Does the Coexistence of Chronic Obstructive Pulmonary Disease and Atrial Fibrillation Affect Nox2 Activity and Urinary Isoprostanes Excretion?

Chronic obstructive pulmonary disease (COPD) and atrial fibrillation (AF) are characterized by increased oxidative stress, but the impact of the coexistence of COPD and AF on systemic oxidative stress is unclear. We performed a cross-sectional study including 157 outpatients to investigate the Nox2-related oxidative stress in patients with AF and COPD. COPD was defined by an FEV1/FVC <0.70. Oxidative stress was measured by sNox2-dp, a marker of Nox2 activation, and urinary isoprostanes. We divided patients into four groups: Group 0: hypertension (n = 49, controls); Group 1: COPD (n = 42); Group 2: AF (n = 33); and Group 3: COPD and AF (n = 33). Mean age was 68.3 ± 11.0 years, and 46.5% were women. Patients with COPD or AF showed increased levels of sNox2-dp as compared with group 0; sNox2-dp further increased in patients with COPD + AF. In these patients, sNox2-dp was higher than in those with COPD (p < 0.001) or AF (p = 0.003). At multivariable logistic regression analysis, chronic kidney disease, COPD, and AF were associated with sNox2-dp above median. Similar results were observed for urinary isoprostanes. We hypothesize that the coexistence of COPD in AF patients may be associated with an increased systemic oxidative stress by the upregulation of Nox2. Antioxid. Redox Signal. 31, 786-790.

Relationship of PCSK9 and Urinary Thromboxane Excretion to Cardiovascular Events in Patients With Atrial Fibrillation.

BACKGROUND: Soluble proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to be predictive of cardiovascular events (CVEs) in patients who are at high cardiovascular risk. No data on the effect of PCSK9 levels in patients with atrial fibrillation (AF) are available. OBJECTIVES: This study investigated the association between PCSK9 and CVEs in AF as well as the relationship between PCSK9 and urinary 11-dehydro-thromboxane B2 (11-dh-TxB2), a marker of platelet activation. METHODS: We conducted a prospective, single-center cohort study, including 907 patients with AF treated with vitamin K antagonists (3,865 patient-years), to assess CVEs, including fatal and nonfatal myocardial infarction, ischemic stroke, and cardiovascular death. At admission, plasma PCSK9 and urinary 11-dh-TxB2 (n = 852) were measured. The population was divided into tertiles of PCSK9 for the analysis. RESULTS: The mean age of patients was 73.5 ± 8.2 years, and 43.0% were women. At follow-up, 179 CVEs (4.6%/year) occurred: 43 (15.3%), 49 (15.5%), and 87 (28.0%) in the first, second, and third tertiles of PCSK9, respectively (log-rank test p = 0.009). Patients with CVEs had higher median PCSK9 compared with those without (1,500 pg/ml [IQR: 1,000 to 2,300 pg/ml] vs. 1,200 pg/ml [IQR: 827 to 1,807 pg/ml], respectively; p < 0.001). Multivariable Cox regression analysis showed that the third versus the first tertile of PCSK9 (hazard ratio: 1.640; 95% confidence interval: 1.117 to 2.407; p = 0.012), female sex, age, diabetes, smoking, heart failure, previous cerebrovascular and cardiac events, digoxin use, and total cholesterol to high-density lipoprotein cholesterol ratio were associated with CVEs. In 682 patients not treated with antiplatelet therapy, circulating PCSK9 and 11-dh-TxB2 were significantly correlated (Spearman's rho: 0.665; p < 0.001). CONCLUSIONS: Plasma PCSK9 levels are associated with an increased risk of CVEs in patients with AF. The direct correlation between PCSK9 and 11-dh-TxB2 suggests PCSK9 as a mechanism potentially implicated in platelet activation.

Anti Xa oral anticoagulants inhibit in vivo platelet activation by modulating glycoprotein VI shedding.

