Search

Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease.ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426.Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77).In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care.UK National Institute for Health and Care Research.

Supplemental Digital Content is available in the text., Background: SGLT2 (sodium-glucose cotransporter-2) inhibitors improve heart failure–associated outcomes in patients with type 2 diabetes. In patients with heart failure, SGLT2 inhibitors will likely be coprescribed with a loop diuretic, but this combined effect is not well-defined. Our aim was to assess the diuretic and natriuretic effect of empagliflozin in combination with loop diuretics. Methods: The RECEDE-CHF trial (SGLT2 Inhibition in Combination With Diuretics in Heart Failure) was a randomized, double-blind, placebo-controlled, crossover trial of patients with type 2 diabetes and heart failure with reduced ejection fraction taking regular loop diuretic who were randomized to empagliflozin 25 mg once daily or placebo for 6 weeks with a 2-week washout period. The primary outcome was change in 24-hour urinary volume from baseline to week 6. Results: Twenty-three participants (mean age, 69.8 years; 73.9% male; mean furosemide dose, 49.6±31.3 mg/d; mean HbA1c, 7.9±3.8%) were recruited. Compared with placebo, empagliflozin caused a significant increase in 24-hour urinary volume at both day 3 (mean difference, 535 mL [95% CI, 133–936]; P=0.005) and week 6 (mean difference, 545 mL [95% CI, 136–954]; P=0.005) after adjustment for treatment order, baseline 24-hour urine volume, and percentage change in loop diuretic dose. At 6 weeks, empagliflozin did not cause a significant change in 24-hour urinary sodium (mean difference, −7.85 mmol/L [95% CI, −2.43 to 6.73]; P=0.57). Empagliflozin caused a nonsignificant increase in fractional excretion of sodium at day 3, which was absent at week 6 (mean difference day 3, 0.30% [95% CI, −0.03 to 0.63]; P=0.09; week 6, 0.11% [95% CI, −0.22 to 0.44]; P>0.99), and a significant increase in electrolyte-free water clearance at week 6 (mean difference, 312 mL [95% CI, 26–598]; P=0.026) compared with placebo. Empagliflozin also caused significant reductions in body weight and serum urate at week 6. Conclusions: Empagliflozin caused a significant increase in 24-hour urine volume without an increase in urinary sodium when used in combination with loop diuretic. Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03226457.

BACKGROUND: Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. METHODS: To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15–45 ml/min per 1.73 m(2)). We randomly assigned participants to receive 400 μg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. RESULTS: We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. CONCLUSIONS: Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Vitamin K therapy to improve vascular health in patients with chronic kidney disease, ISRCTN21444964 (www.isrctn.com)

OBJECTIVE To determine the effects of dapagliflozin in patients with heart failure (HF) and type 2 diabetes mellitus (T2DM) on left ventricular (LV) remodeling using cardiac MRI. RESEARCH DESIGN AND METHODS We randomized 56 patients with T2DM and HF with LV systolic dysfunction to dapagliflozin 10 mg daily or placebo for 1 year, on top of usual therapy. The primary end point was difference in LV end-systolic volume (LVESV) using cardiac MRI. Key secondary end points included other measures of LV remodeling and clinical and biochemical parameters. RESULTS In our cohort, dapagliflozin had no effect on LVESV or any other parameter of LV remodeling. However, it reduced diastolic blood pressure and loop diuretic requirements while increasing hemoglobin, hematocrit, and ketone bodies. There was a trend toward lower weight. CONCLUSIONS We were unable to determine with certainty whether dapagliflozin in patients with T2DM and HF had any effect on LV remodeling. Whether the benefits of dapagliflozin in HF are due to remodeling or other mechanisms remains unknown.

Aim We tested the hypothesis that metformin may regress left ventricular hypertrophy (LVH) in patients who have coronary artery disease (CAD), with insulin resistance (IR) and/or pre-diabetes. Methods and results We randomly assigned 68 patients (mean age 65 ± 8 years) without diabetes who have CAD with IR and/or pre-diabetes to receive either metformin XL (2000 mg daily dose) or placebo for 12 months. Primary endpoint was change in left ventricular mass indexed to height1.7 (LVMI), assessed by magnetic resonance imaging. In the modified intention-to-treat analysis (n = 63), metformin treatment significantly reduced LVMI compared with placebo group (absolute mean difference −1.37 (95% confidence interval: −2.63 to −0.12, P = 0.033). Metformin also significantly reduced other secondary study endpoints such as: LVM (P = 0.032), body weight (P = 0.001), subcutaneous adipose tissue (P = 0.024), office systolic blood pressure (BP, P = 0.022) and concentration of thiobarbituric acid reactive substances, a biomarker for oxidative stress (P = 0.04). The glycated haemoglobin A1C concentration and fasting IR index did not differ between study groups at the end of the study. Conclusion Metformin treatment significantly reduced LVMI, LVM, office systolic BP, body weight, and oxidative stress. Although LVH is a good surrogate marker of cardiovascular (CV) outcome, conclusive evidence for the cardio-protective role of metformin is required from large CV outcomes trials.

Purpose To quantify the burden and distribution of asymptomatic atherosclerosis in a population with a low to intermediate risk of cardiovascular disease. Materials and Methods Between June 2008 and February 2013, 1528 participants with 10-year risk of cardiovascular disease less than 20% were prospectively enrolled. They underwent whole-body magnetic resonance (MR) angiography at 3.0 T by using a two-injection, four-station acquisition technique. Thirty-one arterial segments were scored according to maximum stenosis. Scores were summed and normalized for the number of assessable arterial segments to provide a standardized atheroma score (SAS). Multiple linear regression was performed to assess effects of risk factors on atheroma burden. Results A total of 1513 participants (577 [37.9%] men; median age, 53.5 years; range, 40-83 years) completed the study protocol. Among 46 903 potentially analyzable segments, 46 601 (99.4%) were interpretable. Among these, 2468 segments (5%) demonstrated stenoses, of which 1649 (3.5%) showed stenosis less than 50% and 484 (1.0%) showed stenosis greater than or equal to 50%. Vascular stenoses were distributed throughout the body with no localized distribution. Seven hundred forty-seven (49.4%) participants had at least one stenotic vessel, and 408 (27.0%) participants had multiple stenotic vessels. At multivariable linear regression, SAS correlated with age (B = 3.4; 95% confidence interval: 2.61, 4.20), heart rate (B = 1.23; 95% confidence interval: 0.51, 1.95), systolic blood pressure (B = 0.02; 95% confidence interval: 0.01, 0.03), smoking status (B = 0.79; 95% confidence interval: 0.44, 1.15), and socioeconomic status (B = -0.06; 95% confidence interval: -0.10, -0.02) (P < .01 for all). Conclusion Whole-body MR angiography identifies early vascular disease at a population level. Although disease prevalence is low on a per-vessel level, vascular disease is common on a per-participant level, even in this low- to intermediate-risk cohort. © RSNA, 2018 Online supplemental material is available for this article.

The present study was funded by the Souter Charitable Foundation and the Chest, Heart and Stroke Scotland Charity. The statistician was funded by TENOVUS, Tayside. JRWM is supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (Grant no. WT 085664) in the form of a Clinical Research Fellowship. Background: Arteriosclerosis (arterial stiffening) is associated with future cardiovascular events, with this effect postulated to be due to its effect on cardiac afterload, atherosclerosis (plaque formation) progression or both, but with limited evidence examining these early in disease formation. The aim of the current study is to examine the association between arteriosclerosis, atherosclerosis and ventricular remodelling in a population at low-intermediate cardiovascular risk. Methods: One thousand six hundred fifty-one subjects free of clinical cardiovascular disease and with a

Aim We tested the hypothesis that dapagliflozin may regress left ventricular hypertrophy (LVH) in people with type 2 diabetes (T2D). Methods and results We randomly assigned 66 people (mean age 67 ± 7 years, 38 males) with T2D, LVH, and controlled blood pressure (BP) to receive dapagliflozin 10 mg once daily or placebo for 12 months. Primary endpoint was change in absolute left ventricular mass (LVM), assessed by cardiac magnetic resonance imaging. In the intention-to-treat analysis, dapagliflozin significantly reduced LVM compared with placebo with an absolute mean change of −2.82g [95% confidence interval (CI): −5.13 to −0.51, P = 0.018]. Additional sensitivity analysis adjusting for baseline LVM, baseline BP, weight, and systolic BP change showed the LVM change to remain statistically significant (mean change −2.92g; 95% CI: −5.45 to −0.38, P = 0.025). Dapagliflozin significantly reduced pre-specified secondary endpoints including ambulatory 24-h systolic BP (P = 0.012), nocturnal systolic BP (P = 0.017), body weight (P < 0.001), visceral adipose tissue (VAT) (P < 0.001), subcutaneous adipose tissue (SCAT) (P = 0.001), insulin resistance, Homeostatic Model Assessment of Insulin Resistance (P = 0.017), and high-sensitivity C-reactive protein (hsCRP) (P = 0.049). Conclusion Dapagliflozin treatment significantly reduced LVM in people with T2D and LVH. This reduction in LVM was accompanied by reductions in systolic BP, body weight, visceral and SCAT, insulin resistance, and hsCRP. The regression of LVM suggests dapagliflozin can initiate reverse remodelling and changes in left ventricular structure that may partly contribute to the cardio-protective effects of dapagliflozin. ClinicalTrials.gov Identifier NCT02956811

