allopurinol and Atrial-Fibrillation

Oxidative stress could be a possible mechanism and a therapeutic target of atrial fibrillation (AF). However, the effects of the xanthine oxidase (XO) inhibition for AF remain to be fully elucidated. We investigated the effects of a novel XO inhibitor febuxostat on AF compared with allopurinol in hypertension rat model. Five-week-old Dahl salt-sensitive rats were fed either low-salt (LS) (0.3% NaCl) or high-salt (HS) (8% NaCl) diet. After 4 weeks of diet, HS diet rats were divided into three groups: orally administered to vehicle (HS-C), febuxostat (5 mg/kg/day) (HS-F), or allopurinol (50 mg/kg/day) (HS-A). After 4 weeks of treatment, systolic blood pressure (SBP) was significantly higher in HS-C than LS, and it was slightly but significantly decreased by treatment with each XO inhibitor. AF duration was significantly prolonged in HS-C compared with LS, and significantly suppressed in both HS-F and HS-A (LS; 5.8 ± 3.5 s, HS-C; 33.9 ± 23.7 s, HS-F; 15.0 ± 14.1 s, HS-A; 20.1 ± 11.9 s: P<0.05). Ca2+ spark frequency was obviously increased in HS-C rats and reduced in the XO inhibitor-treated rats, especially in HS-F group. Western blotting revealed that the atrial expression levels of Met281/282-oxidized Ca2+/Calmodulin-dependent kinase II (CaMKII) and Ser2814-phosphorylated ryanodine receptor 2 were significantly increased in HS-C, and those were suppressed in HS-F and HS-A. Decreased expression of gap junction protein connexin 40 in HS-C was partially restored by treatment with each XO inhibitor. In conclusion, XO inhibitor febuxostat, as well as allopurinol, could reduce hypertension-related increase in AF perpetuation by restoring Ca2+ handling and gap junction.

Topics: Allopurinol; Animals; Atrial Fibrillation; Calcium Signaling; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Connexins; Disease Models, Animal; Enzyme Inhibitors; Febuxostat; Fibrosis; Gap Junction alpha-5 Protein; Gap Junctions; Hypertension; Male; Myocytes, Cardiac; Oxidation-Reduction; Phosphorylation; Rats, Inbred Dahl; Ryanodine Receptor Calcium Release Channel; Sodium Chloride, Dietary; Xanthine Oxidase

Topics: Aged; Allopurinol; Atrial Fibrillation; Febuxostat; Gout; Gout Suppressants; Humans; Medicare; United States

Gout is associated with a higher risk of atrial fibrillation (AF). Comparative effectiveness of allopurinol or febuxostat for reducing the AF risk is unknown, which was our study's main objective.. We used the 5% Medicare Beneficiary cohort (≥65 years) from 2006 to 2012 to identify people with a new filled prescription for allopurinol or febuxostat, with a baseline period of 365 days without respective medication and without AF. We used 5:1 propensity-matched Cox regression analyses to assess whether allopurinol use differed from febuxostat use regarding the hazard ratio (HR) of incident AF. We found 25 732 eligible episodes in 23 135 beneficiaries. Of these, 2311 incident allopurinol or febuxostat use episodes (9%) ended in incident AF with crude incidence rates of 8.0 and 10.5 per 100 person-years, respectively. In propensity-matched analyses, compared with allopurinol, febuxostat was associated with higher HR of AF, 1.25 [95% confidence interval (CI) 1.05-1.48]. Compared with allopurinol <200 mg/day, febuxostat 80 mg/day was associated with significantly higher HR of AF, 1.62 (95% CI 1.16-2.27), but not febuxostat 40 mg/day or higher allopurinol doses. Compared with 1-180 days of allopurinol use, febuxostat use for 1-180 days was associated with significantly higher HR of AF, 1.36 (95% CI 1.10-1.67), but longer durations were not.. Febuxostat was associated with a higher risk of AF compared with allopurinol in older adults. Increased AF risk was noted with febuxostat 80 mg/day dose and was most evident in the first 6 months of use. These findings need replication.