Anti Xa non-vitamin K oral anticoagulants (anti Xa NOACs) seem to possess antiplatelet effect in vitro, but it is unclear if this occurs also in vivo. Aim of the study was to compare the effect on platelet activation of two anti Xa NOACs, namely apixaban and rivaroxaban, to warfarin, and to investigate the potential underlying mechanism by evaluating soluble glycoprotein GPVI (sGPVI), a protein involved in platelet activation. We performed a cross-sectional including AF patients treated with warfarin (n=30), or apixaban 10mg/day (n=40), or rivaroxaban 20mg/day (n=40). Patients were balanced for sex, age and cardiovascular risk factors. Platelet activation by urinary excretion of 11-dehydro-thromboxane (Tx) B2 and soluble GPVI (sGPVI) were analysed at baseline and after 3 months of treatment. Baseline TxB2 value was 155.2±42.7ng/mg creatinine. The 3 months-variation of urinary excretion of TxB2 was -6.5% with warfarin (p=0.197), -29% with apixaban (p<0.001) and -31% with rivaroxaban (p<0.001). Use of anti Xa NOACs was independently associated to the variation of urinary TxB2 (B: -0.469, p<0.001), after adjustment for clinical characteristics; sGPVI was significantly lower in patients treated with NOACs at 3 months (p<0.001), while only a trend for the warfarin group (p=0.116) was observed. The variation of sGPVI was correlated with that of TxB2 in the NOACs group (Rs: 0.527, p<0.001). In 15 patients (5 per each group) platelet recruitment was significantly lowered at 3 months by NOACs (p<0.001), but not by warfarin. The study provides evidence that anti Xa NOACs significantly inhibit urinary TxB2 excretion compared to warfarin, suggesting that NOACs possess antiplatelet property.

The value of urine albumin in predicting thromboembolic events for patients with non-valvular atrial fibrillation.

BACKGROUND: Accurate risk stratification is important in the management of patients with non-valvular atrial fibrillation (NVAF). However, one cohort study demonstrated an annual ischemic stroke rate of 1.61% in the group of patients classified in "the true low risk" according to CHA2DS2-VASc. We aimed to find out more indicators and evaluate their abilities in predicting thromboembolic events (TE). METHODS: We assigned 58 patients with TE to the thrombosis group, and 157 patients without TE to the non-thrombosis group. The clinical parameters of these patients were subjected to univariate analysis and unconditioned logistic regression analysis for screening the risk factor, which was urine albumin (UA) according to the result. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off point of the UA. Then we formed the CHA2DS2-VASc-UA2 score and made a comparison with CHA2DS2-VASc score. RESULTS: Mean UA of the thrombosis group was significantly higher than that of the non-thrombosis group (0.1g/L vs 0.0g/L, P<0.01). The results of unconditioned logistic regression analysis showed that OR of UA was 40.98 (95% CI: 3.58-468.88, P<0.01). The Area Under the Curve (AUC) of UA was 0.700 with an optimal cut-off point of 0.03g/L. ROC curve analysis result showed that AUC of CHA2DS2-VASc-UA2 score was larger than that of CHA2DS2-VASc score (0.873 vs 0.860, P<0.01). CONCLUSION: UA≥0.03g/L is the independent predictive factor of TE for NVAF patients. And the CHA2DS2-VASc-UA2 score might perform better in predicting TE compared with the CHA2DS2-VASc score.

Age-related increase of thromboxane B2 and risk of cardiovascular disease in atrial fibrillation.

Aging is strictly associated with an increased incidence of cardiovascular events (CVEs) in the general population. Mechanisms underlying the risk of CVEs are still unclear. Platelet activation contributes to the onset of cardiovascular complications. The incidence of atrial fibrillation (AF) increases with age, and the natural history of AF is often complicated by CVEs. We prospectively investigated the relationship between age, urinary thromboxane (Tx) B2, which reflects platelet activation, and CVEs in 833 AF patients. Median TxB2 level was 120 [66-200] ng/mg of urinary creatinine. At multivariable linear regression analysis, age (B: 0.097, p=0.005) and previous MI/CHD (B: 0.069, p=0.047) were associated with log-TxB2 levels. When we divided our population into age classes (i.e. < 60, 60-69, 70-79, ≥ 80 years), we found a significant difference in TxB2 levels across classes (p=0.005), with a significant elevation at 74.6 years. During a mean follow-up of 40.9 months, 128 CVEs occurred; the rate of CVEs significantly increased with age classes (Log-rank test, p < 0.001). TxB2 levels were higher in patients with, compared to those without, CVEs in patients aged 70-79 (p < 0.001) and ≥ 80 (p = 0.020) years. In conclusion, TxB2 levels enhance by increasing age, suggesting that platelet activation contributes to CVEs in elderly patients with AF.

