Tommasa Vicario

Incidence of Myocardial Infarction and Vascular Death in Elderly Patients With Atrial Fibrillation Taking Anticoagulants: Relation to Atherosclerotic Risk Factors

BACKGROUND Recent findings suggest that patients with atrial fibrillation (AF), in addition being at thromboembolic risk, are at risk of myocardial infarction (MI). Our aim was to investigate predictors of MI and cardiovascular death in a cohort of patients with AF who were taking anticoagulants. METHODS We prospectively followed up 1,019 patients with AF for a median of 33.7 months (3,223 person-years). All patients were treated with oral vitamin K antagonists. Primary outcome was a composite end point of cardiovascular events (CVEs) including fatal/nonfatal MI, cardiac revascularization, and cardiovascular death. RESULTS The mean age of the patients was 73.2 years, and 43.8% were women. At follow-up, 111 CVEs (3.43%/y) had occurred: 47 fatal-nonfatal MI/revascularization and 64 cardiovascular deaths. In addition, 31 stroke/transient ischemic attacks (0.96%/y) were recorded. Patients experiencing CVEs were older (P < .001) and had a higher prevalence of metabolic syndrome (MetS) (P = .005), heart failure (P = .001), and prior cardiac (P < .001) and cerebrovascular events (P < .001). On a Cox proportional hazard analysis, age (hazard ratio [HR], 1.083; 95% CI, 1.053-1.113; P < .001), smoking (HR, 2.158; 95% CI, 1.193-3.901; P = .011), history of cerebrovascular (HR, 1.704; 95% CI, 1.119-2.597; P = .013) and cardiac (HR, 1.658; 95% CI, 1.105-2.489; P = .015) events, MetS (HR, 1.663; 95% CI, 1.107-2.499; P = .014), heart failure (HR, 1.584; 95% CI, 1.021-2.456; P = .040), and male sex (HR, 1.499; 95% CI, 1.010-2.223; P = .044) predicted CVEs. CONCLUSIONS Patients with AF still experience a high rate of CVEs despite receiving anticoagulant treatment. MetS is a common clinical feature in patients with AF, which increases the risk of CVEs. A holistic approach is needed to reduce the cardiovascular risk in patients with AF. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01882114; URL: www.clinicaltrials.gov.

Inadequate anticoagulation by Vitamin K Antagonists is associated with Major Adverse Cardiovascular Events in patients with atrial fibrillation

BACKGROUND Time in therapeutic range (TTR) reflects the quality of anticoagulation and is inversely correlated with ischemic stroke in atrial fibrillation (AF) patients. Few data on the relationship between TTR and myocardial infarction (MI) are available. We investigated the association between TTR and Major Adverse Cardiovascular Events (MACE) in a cohort of anticoagulated AF patients. METHODS We calculated TTR for 627 AF patients on vitamin K antagonists, who were followed for a median of 30.8 months (1755 patients/year). The primary outcome was a combined endpoint of MACE including fatal/nonfatal MI and cardiovascular death. RESULTS Mean age was 73.3 (±8.2) years, and 40.2% were women. During follow-up, we recorded 67 events: 19 stroke/TIA (1.1%/year) and 48 MACE (2.9%/year): 24 MI and 24 cardiovascular deaths. The cohort was categorized according to tertiles of TTR values: TTR 13-58%, 59-74%, and 75-100%. There was a significant increased rate of MACE across tertiles of TTR (Log-Rank test: p<0.001). On Cox proportion hazard analysis, the 2nd vs. 1st tertile of TTR (p=0.002, hazard ratio [HR] 0.347, confidence interval [CI] 95% 0.177-0.680), 3rd vs. 1st tertile of TTR (p<0.001, HR 0.164, CI 95% 0.067-0.402), age (p<0.001, HR 1.094, CI 95% 1.042-1.148), history of stroke/TIA (p=0.015, HR 2.294, CI 95% 1.172-4.490) and smoking (p=0.003, HR 3.450, CI 95% 1.532-7.769) predicted MACE. CONCLUSION TTR was an independent predictor of MACE in our cohort of AF patients. Our findings suggest that a good anticoagulation control is necessary to reduce not only the risk of stroke but also that of MACE.