Background E-cigarette (EC) use is increasing exponentially worldwide. The early cardiovascular effects of switching from tobacco cigarettes (TC) to EC in chronic smokers is unknown. Meta-analysis of flow-mediated dilation (FMD) studies indicate 13% lower pooled, adjusted relative risks of cardiovascular events with every 1% improvement in FMD. Objectives This study sought to determine the early vascular impact of switching from TC to EC in chronic smokers. Methods The authors conducted a prospective, randomized control trial with a parallel nonrandomized preference cohort and blinded endpoint of smokers ≥18 years of age who had smoked ≥15 cigarettes/day for ≥2 years and were free from established cardiovascular disease. Participants were randomized to EC with nicotine or EC without nicotine for 1 month. Those unwilling to quit continued with TC in a parallel preference arm. A propensity score analysis was done to adjust for differences between the randomized and preference arms. Vascular function was assessed by FMD and pulse wave velocity. Compliance with EC was measured by carbon monoxide levels. Results Within 1 month of switching from TC to EC, there was a significant improvement in endothelial function (linear trend β = 0.73%; 95% confidence interval [CI]: 0.41 to 1.05; p, Central Illustration

Background: Low 25‐hydroxyvitamin D levels are associated with an increased risk of cardiovascular events, but the effect of vitamin D supplementation on markers of vascular function associated with major adverse cardiovascular events is unclear.Methods and Results: We conducted a systematic review and individual participant meta‐analysis to examine the effect of vitamin D supplementation on flow‐mediated dilatation of the brachial artery, pulse wave velocity, augmentation index, central blood pressure, microvascular function, and reactive hyperemia index. MEDLINE, CINAHL, EMBASE, Cochrane Central Register of Controlled Trials, and http://www.ClinicalTrials.gov were searched until the end of 2016 without language restrictions. Placebo‐controlled randomized trials of at least 4 weeks duration were included. Individual participant data were sought from investigators on included trials. Trial‐level meta‐analysis was performed using random‐effects models; individual participant meta‐analyses used a 2‐stage analytic strategy, examining effects in prespecified subgroups. 31 trials (2751 participants) were included; 29 trials (2641 participants) contributed data to trial‐level meta‐analysis, and 24 trials (2051 participants) contributed to individual‐participant analyses. Vitamin D3 daily dose equivalents ranged from 900 to 5000 IU; duration was 4 weeks to 12 months. Trial‐level meta‐analysis showed no significant effect of supplementation on macrovascular measures (flow‐mediated dilatation, 0.37% [95% confidence interval, −0.23 to 0.97]; carotid‐femoral pulse wave velocity, 0.00 m/s [95% confidence interval, −0.36 to 0.37]); similar results were obtained from individual participant data. Microvascular function showed a modest improvement in trial‐level data only. No consistent benefit was observed in subgroup analyses or between different vitamin D analogues.Conclusions: Vitamin D supplementation had no significant effect on most markers of vascular function in this analysis. Beveridge LA Beveridge, LA Author Khan F Khan, F Author 0000-0002-9889-0229 Struthers AD Struthers, AD Author

Background:\ud \ud Growth differentiation factor-15 (GDF-15) may be a biomarker of disease, protective response and/or prognosis, in older people with hypertension.\ud \ud Aims:\ud \ud To correlate baseline GDF-15 levels with physical and vascular health data in this population.\ud \ud Methods:\ud \ud Baseline blood samples were analysed using a GDF-15 ELISA assay kit. Correlations with baseline and 12-month outcome data, including measures of physical and vascular function, were performed.\ud \ud Results:\ud \ud A total of 147 individuals, mean age 76.8 ± 4.7 years, were included. 77 (52 %) were male. Baseline log10GDF-15 showed significant correlations with age (r = 0.37, p < 0.001), total cholesterol (r = −0.33, p < 0.001) and 6-min walking distance (r = −0.37, p < 0.001). Age remained significantly associated with log10GDF-15 in multivariable analysis (beta = −0.29, p = 0.001). Baseline log10GDF-15 was significantly associated with decline in 6-min walk distance over 12 months (beta = −0.27, p = 0.01) in multivariable models. No significant correlations were seen with changes in vascular function over 12 months.\ud \ud Conclusion:\ud \ud Baseline GDF-15 predicts declining physical, but not vascular, function in our population.

Background Left ventricular (LV) function has traditionally been the focus for cardiac magnetic resonance imaging (MRI) investigations, but similar methods can also be applied to the left atrium (LA). Previous studies elsewhere have almost entirely involved the use of 1.5T systems, but 3T MRI can provide faster data acquisition with thinner image slices, and may be more suitable for quantifying the structure and function of the LA. Purpose To evaluate 3T-MRI for LA volume assessments in: (i) healthy volunteers (HV); (ii) patients with LV-hypertrophy and ischemia (LVHI); and (iii) patients with LV-hypertrophy and diabetes (LVHD). Material and Methods Participants were imaged using a balanced steady-state free precession sequence. Healthy volunteers were scanned twice and patients were scanned on one occasion. Volumes were segmented by two observers, and coefficients of repeatability (CoR) were derived. Results For LA volumes (indexed to body surface area), CoRs were in the range of 1.3–4.6 mL/m2. The LVHI patients had enlarged LA volumes (diastolic, 46.4 mL/m2; systolic, 25.9 mL/m2) and reduced ejection fraction (EF) (44.9%) relative to the HV (diastolic, 39.0 mL/m2; systolic, 17.8 mL/m2; EF, 54.5%) and LVHD groups (diastolic, 41.4 mL/m2; systolic, 20.2 mL/m2; EF, 50.7%). LA volumes were moderately correlated with LV mass in the HV group (R2 = 0.59 for LA end-systolic volume), but became weaker (R2 ≤ 0.17) for patient groups. Conclusion 3T-MRI derived LA volume measurements are simple and repeatable, and can elicit clear differences between LVHI patients and HVs. These MRI endpoints provide scope for improved radiological interpretation of LA structure and function, and the high degree of repeatability validates their use for longitudinal investigations where precision work is essential.

Objective Magnetic femoral nerve stimulation to test muscle function has been largely unexplored in older people. We assessed acceptability, feasibility, along with reproducibility and correlation with other physical function measures. Results Study 1 recruited older people with sarcopenia. Stimulation was performed at baseline and 2 weeks along with six minute walk (6MW), maximum voluntary quadriceps contraction, short physical performance battery and grip strength. Acceptability was measured using visual analog scales. Study 2 used baseline data from a trial of older people. We correlated stimulation results with 6MW, maximal voluntary contraction and muscle mass. Maximum quadriceps twitch tension was measured in both studies, evoked using biphasic magnetic stimulation of the femoral nerve. In study 1 (n = 12), magnetic stimulation was well tolerated with mean discomfort rating of 9% (range 0–40%) on a visual analog scale. Reproducibility was poor (intraclass correlation coefficient 0.06; p = 0.44). Study 2 (n = 64) showed only weak to moderate correlations for maximum quadriceps twitch tension with other measures of physical function (6 minute walk test r = 0.24, p = 0.06; maximal voluntary contraction r = 0.26; p = 0.04). We conclude that magnetic femoral nerve stimulation is acceptable and feasible but poorly reproducible in older, functionally impaired people.