Urinary 11-dehydro-thromboxane B2 is associated with cardiovascular events and mortality in patients with atrial fibrillation.

BACKGROUND: Patients with nonvalvular atrial fibrillation (AF) show high residual cardiovascular (CV) risk despite oral anticoagulants. Urinary 11-dehydro-thromboxane B2 (TxB2) is associated with an increased risk of CV events (CVEs), but its predictive value in patients with anticoagulated AF is unknown. METHODS: A prospective single-center cohort study, including 837 patients with AF, was conducted. Mean time of follow-up was 30.0 months, yielding 2,062 person-years of observation. Urinary 11-dehydro-TxB2 was measured at baseline. The primary end point was the occurrence of a CVE including fatal/nonfatal myocardial infarction and ischemic stroke, transient ischemic attack, cardiac revascularization, and CV death. RESULTS: Mean age of patients was 73.1 years, and 43.6% were women. Median 11-dehydro-TxB2 levels were 100 (interquartile range 50-187) ng/mg of urinary creatinine. Overall, the anticoagulation control was adequate (63.9% of mean time in therapeutic range). A CVE occurred in 99 (11.8%) patients, and 55 were CV deaths. At baseline, 11-dehydro-TxB2 levels were higher in patients with a CVE compared with those without (186 [107-400] vs 98 [52-170], P < .001). An increased rate of CVEs (log-rank test, P < .001) and CV deaths (P < .001) was observed across tertiles of 11-dehydro-TxB2. Cardiovascular events were associated with age (hazard ratios [HR] 1.72 per 1 SD, 95% CI 1.33-2.21, P < .001), diabetes mellitus (HR 1.89, 95% CI 1.20-2.96, P = .005), heart failure (HR 1.60, 95% CI 1.01-2.54, P = .044), history of stroke/transient ischemic attack (HR 1.96, 95% CI 1.25-3.06, P = .003), and 11-dehydro-TxB2 (HR 1.64 per 1 SD, 95% CI 1.42-1.89, P < .001). CONCLUSIONS: Urinary 11-dehydro-TxB2 levels are associated with a residual risk of CVEs and CV mortality in patients with AF despite anticoagulant treatment.

Serum NOX2 and urinary isoprostanes predict vascular events in patients with atrial fibrillation.

There are limited prospective data evaluating the role of urinary F2-IsoP and NOX2 as predictive markers in atrial fibrillation (AF). The aim of this study was to analyse the role of urinary prostaglandin PGF2alpha (8-iso-PGF2α) and NOX2, markers of systemic oxidative stress, in predicting cardiovascular (CV) events and mortality in anticoagulated non-valvular AF patients. This was a prospective study including 1,002 anticoagulated AF patients, followed for a median time of 25.7 months (interquartile range: 14.8-50.9). All major CV events, CV deaths and all-cause deaths were considered as primary outcomes of the study. CV events included fatal/nonfatal ischaemic stroke, fatal/nonfatal myocardial infarction (MI), cardiac revascularisation and transient ischaemic attack (TIA). Oxidative stress biomarkers, such as urinary 8-iso-PGF2α and serum sNOX2-dp, a marker of NOX2 activation, were measured. A CV event occurred in 125 patients (12.5 %); 78 CV deaths and 31 non-CV deaths were registered. 8-iso-PGF2α and sNOX2-dp were correlated (Rs=0.765 p< 0.001). A significant increased cumulative incidence of CV events and CV deaths was observed across tertiles for 8-iso-PGF2α and sNOX2-dp. An increased rate of all-cause death was observed across tertiles of urinary 8-iso-PGF2α. In Cox or Fine and Gray models, 8-iso-PGF2α predicted CV events and CV and non-CV deaths. The addition of tertiles of 8-iso-PGF2α to CHA2DS2-VASc score improved ROC curves for each outcome and NRI for CV events (0.24 [0.06-0.53] p=0.0067). The study shows that in AF patients 8-iso-PGF2α and NOX2 levels are predictive of CV events and total mortality. F2-IsoP may complement conventional risk factors in prediction of CV events.

