Role of urate, xanthine oxidase and the effects of allopurinol in vascular oxidative stress

Oxidative stress plays an important role in the progression of vascular endothelial dysfunction. The two major systems generating vascular oxidative stress are the NADPH oxidase and the xanthine oxidase pathways. Allopurinol, a xanthine oxidase inhibitor, has been in clinical use for over 40 years in the treatment of chronic gout. Allopurinol has also been shown to improve endothelial dysfunction, reduce oxidative stress burden and improve myocardial efficiency by reducing oxygen consumption in smaller mechanistic studies involving various cohorts at risk of cardiovascular events. This article aims to explain the role of xanthine oxidase in vascular oxidative stress and to explore the mechanisms by which allopurinol is thought to improve vascular and myocardial indices

Effect of allopurinol on phosphocreatine recovery and muscle function in older people with impaired physical function:a randomised controlled trial

Background: Allopurinol has vascular antioxidant effects and participates in purinergic signalling within muscle. We tested whether allopurinol could improve skeletal muscle energetics and physical function in older people with impaired physical performance. Methods: We conducted a randomised, double blind, parallel group, placebo-controlled trial, comparing 20 weeks of allopurinol 600 mg once daily versus placebo. We recruited community-dwelling participants aged 65 and over with baseline 6-min walk distance of &lt;400 m and no contraindications to magnetic resonance imaging scanning. Outcomes were measured at baseline and 20 weeks. The primary outcome was post-exercise phosphocreatine (PCr) recovery rate measured using 31P magnetic resonance spectroscopy of the calf. Secondary outcomes included 6-min walk distance, short physical performance battery (SPPB), lean body mass measured by bioimpedance, endothelial function and quality of life. Results: In total, 124 participants were randomised, mean age 80 (SD 6) years. A total of 59 (48%) were female, baseline 6-min walk distance was 293 m (SD 80 m) and baseline SPPB was 8.5 (SD 2.0). Allopurinol did not significantly improve PCr recovery rate (treatment effect 0.10 units [95% CI, −0.07 to 0.27], P = 0.25). No significant changes were seen in endothelial function, quality of life, lean body mass or SPPB. Allopurinol improved 6-min walk distance (treatment effect 25 m [95% 4–46, P = 0.02]). This was more pronounced in those with high baseline oxidative stress and urate. Conclusion: Allopurinol improved 6-min walk distance but not PCr recovery rate in older people with impaired physical function. Antioxidant strategies to improve muscle function for older people may need to be targeted at subgroups with high baseline oxidative stress. </p

QT peak prolongation predicts cardiac death following stroke

Cardiac death has been linked in many populations to prolongation of the QT interval (QTe). However, basic science research suggested that the best estimate of the time point when repolarisation begins is near the T-wave peak. We found QT peak (QTp) was longer in hypertensive subjects with LVH. A prolonged “depolarisation” phase, rather than “repolarisation” (T peak to T end) might therefore account for the higher incidence of cardiac death linked to long QT. Hypothesis: We have tested the hypothesis that QT peak (QTp) prolongation predicts cardiac death in stroke survivors. Methods and Results: ECGs were recorded from 296 stroke survivors (152 male), mean age 67.2 (SD 11.6) approximately 1 year after the event. Their mean blood pressure was 152/88 mmHg (SD 29/15mmHg). These ECGs were digitised by one observer who was blinded to patient outcome. The patients were followed up for a median of 3.3 years. The primary endpoint was cardiac death. A prolonged heart rate corrected QT peak (QTpc) of lead I carried the highest relative risk of death from all cause as well as cardiac death, when compared with the other more conventional QT indices. In multivariate analyses, when adjusted for conventional risk factors of atherosclerosis, a prolonged QTpc of lead I was still associated with a 3-fold increased risk of cardiac death. (adjusted relative risk 3.0 [95% CI 1.1 - 8.5], p=0.037). Conclusion: QT peak prolongation in lead I predicts cardiac death after strok

Assessment of proximal pulmonary arterial stiffness using magnetic resonance imaging:effects of technique, age and exercise

INTRODUCTION: To compare the reproducibility of pulmonary pulse wave velocity (PWV) techniques, and the effects of age and exercise on these. METHODS: 10 young healthy volunteers (YHV) and 20 older healthy volunteers (OHV) with no cardiac or lung condition were recruited. High temporal resolution phase contrast sequences were performed through the main pulmonary arteries (MPAs), right pulmonary arteries (RPAs) and left pulmonary arteries (LPAs), while high spatial resolution sequences were obtained through the MPA. YHV underwent 2 MRIs 6 months apart with the sequences repeated during exercise. OHV underwent an MRI scan with on-table repetition. PWV was calculated using the transit time (TT) and flow area techniques (QA). 3 methods for calculating QA PWV were compared. RESULTS: PWV did not differ between the two age groups (YHV 2.4±0.3/ms, OHV 2.9±0.2/ms, p=0.1). Using a high temporal resolution sequence through the RPA using the QA accounting for wave reflections yielded consistently better within-scan, interscan, intraobserver and interobserver reproducibility. Exercise did not result in a change in either TT PWV (mean (95% CI) of the differences: −0.42 (−1.2 to 0.4), p=0.24) or QA PWV (mean (95% CI) of the differences: 0.10 (−0.5 to 0.9), p=0.49) despite a significant rise in heart rate (65±2 to 87±3, p<0.0001), blood pressure (113/68 to 130/84, p<0.0001) and cardiac output (5.4±0.4 to 6.7±0.6 L/min, p=0.004). CONCLUSIONS: QA PWV performed through the RPA using a high temporal resolution sequence accounting for wave reflections yields the most reproducible measurements of pulmonary PWV