Topics: Aged; Allopurinol; Atrial Fibrillation; Cohort Studies; Febuxostat; Female; Gout; Gout Suppressants; Humans; Male; Medicare; United States

Topics: Aged; Allopurinol; Atrial Fibrillation; Cardiovascular Diseases; Febuxostat; Humans; Medicare; Risk Factors; United States; Uric Acid

In a canine rapid atrial stimulation model of atrial fibrillation (AF), we have demonstrated an increased production of reactive oxygen species (ROS) along with electrical and structural remodeling. In the present study, we hypothesized that antioxidants can suppress atrial remodeling canines with AF. We therefore evaluated the effect of febuxostat, a xanthine oxidase (XO) inhibitor and a pure antioxidant, on atrial remodeling.AF was produced by performing a 3-week rapid atrial pacing (400 bpm) in 13 dogs divided into three groups: pacing + febuxostat group (n = 5; atrial pacing with 50 mg/day of febuxostat (administration); pacing control group (n = 5; atrial pacing without any drug administration); and non-pacing group (n = 3). Electrophysiological studies were conducted in the first 2 groups every week. Atrial tissue fibrosis was evaluated by Azan and immunofluorescent staining of fibronectin. Oxidative stress was evaluated by DHE and FCF-DA staining.Shortening of the refractory period and increase in AF inducibility appeared gradually in the pacing control group, but such changes were suppressed in the pacing + febuxostat group (P = 0.05). The pacing control group showed increase in fibrosis, which was suppressed in the febuxostat group. In DHE and DCF-DA staining, the pacing control group showed an increase in oxidative stress, which was suppressed in the pacing + febuxostat group. The pacing control group exhibited fibronectin expression, which was suppressed in the pacing + febuxostat group.The antioxidant effect of febuxostat may achieve an inhibition of new-onset AF in canines.

Topics: Animals; Antioxidants; Atrial Fibrillation; Atrial Remodeling; Disease Models, Animal; Dogs; Echocardiography; Febuxostat; Female; Fibronectins; Fibrosis; Gout Suppressants; Heart Atria; Hemodynamics; Oxidative Stress; Reactive Oxygen Species; Xanthine Oxidase

The aim of this study was to evaluate factors of digoxin use and its relation to mortality in ED patients with atrial fibrillation (AF).. The Chinese AF registry enrolled 2016 AF patients from 20 representative EDs, and the period of study was one year. Predictors of digoxin use and its relation to mortality were assessed by logistic and Cox regression analyses.. Digoxin was assigned in 609 patients (30.6%), and younger age, lower body mass index values, and existence of permanent AF, heart failure (HF), chronic obstructive pulmonary disease, and valvular heart disease were identified to be factors associated with digoxin use. During the follow-up, compared to patients without digoxin therapy, digoxin-treated patients had significantly higher risk of all-cause death (17.2% vs. 13.0%, P=0.012) and cardiovascular death (15.1% vs. 6.7%, P<0.001), but similar risk of sudden cardiac death (1.1% vs. 0.7%, P=0.341). However, after adjustment for related covariates, digoxin use was no longer notably associated with increased all-cause mortality (hazards ratio [HR] 0.973, 95% confidence interval [CI] 0.718-1.318) and cardiovascular death (HR 1.313, 95% CI 0.905-1.906). Besides, neutral associations of digoxin treatment to mortality were obtained in relevant subgroups, with no interactions observed between digoxin and gender, HF, valvular heart disease, or concomitant warfarin treatment in mortality risk.. In ED patients with AF, digoxin was more frequently assigned to vulnerable patients with concomitant HF or valvular heart disease, and digoxin use was not related to a significantly increased risk of mortality.

