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

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

966-45 QT Dispersion in Essential Hypertension

Increased QT dispersion (QTd) reflects regional variation in ventricular repolarisation, and has been shown in heart failure and hypertrophic cardiomyopathy to relate to an increased incidence of sudden death. As essential hypertensives (EH) are also at increased risk of sudden death we aimed to determine whether increased QTd is found in those EH who are known to be at the highest risk of sudden death. In 50 EH we measured QTd (maximum corrected QT interval minus minimum corrected QT interval), echocardiographic left ventricular mass index (LVMI) (n=46 as 4 patients non-echogenic), office systolic and diastolic blood pressure (SSP, DSP), and 24 hour ambulatory systolic and diastolic blood pressure (24 SSP, 24 DSP) (n=40). Univariate analysis demonstrated no relationship between QTd and age, sex, height, weight, 24 SSP or 24 DBP. Significant relationships existed between QTd and LVMI (R2=0.25, P<0.001), SSP (R2=0.16, P<0.01), DSP (R2=0.08, P<0.05). Multiple linear regression analysis revealed the only relationships to QTd were LVMI (p<0.01) and SSP (p<0.05). Excluding 4 patients with electro-cardiographic left ventricular hypertrophy (ECG-LVH) from the analysis a significant relationship between QTd and LVMI (R2=0.13, P<0.05) and SSP (R2=0.10, P<0.05) persists. These demonstrate that increased QTd is found in EH with the highest risk of sudden death (greatest SSP and LVMI). This relationship persists in the absence of ECG-LVH. Further study of QTd, as a predictor of sudden death in EH is warranted

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

A randomized controlled trial of dapagliflozin on left ventricular hypertrophy in people with type two diabetes:The DAPA-LVH Trial

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: NCT0295681

Allopurinol in Patients with Pulmonary Hypertension Associated with Chronic Lung Disease.

BACKGROUND: Oxidative stress (OS) has been implicated in the development of pulmonary hypertension (PH) and ventricular hypertrophy. Xanthine oxidase is a well-recognised source of reactive oxygen species, which lead to OS. The aim of this proof of concept study was to assess whether allopurinol (xanthine oxidase inhibitor) would reduce right ventricular mass (RVM) in patients with PH-associated chronic lung disease (PH-CLD). METHODS: We conducted a randomised, double-blind, parallel-group, placebo-controlled trial in patients with PH-CLD (93% COPD, 7% IPF) who were randomly assigned to receive allopurinol or placebo for 12 months. The primary outcome was the mean change in RVM, as assessed by cardiac magnetic resonance imaging (CMRI). Secondary outcomes included quality of life (QOL), spirometry and six-minute walk test (6MWT). RESULTS: Seventy-one patients were recruited: mean age 71 years, mean pulmonary arterial pressure 30 mm Hg, FEV1 60% and resting SpO2 96%. After 12 months, there was no significant difference in the change in RVM from baseline (allopurinol 1.85g vs placebo 0.97g with mean difference 0.88g, CI -4.77 to 3.01, p =0.7). There were also no significant changes in other cardiac parameters measured on MRI, in QOL, spirometry and 6MWT. Subgroup analysis showed that allopurinol significantly reduced RVM compared to placebo with -6.16g vs 0.75g and mean difference 6.92g (CI 1.14 to 12.69, p = 0.02) in COPD patients with more severe airflow limitation. CONCLUSION: Allopurinol had no overall impact on patients with PH-CLD but had potential benefit in COPD patients with more severe airflow limitation