Analysis of oxidative stress expressed by urinary level of 8-hydroxy-2'-deoxyguanosine and biopyrrin in atrial fibrillation: effect of sinus rhythm restoration.

BACKGROUND: Oxidative stress is considered to contribute to the pathological consequences of atrial fibrillation (AF). We examined the level of oxidative stress in AF patients and changes in its level following sinus rhythm restoration. METHODS: Oxidative stress level was evaluated by urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of oxidative DNA damage, and urinary biopyrrin, an oxidative metabolite of bilirubin. In Study 1, we compared 8-OHdG/creatinine levels between patients with permanent AF (AF-group, n=40) and sinus rhythm (SR-group, n=133). In Study 2, we examined the changes in 8-OHdG and biopyrrin levels in 36 patients with persistent AF following sinus rhythm restoration by electrical or pharmacological cardioversion (n=15) and radiofrequency catheter ablation (n=21). RESULTS: In Study 1, 8-OHdG/creatinine levels were significantly higher in AF-group than in SR-group (19.1 ± 8.6 vs. 12.3 ± 5.5 ng/mg, p<0.001). Multivariate analysis showed that the presence of AF was an independent factor that significantly correlated with 8-OHdG/creatinine level after adjustment for other covariates to oxidative stress (ß=0.36, p<0.001). Sinus rhythm was maintained at the chronic phase in patients of all Study 2 (7.2 ± 5.8 months after cardioversion or catheter ablation). 8-OHdG/creatinine and biopyrrin/creatinine levels at the chronic phase were significantly lower than those before cardioversion or catheter ablation (8.7 ± 3.2 vs. 21.7 ± 15.1 ng/mg, p<0.0001 and 1.7 ± 1.1 vs. 3.0 ± 1.9 mU/mg, p<0.0001). CONCLUSIONS: Oxidative stress level is significantly increased in AF patients, but can be improved by restoration of sinus rhythm. The results suggest that the pathogenic process of AF is promoted by AF itself through the production of oxidative stress.

Role of inflammation and oxidative stress in atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice. Increasing evidence indicates that inflammation and oxidative stress contribute to the pathogenesis of AF, but their role remains poorly defined. In addition, whether inflammation and oxidative stress are associated with particular types of AF is unclear. OBJECTIVE: The purpose of this study was to define the role of inflammation and oxidative stress in AF. METHODS: Using a case-control study design, 305 patients with AF were compared with 150 control patients. AF was categorized into lone and typical AF and further subcategorized as paroxysmal, persistent, or permanent AF. Serum concentrations of interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, vascular endothelial growth factor (VEGF), N-terminal pro-brain (B-type) natriuretic peptide (NTpBNP), and urinary F(2)-isoprostanes, a measure of oxidative stress, were measured. RESULTS: IL-6, IL-8, IL-10, TNF-alpha, MCP1, VEGF, and NTpBNP concentrations were independently associated with AF (all P <.05). However, F(2)-isoprostane excretion was not elevated (P = .50). Graded increases in TNF-alpha [median (interquartile range) 6.8 (3.4-11.3), 8.0 (5.6-10.9), 10.1 (5.7-12.4) pg/mL, P <.05] and NTpBNP [170.6 (67.3-481.9), 681.39 (310.3-1,439.0), 1,179.9 (653.1-2,096.0) pg/mL, P <.001] were seen among the subgroups of paroxysmal, persistent, and permanent AF, respectively. CONCLUSION: Inflammatory biomarkers were significantly increased in patients with AF, supporting a strong association between inflammation and AF. Surprisingly, urinary F(2)-isoprostanes, a sensitive index of systemic oxidative stress in vivo, were not increased in AF overall or in different subtypes of AF.

Atrial fibrillation and changes in serum and urinary electrolyte levels after coronary artery bypass grafting surgery.