Background Sarcopenia (the age-related loss of muscle mass and function) is a major contributor to loss of mobility, falls, loss of independence, morbidity and mortality in older people. Although resistance training is effective in preventing and reversing sarcopenia, many older people are sedentary and either cannot or do not want to exercise. This trial examines the efficacy of supplementation with the amino acid leucine and/or angiotensin converting enzyme inhibition to potentially improve muscle mass and function in people with sarcopenia. Promising preliminary data exist from small studies for both interventions, but neither has yet been tested in adequately powered randomised trials in patients with sarcopenia. Methods Leucine and ACE inhibitors in sarcopenia (LACE) is a multicentre, masked, placebo-controlled, 2 × 2 factorial randomised trial evaluating the efficacy of leucine and perindopril (angiotensin converting enzyme inhibitor (ACEi)) in patients with sarcopenia. The trial will recruit 440 patients from primary and secondary care services across the UK. Male and female patients aged 70 years and over with sarcopenia as defined by the European Working Group on Sarcopenia (based on low total skeletal muscle mass on bioimpedance analysis and either low gait speed or low handgrip strength) will be eligible for participation. Participants will be excluded if they have a contraindication to, or are already taking, an ACEi, angiotensin receptor blocker or leucine. The primary clinical outcome for the trial is the between-group difference in the Short Physical Performance Battery score at all points between baseline and 12 months. Secondary outcomes include appendicular muscle mass measured using dual-energy X-ray absorptiometry, muscle strength, activities of daily living, quality of life, activity using pedometer step counts and falls. Participants, clinical teams, outcomes assessors and trial analysts are masked to treatment allocation. A panel of biomarkers including microRNAs, neurohormones, genetic polymorphisms and markers of inflammation relevant to muscle pathophysiology will be measured to explore predictors of response and further elucidate mechanisms underlying sarcopenia. Participants will receive a total of 12 months of either perindopril or placebo and either leucine or placebo. Discussion The results will provide the first robust test of the overall clinical and cost-effectiveness of these novel therapies for older patients with sarcopenia. Trial registration ISRCTN, ISRCTN90094835. Registered on 18 February 2015. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2390-9) contains supplementary material, which is available to authorized users.

Left ventricular hypertrophy (LVH) is a significant cardiac risk factor, associated with increased mortality. The impact of LVH on mortality in chronic obstructive pulmonary disease (COPD) is unknown. We evaluated the impact of LVH on mortality in COPD patients by measurement of left ventricular dimensions by echocardiography. Retrospective cohort study utilizing a NHS database of COPD patients (TARDIS), in Tayside, Scotland (2001–2010), linked with databases regarding echocardiograms, pharmacy prescription, and the General Register Office for Scotland death registry. Cox proportional hazard regression was used to determine hazard ratios for mortality and hospital admissions based upon left ventricular mass index (LVMI) and left ventricular internal diastolic diameter after correction for all available influential covariates. Increased LVIDd was defined as >5.3 cm (female) and >5.9 cm (male). LVH was defined as an LVMI of >95 g/m2 (female) and >115 g/m2 (male). 617 patients were included for analysis. Mean (SD) age at diagnosis, 70 (9); mean FEV1 % (SD), 60.6 (19.3); mean resting SaO2 % (SD), 92.7 (10). Mean follow-up 4.5 years. Increased LVIDd was not associated with increased mortality, χ 2= 0.767, p = 0.381. Increased LVMI was associated with a significant increased risk of mortality, χ 2 = 5.447, p = 0.02 with an adjusted HR (95 % CI) of 1.542 (1.068–2.228), p = 0.021. The presence of LVH, demonstrated by elevated left ventricular mass index is associated with a significantly increased risk of mortality in COPD patients. Therapeutic interventions are required to address this important modifiable risk factor in COPD patients.

Current distance measurement techniques for pulse wave velocity (PWV) calculation are susceptible to intercenter variability. The aim of this study was to derive and validate a formula for this distance measurement. Based on carotid femoral distance in 1183 whole-body magnetic resonance angiograms, a formula was derived for calculating distance. This was compared with distance measurements in 128 whole-body magnetic resonance angiograms from a second study. The effects of recalculation of PWV using the new formula on association with risk factors, disease discrimination, and prediction of major adverse cardiovascular events were examined within 1242 participants from the multicenter SUMMIT study (Surrogate Markers of Micro- and Macrovascular Hard End-Points for Innovative Diabetes Tools) and 825 participants from the Caerphilly Prospective Study. The distance formula yielded a mean error of 7.8 mm (limits of agreement =-41.1 to 56.7 mm

Coronary heart disease and peripheral arterial disease (PAD) affect different vascular territories. Supplementing baseline findings with assays from stored serum, we compared their 20-year predictors.We randomly recruited 15 737 disease-free men and women aged 30 to 75 years across Scotland between 1984 and 1995 and followed them through 2009 for death and hospital diagnoses. Of these, 3098 developed coronary heart disease (19.7%), and 499 PAD (3.2%). Hazard ratios for 45 variables in the Cox model were adjusted for age and sex and for factors in the 2007 ASSIGN cardiovascular risk score. Forty-four of them were entered into parsimonious predictive models, tested by c-statistics and net reclassification improvements. Many hazard ratios diminished with adjustment and parsimonious modeling, leaving significant survivors. The hazard ratios were mostly higher in PAD. New parsimonious models increased the c-statistic and net reclassification improvements over ASSIGN variables alone but varied in their components and ranking. Coronary heart disease and PAD shared 7 of the 9 factors from ASSIGN: age, sex, family history, socioeconomic status, diabetes mellitus, tobacco smoking, and systolic blood pressure (but neither total nor high-density lipoprotein cholesterol); plus 4 new ones: NT-pro-BNP, cotinine, high-sensitivity C-reactive protein, and cystatin-C. The highest ranked hazard ratios for continuous factors in coronary heart disease were those for age, total cholesterol, high-sensitivity troponin, NT-pro-BNP, cotinine, apolipoprotein A, and waist circumference (plus 10 more); in PAD they were age, high-sensitivity C-reactive protein, systolic blood pressure, expired carbon monoxide, cotinine, socioeconomic status, and lipoprotein (a) (plus 5 more).The mixture of shared with disparate determinants for arterial disease in the heart and the legs implies nonidentical pathogenesis: cholesterol dominant in the former, and inflammation (high-sensitivity C-reactive protein, diabetes mellitus, smoking) in the latter.

Background Pulmonary pulse wave velocity (PWV) allows the non-invasive measurement of pulmonary arterial stiffening, but has not previously been assessed in COPD. The aim of the current study was to assess PWV in COPD and its association with right ventricular (RV) remodelling. Methods Fifty-eight participants with COPD underwent pulmonary function tests, 6-min walk test and cardiac MRI, while 21 healthy controls (HCs) underwent cardiac MRI. Thirty-two COPD patients underwent a follow-up MRI to assess for longitudinal changes in RV metrics. Cardiac MRI was used to quantify RV mass, volumes and PWV. Differences in continuous variables between the COPD and HC groups was tested using an independent t-test, and associations between PWV and right ventricular parameters was examined using Pearson’s correlation coefficient. Results Those with COPD had reduced pulsatility (COPD (mean±SD):24.88±8.84% vs. HC:30.55±11.28%, p=0.021), pulmonary acceleration time (COPD:104.0±22.9ms vs. HC: 128.1±32.2ms, p

The role of endothelial dysfunction and oxidative stress in the pathogenesis of cardiac syndrome X has recently been recognised. Allopurinol has previously been shown to improve endothelial dysfunction, reduce oxidative stress burden and improve myocardial efficiency. In this ‘proof of concept’ study, we investigated the effect of allopurinol on exercise capacity, coronary and peripheral endothelial function, and serum B-type natriuretic peptide (BNP: a marker of cardiac function and myocardial ischaemia) in patients with cardiac syndrome X. Methods and Results This study was a randomised, double-blind, placebo-control crossover trial. Nineteen patients (mean age 59±10 years, 11 women & 8 men) with cardiac syndrome X were randomised to a 6-week treatment with either allopurinol (600mg/day) or placebo. After 4 weeks of washout period, they were crossed over to the other arm. Outcomes measured at baseline and after treatment were maximum exercise time (ET) derived from Bruce protocol exercise treadmill test, serum BNP measurement, coronary flow reserve (CFR) as assessed by measuring response of flow velocity in the left anterior descending artery to adenosine and flow-mediated vasodilatation of the brachial artery (FMD). Allopurinol significantly reduced serum uric acid levels when compared with placebo (-48±24% vs 1·9±11%, p

