressing the common barrier of a "lack of time". The benefit HIIT and vigorous-intensity physical activity (VPA) have on cardiorespiratory fitness is well established however, the effects on glucose regulation and insulin sensitivity in individuals at high risk of type 2 diabetes (T2DM) are less clear. Aims: The aims of this thesis were: to pool the available evidence regarding the effects of HIIT on markers of glycaemic control and insulin sensitivity, conduct observational analyses investigating the relationship between A) continuously and intermittently (≥10 minutes and <10 minutes, respectively) accumulated physical activity and B) increasing exercise intensity with markers of insulin sensitivity, and finally, to design and undertake an acute experimental study comparing the effect of high-intensity interval and moderate-intensity continuous exercise with sitting on post-challenge glucose and insulin responses. Key findings: In individuals at high risk of T2DM, HIIT improves HbA1c and insulin sensitivity to a similar extent as moderate-intensity continuous training, despite a lower overall workload. Continuously, but not sporadically, accumulated physical activity is positively associated with insulin sensitivity, and increasing physical activity intensity is associated with increasingly greater benefits in glucose regulation and insulin sensitivity. High-intensity interval exercise significantly improves the postprandial insulin response to a greater extent than moderate-intensity continuous exercise and sitting. Both forms of exercise are effective at reducing glycaemic variability. Conclusions: This thesis demonstrates that VPA is more effective than moderate-intensity physical activity at improving insulin sensitivity for a given unit of time. It shows that these benefits of vigorous-intensity physical activity can be achieved by performing HIIT, which may be a viable option for individuals at high risk of T2DM. HIIT could therefore be incorporated into the physical activity guidelines as a recommended health tool for improving diabetes outcomes. 2018-02-20T14:52:51Z The changing trends in new ICD and CRT-D implants over the last 20 years at a single large tertiary cardiology centre http://hdl.handle.net/2381/41182 Title: The changing trends in new ICD and CRT-D implants over the last 20 years at a single large tertiary cardiology centre Authors: Vali, Z.; Mistry, A.; Nicolson, W. B.; Chu, G.; Li, X.; Sandilands, A. J.; Somani, R.; Chelliah, R.; Chin, D.; Pathmanathan, R.; Stafford, P.; Ng, G. A . Abstract: Introduction: Since their introduction to standard clinical practice, implantable cardioverter defibrillators (ICD) have been shown in a number of clinical trials to improve survival. We review the changes seen in the numbers and demographics of patients receiving ICD or CRT-D implants at one large tertiary cardiology centre (Glenfield Hospital) with a catchment population of approximately 2 million. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-02-15T10:26:23Z Fibroblast growth factor 23 is related to profiles indicating volume overload, poor therapy optimization and prognosis in patients with new-onset and worsening heart failure http://hdl.handle.net/2381/41148 Title: Fibroblast growth factor 23 is related to profiles indicating volume overload, poor therapy optimization and prognosis in patients with new-onset and worsening heart failure Authors: ter Maaten, Jozine M.; Voors, Adriaan A.; Damman, Kevin; van der Meer, Peter; Anker, Stefan D.; Cleland, John G.; Dickstein, Kenneth; Filippatos, Gerasimos; van der Harst, Pim; Hillege, Hans L.; Lang, Chim C.; Metra, Marco; Navis, Gerjan; Ng, Leong; Ouwerkerk, Wouter; Ponikowski, Piotr; Samani, Nilesh J.; van Veldhuisen, Dirk J.; Zannad, Faiez; Zwinderman, Aeilko H.; de Borst, Martin H. Abstract: Background Fibroblast growth factor (FGF) 23 is a hormone that increases urinary phosphate excretion and regulates renal sodium reabsorption and plasma volume. We studied the role of plasma FGF23 in therapy optimization and outcomes in patients with new-onset and worsening heart failure (HF). Methods We measured plasma C-terminal FGF23 levels at baseline in 2399 of the 2516 patients included in the BIOlogy Study to Tailored Treatment in Chronic HF (BIOSTAT-CHF) trial. The association between FGF23 and outcome was evaluated by Cox regression analysis adjusted for potential confounders. Results Median FGF23 was 218.0 [IQR: 117.1–579.3] RU/ml; patients with higher FGF23 levels had a worse NYHA class, more signs of congestion, and were less likely to use an ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARBs) at baseline (all P < 0.01). Higher FGF23 levels were independently associated with higher BNP, lower eGFR, the presence of oedema and atrial fibrillation (all P < 0.001). In addition, higher FGF23 was independently associated with impaired uptitration of ACEi/ARBs after 3 months, but not of beta-blockers. In multivariable Cox regression analysis, FGF23 was independently associated with all-cause mortality (hazard ratio: 1.17 (1.09–1.26) per log increase, P < 0.001), and the combined endpoint of all-cause mortality and HF hospitalization (1.15 (1.08–1.22) per log increase, P < 0.001). Conclusions In patients with new-onset and worsening HF, higher plasma FGF23 levels were independently associated with volume overload, less successful uptitration of ACEi/ARBs and an increased risk of all-cause mortality and HF hospitalization. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-02-13T10:24:37Z Adrenergic control mechanisms of heart rate - down to a T ? http://hdl.handle.net/2381/41117 Title: Adrenergic control mechanisms of heart rate - down to a T ? Authors: Ng, G. Andre Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-02-08T09:45:15Z Socioeconomic status and outcomes in heart failure with reduced ejection http://hdl.handle.net/2381/41054 Title: Socioeconomic status and outcomes in heart failure with reduced ejection Authors: Squire, Iain Abstract: [First paragraph] As we are almost invariably reminded each time we open a research paper on the subject of chronic heart failure (CHF), the condition is increasingly prevalent and only likely to become so as our population ages.1 In the most recent iteration of the National Heart Failure audit, from 2015 to 2016, data from over 66 000 admissions to hospitals in England and Wales were included; soberingly, this number represents somewhere around 80% of the total for this condition recorded in the first diagnostic position.2 Thus, the societal burden associated with CHF is enormous and growing. Similarly, the individual patient burden associated with a diagnosis of CHF is potentially high; this remains a condition associated with significant morbidity and mortality. 2018-01-29T17:24:25Z Reallocating sitting time to standing or stepping through isotemporal analysis: associations with markers of chronic low-grade inflammation. http://hdl.handle.net/2381/41044 Title: Reallocating sitting time to standing or stepping through isotemporal analysis: associations with markers of chronic low-grade inflammation. Authors: Henson, Joseph; Edwardson, Charlotte L.; Bodicoat, Danielle H.; Bakrania, Kishan; Davies, Melanie J.; Khunti, Kamlesh; Talbot, Duncan C. S.; Yates, Thomas Abstract: Although high levels of sitting time are adversely related to health, it is unclear whether moving from sitting to standing provides a sufficient stimulus to elicit benefits upon markers of chronic low-grade inflammation in a population at high risk of type 2 diabetes (T2DM). Three hundred and seventy two participants (age = 66.8 ± 7.5years; body mass index (BMI) = 31.7 ± 5.5kg/m2; Male = 61%) were included. Sitting, standing and stepping was determined using the activPAL3TM device. Linear regression modelling employing an isotemporal substitution approach was used to quantify the association of theoretically substituting 60 minutes of sitting per day for standing or stepping on interleukin-6 (IL-6), C-reactive protein (CRP) and leptin. Reallocating 60 minutes of sitting time per day for standing was associated with a -4% (95% CI -7%, -1%) reduction in IL-6 (p = 0.048). Reallocating 60 minutes of sitting time for light stepping was also associated with lower IL-6 levels (-28% (-46%, -4%; p = 0.025)). Substituting sitting for moderate-to-vigorous (MVPA) stepping was associated with lower CRP (-41% (-75%, -8%; p = 0.032)), leptin (-24% (-34%, -12%; p ≤ 0.001)) and IL-6 (-16% (-28%, 10%; p = 0.036). Theoretically replacing 60 minutes of sitting per day with an equal amount of either standing or stepping yields beneficial associations upon markers of chronic-low grade inflammation. Description: The file associated with this record is under embargo until 18 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-01-26T17:41:25Z Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in heart failure with preserved ejection fraction - implications for clinical trials. http://hdl.handle.net/2381/41036 Title: Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in heart failure with preserved ejection fraction - implications for clinical trials. Authors: Kanagala, Prathap; Cheng, Adrian S. H.; Singh, Anvesha; McAdam, John; Marsh, Anna-Marie; Arnold, Jayanth R.; Squire, Iain B.; Ng, Leong L.; McCann, Gerry P. Abstract: BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a poorly characterized condition. We aimed to phenotype patients with HFpEF using multiparametric stress cardiovascular magnetic resonance imaging (CMR) and to assess the relationship to clinical outcomes. METHODS: One hundred and fifty four patients (51% male, mean age 72 ± 10 years) with a diagnosis of HFpEF underwent transthoracic echocardiography and CMR during a single study visit. The CMR protocol comprised cine, stress/rest perfusion and late gadolinium enhancement imaging on a 3T scanner. Follow-up outcome data (death and heart failure hospitalization) were captured after a minimum of 6 months. RESULTS: CMR detected previously undiagnosed pathology in 42 patients (27%), who had similar baseline characteristics to those without a new diagnosis. These diagnoses consisted of: coronary artery disease (n = 20, including 14 with 'silent' infarction), microvascular dysfunction (n = 11), probable or definite hypertrophic cardiomyopathy (n = 10) and constrictive pericarditis (n = 5). Four patients had dual pathology. During follow-up (median 623 days), patients with a new CMR diagnosis were at higher risk of adverse outcome for the composite endpoint (log rank test: p = 0.047). In multivariate Cox proportional hazards analysis, a new CMR diagnosis was the strongest independent predictor of adverse outcome (hazard ratio: 1.92; 95% CI: 1.07 to 3.45; p = 0.03). CONCLUSIONS: CMR diagnosed new significant pathology in 27% of patients with HFpEF. These patients were at increased risk of death and heart failure hospitalization. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03050593 . Retrospectively registered; Date of registration: February 06, 2017. Description: The datasets generated during and/or analysed during the current study are available from the corresponding author (GPM) upon reasonable request. 2018-01-26T15:38:14Z Corrigendum: Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. http://hdl.handle.net/2381/41024 Title: Corrigendum: Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Authors: Warren, Helen R.; Evangelou, Evangelos; Cabrera, Claudia P.; Gao, He; Ren, Meixia; Mifsud, Borbala; Ntalla, Ioanna; Surendran, Praveen; Liu, Chunyu; Cook, James P.; Kraja, Aldi T.; Drenos, Fotios; Loh, Marie; Verweij, Niek; Marten, Jonathan; Karaman, Ibrahim; Segura Lepe, Marcelo P.; O'Reilly, Paul F.; Knight, Joanne; Snieder, Harold; Kato, Norihiro; He, Jiang; Tai, E. Shyong; Said, M. Abdullah; Porteous, David; Alver, Maris; Poulter, Neil; Farrall, Martin; Gansevoort, Ron T.; Padmanabhan, Sandosh; Mägi, Reedik; Stanton, Alice; Connell, John; Bakker, Stephan J. L.; Metspalu, Andres; Shields, Denis C.; Thom, Simon; Brown, Morris; Sever, Peter; Esko, Tõnu; Hayward, Caroline; van der Harst, Pim; Saleheen, Danish; Chowdhury, Rajiv; Chambers, John C.; Chasman, Daniel I.; Chakravarti, Aravinda; Newton-Cheh, Christopher; Lindgren, Cecilia M.; Levy, Daniel; Kooner, Jaspal S.; Keavney, Bernard; Tomaszewski, Maciej; Samani, Nilesh J.; Howson, Joanna M. M.; Tobin, Martin D.; Munroe, Patricia B.; Ehret, Georg B.; Wain, Louise V.; International Consortium of Blood Pressure (ICBP) 1000G Analyses; The CHD Exome+ Consortium; The ExomeBP Consortium; The T2D-GENES Consortium; The GoT2DGenes Consortium; The Cohorts for Heart and Ageing Research in Genome Epidemiology (CHARGE) BP Exome Consortium; The International Genomics of Blood Pressure (iGEN-BP) Consortium; Barnes, Michael R.; Tzoulaki, Ioanna; Caulfield, Mark J.; Elliott, Paul; UK Biobank CardioMetabolic Consortium BP working group Abstract: Nat. Genet.; doi:10.1038/ng.3768; corrected online 20 February 2017 In the version of this article initially published online, the name of Chiara Batini was misspelled as Chiara Battini in the list of collaborators affiliated with International Consortium of Blood Pressure (ICBP) 1000G Analyses. The error has been corrected in the print, PDF and HTML versions of this article. 2018-01-25T14:07:03Z Genome-wide association study identifies 74 loci associated with educational attainment. http://hdl.handle.net/2381/41014 Title: Genome-wide association study identifies 74 loci associated with educational attainment. Authors: Okbay, Aysu; Beauchamp, Jonathan P.; Fontana, Mark Alan; Lee, James J.; Pers, Tune H.; Rietveld, Cornelius A.; Turley, Patrick; Chen, Guo-Bo; Emilsson, Valur; Meddens, S. Fleur W.; Oskarsson, Sven; Pickrell, Joseph K.; Thom, Kevin; Timshel, Pascal; de Vlaming, Ronald; Abdellaoui, Abdel; Ahluwalia, Tarunveer S.; Bacelis, Jonas; Baumbach, Clemens; Bjornsdottir, Gyda; Brandsma, Johannes H.; Pina Concas, Maria; Derringer, Jaime; Furlotte, Nicholas A.; Galesloot, Tessel E.; Girotto, Giorgia; Gupta, Richa; Hall, Leanne M.; Harris, Sarah E.; Hofer, Edith; Horikoshi, Momoko; Huffman, Jennifer E.; Kaasik, Kadri; Kalafati, Ioanna P.; Karlsson, Robert; Kong, Augustine; Lahti, Jari; van der Lee, Sven J.; deLeeuw, Christiaan; Lind, Penelope A.; Lindgren, Karl-Oskar; Liu, Tian; Mangino, Massimo; Marten, Jonathan; Mihailov, Evelin; Miller, Michael B.; van der Most, Peter J.; Oldmeadow, Christopher; Payton, Antony; Pervjakova, Natalia; Peyrot, Wouter J.; Qian, Yong; Raitakari, Olli; Rueedi, Rico; Salvi, Erika; Schmidt, Börge; Schraut, Katharina E.; Shi, Jianxin; Smith, Albert V.; Poot, Raymond A.; St Pourcain, Beate; Teumer, Alexander; Thorleifsson, Gudmar; Verweij, Niek; Vuckovic, Dragana; Wellmann, Juergen; Westra, Harm-Jan; Yang, Jingyun; Zhao, Wei; Zhu, Zhihong; Alizadeh, Behrooz Z.; Amin, Najaf; Bakshi, Andrew; Baumeister, Sebastian E.; Biino, Ginevra; Bønnelykke, Klaus; Boyle, Patricia A.; Campbell, Harry; Cappuccio, Francesco P.; Davies, Gail; De Neve, Jan-Emmanuel; Deloukas, Panos; Demuth, Ilja; Ding, Jun; Eibich, Peter; Eisele, Lewin; Eklund, Niina; Evans, David M.; Faul, Jessica D.; Feitosa, Mary F.; Forstner, Andreas J.; Gandin, Ilaria; Gunnarsson, Bjarni; Halldórsson, Bjarni V.; Harris, Tamara B.; Heath, Andrew C.; Hocking, Lynne J.; Holliday, Elizabeth G.; Homuth, Georg; Horan, Michael A.; Hottenga, Jouke-Jan; de Jager, Philip L.; Joshi, Peter K. Joshi; Jugessur, Astanand; Kaakinen, Marika A.; Kähönen, Mika; Kanoni, Stavroula; Keltigangas-Järvinen, Liisa; Kiemeney, Lambertus A. L. M.; Kolcic, Ivana; Koskinen, Seppo; Kraja, Aldi T.; Kroh, Martin; Kutalik, Zoltan; Latvala, Antti; Launer, Lenore J.; Lebreton, Maël P.; Levinson, Douglas F.; Lichtenstein, Paul; Lichtner, Peter; Liewald, David C. M.; LifeLines Cohort Study; Loukola, Anu; Madden, Pamela A.; Mägi, Reedik; Mäki-Opas, Tomi; Marioni, Riccardo E.; Marques-Vidal, Pedro; Meddens, Gerardus A.; McMahon, George; Meisinger, Christa; Meitinger, Thomas; Milaneschi, Yusplitri; Milani, Lili; Montgomery, Grant W.; Myhre, Ronny; Nelson, Christopher P.; Nyholt, Dale R.; Ollier, William E. R.; Palotie, Aarno; Paternoster, Lavinia; Pedersen, Nancy L.; Petrovic, Katja E.; Porteous, David J.; Räikkönen, Katri; Ring, Susan M.; Robino, Antonietta; Rostapshova, Olga; Rudan, Igor; Rustichini, Aldo; Salomaa, Veikko; Sanders, Alan R.; Sarin, Antti-Pekka; Schmidt, Helena; Scott, Rodney J.; Smith, Blair H.; Smith, Jennifer A.; Staessen, Jan A.; Steinhagen-Thiessen, Elisabeth; Strauch, Konstantin; Terracciano, Antonio; Tobin, Martin D.; Ulivi, Sheila; Vaccargiu, Simona; Quaye, Lydia; van Rooij, Frank J. A.; Venturini, Cristina; Vinkhuyzen, Anna A. E.; Völker, Uwe; Völzke, Henry; Vonk, Judith M.; Vozzi, Diego; Waage, Johannes; Ware, Erin B.; Willemsen, Gonneke; Attia, John R.; Bennett, David A.; Berger, Klaus; Bertram, Lars; Bisgaard, Hans; Boomsma, Dorret I.; Borecki, Ingrid B.; Bültmann, Ute; Chabris, Christopher F.; Cucca, Francesco; Cusi, Daniele; Deary, Ian J.; Dedoussis, George V.; van Duijn, Cornelia M.; Eriksson, Johan G.; Franke, Barbara; Franke, Lude; Gasparini, Paolo; Gejman, Pablo V.; Gieger, Christian; Grabe, Hans-Jörgen; Gratten, Jacob; Groenen, Patrick J. F.; Gudnason, Vilmundur; van der Harst, Pim; Hayward, Caroline; Hinds, David A.; Hoffmann, Wolfgang; Hyppönen, Elina; Iacono, William G.; Jacobsson, Bo; Järvelin, Marjo-Riitta; Jöckel, Karl-Heinz; Kaprio, Jaakko; Kardia, Sharon L. R.; Lehtimäki, Terho; Lehrer, Steven F.; Magnusson, Patrik K. E.; Martin, Nicholas G.; McGue, Matt; Metspalu, Andres; Pendleton, Neil; Penninx, Brenda W. J. H.; Perola, Markus; Pirastu, Nicola; Pirastu, Mario; Polasek, Ozren; Posthuma, Danielle; Power, Christine; Province, Michael A.; Samani, Nilesh J.; Schlessinger, David; Schmidt, Reinhold; Sørensen, Thorkild I. A.; Spector, Tim D.; Stefansson, Kari; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tiemeier, Henning; Tung, Joyce Y.; Uitterlinden, André G.; Vitart, Veronique; Vollenweider, Peter; Weir, David R.; Wilson, James F.; Wright, Alan F.; Conley, Dalton C.; Krueger, Robert F.; Davey Smith, George; Hofman, Albert; Laibson, David I.; Medland, Sarah E.; Meyer, Michelle N.; Yang, Jian; Johannesson, Magnus; Visscher, Peter M.; Esko, Tõnu; Koellinger, Philipp D.; Cesarini, David; Benjamin, Daniel J. Abstract: Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases. Description: Supplementary Information is available in the online version of the paper. 2018-01-25T10:51:45Z Increased blood pressure variability upon standing up improves reproducibility of cerebral autoregulation indices http://hdl.handle.net/2381/41013 Title: Increased blood pressure variability upon standing up improves reproducibility of cerebral autoregulation indices Authors: Mahdi, Adam; Nikolic, Dragana; Birch, Anthony A.; Olufsen, Mette S.; Panerai, Ronney B.; Simpson, David M.; Payne, Stephen J. Abstract: Dynamic cerebral autoregulation, that is the transient response of cerebral blood flow to changes in arterial blood pressure, is currently assessed using a variety of different time series methods and data collection protocols. In the continuing absence of a gold standard for the study of cerebral autoregulation it is unclear to what extent does the assessment depend on the choice of a computational method and protocol. We use continuous measurements of blood pressure and cerebral blood flow velocity in the middle cerebral artery from the cohorts of 18 normotensive subjects performing sit-to-stand manoeuvre. We estimate cerebral autoregulation using a wide variety of black-box approaches (including the following six autoregulation indices ARI, Mx, Sx, Dx, FIR and ARX) and compare them in the context of reproducibility and variability. For all autoregulation indices, considered here, the intra-class correlation was greater during the standing protocol, however, it was significantly greater (Fisher's Z-test) for Mx (p < 0.03), Sx (p < 0.003) and Dx (p < 0.03). In the specific case of the sit-to-stand manoeuvre, measurements taken immediately after standing up greatly improve the reproducibility of the autoregulation coefficients. This is generally coupled with an increase of the within-group spread of the estimates. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-01-25T10:46:49Z Patient, health service factors and variation in mortality following resuscitated out-of-hospital cardiac arrest in acute coronary syndrome: analysis of the Myocardial Ischaemia National Audit Project http://hdl.handle.net/2381/40950 Title: Patient, health service factors and variation in mortality following resuscitated out-of-hospital cardiac arrest in acute coronary syndrome: analysis of the Myocardial Ischaemia National Audit Project Authors: Couper, Keith; Kimani, Peter K.; Gale, Chris P.; Quinn, Tom; Squire, Iain B.; Marshall, Andrea; Black, John J. M.; Cooke, Matthew W.; Ewings, Bob; Long, John; Perkins, Gavin D. Abstract: Aims To determine patient and health service factors associated with variation in hospital mortality among resuscitated cases of out-of-hospital cardiac arrest (OHCA) with acute coronary syndrome (ACS). Methods In this cohort study, we used the Myocardial Ischaemia National Audit Project database to study outcomes in patients hospitalised with resuscitated OHCA due to ACS between 2003 and 2015 in the United Kingdom. We analysed variation in inter-hospital mortality and used hierarchical multivariable regression models to examine the association between patient and health service factors with hospital mortality. Results We included 17604 patients across 239 hospitals. Overall hospital mortality was 28.7%. In 94 hospitals that contributed at least 60 cases, mortality by hospital ranged from 10.7% to 66.3% (median 28.6%, IQR 23.2% to 39.1%)). Patient and health service factors explained 36.1% of this variation. After adjustment for covariates, factors associated with higher hospital mortality included increasing serum glucose, ST-Elevation myocardial infarction (STEMI) diagnosis, and initial admission to a primary percutaneous coronary intervention (pPCI) capable hospital. Hospital OHCA volume was not associated with mortality. The key modifiable factor associated with lower mortality was early reperfusion therapy in STEMI patients. Conclusion There was wide variation in inter-hospital mortality following resuscitated OHCA due to ACS that was only partially explained by patient and health service factors. Hospital OHCA volume and pPCI capability were not associated with lower mortality. Early reperfusion therapy was associated with lower mortality in STEMI patients. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-01-19T11:22:53Z Five-year forward view: lessons from emergency care at the extremes of age. http://hdl.handle.net/2381/40919 Title: Five-year forward view: lessons from emergency care at the extremes of age. Authors: Minhas, J. S.; Minhas, D.; Coats, T.; Banerjee, J.; Roland, D. Abstract: Objective The progressive rise in demand on NHS emergency care resources is partly attributable to increases in attendances of children and older people. A quality gap exists in the care provision for the old and the young. The Five Year Forward View suggested new models of care but that the "answer is not one-size-fits-all". This article discusses the urgent need for person-centred outcome measures to bridge the gap that exists between demand and provision. Design This review is based on evidence gathered from literature searching across several platforms using a variety of search terms to account for the obvious heterogeneity, drawing on key 'think-tank' evidence. Settings Qualitative and quantitative studies examining approaches to caring for individuals at the extremes of age. Participants Individuals at the extremes of age (infants and older people). Main Outcome Measures Understanding similarities and disparities in the care of individuals at the extremes of age in an emergency and non-emergency context. Results There exists several similarities and disparities in the care of individuals at the extremes of age. The increasing burden of health disease on the economy must acknowledge the challenges that exist in managing patients in emergency settings at the extremes of age and build systems to acknowledge the traits these individuals exhibit. Conclusion Commissioners of services must optimise the models of care delivery by appreciating the similarities and differences between care requirements in these two large groups seeking emergency care. 2018-01-17T11:15:41Z Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. http://hdl.handle.net/2381/40915 Title: Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Authors: Bath, Philip M.; Woodhouse, Lisa J.; Appleton, Jason P.; Beridze, Maia; Christensen, Hanne; Dineen, Robert A.; Duley, Lelia; England, Timothy J.; Flaherty, Katie; Havard, Diane; Heptinstall, Stan; James, Marilyn; Krishnan, Kailash; Markus, Hugh S.; Montgomery, Alan A.; Pocock, Stuart J.; Randall, Marc; Ranta, Annemare; Robinson, Thompson G.; Scutt, Polly; Venables, Graham S.; Sprigg, Nikola; TARDIS Investigators Abstract: BACKGROUND: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. METHODS: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. FINDINGS: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67-1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05-3·16, p<0·0001). INTERPRETATION: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. FUNDING: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation. 2018-01-17T10:30:29Z A qualitative study exploring patients', with mild to moderate stroke, and their carers' perceptions of healthy lifestyles http://hdl.handle.net/2381/40894 Title: A qualitative study exploring patients', with mild to moderate stroke, and their carers' perceptions of healthy lifestyles Authors: Clague-Baker, Nicola; Carpenter, Christine; Robinson, Thompson; Hagenberg, Annegret; Drewry, Sophie; Singh, Sally Abstract: Background/Aims: To explore patients', with mild to moderate stroke, and their carers' experiences after a stroke and to explore their perceptions of healthy lifestyles. Methods: A qualitative study using semi-structured interviews was undertaken with 20 people (12 males and 8 females) with mild to moderate stroke or transient ischaemic attack (1 week to 6 months' post event) and seven of their carers. Each interview was transcribed and a thematic analysis approach guided the analytic process. Results: Patients with sub-acute, mild to moderate stroke were positive about healthy lifestyles and their ability to achieve them post stroke. Three core themes were identified: perceptions related to exercise; perceptions related to other lifestyle factors; and understanding of stroke and healthy lifestyles. Conclusions: In the sub-acute phase of stroke recovery, barriers to exercise such as lack of motivation do not appear to be an issue. People with stroke have a lack of understanding of healthy guidelines, risk factors and cause of their stroke. It is not clear if this is due to a lack of information provision or a lack of recall. They also do not appear to make the link between lifestyle choices and the cause of their stroke. Description: The file associated with this record is under embargo until 6 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-01-16T16:07:38Z Early Cognitive Impairment after Intracerebral Hemorrhage in the INTERACT1 Study. http://hdl.handle.net/2381/40893 Title: Early Cognitive Impairment after Intracerebral Hemorrhage in the INTERACT1 Study. Authors: You, S.; Wang, X.; Lindley, R. I.; Robinson, T.; Anderson, C. S.; Cao, Y.; Chalmers, J. Abstract: BACKGROUND: Data on cognitive impairment after acute intracerebral hemorrhage (ICH) are limited. This study is aimed at determining the frequency and predictors of cognitive impairment among participants of the pilot phase, Intensive Blood Pressure (BP) Reduction in Acute Cerebral Hemorrhage Trial (INTERACT1). METHODS: INTERACT1 was an open randomized trial of early intensive (target systolic BP <140 mm Hg) compared with contemporaneous guideline-recommended BP lowering in 404 patients with elevated systolic BP (150-220 mm Hg) within 6 h of ICH onset. Cognitive impairment was defined by scores ≤24 on the Mini-Mental State Examination (MMSE) assessed by interview on follow-up at 90 days. RESULTS: A total of 231 (64.5%) of 358 90-day survivors had MMSE scores for analyses, and 75 (32.5%) had cognitive impairment. In multivariable analysis, older age (OR 2.48, 95% CI 1.73-3.56 per 10-year increase; p < 0.001), female sex (OR 2.06, 95% CI 1.00-4.23; p = 0.049), prior ICH (OR 2.87, 95% CI 1.08-7.65; p = 0.035), high baseline National Institute of Health Stroke Scale score (OR 1.06, 95% CI 1.00-1.13; p = 0.044), and high mean systolic BP over the first 24 h post-randomization (OR 1.34, 95% CI 1.07-1.68/10 mm Hg increase; p = 0.011) were independently associated with cognitive impairment. CONCLUSIONS: One third of patients have significant cognitive impairment early after ICH, which is more frequent in the elderly, females, those with prior ICH, and more severe initial neurological deficit and with persistently high early systolic BP. 2018-01-16T15:58:10Z Low-Dose vs Standard-Dose Alteplase for Patients With Acute Ischemic Stroke: Secondary Analysis of the ENCHANTED Randomized Clinical Trial. http://hdl.handle.net/2381/40892 Title: Low-Dose vs Standard-Dose Alteplase for Patients With Acute Ischemic Stroke: Secondary Analysis of the ENCHANTED Randomized Clinical Trial. Authors: Wang, Xia; Robinson, Thompson G.; Lee, Tsong-Hai; Li, Qiang; Arima, Hisatomi; Bath, Philip