The role of urate and xanthine oxidase in vascular oxidative stress:Future directions

Vascular oxidative stress has been shown to be a potent factor in the pathophysiology of endothelial dysfunction. Despite current optimal evidence-based therapy, mortality from various cardiovascular disorders remains high. The search for newer, novel ways of attenuating endothelial dysfunction has yielded several new and exciting possibilities, one of which is the manipulation of urate levels using xanthine oxidase inhibitors. Agents such as allopurinol have shown marked improvements in vascular endothelial function in various cohorts at risk of cardiovascular events. Most of the evidence so far comes from smaller mechanistic studies. The few large randomized controlled trials have failed to show any significant mortality benefit using these agents. This article highlights the potential avenues of further research such as dose-response, and the potential for these agents to regress left ventricular hypertrophy. The role of newer agents such as febuxostat and oxypurinol are discussed as well as potential reasons why some of the current newer agents have failed to live up to the promising early-phase data. It is crucial that these remaining questions surrounding urate, xanthine oxidase and the role of various agents that affect this important oxidative stress-generating system are answered, and therefore these promising agents should not be discarded prematurely

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

Recursive integral method for transmission eigenvalues

Recently, a new eigenvalue problem, called the transmission eigenvalue problem, has attracted many researchers. The problem arose in inverse scattering theory for inhomogeneous media and has important applications in a variety of inverse problems for target identification and nondestructive testing. The problem is numerically challenging because it is non-selfadjoint and nonlinear. In this paper, we propose a recursive integral method for computing transmission eigenvalues from a finite element discretization of the continuous problem. The method, which overcomes some difficulties of existing methods, is based on eigenprojectors of compact operators. It is self-correcting, can separate nearby eigenvalues, and does not require an initial approximation based on some a priori spectral information. These features make the method well suited for the transmission eigenvalue problem whose spectrum is complicated. Numerical examples show that the method is effective and robust.Comment: 18 pages, 8 figure

Tadalafil in patients with chronic obstructive pulmonary disease:a randomised, double-blind, parallel-group, placebo-controlled trial

SummaryBackgroundPhosphodiesterase-5 (PDE5) inhibitors improve exercise capacity and quality of life in patients with idiopathic pulmonary arterial hypertension. However, whether such beneficial effects take place in selected populations with chronic obstructive pulmonary disease (COPD) remains uncertain. We aimed to assess the effects of tadalafil—a PDE5 inhibitor—on exercise capacity and quality of life in patients with COPD and mild pulmonary hypertension.MethodsWe did a randomised, double-blind, parallel-group, placebo-controlled trial at three centres in Scotland, UK, between Sept 1, 2010, and Sept 1, 2012. Patients with moderate to severe COPD were randomly assigned (1:1), via centralised randomisation with a computer-generated sequence and block sizes of four, to receive daily tadalafil 10 mg or placebo for 12 weeks. Patients, study investigators, outcome assessors, and those administering drugs were masked to group allocation. The primary endpoint was the mean placebo-corrected difference between the baseline and final 6 min walk distance after 12 weeks. We measured change in quality of life at baseline, 8 weeks, and 12 weeks, with standardised questionnaires. Analysis was per protocol and by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01197469.Findings120 patients were randomly assigned to receive tadalafil (n=60) or placebo (n=60), of whom 56 (93%) versus 57 (95%) completed the study. At 12 weeks the difference in 6 min walking distance between the tadalafil and placebo groups was 0·5 m (95% CI −11·6 to 12·5; p=0·937). We recorded no statistically significant changes in quality of life (between-group difference on the St George's Respiratory Questionnaire −2·64 [95% CI −6·43 to 1·15]; Research and Development version 1 short-form-36 4·08 [–1·35 to 9·52]; Minnesota Living with Heart Failure questionnaire −2·31 [–7·06 to 2·45]). 19 (32%) of 60 patients in the treatment group had dyspepsia; the severity of dyspepsia ranged from mild to severe, with four (21%) of 19 patients needing a proton-pump inhibitor. Five (8%) of 60 participants had dyspepsia in the placebo group. Headache was noted in 17 (28%) patients in the treatment group versus 5 (8%) in the placebo group, but was mild in all patients. Two (3%) patients in the treatment group had facial flushing, which resulted in one withdrawal. Other withdrawals within the tadalafil group happened after a transient ischaemic attack and two deaths (ruptured abdominal aortic aneurysm and pneumonia).InterpretationTadalafil does not improve exercise capacity or quality of life despite exerting pulmonary vasodilation.FundingChief Scientist Office for Scotland

Twenty year predictors of peripheral arterial disease (PAD) compared with coronary heart disease (CHD) in the Scottish Heart Health Extended Cohort (SHHEC)

Background Coronary heart disease (CHD) and peripheral arterial disease (PAD) affect different vascular territories. Supplementing baseline findings with assays from stored serum, we compared their twenty-year predictors. Methods and Results Recruited randomly across Scotland 1984-1995 and followed through 2009 for death and hospital diagnoses, of 15 737 disease-free men and women aged 30-75y, 3098 developed CHD (19.7%), and 499 PAD (3.2%). Hazard ratios (HRs) 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 were entered into parsimonious predictive models, tested by c-statistics and NRIs (Net Reclassification Improvements). Many HRs diminished with adjustment and parsimonious modeling, leaving significant survivors. HRs were mostly higher in PAD. New parsimonious models increased the c-statistic and NRI over ASSIGN variables alone, but varied in their components and ranking. CHD and PAD shared seven of the nine factors from ASSIGN: age, sex, family history, socioeconomic status, diabetes mellitus, tobacco smoking, and systolic blood pressure (SBP), (but not total, nor HDL-cholesterol), plus four new ones: NT-pro BNP, cotinine, hsC-Reactive Protein, and cystatin-C. Highest ranked HRs for continuous factors in CHD were: age, total cholesterol, hsTroponin, NT-pro-BNP, cotinine, apolipoprotein A, waist circumference, (…plus ten more); in PAD: age, hsCRP, SBP, expired carbon monoxide, cotinine, socioeconomic status, lipoprotein (a), (…plus five more). Conclusion The mixture of shared with disparate determinants for arterial disease in the heart and the legs implies non-identical pathogenesis–cholesterol dominant in the former–inflammation (hsCRP, diabetes, smoking) in the latter