Angiotensin converting enzyme inhibitors may improve exercise capacity and muscle function in older people but are often thought to increase falls risk. We investigated the effect of perindopril on postural stability in older people with a history of falls. Design double-blind, parallel group, placebo-controlled randomised trial. Methods we recruited people aged >65 years with at least one fall in the previous year. Participants received 4 mg perindopril or placebo daily for 15 weeks. The primary outcome was the between-group difference in force-plate measured anteroposterior (AP) sway at 15 weeks. Secondary outcomes included other measures of postural sway, limits of stability during maximal forward, right and left leaning, blood pressure, muscle strength, 6-min walk distance and falls. The primary outcome was assessed using two-way ANOVA, adjusted for baseline factors. Results we randomised 80 participants. Mean age was 78.0 (SD 7.4) years; 60 (75%) were female. About 77/80 (96%) completed the trial. At 15 weeks there were no significant between-group differences in AP sway with eyes open (mean difference 0 mm, 95% CI −8 to 7 mm, P = 0.91) or eyes closed (mean difference 2 mm, 95% CI −7 to 12 mm, P = 0.59); no differences in other measures of postural stability, muscle strength or function. About 16/40 (42%) of patients in each group had orthostatic hypotension at follow-up. The median number (IQR) of falls was 1 (0,4) in the perindopril versus 1 (0,2) in the placebo group (P = 0.24). Conclusions perindopril did not improve postural sway in older people at risk of falls. Clinical Trials Registration ISRCTN58995463

To determine all-cause mortality in patients with a first myocardial infarct who were treated with simvastatin compared with high-potency statin and simvastatin/ezetimibe combination.Despite statin use, residual cardiovascular risk remains. Therapeutic options include more potent statins or addition of ezetimibe. There is no clinical outcome data on the use of ezetimibe in such patients.Retrospective longitudinal study using the United Kingdom General Practice Research Database. Patients who had survived 30 days after their first acute myocardial infarct (AMI), had not received prior statin or ezetimibe therapy and were started on a statin within 30 days of AMI were included. Three groups were identified according to their follow-up: (i) simvastatin monotherapy; (ii) high-potency statin group (patients who started on simvastatin and switched to atorvastatin or rosuvastatin); and (iii) ezetimibe/statin combination group (patients who received ezetimibe in addition to statin).9597 patients (57% male, mean age of 65 ± 13 years) matched study criteria: simvastatin (n=6990 (72.8%)); high-potency statin (n=1883, (19.6%)); and ezetimibe/statin combination (n=724 (7.5%)). During a mean follow-up of 3.2 years, there were 1134 (12%) deaths. In the multivariate proportional hazards model, the adjusted HR for high-potency statin and ezetimibe group were 0.72 (95% CI 0.59 to 0.88, p0.001) and 0.96 (95% CI 0.64 to 1.43, p=0.85), respectively. A similar result was also obtained in the propensity score analysis that took into account covariates that predicted drug treatment groups.Patients switched to a high-potency statin had a significantly reduced mortality compared with simvastatin monotherapy. There was no observed mortality benefit in the ezetimibe group.

Aims Our aim was to test the prediction and clinical applicability of high-sensitivity assayed troponin I for incident cardiovascular events in a general middle-aged European population. Methods and results High-sensitivity assayed troponin I was measured in the Scottish Heart Health Extended Cohort ( n = 15 340) with 2171 cardiovascular events (including acute coronary heart disease and probable ischaemic strokes), 714 coronary deaths (25% of all deaths), 1980 myocardial infarctions, and 797 strokes of all kinds during an average of 20 years follow-up. Detection rate above the limit of detection (LoD) was 74.8% in the overall population and 82.6% in men and 67.0% in women. Troponin I assayed by the high-sensitivity method was associated with future cardiovascular risk after full adjustment such as that individuals in the fourth category had 2.5 times the risk compared with those without detectable troponin I ( P < 0.0001). These associations remained significant even for those individuals in whom levels of contemporary-sensitivity troponin I measures were not detectable. Addition of troponin I levels to clinical variables led to significant increases in risk prediction with significant improvement of the c-statistic ( P < 0.0001) and net reclassification ( P < 0.0001). A threshold of 4.7 pg/mL in women and 7.0 pg/mL in men is suggested to detect individuals at high risk for future cardiovascular events. Conclusion Troponin I, measured with a high-sensitivity assay, is an independent predictor of cardiovascular events and might support selection of at risk individuals.

Plasma BNP and high-sensitivity cardiac troponin-T (hs-TnT) are elevated by both ischaemia and LV systolic dysfunction (LVSD). As a result, it is unknown whether BNP and/or hs-TnT could be useful biomarkers to identify ischaemia in the presence of LVSD.Three separate patient populations were studied. Study A (n = 500) involved consecutive patients undergoing clinically indicated myocardial perfusion scintigraphy, study B (n = 100) included patients with vascular disease but no known cardiac disease, and study C (n = 300) recruited primary prevention patients with controlled risk factors. Levels of BNP and hs-TnT were measured prior to the stress testing to detect myocardial ischaemia. The prevalence of myocardial ischaemia was 28.2, 28, and 6.3% in study A, B, and C, respectively. For BNP, area under curve (AUC) values to identify ischaemia in the presence and absence of coincidental LVSD were: 0.73 vs. 0.63 (study A), 0.90 vs. 0.81 (study B), and 0.83 vs. 0.80 (study C). Equivalent figures for hs-TnT were: 0.64 vs. 0.60 (study A), 0.75 vs. 0.68 (study B), and 0.53 vs. 0.68 (study C). BNP and hs-cTnT, when combined together, performed better with an AUC of 0.75 vs. 0.65 (study A), 0.91 vs. 0.92 (study B), and 0.84 vs. 0.83 (study C).In three separate populations a consistent finding is that BNP is increased further by myocardial ischaemia even in the presence of LVSD. A disproportionately high BNP for the degree of LVSD might be due to (unsuspected) ischaemia, and a disproportionately low BNP could be useful as a 'rule out' test for ischaemia even in the presence of LVSD.

Objectives This study sought to ascertain whether high-dose allopurinol causes regression of left ventricular mass (LVM) in patients with type 2 diabetes mellitus (T2DM). Background Left ventricular hypertrophy (LVH) is common in T2DM and contributes to patients9 high cardiovascular (CV) event rate. Oxidative stress (OS) has been implicated in LVH development, and allopurinol has been previously shown to reduce vascular OS. We therefore investigated whether allopurinol causes regression of LVH in patients with T2DM. Methods We conducted a randomized, double-blind, placebo-controlled study of 66 optimally-treated T2DM patients with echocardiographic evidence of LVH. Allopurinol, 600 mg/day, or placebo was given over the study period of 9 months. The primary outcome was reduction in LVM as calculated by cardiac magnetic resonance imaging at baseline and at 9 months9 follow-up. Secondary endpoints were change in flow-mediated dilation and augmentation index. Results Allopurinol significantly reduced absolute LVM (−2.65 ± 5.91 g vs. placebo group +1.21 ± 5.10 g [p = 0.012]) and LVM indexed to body surface area (−1.32 ± 2.84 g/m2 vs. placebo group +0.65 ± 3.07 g/m2 [p = 0.017]). No significant changes were seen in either flow-mediated dilation or augmentation index. Conclusions Allopurinol causes regression of LVM in patients with T2DM and LVH. Regression of LVH has been shown previously to improve CV mortality and morbidity. Therefore, allopurinol therapy may become useful to reduce CV events in T2DM patients with LVH. (Allopurinol in Patients with Diabetes and LVH; UKCRN 8766)

Introduction Myocardial fibrosis is dysrhythmogenic and may contribute to the high incidence of cardiac death in stroke survivors, especially if they have long QTc. We tested the hypothesis that procollagen-1-carboxy terminal peptide (P1CP), a biomarker of myocardial fibrosis, might be improved following treatment with spironolactone or amiloride in stroke survivors. We also tested the hypothesis that both drugs would shorten QTc. Methods Study design: randomised, double-blinded, placebo-controlled, cross-over trial (spironolactone vs. amiloride vs. placebo). Duration of Study: 3months (1month per drug). Primary endpoints: P1CP, QTc Results 11 stroke survivors (5 female), aged 71+4, BP 139/81mmHg+20/11mmHg, completed the study. Both spironolactone and amiloride significantly reduced P1CP [Spironolactone–Placebo=−24 ug/L, 95% CI=−40 to −6.9; Amiloride–Placebo=−28 ug/L, 95% CI=−44 to −11]. Spironolactone and amiloride both shortened QTc [Spironolactone vs. Placebo=−18ms 1/2 , 95% CI=−36 to −0.55; Amiloride vs Placebo=−25ms 1/2 , 95% CI=−42 to −7.5]. Conclusions Procollagen-1-carboxy terminal peptide was reduced following treatment with spironolactone within a month. Further, this is the first study demonstrating amiloride could also improve myocardial fibrosis. The beneficial effects of both drugs on myocardial fibrosis, coupled with their effects on raising potassium translated to a shortening of QTc. Future studies should test the hypothesis that these drugs might reduce the risk of sudden cardiac death in stroke survivors.