M.; Billot, Laurent; Broderick, Joseph; Demchuk, Andrew M.; Donnan, Geoffrey; Kim, Jong S.; Lavados, Pablo; Lindley, Richard I.; Martins, Sheila O.; Olavarria, Veronica V.; Pandian, Jeyaraj D.; Parsons, Mark W.; Pontes-Neto, Octavio M.; Ricci, Stefano; Sharma, Vijay K.; Thang, Nguyen H.; Wang, Ji-Guang; Woodward, Mark; Anderson, Craig S.; Chalmers, John; Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) Investigators Abstract: Importance: A lower dose of intravenous alteplase appears to be a safer treatment option than the standard dose, reducing the risk of symptomatic intracerebral hemorrhage. There is uncertainty, however, over how this effect translates into an overall clinical benefit for patients with acute ischemic stroke (AIS). Objective: To assess whether older, Asian, or severely affected patients with AIS who are considered at high risk of thrombolysis may benefit more from low-dose rather than standard-dose alteplase treatment. Design, Setting, and Participants: This study is a prespecified secondary analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED), an international, randomized, open-label, blinded, end-point clinical trial of low-dose vs standard-dose intravenous alteplase for patients with AIS. From March 1, 2012, to August 31, 2015, a total of 3310 patients who had a clinical diagnosis of AIS as confirmed by brain imaging and who fulfilled the local criteria for thrombolysis treatment were included in the alteplase-dose arms. Patients were randomly assigned to receive low-dose (0.6 mg/kg; 15% as bolus and 85% as infusion over 1 hour) or standard-dose (0.9 mg/kg; 10% as bolus and 90% as infusion over 1 hour) alteplase. Of the 3310 randomized patients, 13 patients were excluded for missing consent, mistaken randomization, and duplicate randomization numbers. This secondary analysis was conducted between May 1, 2016, and April 28, 2017. Main Outcomes and Measures: The primary end point was a poor outcome defined by the combination of death and any disability as scored by the modified Rankin Scale (scores range from 2 to 6, with the highest score indicating death) at 90 days. Results: Of the 3297 patients included in the analysis, 1248 (37.9%) were women, and the mean (SD) age was 67 (13) years. No significant differences in the treatment effects were observed between low- and standard-dose alteplase for poor outcomes (death or disability) by age, ethnicity, or severity (all P > .37 for interaction). Similarly, the treatment effects of low- vs standard-dose alteplase on function outcome (ordinal shift of the modified Rankin Scale) in Asians (odds ratio, 1.05; 95% CI, 0.90-1.22) was consistent with non-Asians (odds ratio, 0.93; 95% CI, 0.76-1.14) (P = .32 for interaction). There were generally consistent reductions in rates of symptomatic intracerebral hemorrhage with low-dose alteplase, although this reduction was not statistically significant by age, ethnicity, or severity. Conclusions and Relevance: This analysis found that the effects of low-dose alteplase were not clearly superior to the effects of standard-dose alteplase on death or disability in key demographic subgroups of patients with AIS. Further investigation is required to identify patients with AIS who may benefit from low-dose alteplase. Trial Registration: clinicaltrials.gov Identifier: NCT01422616. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-01-16T15:44:35Z 26 Protocol for the upcoming study: patient input monitoring of pain in the emergency room: novel electronic log (PIMPERNEL): a randomised controlled trial of an electronic pain score display in adults in the emergency department. http://hdl.handle.net/2381/40883 Title: 26 Protocol for the upcoming study: patient input monitoring of pain in the emergency room: novel electronic log (PIMPERNEL): a randomised controlled trial of an electronic pain score display in adults in the emergency department. Authors: Thornton, Hilary; Coats, Timothy Abstract: BACKGROUND: Patient surveys and research have shown that Emergency Department attendees do not receive adequate analgesia. Pain monitoring has not been automated and usually involves a member of staff asking the patient to rate their score with no continuous record, often no specific place to record it and no automated alarm system for scores outside accepted parameters. Few patients have regular monitoring of their pain and our own preliminary research showed that over one week only 58% of patients with moderate to severe pain had a second or subsequent score recorded. EQUIPMENT: A small pain monitoring display has been developed at the University of Leicester and acts as an electronic version of the 11 point numerical rating scale. Data are transmitted to a tablet through a wireless connexion. PIMPERNEL (Patient Input Monitoring of Pain in the Emergency Room: Novel Electronic Log) is a feasibility study testing this for the first time. OBJECTIVES: The primary objective is to determine the feasibility of studying the effect of an electronic pain monitoring display on the pain experienced by emergency care patients. Secondary objectives include determining whether patients use the display, whether pain ratings correlate with routine records, how pain changes over time, whether patients use the display for reasons other than pain, which potential stratification factors may be useful for a subsequent multi-centre study and whether analgesia prescription changes. We will also obtain patient and staff feedback. INCLUSION CRITERIA: Adults, initial pain score 5 or more, likely to be staying for at least 2 hours, able to consent and understand English. STUDY PROCEDURE: We aim to recruit 200 patients (100 per arm) from the emergency department at Leicester Royal Infirmary. All patients will use the display. This is a parallel group, two arm superiority trial with a 1:1 allocation ratio. Patients will be randomised to have their pain score on display (intervention) or hidden (control). Blinding is not possible. The display beeps every 15 min to remind patients to enter their pain score. Treatment will not be constrained by study protocol and will depend on the judgment of the treating clinician. The study will continue for up to 6 hours to allow time for the first dose of analgesia to wear off. Data collection will cease when the patient leaves the department. Questionnaires will be given to participants and the staff nursing them. 2018-01-15T17:36:17Z Phase- and Frequency- Domain Analysis of the Intracardiac Signals of Persistent Atrial Fibrillation in Humans http://hdl.handle.net/2381/40859 Title: Phase- and Frequency- Domain Analysis of the Intracardiac Signals of Persistent Atrial Fibrillation in Humans Authors: Dastagir Sakwan, Nawshin Abstract: Identification of critical areas for successful ablation in persistent atrial fibrillation (persAF) patients remains a challenge. Atrial electrograms (AEGs) with high dominant frequency (HDF) are believed to represent atrial substrates with periodic activation responsible for maintaining persAF. Phase is a descriptor that tracks the progression of the action potential through atria and has been demonstrated to be effective in analysing spatiotemporal changes during persAF. DF has been used as a way to express local atrial activation rate of the AEGs during AF. HDF sites were analysed consecutively to produce HDF density maps and its spatiotemporal behaviour during persAF was investigated. An algorithm based on topological charge index was also implemented to obtain phase singularity points (PSs). This algorithm's performance was compared with two other PS detection techniques for detecting PSs and has been demonstrated to have more accurate results with reduced processing time (near-real time) to calculate targets. Additionally, the effect of varying filter type and settings on the detection of PSs was also studied, From this it is understood that filter settings could affect PS detections, which result in misleading identification of the atrial substrate and hence ablation targets. Furthermore, the spatiotemporal dynamics of the PSs was also investigated by tracking them in space and time to identify 'rotors'. Rotors were not seen very often and were associated with higher atrial rate as well as disorganised AEGs. Finally, the combination of frequency and phase analysis was studied to elucidate the mechanism of wave propagation and to identify potential drivers perpetuating persAF. There is some evidence of a cause-effect relationship between the HDF and PS density maps which leads to the spatiotemporal organization in the activation patterns during sustained A. Consequently, analysing the behaviour of the two parameters can help clinicians to develop strategies for ablation. 