OBJECTIVE: Our study was designed to assess the incidence of atrial fibrillation, changes in serum electrolyte concentrations and urinary electrolyte excretion following coronary artery bypass grafting surgery. MATERIAL AND METHODS: A total of 165 patients who underwent elective coronary artery bypass grafting surgery at the Department of Cardiac Surgery (Heart Center) during the period of 2004-2005 were enrolled. Serum K(+), Na(+), Mg(2+), Ca(2+), Cl(-), and P(-) concentrations were measured before cardiopulmonary bypass (CPB), on the arrival to an intensive care unit, and 15-18 hours after the surgery. Urinary excretion of K(+), Na(+), Mg(2+), Ca(2+), Cl(-), and P(-) was estimated 24 hours before the surgery, during the surgery, and 24 hours after the surgery. Cardiac rhythm was monitored throughout the study. All patients randomly were divided into the group 1 (n=55), which received magnesium sulphate infusion, and group 2 (n=110), which did not receive magnesium sulphate. RESULTS: The overall incidence of atrial fibrillation was 27.4%. The patients in the group 1 had significantly higher levels of serum magnesium before CPB and serum chloride after the surgery. Urinary magnesium and calcium excretion was significantly higher in the group 1 during and after the surgery. Before the surgery and 24 hours after the surgery, phosphate excretion was significantly higher in the group 1. CONCLUSIONS: The incidence of atrial fibrillation after myocardial revascularization surgery remains high (27.4%). Serum electrolyte concentrations after myocardial revascularization varied within normal ranges. Magnesium sulphate infusion did not decrease the rate of postoperative atrial fibrillation during the early postoperative period in normomagnesemic patients.

Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects.

OBJECTIVE: To investigate the influence of nonvalvular atrial fibrillation (NVAF) on the pharmacokinetic (PK) properties of the oral direct thrombin inhibitor ximelagatran and its active form, melagatran. METHODS: In an open study, 12 patients with persistent NVAF and 12 age- and gender-matched, healthy control subjects received a 10-min intravenous (i.v.) infusion of 2.66 mg melagatran followed by oral ximelagatran, 36 mg twice daily, for the subsequent five study days. Plasma and urine samples for PK analyses were collected after i.v. and single and repeated oral dosing. RESULTS: The oral absorption of ximelagatran was rapid, and maximum plasma concentrations of ximelagatran (Cmax) were achieved at about 1 h post-dosing. There were no differences between NVAF patients and controls for the area under the plasma concentration versus time curve, Cmax, half-life (t1/2), or bioavailability (F) of melagatran after oral dosing with ximelagatran. The Cmax of melagatran, formed by the rapid bioconversion of ximelagatran, occurred approximately 3 h post-dosing. The geometric means of the t1/2 for melagatran were 4.0 h and 4.2 h for the first and last doses, respectively, in patients, and 3.5 h and 3.7 h, respectively, in controls. Geometric means of F of melagatran following oral administration of ximelagatran were 22% and 24% for the first and last doses, respectively, in patients and 21% and 23%, respectively, in controls. Approximately 80% of the i.v. dose of melagatran was excreted in urine in patients and in controls. CONCLUSION: The PK properties of oral ximelagatran and i.v. melagatran in elderly patients with NVAF are consistent with those in matched, healthy controls.

Evaluation of CYP2D6 oxidation of dextromethorphan and propafenone in a Chinese population with atrial fibrillation.

The objective of this study was to determine the percentage of patients with paroxysmal atrial fibrillation who were poor metabolizers of CYP2D6 in a Chinese population from Hong Kong and to assess the relationship between the dextromethorphan/dextrorphan ratio and the propafenone/5-hydroxypropafenone ratio or the steady-state propafenone concentration. Patients (n = 60) were recruited from the Arrhythmia Clinic at the University of Hong Kong and given dextromethorphan 30 mg. The dextromethorphan and dextrorphan concentrations in urine over the next 8 hours were used to determine metabolizer status. If the metabolic ratio was greater than 0.3, the patient was determined to be a poor metabolizer. In phase 2, patients (n = 38) were given propafenone 150 mg twice daily, and at steady state, the propafenone and 5-OH propafenone plasma concentrations were determined. It was found that 15% of the patients were poor metabolizers of dextromethorphan. There was a significant correlation between the metabolic ratios of dextromethorphan/dextrorphan and propafenone/5-OH propafenone (r = 0.49, p = 0.0019) and between the dextromethorphan/dextrorphan ratio and the concentration of propafenone (r = 0.32, p = 0.05). No correlations were found in the extensive or poor metabolizer subgroups. It was concluded that the percentage of poor metabolizers in atrial fibrillation patients from Hong Kong was much larger than in previous studies of Chinese patients who were not from Hong Kong. The ability to metabolize dextromethorphan to dextrorphan is related to the ability to metabolize propafenone to 5-hydroxypropafenone.