Topics: Age Factors; Aged; Aged, 80 and over; Allopurinol; Anti-Arrhythmia Agents; Atrial Fibrillation; Body Mass Index; Cardiovascular Diseases; Cause of Death; China; Comorbidity; Death, Sudden, Cardiac; Digoxin; Emergency Service, Hospital; Female; Heart Failure; Heart Valve Diseases; Humans; Male; Middle Aged; Mortality; Proportional Hazards Models; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Registries; Risk Factors

To assess the effect of allopurinol use on the risk of incident atrial fibrillation (AF) in the elderly.. We used the 5% random Medicare Claims data from 2006 to 2012 to examine the association of allopurinol use and incident AF in a cohort of patients with an absence of AF at baseline (at least 365 days). Multivariable-adjusted Cox regression analyses compared allopurinol exposed and non-exposed periods for the risk of AF, controlling for age, sex, race, Charlson-Romano comorbidity index and use of statins, diuretics, ACE inhibitors and β-blockers. HR with 95% CIs was calculated. Sensitivity analyses considered a longer baseline period (365 days vs 183 days) and individual comorbidities.. There were 9244 episodes of incident allopurinol use in 8569 beneficiaries, of which 1366 episodes (14.8%) had incident AF. In multivariable-adjusted analyses, allopurinol use was associated with an HR of 0.83 (95% CI 0.74 to 0.93) for incident AF. In a separate multivariable-adjusted model, compared with no allopurinol use, longer allopurinol use durations were associated with a lower HR of AF: 180 days-2 years, 0.85 (95% CI 0.73 to 0.99) and >2 years, 0.65 (95% CI 0.52 to 0.82). Other factors significantly associated with a higher hazard of AF were: age 75-<85 years and ≥85 years, higher Charlson index score and current β-blocker use. Sensitivity analyses confirmed these findings with minimal/no attenuation of HRs.. Allopurinol use was associated with a reduced risk of incident AF in the elderly, especially its use for >6 months duration. Future studies should assess the mechanisms underlying this beneficial effect of allopurinol.

Topics: Administrative Claims, Healthcare; Adrenergic beta-Antagonists; Age Factors; Aged; Aged, 80 and over; Allopurinol; Atrial Fibrillation; Comorbidity; Female; Gout Suppressants; Humans; Incidence; Male; Medicare; Retrospective Studies; Risk Assessment; Risk Factors; United States

Paroxysmal atrial fibrillation (PAF) can increase thrombogenesis risk, especially in the left atrium (LA). The exact mechanism is still unclear.. We assessed the effects of PAF on endothelial function, and investigated if febuxostat (FX) can attenuate endothelial dysfunction by inhibition of xanthine oxidase (XO).. Eighteen male New Zealand white rabbits were divided randomly into sham-operated (S), PAF (P) or FX+pacing (FP) groups. Group P and group FP received rapid atrial pacing (RAP). Group FP was administered febuxostat (FX) for 7days before RAP. Post-procedure, blood samples were collected from the LA, right atrium (RA) and peripheral circulation. Tissues from the LA and RA were obtained. Endothelial dysfunction (thrombomodulin [TM], von Willebrand factor [VWF], asymmetric dimethylarginine [ADMA]), and indirect thrombin generation (thrombin-antithrombin complex [TAT], prothrombin fragment 1+2 [F1.2]) and oxidative stress in atrial tissue (xanthine oxidase [XO], superoxide dismutase [SOD], malondialdehyde [MDA]) were measured using an Enzyme-linked immunosorbent assay. Atrial endothelial expression of TM and VWF was measured by histology/western blotting.. Endothelial dysfunction (TM, VWF, ADMA), TAT generation and oxidative stress (XO, SOD, MDA) in group P were more significant compared with that in group S (p<0.05, respectively). In group P, all of these changes occurred to a greater extent in the LA compared with those in the RA or peripheral circulation. In group FP, FX attenuated endothelial dysfunction and reduced TAT levels by inhibition of XO-mediated oxidative stress. PAF can lead to endothelial dysfunction and TAT generation by XO-mediated oxidative stress. The LA is more susceptible to these effects. FX can attenuate these changes by inhibition XO and XO-mediated oxidative stress.