2018-01-15T12:15:39Z Proteomic diversity of high-density lipoprotein explains its association with clinical outcome in patients with heart failure. http://hdl.handle.net/2381/40855 Title: Proteomic diversity of high-density lipoprotein explains its association with clinical outcome in patients with heart failure. Authors: Emmens, Johanna Elisabeth; Jones, Donald J. L.; Cao, Thong H.; Chan, Daniel C. S.; Romaine, Simon P. R.; Quinn, Paulene A.; Anker, Stefan D.; Cleland, John G.; Dickstein, Kenneth; Filippatos, Gerasimos; Hillege, Hans L.; Lang, Chim C.; Ponikowski, Piotr; Samani, Nilesh J.; van Veldhuisen, Dirk J.; Zannad, Faiz; Zwinderman, Aeilko H.; Metra, Marco; de Boer, Rudolf A.; Voors, Adrian A.; Ng, Leong L. Abstract: AIMS: Previously, low high-density lipoprotein (HDL) cholesterol was found to be one of the strongest predictors of mortality and/or heart failure (HF) hospitalisation in patients with HF. We therefore performed in-depth investigation of the multifunctional HDL proteome to reveal underlying pathophysiological mechanisms explaining the association between HDL and clinical outcome. METHODS AND RESULTS: We selected a cohort of 90 HF patients with 1:1 cardiovascular death/survivor ratio from BIOSTAT-CHF. A novel optimised protocol for selective enrichment of lipoproteins was used to prepare plasma. Enriched lipoprotein content of samples was analysed using high resolution nanoscale liquid chromatography-mass spectrometry-based proteomics, utilising a label free approach. Within the HDL proteome, 49 proteins significantly differed between deaths and survivors. An optimised model of 12 proteins predicted death with 76% accuracy (Nagelkerke R2 =0.37, P < 0.001). The strongest contributors to this model were filamin-A (related to crosslinking of actin filaments) [odds ratio (OR) 0.31, 95% confidence interval (CI) 0.15-0.61, P = 0.001] and pulmonary surfactant-associated protein B (related to alveolar capillary membrane function) (OR 2.50, 95% CI 1.57-3.98, P < 0.001). The model predicted mortality with an area under the curve of 0.82 (95% CI 0.77-0.87, P < 0.001). Internal cross validation resulted in 73.3 ± 7.2% accuracy. CONCLUSION: This study shows marked differences in composition of the HDL proteome between HF survivors and deaths. The strongest differences were seen in proteins reflecting crosslinking of actin filaments and alveolar capillary membrane function, posing potential pathophysiological mechanisms underlying the association between HDL and clinical outcome in HF. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-01-11T16:13:01Z Latest developments in clinical stroke care http://hdl.handle.net/2381/40832 Title: Latest developments in clinical stroke care Authors: Minhas, JS; Robinson, TG Abstract: Stroke medicine has seen rapid developments in diagnosis and management, and consequently improved prognosis. Management of ischaemic stroke, in particular, has benefited from these advances. The approach to management has evolved from one of historical passivity to active intervention with time of the essence following stroke onset. The last decade has seen the comparative effectiveness of several pharmacological agents being tested, creating significant randomised controlled trial evidence to support the management of common clinical problems following acute stroke. While several of these interventions are widely available, some remain less accessible. This review will discuss the latest developments in clinical stroke medicine, based on a symposium presentation at the Royal College of Physicians of Edinburgh, and reference key randomised controlled trial evidence in an effort to provide a balanced perspective on our current understanding of acute ischaemic and haemorrhagic stroke. 2018-01-11T10:48:03Z Editorial on "Characteristics of extension and de novo recurrent spontaneous coronary artery dissection". http://hdl.handle.net/2381/40781 Title: Editorial on "Characteristics of extension and de novo recurrent spontaneous coronary artery dissection". Authors: Adlam, David; Wood, Alice; Al-Hussaini, Abtehale Description: The file associated with this record is under a permanent embargo in accordance with the publisher's policy. The full text may be available through the publisher links provided above. 2018-01-09T14:29:53Z Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis. http://hdl.handle.net/2381/40714 Title: Genetic Association of Lipids and Lipid Drug Targets With Abdominal Aortic Aneurysm: A Meta-analysis. Authors: Harrison, Seamus C.; Holmes, Michael V.; Burgess, Stephen; Asselbergs, Folkert W.; Jones, Gregory T.; Baas, Annette F.; van 't Hof, F. N.; de Bakker, Paul I. W.; Blankensteijn, Jan D.; Powell, Janet T.; Saratzis, Athanasios; de Borst, Gert J.; Swerdlow, Daniel I.; van der Graaf, Yolanda; van Rij, Andre M.; Carey, David J.; Elmore, James R.; Tromp, Gerard; Kuivaniemi, Helena; Sayers, Robert D.; Samani, Nilesh J.; Bown, Matthew J.; Humphries, Steve E. Abstract: Importance: Risk factors for abdominal aortic aneurysm (AAA) are largely unknown, which has hampered the development of nonsurgical treatments to alter the natural history of disease. Objective: To investigate the association between lipid-associated single-nucleotide polymorphisms (SNPs) and AAA risk. Design, Setting, and Participants: Genetic risk scores, composed of lipid trait-associated SNPs, were constructed and tested for their association with AAA using conventional (inverse-variance weighted) mendelian randomization (MR) and data from international AAA genome-wide association studies. Sensitivity analyses to account for potential genetic pleiotropy included MR-Egger and weighted median MR, and multivariable MR method was used to test the independent association of lipids with AAA risk. The association between AAA and SNPs in loci that can act as proxies for drug targets was also assessed. Data collection took place between January 9, 2015, and January 4, 2016. Data analysis was conducted between January 4, 2015, and December 31, 2016. Exposures: Genetic elevation of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Main Outcomes and Measures: The association between genetic risk scores of lipid-associated SNPs and AAA risk, as well as the association between SNPs in lipid drug targets (HMGCR, CETP, and PCSK9) and AAA risk. Results: Up to 4914 cases and 48 002 controls were included in our analysis. A 1-SD genetic elevation of LDL-C was associated with increased AAA risk (odds ratio [OR], 1.66; 95% CI, 1.41-1.96; P = 1.1 × 10-9). For HDL-C, a 1-SD increase was associated with reduced AAA risk (OR, 0.67; 95% CI, 0.55-0.82; P = 8.3 × 10-5), whereas a 1-SD increase in triglycerides was associated with increased AAA risk (OR, 1.69; 95% CI, 1.38-2.07; P = 5.2 × 10-7). In multivariable MR analysis and both MR-Egger and weighted median MR methods, the association of each lipid fraction with AAA risk remained largely unchanged. The LDL-C-reducing allele of rs12916 in HMGCR was associated with AAA risk (OR, 0.93; 95% CI, 0.89-0.98; P = .009). The HDL-C-raising allele of rs3764261 in CETP was associated with lower AAA risk (OR, 0.89; 95% CI, 0.85-0.94; P = 3.7 × 10-7). Finally, the LDL-C-lowering allele of rs11206510 in PCSK9 was weakly associated with a lower AAA risk (OR, 0.94; 95% CI, 0.88-1.00; P = .04), but a second independent LDL-C-lowering variant in PCSK9 (rs2479409) was not associated with AAA risk (OR, 0.97; 95% CI, 0.84-1.02; P = .28). Conclusions and Relevance: The MR analyses in this study lend support to the hypothesis that lipids play an important role in the etiology of AAA. Analyses of individual genetic variants used as proxies for drug targets support LDL-C lowering as a potential effective treatment strategy for preventing and managing AAA. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2018-01-04T13:55:09Z Personalising approaches to reducing sedentary behaviour in the promotion of metabolic health: extending the evidence base http://hdl.handle.net/2381/40695 Title: Personalising approaches to reducing sedentary behaviour in the promotion of metabolic health: extending the evidence base Authors: McCarthy, Matthew Abstract: Background: Sedentary behaviour has emerged as an independent risk factor for unfavourable metabolic health outcomes, including Type 2 Diabetes Mellitus (T2DM). Through an acute experimental setting, it has recently been demonstrated that breaking up sitting time through short, regular light physical activity breaks (in the form of standing, walking and resistance exercise) can be an effective way to reduce postprandial glycaemia. In order to embark on a personalised approach to reducing sedentary behaviour, more information is required about how other health behaviours interact with it, and whether alternative modes of activity breaks can instigate glycaemic improvements. It is also apparent that little is known about the chronic glycaemic impacts of reducing sedentary time when accounting for other health behaviours, this warrants further exploration. Aims: 1. Design and conduct an experimental trial establishing the modifying impact of cardio‐respiratory fitness (CRF) on glycaemic responses to prolonged sitting and light activity breaks. 2. Design and conduct an experimental trial establishing whether breaking up sedentary time with activity breaks, while remaining in a seated posture, is an effective way to attenuate postprandial glycaemia in those at high risk. 3. Prospectively determine whether reductions in sedentary time are associated with long‐term glycaemic benefit in those at high risk when accounting for other health behaviours such as weight management and exercise. Key Findings: 1. Individuals with low CRF had worse glycaemic responses during prolonged sitting and gained the most metabolic benefit from light activity breaks. 2. Performing regular, short bouts of upper body activity during prolonged sitting effectively reduced postprandial glycaemia despite maintaining a seated posture. 3. Change in sedentary time was not significantly associated with change in HbA1c after adjustment for change in MVPA time. Conclusions: Efforts to tackle sedentary behaviour in the promotion of metabolic health may be optimised by tailoring to an individual's CRF level. This and the notion that sitting per se may not be responsible for the metabolic downfalls of sedentary behaviour demonstrates potential for personalisation of strategies in those with contraindication to weight bearing activity. Future research directly extending acute trials through longer term interventions are necessary to truly elucidate whether glycaemic adaptations, such as a change in HbA1c, are evident from reductions in sedentary time over a prolonged period. 