The treatment of primary hypertension has been one of the major success stories of clinical medicine over the last 50 years. However, there is still room for further improvement because it is now appreciated that optimally treated hypertensives still have considerable residual cardiovascular (CV) risk. A recent article showed that even after correcting for systolic blood pressure (BP), a treated hypertensive patient has a 50% increased risk of any CV event.1 Intriguingly this is not the case for lipid-lowering therapy, which is able to negate all of the increased risk caused by hyperlipidemia. When the total CV risk in treated hypertension was broken down further, the increased risk of coronary disease was 46%, for stroke it was 75%, and for CV death it was 62%. Numerous other studies have found the same increased residual CV risk in treated hypertensives.2–7 A 65-year-old man was diagnosed with primary hypertension 15 years ago at the age of 50 years. There were no noteworthy features about this man and his family history was unremarkable. He was an ex-smoker (only 4 years) with a body mass index of 24, who ingested 10 U of alcohol per week. His hypertension was well controlled on a combination of lisinopril (20 mg) and amlodipine (5 mg). His office BPs were 130/78 mm Hg. His home BPs, recorded by himself, averaged 116/78 mm Hg. His lipid profile was normal but he was commenced on a statin 3 years ago (atorvastatin 10 mg) in view of the earlier ASCOT/LLA (Anglo Scandinavian Cardiac Outcomes Trial/Lipid Lowering Arm) study results. Despite the above, he was admitted to hospital with an anterior ST-segment–elevation myocardial infarction (STEMI), which was appropriately treated with angioplasty and all other routine therapy, including the addition in the long term of aspirin, a β-blocker, and an increase …

BackgroundInterventions that improve muscle function may slow decline in physical function and disability in later life. Recent evidence suggests that inhibition of the renin-angiotensin-aldosterone system may maintain muscle function. We evaluated the effect of aldosterone blockade on physical performance in functionally impaired older people without heart failure.MethodsIn this parallel-group, double-blind, randomized, placebo-controlled trial, community-dwelling participants aged ≥65 years with self-reported problems with activities of daily living were randomized to receive 25 mg spironolactone or identical placebo daily for 20 weeks. The primary outcome was change in 6-minute walking distance over 20 weeks. Secondary outcomes were changes in Timed Up and Go test, Incremental Shuttle Walk Test, Functional Limitation Profile, EuroQol EQ-5D, and Hospital Anxiety and Depression Scale over 20 weeks.ResultsParticipants’ mean (standard deviation) age was 75 (6) years. Of the 93% of participants (112/120) who completed the study, 106 remained on medication at 20 weeks. There was no significant difference in change in 6-minute walking distance at 20 weeks between the spironolactone and placebo groups (mean change, −3.2 m; 95% confidence interval, −28.9 to 22.5; P = .81). Quality of life improved significantly at 20 weeks, with an increase in EuroQol EQ-5D score of 0.10 (95% confidence interval, 0.03-0.18; P < .01) in the spironolactone group relative to the placebo group. There were no significant differences in between-group change for other secondary outcomes.ConclusionsSpironolactone was well tolerated but did not improve physical function in older people without heart failure. Quality of life improved significantly, and the possible mechanisms for this require further study.

Introduction Ischaemic heart disease (IHD) is one of the most common causes of death in the UK and treatment of patients with IHD costs the National Health System (NHS) billions of pounds each year. Allopurinol is a xanthine oxidase inhibitor used to prevent gout that also has several positive effects on the cardiovascular system. The ALL-HEART study aims to determine whether allopurinol improves cardiovascular outcomes in patients with IHD. Methods and analysis The ALL-HEART study is a multicentre, controlled, prospective, randomised, open-label blinded end point (PROBE) trial of allopurinol (up to 600 mg daily) versus no treatment in a 1:1 ratio, added to usual care, in 5215 patients aged 60 years and over with IHD. Patients are followed up by electronic record linkage and annual questionnaires for an average of 4 years. The primary outcome is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes include all-cause mortality, quality of life and cost-effectiveness of allopurinol. The study will end when 631 adjudicated primary outcomes have occurred. The study is powered at 80% to detect a 20% reduction in the primary end point for the intervention. Patient recruitment to the ALL-HEART study started in February 2014. Ethics and dissemination The study received ethical approval from the East of Scotland Research Ethics Service (EoSRES) REC 2 (13/ES/0104). The study is event-driven and results are expected after 2019. Results will be reported in peer-reviewed journals and at scientific meetings. Results will also be disseminated to guideline committees, NHS organisations and patient groups. Trial registration number 32017426, pre-results.

Vitamin K insufficiency is common and linked to an increased risk of cardiovascular disease and osteoporotic fractures. The aim of this study was to examine whether daily supplementation with oral vitamin K could improve vascular health and physical function in older people with established vascular disease. A double blind, randomised, placebo-controlled trial. Participants aged ≤ 70 years with a history of vascular disease were randomised to receive 6 months of daily oral 100mcg vitamin K2 (MK7 subtype) or matching placebo with outcomes measured at 0, 3 and 6 months. The primary outcome was between-group difference in endothelial function assessed using flow-mediated dilatation of the brachial artery at 6 months. Secondary outcomes included carotid-radial pulse wave velocity, augmentation index, blood pressure, carotid intima-media thickness, C-reactive protein, B-type natriuretic peptide, cholesterol and desphospho-uncarboxylated matrix Gla protein levels. Handgrip strength and the Short Physical Performance Battery assessed physical function, while postural sway was measured using a 3-dimensional force platform. 80 participants were randomised, mean age 77 (SD 5) years; 44/80 were male. Vitamin K levels rose in the intervention arm compared to placebo (+48 pg/ml vs −6 pg/ml, p=0.03) at 6 months. Desphospho-uncarboxylated Matrix Gla protein levels fell in the intervention group compared to placebo at 6 months (−130 [SD 117] pmol/L vs +13 [SD 180] pmol/L, p

Aims Chronic heart failure (CHF) is an insulin-resistant state. The degree of insulin resistance (IR) correlates with disease severity and is associated with reduced exercise capacity. In this proof of concept study, we have examined the effect of metformin on IR and exercise capacity in non-diabetic CHF patients identified to have IR. Methods and results In a double-blind, placebo-controlled study, 62 non-diabetic IR CHF patients (mean age, 65.2 ± 8.0 years; male, 90%; left ventricular ejection fraction, 32.6 ± 8.3%; New York Heart Association class I/II/III/IV, 11/45/6/0) were randomized to receive either 4 months of metformin (n = 39, 2 g/day) or matching placebo (n = 23). IR was defined by a fasting insulin resistance index (FIRI) ≥2.7. Cardiopulmonary exercise testing and FIRI were assessed at baseline and after 4 months of intervention. Compared with placebo, metformin decreased FIRI (from 5.8 ± 3.8 to 4.0 ± 2.5, P < 0.001) and resulted in a weight loss of 1.9 kg (P < 0.001). The primary endpoint of the study, peak oxygen uptake (VO2), did not differ between treatment groups. However, metformin improved the secondary endpoint of the slope of the ratio of minute ventilation to carbon dioxide production (VE/VCO2 slope), from 32.9 ± 15.9 to 28.1 ± 8.8 (P = 0.034). In the metformin-treated group, FIRI was significantly related to the reduction of the VE/VCO2 slope (R = 0.41, P = 0.036). Conclusion Metformin treatment significantly improved IR but had no effect on peak VO2, the primary endpoint of our study. However, metformin treatment did result in a significant improvement in VE/VCO2 slope. Trial registration: NCT00473876.

Neuroendocrine activation may be an important adjunctive mechanism for left ventricular hypertrophy (LVH) development. Controversy exists to as to whether LVH regression occurs due to blood pressure (BP) reduction alone or if adjunctive mechanisms play a role. We planned to test the hypothesis that for a similar BP reduction, LVH regression would be greater using a drug combination selected specifically to reduce neuroendocrine activity compared with one that did not.Forty-two patients with hypertension and cardiovascular magnetic resonance (CMR) proven LVH were allocated to one of two equipotent antihypertensive regimens for 6 months. Treatments were chosen on the basis of opposing mechanistic actions on the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS); one arm inhibitory (valsartan and moxonidine), the other neutral (bendroflumethiazide and amlodipine). The primary end point was absolute reduction in CMR-determined left ventricular mass (LVM).All BP indices were highly comparable at the start and end of the trial (P 0.6 between groups). BP was reduced (always P 0.0001) by 37/17 mmHg in the valsartan and moxonidine group and 38/19 mmHg in the bendroflumethiazide and amlodipine group. CMR quantified LVM was comparable between the two groups at baseline and decreased significantly in both treatment groups (P 0.0001). Reduction in LVM was significantly greater in valsartan and moxonidine [-25.9 g; 95% confidence interval (CI) -31.6 to -20.2] compared with bendroflumethiazide and amlodipine (-18.3 g; -23.3 to -13.4) (P 0.05).The magnitude of LVH regression achieved by inhibiting the RAAS and SNS neuroendocrine pathways is greater than that produced by comparable BP reduction alone. This supports the hypothesis that neuroendocrine mechanisms are important in the regression of LVH.