Topics: Animals; Atrial Fibrillation; Endothelium; Enzyme Inhibitors; Febuxostat; Heart Atria; Male; Oxidative Stress; Rabbits; Xanthine Oxidase

Hyperuricemia/gout and atrial fibrillation (AF) are two pathological conditions that are highly prevalent in type 2 diabetes and share multiple cardiovascular risk factors. However, the relationship between elevated levels of serum uric acid and risk of AF in type 2 diabetes is currently poorly known.. We studied a hospital-based sample of 842 (male/female = 463/379) patients with type 2 diabetes discharged from our Division of Endocrinology during 2007-2011. Hyperuricemia was defined as a serum uric acid level >7 mg/dl for men and >6 mg/dl for women or allopurinol use. The diagnosis of AF was confirmed in affected participants on the basis of ECGs and medical history by experienced cardiologists.. Overall, 243 (28.9 %) patients had hyperuricemia and 91 (10.8 %) patients had persistent or permanent AF. Compared with those with normal serum uric acid levels, patients with hyperuricemia had a remarkably greater prevalence of AF (20.6 vs. 7.1 %; p < 0.001). Hyperuricemia was significantly associated with an increased risk of prevalent AF (odds ratio 3.41, 95 % CI 2.19-5.32; p < 0.001). Adjustments for age, sex, smoking, hemoglobin A1c, hypertension status, chronic kidney disease, chronic obstructive pulmonary disease and previous histories of hyperthyroidism, ischemic heart disease and valvular heart diseases did not weaken this association (adjusted-odds ratio 6.27, 95 % CI 1.82-21.5; p < 0.01).. These results indicate that hyperuricemia is associated with an increased prevalence of AF in hospitalized patients with type 2 diabetes, independently of multiple risk factors and potential confounders.

Topics: Aged; Aged, 80 and over; Allopurinol; Atrial Fibrillation; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Electronic Health Records; Female; Gout; Gout Suppressants; Hospitalization; Hospitals, University; Humans; Hyperuricemia; Italy; Male; Middle Aged; Prevalence; Retrospective Studies; Risk; Uric Acid

Oxidative stress could be a possible mechanism and a therapeutic target of atrial fibrillation (AF). Xanthine oxidase (XO) inhibition reduces oxidative stress, but the effects of XO inhibitor on AF have not been evaluated. Hence, we assessed the effects of XO inhibitor, allopurinol, on progression of atrial vulnerability in dogs associated with tachycardia-induced cardiomyopathy.. The dogs were subjected to atrial tachypacing (ATP, 400 bpm) without atrioventricular block for 4 weeks. The dynamics of atrial-tachycardia remodeling were evaluated in allopurinol-treated dogs (ALO, n = 5), placebo-treated controls (CTL, n = 6), and sham-operated dogs (n = 6). In CTL dogs, 4 weeks of ATP significantly increased AF duration (DAF; from 0.2 ± 0.2 seconds to 173 ± 67 seconds, P < 0.05) and decreased atrial effective refractory period (ERP; from 152 ± 9 milliseconds to 80 ± 4 milliseconds at a cycle length of 350 milliseconds, P < 0.01). Allopurinol attenuated the ATP effects on ERP (118 ± 6 milliseconds, P < 0.01) or DAF (0.6 ± 0.3 seconds, P < 0.05). In CTL dogs, ATP-induced rapid ventricular responses decreased left ventricular ejection fraction (LVEF; from 58.6 ± 0.1 to 23.5 ± 2.4%, P < 0.01), and increased left atrial diameter (LAD; from 17 ± 1 mm to 24 ± 1 mm, P < 0.01). ATP increased atrial fibrosis when compared with sham-operated dogs (CTL 10.7 ± 0.8% vs Sham 1.1 ± 0.3%, P < 0.01). Allopurinol suppressed atrial fibrosis (2.3 ± 0.6%, P < 0.01 vs CTL) and eNOS reduction without affecting LVEF (20.6 ± 2.2%, ns) and LAD (23 ± 1 mm, ns).. Allopurinol suppresses AF promotion by preventing both electrical and structural remodeling. These results suggest that XO may play an important role in enhancement of atrial vulnerability, and might be a novel target of AF therapy.