2017-12-20T13:48:10Z Development and validation of multivariable models to predict mortality and hospitalization in patients with heart failure. http://hdl.handle.net/2381/40671 Title: Development and validation of multivariable models to predict mortality and hospitalization in patients with heart failure. Authors: Voors, Adriaan A.; Ouwerkerk, Wouter; Zannad, Faiez; van Veldhuisen, Dirk J.; Samani, Nilesh J.; Ponikowski, Piotr; Ng, Leong L.; Metra, Marco; Ter Maaten, Jozine M.; Lang, Chim C.; Hillege, Hans L.; van der Harst, Pim; Filippatos, Gerasimos; Dickstein, Kenneth; Cleland, John G.; Anker, Stefan D.; Zwinderman, Aeilko H. Abstract: INTRODUCTION: From a prospective multicentre multicountry clinical trial, we developed and validated risk models to predict prospective all-cause mortality and hospitalizations because of heart failure (HF) in patients with HF. METHODS AND RESULTS: BIOSTAT-CHF is a research programme designed to develop and externally validate risk models to predict all-cause mortality and HF hospitalizations. The index cohort consisted of 2516 patients with HF from 69 centres in 11 European countries. The external validation cohort consisted of 1738 comparable patients from six centres in Scotland, UK. Patients from the index cohort had a mean age of 69 years, 27% were female, 83% were in New York Heart Association (NYHA) class II-III and the mean left ventricular ejection fraction (LVEF) was 31%. The full prediction models for mortality, hospitalization owing to HF, and the combined outcome, yielded c-statistic values of 0.73, 0.69, and 0.71, respectively. Predictors of mortality and hospitalization owing to HF were remarkably different. The five strongest predictors of mortality were more advanced age, higher blood urea nitrogen and N-terminal pro-B-type natriuretic peptide, lower haemoglobin, and failure to prescribe a beta-blocker. The five strongest predictors of hospitalization owing to HF were more advanced age, previous hospitalization owing to HF, presence of oedema, lower systolic blood pressure and lower estimated glomerular filtration rate. Patients from the validation cohort were aged 74 years, 34% were female, 85% were in NYHA class II-III, and mean LVEF was 41%; c-statistic values for the full and compact model were comparable to the index cohort. CONCLUSION: A small number of variables, which are usually readily available in the routine clinical setting, provide useful prognostic information for patients with HF. Predictors of mortality were remarkably different from predictors of hospitalization owing to HF. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2017-12-08T16:15:13Z Coronary angiography in worsening heart failure: determinants, findings and prognostic implications. http://hdl.handle.net/2381/40670 Title: Coronary angiography in worsening heart failure: determinants, findings and prognostic implications. Authors: Ferreira, João Pedro; Rossignol, Patrick; Demissei, Biniyam; Sharma, Abhinav; Girerd, Nicolas; Anker, Stefan D.; Cleland, John G.; Dickstein, Kenneth; Filippatos, Gerasimos; Hillege, Hans L.; Lang, Chim C.; Metra, Marco; Ng, Leong L.; Ponikowski, Piotr; Samani, Nilesh J.; van Veldhuisen, Dirk J.; Zwinderman, Aeilko H.; Voors, Adriaan; Zannad, Faiez Abstract: OBJECTIVES: Coronary angiography is regularly performed in patients with worsening signs and/or symptoms of heart failure (HF). However, little is known on the determinants, findings and associated clinical outcomes of coronary angiography performed in patients with worsening HF. METHODS: The BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) programme enrolled 2516 patients with worsening symptoms and/or signs of HF, either hospitalised or in the outpatient setting. All patients were included in the present analysis. RESULTS: Of the 2516 patients included, 315 (12.5%) underwent coronary angiography within the 30 days after the onset of worsening symptoms and/or signs of HF. Subjects who underwent angiography were more often observed as inpatients, had more often an overt acute coronary syndrome, had higher troponin I levels, were younger and had better renal function (all p≤0.01). Patients who underwent coronary angiography had a lower risk of the primary outcome of death and/or HF hospitalisation (adjusted HR=0.71, 95% CI 0.57 to 0.89, p=0.003) and death (adjusted HR=0.59, 95% CI 0.43 to 0.80, p=0.001). Among the patients who underwent coronary angiography, those with a coronary stenosis (39%) had a worse prognosis than those without stenosis (adjusted HR for the primary outcome=1.71, 95% CI 1.10 to 2.64, p=0.016). CONCLUSIONS: Coronary angiography was performed in <13% of patients with symptoms and/or signs of worsening HF. These patients were remarkably different from those who did not undergo coronary angiography and had a lower risk of subsequent events. The presence of coronary stenosis on coronary angiography was associated with a worse prognosis. 2017-12-08T15:52:36Z Regulation of cardiometabolic risk factors by dietary Toll-like receptor stimulants http://hdl.handle.net/2381/40629 Title: Regulation of cardiometabolic risk factors by dietary Toll-like receptor stimulants Authors: Faraj, Tola Abdulsattar Abstract: Atherosclerosis is a chronic inflammatory disease of the arteries, although the causative agents for inducing inflammatory processes related to atherosclerosis remain unclear. Dietary patterns may play a role in the commencement of inflammation, which may contribute to the progression of the disease. This PhD project aimed to investigate potential mechanisms by which processed foods may induce inflammatory responses (in vitro, ex vivo and in vivo) and may increase cardiometabolic risk factors, with an emphasis on the potential roles of Toll-like receptor (TLR)-2 and TLR4 signaling. The present findings establish that TLR2 and TLR4 stimulants present in food are critical mediators of the capacity of food extracts to induce inflammatory signaling in human primary monocytes. Also, chronic dietary PAMP intake in healthy volunteers revealed that a low PAMP diet decreases cardiometabolic markers (leukocyte count, body weight, abdominal circumference, LDL-C level, thrombocyte counts and plasma leptin concentrations) significantly and these effects are rapidly reversed by a high PAMP diet. In addition, murine studies suggested that Kupffer cells, rather than hepatocytes, are the main sensors of dietary TLR2- and TLR4-stimulants, and that IL-1β signaling plays a key role in the expression of the APR and metabolic phenotypes induced by ingested lipopolysaccharide (LPS) in mice. Moreover, food additives may have an adverse role in changing gut barrier function which may results in the increased translocation of dietary TLR-stimulants into the circulation. In conclusion, these findings suggest that dietary TLR2- and TLR4-stimulants may be considered as a new possible risk factor for coronary artery disease. For the prevention of atherosclerosis, novel therapies could be developed to target the mechanisms of cross-talk between the TLR2/4 receptors, inflammatory responses and lipid regulatory pathways recognised by the current project. 2017-11-28T12:35:53Z Large-Scale Analysis of Determinants, Stability, and Heritability of High-Density Lipoprotein Cholesterol Efflux Capacity. http://hdl.handle.net/2381/40610 Title: Large-Scale Analysis of Determinants, Stability, and Heritability of High-Density Lipoprotein Cholesterol Efflux Capacity. Authors: Koekemoer, Andrea L.; Codd, Veryan; Masca, Nicholas G. D.; Nelson, Christopher P.; Musameh, Muntaser D.; Kaess, Bernhard M.; Hengstenberg, Christian; Rader, Daniel J.; Samani, Nilesh J. Abstract: OBJECTIVE: Cholesterol efflux capacity (CEC) has emerged as a biomarker of coronary artery disease risk beyond plasma high-density lipoprotein (HDL) cholesterol (HDL-C) level. However, the determinants of CEC are incompletely characterized. We undertook a large-scale family-based population study to identify clinical, biochemical, and HDL particle parameter determinants of CEC, characterize reasons for the discordancy with HDL-C, quantify its heritability, and assess its stability over 10 to 12 years. APPROACHES AND RESULTS: CEC was quantified in 1988 individuals from the GRAPHIC (Genetic Regulation of Arterial Pressure of Humans in the Community) cohort, comprising individuals from 2 generations from 520 white nuclear families. Serum lipid and lipoprotein levels were determined by ultracentrifugation or nuclear magnetic resonance and HDL particle size and number quantified by nuclear magnetic resonance. Ninety unrelated individuals had repeat CEC measurements in samples collected after 10 to 12 years. CEC was positively correlated with HDL-C (R=0.62; P<0.0001). Among clinical and biochemical parameters, age, systolic blood pressure, alcohol consumption, serum albumin, triglycerides, phospholipids, and lipoprotein(a) were independently associated with CEC. Among HDL particle parameters, HDL particle number, particle size, and apolipoprotein A-II level were independently associated with CEC. Serum triglyceride level partially explained discordancy between CEC and HDL-C. CEC measurements in samples collected 10 to 12 years apart were strongly correlated (r=0.73; P<0.0001). Heritability of CEC was 0.31 (P=3.89×10(-14)) without adjustment for HDL-C and 0.13 (P=1.44×10(-3)) with adjustment. CONCLUSIONS: CEC is a stable trait over time, is influenced by specific clinical, serum, and HDL particle parameters factors beyond HDL-C, can be maintained in persons with a low plasma HDL-C by elevated serum triglyceride level, and is modestly independently heritable. Description: An online visual overview is available for this article. The online-only Data Supplement is available with this article at http://atvb.ahajournals.org/lookup/suppl/doi:10.1161/ATVBAHA.117.309201/-/DC1. 