Objective The role of high sensitivity troponin T (hs-TnT) in the convalescence phase after an acute coronary syndrome (ACS) is unknown. The authors aim to assess the prognostic utility of a single hs-TnT level at 7-week post-ACS. Second, the authors evaluated whether any serial changes in hs-TnT between the index admission and 7 weeks post-ACS had any link with the prognosis. Third, the authors assessed whether the prognostic utility of hs-TnT is independent of various echocardiographic abnormalities. Methods The authors measured hs-TnT levels in 326 consecutive patients at 7 weeks after an ACS event. The composite end point of death from any cause or acute myocardial infarction was evaluated over a median duration of 30 months. Results A high 7-week hs-TnT (>14 ng/l) predicted adverse clinical outcomes independent of conventional risk factors, left ventricular dysfunction and left ventricular hypertrophy on echocardiography (adjusted RR: 2.69 (95% CI 1.45 to 5.00)). Patients with persistent hs-TnT elevation at 7 weeks were also at an increased risk of cardiovascular events compared with those with an initial high hs-TnT which then normalised (unadjusted RR 3.39 (95% CI 2.02 to 5.68)). Conclusion The authors have demonstrated the prognostic utility of a single 7-week hs-TnT measurement in routine ACS patients and that it could be used to assist medium term risk stratification in this patient cohort. In addition, the authors also showed that hs-TnT predicted long-term adverse prognosis independent of various echo parameters. Future studies should evaluate whether tailoring specific treatment interventions to higher risk individuals as identified by an elevated hs-TnT during the convalescence phase of ACS would improve clinical outcomes.

BNP (B-type natriuretic peptide) has been reported to be elevated in preclinical states of vascular damage. To elucidate the relationship between plasma BNP and endothelial function, we have investigated the relationship between BNP and endothelial function in a cohort of subjects comprising healthy subjects as well as at-risk subjects with cardiovascular risk factors. To also clarify the relative contribution of different biological pathways to the individual variation in endothelial function, we have examined the relationship between a panel of multiple biomarkers and endothelial function. A total of 70 subjects were studied (mean age, 58.1±4.6 years; 27% had a history of hypertension and 18% had a history of hypercholesterolaemia). Endothelium-dependent vasodilatation was evaluated by the invasive ACH (acetylcholine)-induced forearm vasodilatation technique. A panel of biomarkers of biological pathways was measured: BNP, haemostatic factors PAI-1 (plasminogen-activator inhibitor 1) and tPA (tissue plasminogen activator), inflammatory markers, including cytokines [hs-CRP (high sensitive C-reactive protein), IL (interleukin)-6, IL-8, IL-18, TNFα (tumour necrosis factor α) and MPO (myeloperoxidase] and soluble adhesion molecules [E-selectin and sCD40 (soluble CD40)]. The median BNP level in the study population was 26.9 pg/ml. Multivariate regression analyses show that age, the total cholesterol/HDL (high-density lipoprotein) ratio, glucose and BNP were independent predictors of endothelial function, and BNP remained an independent predictor (P=0.009) in a binary logistic regression analysis using FBF (forearm blood flow) as a dichotomous variable based on the median value. None of the other plasma biomarkers was independently related to ACH-mediated vasodilatation. In a strategy using several biomarkers to relate to endothelial function, plasma BNP was found to be an independent predictor of endothelial function as assessed by endothelium-dependent vasodilatation in response to ACH.

ObjectivesThe aim of this study was to evaluate the effect of high-dose allopurinol on vascular oxidative stress (OS) and endothelial function in subjects with stable coronary artery disease (CAD).BackgroundAllopurinol, a xanthine oxidase inhibitor, prolongs the time to chest pain during exercise in angina. We sought to ascertain whether allopurinol also improves endothelial dysfunction in optimally treated CAD patients, because such an effect might be of value to reduce future cardiovascular mortality. The mechanism of the anti-ischemic effect of allopurinol could be related to its reducing xanthine oxidase-induced OS, and our second aim was to see whether allopurinol really does reduce vascular tissue OS in CAD patients.MethodsA randomized, double-blind, placebo-controlled, crossover study was conducted in 80 patients with CAD, comparing allopurinol (600 mg/day) with placebo. Endothelial function was assessed by forearm venous occlusion plethysmography, flow-mediated dilation, and pulse wave analysis. Vascular OS was assessed by intra-arterial co-infusion of vitamin C and acetylcholine.ResultsCompared with placebo, allopurinol significantly improved endothelium-dependent vasodilation, by both forearm venous occlusion plethysmography (93 ± 67% vs. 145 ± 106%, p = 0.006) and flow-mediated dilation (4.2 ± 1.8% vs. 5.4 ± 1.7%, p < 0.001). Vascular oxidative stress was completely abolished by allopurinol. Central augmentation index improved significantly with allopurinol (2.6 ± 7.0%, p < 0.001) but not with placebo.ConclusionsOur study demonstrates that, in optimally treated CAD patients, high-dose allopurinol profoundly reduces vascular tissue OS and improves 3 different measures of vascular/endothelial dysfunction. The former effect on OS might underpin the anti-ischemic effect of allopurinol in CAD. Both effects (on OS and endothelial dysfunction) increase the likelihood that high-dose allopurinol might reduce future cardiovascular mortality in CAD, over and above existing optimum therapy. (Exploring the therapeutic potential of xanthine oxidase inhibitor allopurinol in angina; ISRCTN15253766)

Type 2 diabetes mellitus (DM) plus chronic heart failure (CHF) is a common but lethal combination and therapeutic options are limited. Metformin is perceived as being relatively contraindicated in this context, although mounting evidence indicates that it may be beneficial. This study was carried out to investigate the use of metformin therapy for treating patients with DM and CHF in a large population-based cohort study. The Health Informatics Centre-dispensed prescribing database for the population of Tayside, Scotland (population ∼400,000) was linked to the Diabetes Audit and Research in Tayside Scotland (DARTS) information system. Patients with DM and incident CHF from 1994 to 2003 receiving oral hypoglycemic agents but not insulin were identified. Cox regression was used to assess differences in all-cause mortality rates between patients prescribed metformin and patients prescribed sulfonylureas with adjustment for co-morbidities and other therapies. Four hundred twenty-two study subjects (mean ± SD 75.4 ± 0.5 years of age, 46.2% women) were identified: metformin monotherapy (n = 68, mean age 75.5 ± 1.1 years, 48.5% women), sulfonylurea monotherapy (n = 217, mean age 76.7 ± 0.7 years, 45.2% women), and combination (n = 137, mean age, 73.4 ± 0.7 years, 46.7% women). Fewer deaths occurred in metformin users, alone or in combination with sulfonylureas, compared to the sulfonylurea monotherapy cohort at 1 year (0.59, 95% confidence interval 0.36 to 0.96) and over long-term follow up (0.67, 95% confidence interval 0.51 to 0.88). In conclusion, this large observational data suggest that metformin may be beneficial in patients with CHF and DM. These findings need to be verified by a prospective clinical trial.

Low 25-hydroxyvitamin D levels predict future cardiovascular events and are common in patients with type 2 diabetes. We compared the effect of 100,000 and 200,000 IU doses of vitamin D(3) on endothelial function, blood pressure and markers of glycaemic control in patients with type 2 diabetes.This was a randomised, parallel group, placebo-controlled trial. Patients with type 2 diabetes and baseline 25-hydroxyvitamin D levels100 nmol/l were enrolled from community and hospital-based diabetes clinics. Participants were assessed in a university department of clinical pharmacology and received a single oral dose of placebo or vitamin D(3) (100,000 IU or 200,000 IU) at baseline, randomly allocated via numbered bottles prepared offsite; participants and investigators were both blinded to treatment allocation. Endothelial function, office blood pressure, B-type natriuretic peptide, insulin resistance and glycosylated haemoglobin were measured at baseline, and at 8 and 16 weeks.We randomised 61 participants to the three groups (placebo 22, 100,000 IU vitamin D(3) 19, 200,000 IU vitamin D(3) 20). There was no significant difference in the primary outcome of endothelial function at 8 weeks (placebo 5.2%, n = 22; 100,000 IU 4.3%, n = 19; 200,000 IU 4.9%, n = 17) or at 16 weeks. Insulin resistance and glycosylated haemoglobin did not improve with either dose of vitamin D(3). On covariate analysis, systolic blood pressure was significantly lower in both treatment arms than in the placebo group at 8 weeks (placebo 146.4 mmHg, 100,000 IU 141.4 mmHg [p = 0.04 vs placebo], 200,000 IU 136.8 mmHg [p = 0.03 vs placebo]). B-type natriuretic peptide levels were significantly lower in the 200,000 IU group by 16 weeks (placebo 34 pg/ml, 200,000 IU 21 pg/ml, p = 0.02). No significant excess of adverse effects was noted in the treatment arms.High-dose vitamin D(3) improved systolic blood pressure and B-type natriuretic peptide levels, but not endothelial function, insulin resistance or glycosylated haemoglobin in patients with type 2 diabetes.