Topics: Action Potentials; Allopurinol; Animals; Antioxidants; Atrial Fibrillation; Atrial Function, Left; Cardiac Pacing, Artificial; Disease Models, Animal; Dogs; Enzyme Inhibitors; Female; Heart Atria; Hemodynamics; Male; Nitric Oxide Synthase Type III; Oxidative Stress; Recovery of Function; Refractory Period, Electrophysiological; Stroke Volume; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling; Xanthine Oxidase

Increased atrial oxidative stress plays an important role in the pathogenesis of atrial fibrillation. A predisposition for atrial fibrillation can be produced by altering the activities of enzymes related to reactive oxygen species metabolism. Microtubule integrity is necessary for cardio-protection; microtubules are involved in many cellular processes, including enzymatic activity. Taxol, a common microtubule stabilizer, can protect cardiac myocytes from oxidative stress. However, its effects on atrial fibrillation remain unknown.. In vitro rabbit heart models of ischemia-, stretch-, and cholinergic agitation-induced atrial fibrillation were developed. Using either a fluorometric or spectrophotometric assay, we measured reactive oxygen species and the activities of oxidative enzymes including nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, xanthine oxidase, mitochondrial electron transport chain complexes I, mitochondrial electron transport chain complexes III, and superoxide dismutase.. Taxol effectively reduced the incidence of ischemia-, stretch- and cholinergic agitation-induced atrial fibrillation in in vitro rabbit heart models by 50%, 60%, and 40%. Moreover, Taxol decreased the level of reactive oxygen species by 46%, 49%, and 70% in ischemia-, stretch- and cholinergic agitation-induced atrial fibrillation models. Additionally, the activities of NADPH oxidase and xanthine oxidase were increased, whereas those of mitochondrial electron transport chain complexes I and III and superoxide dismutase were not affected.. Taxol, a microtubule stabilizer, prevents atrial fibrillation in in vitro atrial fibrillation model using rabbit hearts. This stabilizer most likely prevents atrial fibrillation by reducing the level of reactive oxygen species.

Topics: Animals; Atrial Fibrillation; Cardiotonic Agents; Cholinergic Agents; Electron Transport Complex I; Electron Transport Complex III; Heart Atria; Male; Microtubules; Models, Animal; Myocytes, Cardiac; NADPH Oxidases; Oxidative Stress; Paclitaxel; Rabbits; Random Allocation; Reactive Oxygen Species; Stress, Mechanical; Superoxide Dismutase; Tubulin Modulators; Xanthine Oxidase

Atrial fibrillation (AF) is associated with an increased risk of stroke due almost exclusively to emboli from left atrial appendage (LAA) thrombi. Recently, we reported that AF was associated with endocardial dysfunction, limited to the left atrium (LA) and LAA and manifest as reduced nitric oxide (NO*) production and increased expression of plasminogen activator inhibitor-1. We hypothesized that reduced LAA NO* levels observed in AF may be associated with increased superoxide (O2*-) production.. After a week of AF induced by rapid atrial pacing in pigs, O2*- production from acutely isolated heart tissue was measured by 2 independent techniques, electron spin resonance and superoxide dismutase-inhibitable cytochrome C reduction assays. Compared with control animals with equivalent ventricular heart rates, basal O2*- production was increased 2.7-fold (P<0.01) and 3.0-fold (P<0.02) in the LA and LAA, respectively. A similar 3.0-fold (P<0.01) increase in LAA O2*- production was observed using a cytochrome C reduction assay. The increases could not be explained by changes in atrial total superoxide dismutase activity. Addition of either apocyanin or oxypurinol reduced LAA O2*-, implying that NADPH and xanthine oxidases both contributed to increased O2*- production in AF. Enzyme assays of atrial tissue homogenates confirmed increases in LAA NAD(P)H oxidase (P=0.04) and xanthine oxidase (P=0.01) activities. Although there were no changes in expression of the NADPH oxidase subunits, the increase in superoxide production was accompanied by an increase in GTP-loaded Rac1, an activator of the NADPH oxidase.. AF increased O2*- production in both the LA and LAA. Increased NAD(P)H oxidase and xanthine oxidase activities contributed to the observed increase in LAA O2*- production. This increase in O2*- and its reactive metabolites may contribute to the pathological consequences of AF such as thrombosis, inflammation, and tissue remodeling.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Fibrillation; Heart Atria; NADPH Oxidases; Superoxides; Swine; Xanthine Oxidase