2017-11-27T15:11:05Z Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells. http://hdl.handle.net/2381/40603 Title: Sildenafil attenuates hypoxic pulmonary remodelling by inhibiting bone marrow progenitor cells. Authors: Favre, Shirley; Gambini, Elisa; Nigro, Patrizia; Scopece, Alessandro; Bianciardi, Paola; Caretti, Anna; Pompilio, Giulio; Corno, Antonio F.; Vassalli, Giuseppe; von Segesser, Ludwig K.; Samaja, Michele; Milano, Giuseppina Abstract: The recruitment of bone marrow (BM)-derived progenitor cells to the lung is related to pulmonary remodelling and the pathogenesis of pulmonary hypertension (PH). Although sildenafil is a known target in PH treatment, the underlying molecular mechanism is still elusive. To test the hypothesis that the therapeutic effect of sildenafil is linked to the reduced recruitment of BM-derived progenitor cells, we induced pulmonary remodelling in rats by two-week exposure to chronic hypoxia (CH, 10% oxygen), a trigger of BM-derived progenitor cells. Rats were treated with either placebo (saline) or sildenafil (1.4 mg/kg/day ip) during CH. Control rats were kept in room air (21% oxygen) with no treatment. As expected, sildenafil attenuated the CH-induced increase in right ventricular systolic pressure and right ventricular hypertrophy. However, sildenafil suppressed the CH-induced increase in c-kit(+) cells in the adventitia of pulmonary arteries. Moreover, sildenafil reduced the number of c-kit(+) cells that colocalize with tyrosine kinase receptor 2 (VEGF-R2) and CD68 (a marker for macrophages), indicating a positive effect on moderating hypoxia-induced smooth muscle cell proliferation and inflammation without affecting the pulmonary levels of hypoxia-inducible factor (HIF)-1α. Furthermore, sildenafil depressed the number of CXCR4(+) cells. Collectively, these findings indicate that the improvement in pulmonary haemodynamic by sildenafil is linked to decreased recruitment of BM-derived c-kit(+) cells in the pulmonary tissue. The attenuation of the recruitment of BM-derived c-kit(+) cells by sildenafil may provide novel therapeutic insights into the control of pulmonary remodelling. Description: Additional Supporting Information may be found online in thesupporting information tab for this article:Figure S1Representative histogram plot for c-kit marker in wholeblood measured by FACS (left panel); right panel indicates the quan-tification of circulating c-kit+cells. Same details as in the manuscript.Figure S2FACS analysis for CXCR4 marker in WB cells: leftpanel shows a representative histogram plot, the right panelindicates the quantification of circulating CXCR4+cells. Samedetails as in the manuscript. 2017-11-27T12:15:25Z The cerebro-cardiovascular response to periodic squat-stand maneuvers in healthy subjects: a time-domain analysis. http://hdl.handle.net/2381/40601 Title: The cerebro-cardiovascular response to periodic squat-stand maneuvers in healthy subjects: a time-domain analysis. Authors: Barnes, Sam C.; Ball, Naomi; Haunton, Victoria Joanna; Robinson, Thompson G.; Panerai, Ronney B. Abstract: BACKGROUND: Squat-stand maneuvers (SSMs) have been used to improve the coherence of transfer function analysis (TFA) estimates during the assessment of dynamic cerebral autoregulation (dCA). There is a need to understand the influence of peripheral changes resulting from SSMs on cerebral blood flow, which might confound estimates of dCA. METHODS: 29 healthy subjects underwent recordings at rest (5 min standing) and 15 SSMs (0.05Hz). Heart rate (3-lead ECG), end-tidal CO2 (capnography), blood pressure (Finometer), cerebral blood velocity (CBV, transcranial Doppler, MCA) and the angle of the thigh (tilt sensor) were measured continuously. The response of CBV to SSMs was decomposed into the relative contributions of mean arterial pressure (MAP), resistance area product (RAP) and critical closing pressure (CrCP). RESULTS: Upon squatting, a rise in MAP (83.6 ± 21.1 % contribution) is followed by increased CBV. A dCA response can be detected, determined by adjustments in RAP and CrCP (left hemisphere) with peak contributions of 24.8 ± 12.7 % and 27.4 ± 22.8 %, respectively, at different times during SSMs. No interhemispheric differences were detected. During standing, the contributions of MAP, RAP and CrCP change considerably. CONCLUSIONS: The changes of CBV subcomponents during repeated SSMs indicate a complex response of CBVms. to SSMs that can only be partially explained by myogenic mechanis More work is needed to clarify the potential contribution of other co-factors, such as breath-to-breath changes in pCO2, HR, stroke volume and the neurogenic component of dynamic CA. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2017-11-24T15:28:28Z The biological impact of blood pressure associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle. http://hdl.handle.net/2381/40599 Title: The biological impact of blood pressure associated genetic variants in the natriuretic peptide receptor C gene on human vascular smooth muscle. Authors: Ren, Meixia; Ng, Fu Liang; Warren, Helen R.; Witkowska, Kate; Baron, Michael; Jia, Zhilong; Cabrera, Claudia; Zhang, Ruoxin; Mifsud, Borbala; Munroe, Patricia B.; Xiao, Qingzhong; Townsend-Nicholson, Andrea; Hobbs, Adrian J.; Ye, Shu; Caulfield, Mark J. Abstract: Elevated blood pressure (BP) is a major global risk factor for cardiovascular disease. Genome-wide association studies have identified several genetic variants at the NPR3 locus associated with BP, but the functional impact of these variants remains to be determined. Here we confirmed, by a genome-wide association study within UK Biobank, the existence of two independent BP-related signals within NPR3 locus. Using human primary vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) from different individuals, we found that the BP-elevating alleles within one linkage disequilibrium block identified by the sentinel variant rs1173771 was associated with lower endogenous NPR3 mRNA and protein levels in VSMCs, together with reduced levels in open chromatin and nuclear protein binding. The BP-elevating alleles also increased VSMC proliferation, angiotensin II-induced calcium flux and cell contraction. However, an analogous genotype-dependent association was not observed in vascular ECs. Our study identifies novel, putative mechanisms for BP-associated variants at the NPR3 locus to elevate BP, further strengthening the case for targeting NPR-C as a therapeutic approach for hypertension and cardiovascular disease prevention. Description: Supplementary Material is available at HMG online. https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddx375#supplementary-data 2017-11-24T15:06:00Z Withdrawal of active treatment after intracerebral haemorrhage in the INTERACT2 study http://hdl.handle.net/2381/40581 Title: Withdrawal of active treatment after intracerebral haemorrhage in the INTERACT2 study Authors: Muñoz Venturelli, Paula; Wang, Xia; Zahuranec, Darin B.; Lavados, Pablo M.; Stapf, Christian; Lindley, Richard; Delcourt, Candice; Chalmers, John; Anderson, Craig S.; Robinson, Thompson G.; Robinson, Thompson G.; INTERACT2 Investigators Abstract: Background: in the second Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2), a minority of patients received withdrawal of active treatment (WAT). We wished to determine the characteristics of these patients, and the relation of this decision-making to subsequent management and final outcome. Methods: the INTERACT2 cohort of acute intracerebral haemorrhage (ICH) patients had a decision of WAT within 7 days after hospital admission recorded. Multivariable logistic regression was used to identify the determinants of WAT and poor outcome at 90 days, defined by modified Rankin scale (mRS) scores 3-6. Results: of 2,779 participants with available data, WAT occurred in 121 (4%) and this was significantly associated with increasing age, greater neurological severity, larger haematoma volume, intraventricular extension and randomisation to intensive BP lowering. Compared to other patients, those with WAT had greater mortality (81/121 [67%] versus 205/2624 [8%]; P < 0.001) and survivors were more likely to be severely disabled (mRS score 4-5, 19/39 [49%] versus 695/2419 [29%]; P = 0.006). Conclusions: WAT was undertaken in patients with recognised predictors of poor prognosis, who subsequently were more likely to die or be left with severe disability. Improved understanding of specific factors determining WAT in ICH patients might improve care delivery and outcomes. Clinical Trial Registration: the INTERACT2 study is registered with ClinicalTrials.gov (NCT00716079). 2017-11-23T10:33:28Z What influences healthcare professionals' treatment preferences for older women with operable breast cancer? An application of the discrete choice experiment http://hdl.handle.net/2381/40580 Title: What influences healthcare professionals' treatment preferences for older women with operable breast cancer? An application of the discrete choice experiment Authors: Morgan, J. L.; Walters, S. J.; Collins, K.; Robinson, Thompson G.; Cheung, K.-L.; Audisio, R.; Reed, M. W.; Wyld, L. Abstract: INTRODUCTION: Primary endocrine therapy (PET) is used variably in the UK as an alternative to surgery for older women with operable breast cancer. Guidelines state that only patients with "significant comorbidity" or "reduced life expectancy" should be treated this way and age should not be a factor. METHODS: A Discrete Choice Experiment (DCE) was used to determine the impact of key variables (patient age, comorbidity, cognition, functional status, cancer stage, cancer biology) on healthcare professionals' (HCP) treatment preferences for operable breast cancer among older women. Multinomial logistic regression was used to identify associations. RESULTS: 40% (258/641) of questionnaires were returned. Five variables (age, co-morbidity, cognition, functional status and cancer size) independently demonstrated a significant association with treatment preference (p < 0.05). Functional status was omitted from the multivariable model due to collinearity, with all other variables correlating with a preference for operative treatment over no preference (p < 0.05). Only co-morbidity, cognition and cancer size correlated with a preference for PET over no preference (p < 0.05). CONCLUSION: The majority of respondents selected treatment in accordance with current guidelines, however in some scenarios, opinion was divided, and age did appear to be an independent factor that HCPs considered when making a treatment decision in this population. 