OBJECTIVES We hypothesized that the aldosterone: renin ratio (ARR) predicts the antihypertensive response to mineralocorticoid receptor antagonist, spironolactone (SPIRO), when compared with bendroflumethiazide (BFZ). METHODS We conducted a randomized, crossover, trial on hypertensive patients with either high ARR (HARR defined as >750 and plasma aldosterone >250 pmol/l) or low ARR (LARR defined as

Purpose: To optimize the contrast agent dose and delivery rate used in a novel whole-body magnetic resonance angiography (MRA) protocol using a 3.0T MR scanner. Materials and Methods: Six groups of 20 consenting volunteers underwent whole-body MRA, with each group receiving a different contrast dose and contrast delivery rate. The arterial tree was divided into 16 segments and the image quality at each of the anatomical locations, covering the whole body, was assessed. Qualitative analysis was carried out using a scoring assessment of image quality, and quantitative assessments were performed by measuring contrast-to-noise (CNR) and a signal-to-noise (SNR) index. Results: Reducing the contrast dose from 40 mL to 25 mL was found to significantly increase the CNR in several vessels of interest in the arterial tree. There was also a significant increase in the qualitative image quality score (P < 0.001). Conclusion: This study demonstrates that reducing the contrast dose at 3.0T can result in an increase in the CNR in the vessels of interest without significantly affecting the SNR. J. Magn. Reson. Imaging 2009;30:1059–1067. © 2009 Wiley-Liss, Inc.

Objective: Left ventricular hypertrophy (LVH) confers high cardiovascular risk. Regression of LVH reduces risk. Patients with blood pressure in the normal range and LVH are common. We investigated whether further reduction in blood pressure would further regress LVH. Methods: 51 subjects with blood pressure in the normal range and echocardiographic left ventricular hypertrophy were randomly assigned to active treatment (antihypertensive medication) or placebo in a ratio of 2:1. The aim was to maintain office systolic blood pressure at 10 mm Hg less than baseline in the active arm and at baseline level in the placebo arm. Cardiac magnetic resonance imaging was used to measure change in left ventricular mass index over 12 months. Results: 35 subjects completed the study (active 23: placebo 12). Average mean baseline office systolic blood pressure was 122 (SD 9) mm Hg in the active group and 124 (9) mm Hg in the placebo group (p = 0.646). The mean baseline left ventricular mass index was 65.88 (11.87) g/m 2 in the active group and 59.16 (11.13) g/m 2 in the placebo group (p = 0.114). The mean difference between baseline and end of study office systolic blood pressure was −9.33 (8.56) mm Hg in the active group and −0.08 (9.27) mm Hg in the placebo group (p = 0.007). The mean change in left ventricular mass index was −4.68 (7.31) g/m 2 in the active group and +1.97 (6.68) g/m 2 in the placebo group (p = 0.014). Conclusions: Reduction in office systolic blood pressure, already in the normal range, of approximately 9 mm Hg, leads to a reduction in left ventricular mass. Further work is required to see if this also leads to a reduction in cardiovascular events. Trial registration number: ISRCTN48331653.

CNP (C-type natriuretic peptide) is a vasodilatory peptide produced by vascular endothelium and the human heart with a short half-life. CNP has been identified within the human kidney; however, few results are available on whether the human kidney is a systemic source of CNP. The aim of the present study was to establish whether CNP is secreted by the human kidney and if synthesis is blunted in CHF (chronic heart failure). A total of 20 male subjects (age, 57 ± 2 years; mean ± S.E.M.) undergoing CHF assessment (n = I3) or investigation of paroxysmal supraventricular arrhythmia (normal left ventricular function in sinus rhythm during procedure) (n = 7) were recruited. Renal CNP production was determined from concomitant plasma concentrations in the aorta and renal vein. When considering all subjects, a significant step-up in plasma CNP was found from the aorta to renal vein (3.0 ± 0.3 compared with 8.3 ± 2.4 pg/ml respectively; P=0.0045). The mean increase in CNP was 5.3 ± 2.4 pg/ml (range, —0.9 to + 45.3 pg/ml). In patients with CHF, the aortic concentration was 3.3 ± 0.4 pg/ml compared with a renal vein concentration of 4.3 ± 0.6 pg/ml (P=0.II). In those with normal left ventricular function, the respective values were 2.5 ± 0.5 and I5.7 ± 6.0 pg/ml (P = 0.0I). In conclusion, CNP is synthesized and secreted into the circulation by the normal human kidney, where it may have paracrine actions. Net renal secretion of CNP appears to be blunted in patients with CHF.

Background Elevated levels of B-type natriuretic peptide (BNP) are associated with adverse clinical outcomes in acute coronary syndrome (ACS), but several questions remain outstanding. Firstly, it has not yet been determined whether an additional BNP sample at 7 weeks post ACS would enhance risk prediction. Secondly, we assessed whether the prognostic potential of BNP in ACS could be explained by echocardiographic abnormalities such as left ventricular hypertrophy (LVH). Methods We measured bedside BNP levels in 443 consecutive patients presenting with ACS and at 7 weeks outpatient follow-up. Main outcome measure was either all-cause mortality, readmission with ACS, or congestive heart failure) at 10 months from presentation. Results Of the 443 patients, 120 patients presented with ST-elevation myocardial infarction (27%). There were 90 cardiovascular (CV) events at 10 months. Adjusting for age, sex, hypertension, diabetes mellitus, smoking status, renal dysfunction, left ventricular ejection fraction, and echocardiographic LVH elevated near patient BNP levels (>80 pg/mL) were still associated with subsequent CV events when measured on admission (adjusted relative risk [RR] 2.63 [95% CI 1.34-5.19)] and also at 7 weeks post ACS (adjusted RR 4.12 [95% CI 1.58-10.72]). Patients with persistent BNP elevation at 7 weeks were also at an increased risk of CV events compared to those with an initial high BNP which then fell (unadjusted RR 4.04 [95% CI 1.24-13.15]). Conclusion In ACS, bedside BNP levels predict CV events at 10 months, independent of many echocardiographic abnormalities including LVH. Furthermore, our study suggests that an additional 7 weeks post ACS BNP enhances risk stratification over and above a one-off high BNP at baseline.

In acute coronary syndrome (ACS), both the Global Registry of Acute Coronary Events (GRACE) score and B-type natriuretic peptide (BNP) predict cardiovascular events. However, it is unknown how BNP compares with GRACE and how their combination performs in ACS.The authors recruited 449 consecutive ACS patients and measured admission GRACE score and bedside BNP levels. The main outcome measure was all-cause mortality, readmission with ACS or congestive heart failure (defined as a cardiovascular event) at 10 months from presentation.Of the 449 patients, 120 patients presented with ST-elevation myocardial infarction (MI) (27%). There were 90 cardiovascular events at 10 months. Both higher GRACE terciles and higher BNP terciles predicted cardiovascular events. There was a significant but only partial correlation between the GRACE score and log BNP (R = 0.552, p0.001). On multivariate analyses, after adjusting for the GRACE score itself, increasing BNP terciles independently predicted cardiovascular events (second BNP tercile adjusted RR 2.28 (95% CI 1.15 to 4.51) and third BNP tercile adjusted RR 4.91 (95% CI 2.62 to 9.22)). Patients with high GRACE score-high BNP were more likely to experience cardiovascular events at 10 months (RR 6.00 (95% CI 2.40 to 14.83)) compared to those with high GRACE score-low BNP (RR 2.40 (95% CI 0.76 to 7.56)).In ACS, most but not all of our analyses suggest that BNP can predict cardiovascular events over and above the GRACE score. The combined use of both the GRACE score and BNP can identify a subset of ACS patients at particularly high risk. This implies that both the GRACE score and BNP reflect somewhat different risk attributes when predicting adverse prognosis in ACS and their synergistic use can enhance risk stratification in ACS to a small but potentially useful extent.

