Xanthine oxidase inhibitors in ischaemic heart disease (original) (raw)
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Circulation, 2002
Background-In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)-derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies. Methods and Results-In 10 CHF patients with normal serum uric acid (UA) levels (315Ϯ42 mol/L) and 9 patients with elevated UA (535Ϯ54 mol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 g/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (PϽ0.05). In a double-blind, crossover design, hyperuricemic CHF patients were randomly allocated to allopurinol 300 mg/d or placebo for 1 week. In 14 patients (UA 558Ϯ21 mol/L, range 455 to 743 mol/L), treatment reduced UA by Ͼ120 mol/L in all patients (mean reduction 217Ϯ15 mol/L, PϽ0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (ϩ24%, Pϭ0.027) and legs (ϩ23%, Pϭ0.029).
Circulation, 2015
Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ≤40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, -4.2 [-4.9, -3.5] mg/dL and -3.5 [-4.2, -2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% ...
Life Sciences, 2008
Xanthine oxidase (XO) expression is increased in the failing heart, and animal studies in rodents and dogs showed that XO inhibition with allopurinol can improve left ventricular (LV) function and myocardial oxygen efficiency in the failing heart. The purpose of this study was to determine whether chronic XO inhibition by allopurinol or febuxostat, an investigational, potent non-purine, selective inhibitor of XO, could prevent or treat the progression of congestive heart failure (CHF) induced by coronary artery ligation in rabbits, a species that exhibits low intrinsic XO activity similar to humans. One day after coronary ligation, rabbits were assigned to one of four groups (n =7-8/group): control group (vehicle for 49 days), early treatment (prevention) group (febuxostat for 49 days), and two delayed-treatment groups (vehicle for 21 days followed by either febuxostat or allopurinol for 28 days). An echocardiogram of the LV was obtained on Days 0 (prior to surgery), 21, and 49. Control rabbits developed CHF by Day 21 (significant reduction in LV shortening fraction and ejection fraction, thinning of the LV posterior wall, and increases in LV internal dimensions and end-diastolic volume). Early preventive treatment with febuxostat significantly lessened the reduction of LV function when compared to vehicle on both Days 21 and 49. These cardiac functional improvements were accompanied by moderately less severe changes in LV dimensional parameters relative to vehicle controls. In contrast, when treatments with XO inhibitors were started after the establishment of CHF, no significant relative improvements in cardiac functional or dimensional parameters were observed. These results suggest that chronic preventive treatment with an XO inhibitor initiated shortly after myocardial infarction can delay or prevent the onset of CHF, and that XO inhibition initiated after establishment of the disease does not offer cardiac protection. In contrast to previous rodent studies which do suggest a cardiovascular (CV) benefit of delayed XO inhibition, the results of this rabbit study are in keeping with those of recently completed studies in severe CHF patients treated with oxypurinol, the active metabolite of allopurinol, in which no clinical benefit was observed. This may be due to the fact that rodents have relatively high levels of XO activity, while the levels in rabbits and humans are intrinsically low, suggesting that the rabbit may be the preferred model for investigating the role of XO in CV diseases.
Xanthine Oxidase Inhibitors in Heart Failure: Where Do We Go From Here?
Circulation, 2015
A A Aff ff ffai a rs s s M M Medical Center, Miami, FL; 3 In In nte te ter r rdisciplinary Stem C C Cel el ell Institute, University o Mi Mi Miam am ami Mi Mi Mill l e e er S Sch hoo oo ool of f M M Med d dic ic ici ine e e, M M Mia ia ami mi mi, FL FL FL Ad Ad Add d dress f f for C C Correspo d d ndence: by guest on October 2, 2016 http://circ.ahajournals.org/ Downloaded from
Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathy
Journal of Cellular and Molecular Medicine, 2009
In this study, we investigated the effect of the xanthine oxidase (XO) inhibitor, allopurinol (ALP), on cardiac dysfunction, oxidative-nitrosative stress, apoptosis, poly(ADP-ribose) polymerase (PARP) activity and fibrosis associated with diabetic cardiomyopathy in mice. Diabetes was induced in C57/BL6 mice by injection of streptozotocin. Control and diabetic animals were treated with ALP or placebo. Left ventricular systolic and diastolic functions were measured by pressure–volume system 10 weeks after established diabetes. Myocardial XO, p22phox, p40phox, p47phox, gp91phox, iNOS, eNOS mRNA and/or protein levels, ROS and nitrotyrosine (NT) formation, caspase3/7 and PARP activity, chromatin fragmentation and various markers of fibrosis (collagen-1, TGF-β, CTGF, fibronectin) were measured using molecular biology and biochemistry methods or immunohistochemistry. Diabetes was characterized by increased myocardial, liver and serum XO activity (but not expression), increased myocardial ROS generation, p22phox, p40phox, p47phox, p91phox mRNA expression, iNOS (but not eNOS) expression, NT generation, caspase 3/7 and PARP activity/expression, chromatin fragmentation and fibrosis (enhanced accumulation of collagen, TGF-β, CTGF and fibronectin), and declined systolic and diastolic myocardial performance. ALP attenuated the diabetes-induced increased myocardial, liver and serum XO activity, myocardial ROS, NT generation, iNOS expression, apoptosis, PARP activity and fibrosis, which were accompanied by improved systolic (measured by the evaluation of both load-dependent and independent indices of myocardial contractility) and diastolic performance of the hearts of treated diabetic animals. Thus, XO inhibition with ALP improves type 1 diabetes-induced cardiac dysfunction by decreasing oxidative/nitrosative stress and fibrosis, which may have important clinical implications for the treatment and prevention of diabetic cardiomyopathy and vascular dysfunction.
Journal of Cardiac Failure, 2005
Background: We examined the effect of fixed-dose combined isosorbide dinitrate/ hydralazine HCl (ISDN/HYD) on event free survival (EFS) and quality of life (QoL) over time as well as the effects in subgroups of the African American population (AA) with advanced heart failure in A-HeFT. Methods: 1,050 AA patients with NYHA class III-IV heart failure with dilated ventricles received either fixed-dose ISDN/HYD or placebo added to background neurohormonal blockade. Time to death or first hospitalization for heart failure measured as event-free survival (EFS) by Kaplan Meier curve, and QoL over time were compared between groups. Subgroup analysis of treatment effect by age, gender, systolic blood pressure, baseline renal function, presence of diabetes mellitus, etiology of heart failure, and medication usage was also performed. Results: Overall, there was a 43% improvement in survival (HR ϭ 0.57, p ϭ 0.01) and a significant improvement in the primary composite score endpoint in the fixed-dose ISDN/HYD group. When EFS was compared between groups, EFS in the ISDN/HYD group was significantly improved (HR ϭ 0.61, p ϭ 0.001); importantly, this benefit emerged early, (50 days of treatment) and was sustained. At the first measurement after randomization (90 days), QoL scores were significantly better in the ISDN/HYD group and this benefit was sustained for the duration of follow-up. Death due to heart failure was reduced by 49% (p ϭ 0.009) and death due to pump failure was reduced by 74% (p ϭ 0.012). Subgroup analysis by age, gender, systolic BP, diabetes, baseline renal insufficiency, etiology of heart failure, and concomitant medications showed consistent treatment benefit of ISDN/ HYD on the primary composite score, end point, and on all cause mortality in all subgroups examined. Conclusion: Thus the benefit of fixed-dose ISDN/HYD added to standard neurohormonal blockade benefited all subgroups, regardless of clinical characteristics or background therapy, and was apparent both early, probably as a result of improved hemodynamics, and late, consistent with a favorable effect on cardiovascular structural remodeling.