2017-11-23T10:11:32Z Regional variation in acute stroke care organisation http://hdl.handle.net/2381/40577 Title: Regional variation in acute stroke care organisation Authors: Muñoz Venturelli, P; Robinson, Thompson; Lavados, PM; Olavarría, VV; Arima, H; Billot, L; Hackett, ML; Lim, JY; Middleton, S; Pontes-Neto, O; Peng, B; Cui, L; Song, L; Mead, G; Watkins, C; Lin, R-T; Lee, T-H; Pandian, J; de Silva, HA; Anderson, CS; HeadPoST Investigators Abstract: BACKGROUND: Few studies have assessed regional variation in the organisation of stroke services, particularly health care resourcing, presence of protocols and discharge planning. Our aim was to compare stroke care organisation within middle- (MIC) and high-income country (HIC) hospitals participating in the Head Position in Stroke Trial (HeadPoST). METHODS: HeadPoST is an on-going international multicenter crossover cluster-randomized trial of 'sitting-up' versus 'lying-flat' head positioning in acute stroke. As part of the start-up phase, one stroke care organisation questionnaire was completed at each hospital. The World Bank gross national income per capita criteria were used for classification. RESULTS: 94 hospitals from 9 countries completed the questionnaire, 51 corresponding to MIC and 43 to HIC. Most participating hospitals had a dedicated stroke care unit/ward, with access to diagnostic services and expert stroke physicians, and offering intravenous thrombolysis. There was no difference for the presence of a dedicated multidisciplinary stroke team, although greater access to a broad spectrum of rehabilitation therapists in HIC compared to MIC hospitals was observed. Significantly more patients arrived within a 4-h window of symptoms onset in HIC hospitals (41 vs. 13%; P<0.001), and a significantly higher proportion of acute ischemic stroke patients received intravenous thrombolysis (10 vs. 5%; P=0.002) compared to MIC hospitals. CONCLUSIONS: Although all hospitals provided advanced care for people with stroke, differences were found in stroke care organisation and treatment. Future multilevel analyses aims to determine the influence of specific organisational factors on patient outcomes. 2017-11-22T10:27:01Z The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis. http://hdl.handle.net/2381/40574 Title: The PCSK9-LDL Receptor Axis and Outcomes in Heart Failure: BIOSTAT-CHF Subanalysis. Authors: Bayes-Genis, Antoni; Núñez, Julio; Zannad, Faiez; Ferreira, João Pedro; Anker, Stefan D.; Cleland, John G.; Dickstein, Kenneth; Filippatos, Gerasimos; Lang, Chim C.; Ng, Leong L.; Ponikowski, Piotr; Samani, Nilesh J.; van Veldhuisen, Dirk J.; Zwinderman, Aeilko H.; Metra, Marco; Lupón, Josep; Voors, Adriaan A. Abstract: BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds low-density lipoprotein receptor (LDLR), preventing its recycling. PCSK9 is a risk predictor and a biotarget in atherosclerosis progression. OBJECTIVES: The aim of this study was to determine whether the PCSK9-LDLR axis could predict risk in patients with heart failure (HF). METHODS: The BIOSTAT-CHF (Biology Study to Tailored Treatment in Chronic Heart Failure) is a multicenter, multinational, prospective, observational study that included patients with worsening HF signs and/or symptoms. The primary endpoints were all-cause mortality and the composite of mortality or unscheduled hospitalizations for HF. We implemented Cox proportional hazard regression to determine the simultaneously adjusted effect of PCSK9 and LDLR on both outcomes when added to the previously validated BIOSTAT-CHF risk scores. RESULTS: This study included 2,174 patients (mean age: 68 ± 12 years; 53.2% had a history of ischemic heart disease). Median (interquartile range) PCSK9 and LDLR levels were 1.81 U/ml (1.45 to 2.18) and 2.98 U/ml (2.45 to 3.53), respectively. During follow-up, 569 deaths (26.2%) and 896 (41.2%) composite endpoints were ascertained. A multivariable analysis, which included BIOSTAT-CHF risk scores, LDLR, and statin treatment as covariates, revealed a positive linear association between PCSK9 levels and the risk of mortality (hazard ratio [HR]: 1.24; 95% confidence interval [CI]: 1.04 to 1.49; p = 0.020) and the composite endpoint (HR: 1.21; 95% CI: 1.05 to 1.40; p = 0.010). A similar analysis for LDLR revealed a negative association with mortality (HR: 0.86; 95% CI: 0.76 to 0.98; p = 0.025) and the composite endpoint (HR: 0.92; 95% CI: 0.83 to 1.01; p = 0.087). Including PCSK9 and LDLR improved risk score performance. CONCLUSIONS: The PCSK9-LDLR axis was associated with outcomes in patients with HF. Future studies must assess whether PCSK9 inhibition will result in better outcomes in HF. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2017-11-21T15:46:16Z Proenkephalin in Heart Failure http://hdl.handle.net/2381/40573 Title: Proenkephalin in Heart Failure Authors: Siong Chan, Daniel Chu; Cao, Thong Huy; Ng, Leong Loke Abstract: The opioid system is activated in heart failure, which may be cardioprotective but may also be counter-regulatory. Recently, systemic proenkephalin activation has been investigated in various conditions predicting mortality and kidney injury. In acute heart failure, proenkephalin independently predicts mortality and heart failure rehospitalization in addition to traditional risk markers. It also predicts worsening renal function, increasingly recognized as an important risk predictor for poor outcome in heart failure. This article explores the role of enkephalins and delta-opioid receptors in the heart, then reviews studies measuring proenkephalin levels in the circulation and their associations with prognosis. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2017-11-21T15:26:32Z Effects of dominant and non-dominant passive arm manoeuvres on the neurovascular coupling response. http://hdl.handle.net/2381/40571 Title: Effects of dominant and non-dominant passive arm manoeuvres on the neurovascular coupling response. Authors: Llwyd, Osian; Panerai, Ronney B.; Robinson, Thompson G. Abstract: PURPOSE: Models designed to study neurovascular coupling (NVC) describe a possible cerebral hemisphere dominance dependent on task completed and preference in handedness. We investigated whether passive arm manoeuvre performed with dominant (Dom-Arm) or non-dominant arm (ND-Arm) stimulated haemodynamic differences in either contralateral (Cont-H) or ipsilateral (Ipsil-H) cerebral hemisphere. METHODS: Healthy individuals lying in supine position, had measurements of beat-to-beat blood pressure (BP, mmHg), electrocardiogram (HR, bpm), end-tidal CO2 (etCO2, mmHg), and bilateral insonation of the middle cerebral arteries (MCA, cm s(-1)). Arm movement was performed for 60 s with passive flexion and extension of the elbow (1 Hz), before manoeuvre was repeated on other arm. Data were normalised and effect of treatment was analysed for differences between manoeuvres and within each time period. RESULTS: Seventeen (eight males) healthy volunteers, aged 56 ± 7 years, were studied. Dom-Arm and ND-Arm manoeuvres stimulated a comparable temporal response in peripheral and cerebral haemodynamic parameters between Cont-H and Ipsil-H. CONCLUSIONS: Both manoeuvres can be used to evoke similar bilateral MCA responses in assessing NVC. This finding should lead to more efficient protocols when using passive arm movement for NVC studies in healthy subjects. Description: The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above. 2017-11-21T15:13:31Z Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack. http://hdl.handle.net/2381/40555 Title: Remote Assessment of Platelet Function in Patients with Acute Stroke or Transient Ischaemic Attack. Authors: Bath, Philip M.; May, Jane; Flaherty, Katie; Woodhouse, Lisa J.; Dovlatova, Natalia; Fox, Sue C.; England, Timothy J.; Krishnan, Kailash; Robinson, Thompson G.; Sprigg, Nikola; Heptinstall, Stan; TARDIS Investigators Abstract: BACKGROUND: The TARDIS trial assessed the safety and efficacy of intensive versus guideline antiplatelet agents given for one month in patients with acute stroke or TIA. The aim of this substudy was to assess the effect of antiplatelet agents taken at baseline on platelet function reactivity and activation. METHODS: Platelet function, assessed by remotely measured surface expression of P-selectin, was assessed in patients at their time of randomisation. Data are median fluorescence values. RESULTS: The aspirin P-selectin test demonstrated that platelet expression was lower in 494 patients taking aspirin than in 162 patients not: mean 210 (SD 188) versus 570 (435), difference 360.3 (95% CI 312.2-408.4) (2p < 0.001). Aspirin did not suppress P-selectin levels below 500 units in 23 (4.7%) patients. The clopidogrel test showed that platelet reactivity was lower in 97 patients taking clopidogrel than in 585 patients not: 655 (296) versus 969 (315), difference 314.5 (95% CI 247.3-381.7) (2p < 0.001). Clopidogrel did not suppress P-selectin level below 860 units in 24 (24.7%) patients. CONCLUSIONS: Aspirin and clopidogrel suppress stimulated platelet P-selectin, although one-quarter of patients on clopidogrel have high on-treatment platelet reactivity. Platelet function testing may be performed remotely in the context of a large multicentre trial. Trial registration ISRCTN47823388. 2017-11-17T15:02:58Z