Preterm birth remains one of the most challenging areas in obstetrics. The pathogenesis of preterm labor is multifactorial and research on preterm birth has focused principally on infection and inflammatory markers. Recently the focus has turned to potential genetic factors influencing preterm birth. Uteroplacental insufficiency and thrombotic vasculopathy are considered part of the pathogenesis of preterm labor. Investigating the gene expression in the maternal/fetal interface seems of importance to expand our knowledge of the pathophysiology of preterm birth. The renin-angiotensin system (RAS) appears to play an important role in fetal/placental development and uteroplacental circulation. Hence, the aim of this study was to investigate angiotensin converting enzyme (ACE) activity and I/D polymorphisms in the ACE gene in mothers and infants with appropriately grown infants in relation to preterm birth and infant birth weight.We conducted a cross-sectional study of 113 term pregnancies (or =37 weeks) and 18 preterm pregnancies (37 weeks). Umbilical cord bloods (venous and arterial) were obtained from the placenta immediately after delivery for serum ACE activity, ACE genotype analysis of the I/D polymorphism and the acid-base status. Maternal venous samples were obtained just after delivery for analysis of ACE activity and ACE genotype.The distribution of the maternal ACE genotypes was similar for preterm and term births as was maternal ACE activity. Preterm infants were more likely to be of the DD genotype than term infants (7/18 (39%) vs. 11/83 (13%), p=0.02) (adjusted p=0.04). There was no correlation between ACE activity and birth weight (r(2) 0.00, p=0.82).These findings suggest that the ACE genotype of the infant may influence the risk of preterm birth among appropriately grown fetuses.

There is increasing evidence that serum uric acid is an independent marker of cardiovascular risk. We have shown previously that high urate is associated with cardiac death in stroke survivors independently of conventional risk factors. We sought to determine in stroke survivors the association between high urate levels and arterial stiffness and endothelial function. One hundred and twenty stroke survivors were recruited. We assessed pulse wave velocity of the carotid artery using an echotracking ultrasound system. Endothelial function was assessed by measuring forearm skin blood flow responses, using laser Doppler imaging, to iontophoresis of acetylcholine (ACh) and sodium nitroprusside (SNP). Patients with high serum urate (0.42-0.71 mmol/l) had a greater pulse wave velocity (P

Objectives The demand–control (D–C) model of job strain has generated a considerable body of empirical support in predicting psychological health outcomes in the context of work. This study aimed to extend previous work using the D–C model of job strain to predict caregiver burden and satisfaction in the informal caregivers of patients with heart failure. Design and method Data were gathered from 60 caregiver/patient dyads in a cross-sectional design. Patients with chronic stable heart failure were recruited from out-patient clinics. The dependent variables were caregiver burden and satisfaction. Demand and control were measured using both patient- and caregiver-derived measures. Results The D–C model accounted for 15 and 19% of the variance in caregiver burden, after controlling for age, gender and relationship to the patient. Lower control was associated with higher burden. The D–C model did not predict caregiver satisfaction. Conclusion The D–C model was associated with caregiver burden, but not satisfaction in caregivers, with control being the dominant predictor. Research linking the theory and findings from job strain and informal caregiving studies may elucidate both fields of research. Using the demand–control model of job strain to predict caregiver burden and caregiver satisfaction in the informal caregivers of heart failure patients.

BACKGROUND Echocardiographic (echo) left ventricular hypertrophy (LVH) is an independent predictor of mortality. Despite this, screening for LVH in patients with overt cardiovascular diseases is not universally done. To help target echo screening for LVH in patient population, we developed and validated a simple clinical score to help identify those likely to have echo LVH. METHODS We performed two studies. The development cohort consisted of 267 patients with angina. The validation cohort consisted of 227 patients with peripheral arterial disease. RESULTS The prevalence of echo LVH in both patient cohorts was 50%. Six independent predictors of LVH were identified in the development cohort: age >65 years (1 point), body mass index >30 kg/m2 (1 point), history of hypertension (1 point), previous myocardial infarction (1 point), clinic blood pressure >130/80 mm Hg (1 point) and bundle branch block (BBB) on electrocardiogram (4 points). Our clinical score was strongly associated with the presence of LVH in the validation cohort. It also showed a significant continuous positive relationship (P trend

Background: Patients complaining of chest pain are frequently referred to secondary care, although the majority have pain of non-cardiac origin. Aim: To investigate whether B-type natriuretic peptide (BNP) levels are predictive of a diagnosis of non-cardiac pain. Design: Cross-sectional study. Methods: Consecutive patients (n = 296) presenting to a rapid-access chest pain clinic (RACPC) received the usual clinical assessment plus near-patient BNP testing, with the assessor blinded to the result. After clinical assessment (including exercise stress testing if clinically indicated), pain was diagnosed likely/definitely cardiac or non-cardiac. Results: Median BNP was higher in those diagnosed with likely/definite cardiac chest pain (26.5 vs. 8 pg/ml) ( p < 0.0001, Wilcoxon rank sum test). The odds ratio for cardiac pain in those with BNP

Summary Background: The assessment of chest pain relies on clinical assessment and markers of cell necrosis such as Troponin T (TnT). B-type natriuretic peptide (BNP) is also raised in myocardial ischaemia and therefore may be useful in deciding if acute chest pain is of cardiac origin or not. Aim: To investigate the role of BNP in the assessment of unselected patients presenting with acute chest pain. Methods: A prospective observational study of 100 patients presenting with chest pain to the Acute Medical Admissions Unit was carried out. All patients had BNP and TnT levels measured. The primary outcome was categorization of chest pain as cardiac or non-cardiac. This was determined by the discharge diagnosis. BNP cutoffs were derived from a receiver operated characteristic (ROC) curve. The sensitivity, specificity, positive predictive accuracy (PPA) and negative predictive accuracy (NPA) were all calculated for BNP, TnT and for the composite of BNP and TnT. Results: Mean BNP in patients with cardiac chest pain was significantly greater than mean BNP for patients with non-cardiac chest pain (P4 0.0001). BNP was significantly more sensitive than TnT (P ¼ 0.003). However TnT was more specific than BNP (98% vs. 75%, P4 0.0001). Combining BNP and TnT increased sensitivity from 55.6% to 95.6%. Conclusion: Our findings suggest that BNP is more sensitive but less specific than TnT in the diagnostic assessment of acute chest pain. However, combining BNP and TnT was a very satisfactory rule out test (negative predictive accuracy 96%) for excluding chest pain that had a cardiac origin.

Background: Physical function and exercise capacity decline with age and are a major source of disability in older people. Recent evidence suggests a potential role for the renin–angiotensin system in modulating muscle function. We sought to examine the effect of the angiotensin-converting-enzyme (ACE) inhibitor perindopril on physical function in elderly people with functional impairment who had no heart failure or left ventricular systolic dysfunction. Methods: In this double-blind randomized controlled trial, participants aged 65 years and older who had problems with mobility or functional impairment were randomly assigned to receive either perindopril or placebo for 20 weeks. The primary outcome was the change in the 6-minute walking distance over the 20 weeks. Secondary outcomes were changes in muscle function, daily activity levels, self-reported function and health-related quality of life. Results: A total of 130 participants were enrolled in the study (mean age 78.7, standard deviation 7.7 years); 95 completed the trial. At 20 weeks, the mean 6-minute walking distance was significantly improved in the perindopril group relative to the placebo group (mean between-group difference 31.4 m, 95% confidence interval [CI] 10.8 to 51.9 m; p = 0.003). There was a significant impact on health-related quality of life: although the mean score for part 1 of the EQ-5D questionnaire deteriorated over time in the placebo group, quality of life was maintained in the perindopril group, for a between-group difference of 0.09 ( p = 0.046). There were no significant differences between the 2 groups in the other outcomes. Interpretation: Use of the ACE inhibitor perindopril improved exercise capacity in functionally impaired elderly people who had no heart failure and maintained health-related quality of life. The degree of improvement was equivalent to that reported after 6 months of exercise training. (International Standard Randomised Controlled Trial Register no. ISRCTN67679521).

Assess the feasibility of whole body magnetic resonance angiography (WB-MRA) for monitoring global atheroma burden in a population with peripheral arterial disease (PAD). 50 consecutive patients with symptomatic PAD referred for clinically indicated MRA were recruited. Whole body MRA (WB-MRA) was performed at baseline, 6 months and 3 years. The vasculature was split into 31 anatomical arterial segments. Each segment was scored according to degree of luminal narrowing: 0 = normal, 1 =