Platelet activation and lipid peroxidation in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: Both platelet activation and lipid peroxidation are potential sources of vasoactive eicosanoids that can be produced via the cyclooxygenase pathway, ie, thromboxane (TX) A2, or by free radical-catalyzed peroxidation of arachidonic acid, ie, isoprostanes. We investigated the biosynthesis of TXA2 and F2-isoprostanes, as reflected by the urinary excretion of 11-dehydro-TXB2 and 8-epi-prostaglandin (PG) F2 alpha respectively, in 62 consecutive patients (30 men, 32 women; mean age, 67 +/- 14 years) with acute ischemic stroke. METHODS: At least two consecutive 6-hour urine samples were obtained during the first 72 hours after onset of symptoms. Urinary eicosanoids were measured by previously described radioimmunoassays. RESULTS: Repeated periods of enhanced thromboxane biosynthesis were found in 52% of patients. Urinary 11-dehydro-TXB2 averaged 221 +/- 207 (mean +/- SD; n = 197; range, 13 to 967) pmol/mmol creatinine in 30 patients treated with cyclooxygenase inhibitors (mostly aspirin) at the time of study versus 392 +/- 392 (n = 186; range, 26 to 2533) in 32 untreated patients (P < .001). The corresponding values for 8-epi-PGF2 alpha excretion were 74 +/- 42 (range, 14 to 206) and 83 +/- 65 (range, 24 to 570) pmol/mmol creatinine (P > .05). The correlation between the two metabolites was moderate in both untreated patients (r = .41, P < .001) and patients with cyclooxygenase inhibitors (r = .31, P < .001). In a multiple regression analysis, increased thromboxane production was independently associated with severity of stroke on admission, atrial fibrillation, and treatment with cyclooxygenase-inhibiting drugs. CONCLUSIONS: We conclude that during the first few days after an acute ischemic stroke (1) platelet activation occurs repeatedly in a cyclooxygenase-dependent fashion; (2) platelet activation is not associated with concurrent changes in isoprostane biosynthesis; (3) platelet activation is independently associated with stroke severity and atrial fibrillation; and (4) isoprostane biosynthesis is largely independent of platelet cyclooxygenase activity.

Urinary 11-dehydro-thromboxane B2: a quantitative index of platelet activation in cerebral infarction.

Thromboxane A2 (TXA2) biosynthesis was studied in healthy subjects, patients with chronic cerebral infarction, patients under chronic aspirin treatment and patients with atrial fibrillation. Urinary 11-dehydro-TXB2, as a major metabolite of TXA2, was measured by radioimmunoassay. The extent of carotid atherosclerosis was determined by B-mode ultrasonography. The mean +/- SD urinary excretion in patients with cerebral infarction and distinct carotid-atherosclerotic lesions (1,725 +/- 239 ng/g creatinine, n = 6) was significantly higher (p less than 0.01) than in healthy subjects (911 +/- 239 ng/g creatinine, n = 44) and patients with cerebral infarction who had no distinct carotid lesion (1,050 +/- 191 ng/g creatinine, n = 6). The urinary excretion of healthy subjects was higher (p less than 0.01) in smokers (1,063 +/- 244 ng/g creatinine, n = 17) than in non-smokers (815 +/- 183 ng/g creatinine, n = 27). Aspirin largely suppressed 11-dehydro-TXB2 excretion (266 +/- 114 ng/g creatinine, n = 7). Three of 5 patients with atrial fibrillation showed very high values. Our results indicated that platelet activation occurs in the atherosclerotic lesions, and that urinary 11-dehydro-TXB2 is the appropriate analytic target for detecting platelet activation.