Spironolactone for People Age 70 Years and Older With Osteoarthritic Knee Pain:A Proof‐of‐Concept Trial

Objective: To determine whether spironolactone could benefit older people with osteoarthritis (OA), based on a previous study showing that spironolactone improved quality of life. Methods: This parallel-group, randomized, placebo-controlled, double-blind trial randomized community-dwelling people ages ≥70 years with symptomatic knee OA to 12 weeks of 25 mg daily oral spironolactone or matching placebo. The primary outcome was between-group difference in change in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale scores. Secondary outcomes included WOMAC stiffness and physical function subscores, EuroQol 5-domain (EQ-5D) 3L score, and mechanistic markers. Analysis was by intent to treat, using mixed-model regression, adjusting for baseline values of test variables. Results: A total of 421 people had eligibility assessed, and 86 were randomized. Mean ± SD age was 77 ± 5 years and 53 of 86 (62%) were women. Adherence to study medication was 99%, and all participants completed the 12-week assessment. No significant improvement was seen in the WOMAC pain score (adjusted treatment effect 0.5 points [95% confidence interval (95% CI) - 0.3, 1.3]; P = 0.19). No improvement was seen in WOMAC stiffness score (0.2 points [95% CI -0.6, 1.1]; P = 0.58), WOMAC physical function score (0.0 points [95% CI -0.7, 0.8]; P = 0.98), or EQ-5D 3L score (0.04 points [95% CI -0.04, 0.12]; P = 0.34). Cortisol, matrix metalloproteinase 3, and urinary C-telopeptide of type II collagen were not significantly different between groups. More minor adverse events were noted in the spironolactone group (47 versus 32), but no increase in death or hospitalization was evident. Conclusion: Spironolactone did not improve symptoms, physical function, or health-related quality of life in older people with knee OA

Renal and Cardiovascular Effects of sodium–glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF):protocol for a randomised controlled double-blind cross-over trial

Introduction: Type 2 diabetes (T2D) and heart failure (HF) are a frequent combination, where treatment options remain limited. There has been increasing interest around the sodium-glucose co-transporter 2 (SGLT2) inhibitors and their use in patients with HF. Data on the effect of SGLT2 inhibitor use with diuretics is limited. We hypothesise that SGLT2 inhibition may augment the effects of loop diuretics. We hypothesise that the benefits of SGLT2 inhibitors extend beyond those of their metabolic (glycaemic parameters and weight loss) and haemodynamic parameters; that the effects of SGLT2 inhibitors as an osmotic diuretic and on natriuresis may underlie the cardiovascular and renal benefits demonstrated in the recent EMPA-REG study.Methods and Analysis: To assess the effect of SGLT2 inhibitors when used in combination with a loop diuretic, the RECEDE-CHF trial is a single centre, randomised double-blind, placebo-controlled, crossover trial conducted in a secondary care setting within NHS Tayside, Scotland. 34 eligible participants, aged between 18 to 80 years, with stable T2D and CHF will be recruited. Renal physiological testing will be performed at two points (week 1 and week 6) on each arm to assess the effect of 25 mg empagliflozin, on the primary and secondary outcomes. Participants will be enrolled in the trial for a total period between 14 to 16 weeks. The primary outcome will assess the effect of empagliflozin versus placebo on urine output. The secondary outcomes are to assess the effect of empagliflozin on glomerular filtration rate, cystatin C, urinary sodium excretion, urinary protein/creatinine ratio, and urinary albumin/creatinine ratio when compared to placebo.Ethics and Dissemination: Ethics approval was obtained by the East of Scotland Research Ethics Service. Results of the trial will be submitted for publication in a peer-reviewed journal.Registration Details: clinicaltrials.gov: NCT03226457. Registered: July 17, 2017

Towards understanding the clinical significance of QT peak prolongation: a novel marker of myocardial ischemia independently demonstrated in two prospective studies

Background: QT peak prolongation identified patients at risk of death or non-fatal MI. We tested the hypothesis that QT peak prolongation might be associated with significant myocardial ischaemia in two separate cohorts to see how widely applicable the concept was. Methods and Results: In the first study, 134 stroke survivors were prospectively recruited and had 12-lead ECGs and Nuclear myocardial perfusion scanning. QT peak was measured in lead I of a 12-lead ECG and heart rate corrected by Bazett’s formula (QTpc). QTpc prolongation to 360ms or more was 92% specific at diagnosing severe myocardial ischaemia. This hypothesis-generating study led us to perform a second prospective study in a different cohort of patients who were referred for dobutamine stress echocardiography. 13 of 102 patients had significant myocardial ischaemia. Significant myocardial ischaemia was associated with QT peak prolongation at rest (mean 354ms, 95% CI 341-367ms, compared with mean 332ms, 95% CI 327-337ms in those without significant ischaemia; p=0.002). QT peak prolongation to 360ms or more was 88% specific at diagnosing significant myocardial ischaemia in the stress echocardiography study. QT peak prolongation to 360ms or more was associated with over 4-fold increase odds ratio of significant myocardial ischaemia. The Mantel- Haenszel Common Odds Ratio Estimate=4.4, 95% CI=1.2-16.0, p=0.023. Conclusion: QT peak (QTpc) prolongation to 360ms or more should make us suspect the presence of significant myocardial ischaemia. Such patients merit further investigations for potentially treatable ischaemic heart disease to reduce their risk of subsequent death or non-fatal MI

Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART 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