Rosuvastatin reduces platelet recruitment by inhibiting NADPH oxidase activation

Rosuvastatin increased vascular endothelial NO and attenuated platelet activation after ischemia-reperfusion in mice; nevertheless, the influence of rosuvastatin on the activation of human platelets and the underlying mechanism has never been investigated. In an in vitro study platelets from 8 healthy donors were incubated with scalar concentrations of rosuvastatin (1-10 μM) before activation. Platelet recruitment (PR), that mimics the propagation of platelet aggregation and is dependent upon isoprostane formation, was investigated. PR was inhibited by rosuvastatin in concentration-dependent manner concomitantly with down-regulation of platelet release of the pro-thrombotic molecule CD40L. This effect was associated with lower production of platelet reactive oxygen species (ROS), isoprostane and activation of the glycoprotein IIb/IIIa and was counteracted by exogenous addition of isoprostanes. Conversely, rosuvastatin concentration-dependently increased platelet NO. Platelet isoprostane formation mainly depends from NADPH oxidase. Rosuvastatin concentration-dependently inhibited platelet sNOX2-dp release, a specific marker of NADPH oxidase activation, PKC phosphorylation and p47(phox) translocation from cytosol to membranes. In an ex vivo study 10 hypercolesterolemic patients were randomly allocated to diet or rosuvastatin (20 mg). We observed that as early as 2h after rosuvastatin PR, platelet isoprostanes formation, platelet CD40L and sNOX2-dp decreased while platelet NO increased; no changes were detected in diet-assigned patients. This study shows that in vitro rosuvastatin impairs platelet activation via inhibition of NOX2-derived oxidative stress. This effect, which is associated ex vivo with acute inhibition of platelet activation, suggests that rosuvastatin behaves as an antiplatelet drug.

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.

Does Mediterranean Diet Reduce Cardiovascular Events and Oxidative Stress in Atrial Fibrillation

Atrial fibrillation (AF) is characterized by enhanced oxidative stress and is complicated by cardiovascular events (CVEs), which are only partially prevented by anticoagulant treatment. The Mediterranean diet (Med-Diet) has a positive effect on atherosclerotic progression. In a prospective cohort of 709 anticoagulated AF patients, adherence to Med-Diet was assessed to investigate whether Med-Diet may reduce CVEs by lowering oxidative stress. The cohort was divided into three groups according to the Med-Diet score: low (0-3 points), medium (4-6 points), and high (7-9 points) adherence. During a mean follow-up of 39.9 months (2604.8 patients/year), we registered 72 (2.8%/year) CVEs: 23.4% in the low-adherence group, 8.4% in the intermediate-adherence group, and 5.3% in the high-adherence group (p<0.001). There were no differences in time in the therapeutic range among groups. The Med-Diet score was inversely correlated with sNOX2-dp (soluble NOX2-derived peptide; Rs: -0.297, p<0.001) and F2-isoprostanes (F2-IsoP; Rs: -0.411, p<0.001). Median values of sNOX2-dp (p<0.001) and F2-IsoP progressively decreased across groups (p<0.001). A Cox regression analysis showed that the Med-Diet score (HR: 0.771, p=0.001), F2-IsoP (HR: 1.002, p=0.004), and heart failure (HR: 1.876, p=0.024) predicted CVEs. In conclusion, these findings raise the hypothesis that adherence to Med-Diet could be associated with a reduction of CVEs, through an antioxidant effect, as shown by a concomitant downregulation of Nox2 and decreased excretion of F2-IsoP.

Different behaviour of NOX2 activation in patients with paroxysmal/persistent or permanent atrial fibrillation

Background NOX2, the catalytic subunit of NADPH oxidase, is suggested to play a role in favouring the occurrence of atrial fibrillation (AF) after cardiac surgery via formation of reactive oxidant species. However, its role in spontaneous AF is still unclear. Objective To define the role of NOX2 and isoprostanes, a marker of oxidative stress, in the different settings of AF. Methods The study was performed on 174 patients with AF (82 with paroxysmal/persistent AF and 92 with permanent AF) and 90 controls matched for sex, age and atherosclerotic risk factors. Urinary isoprostanes and serum levels of soluble NOX2-derived peptide (sNOX2-dp) were measured in each patient. Results Urinary isoprostanes and sNOX2-dp concentrations were significantly higher in patients with paroxysmal/persistent AF than in those with permanent AF and controls. Compared with controls, patients with permanent AF showed a weak increase in sNOX2-dp and no difference in isoprostanes. Multivariable analyses demonstrated that baseline values of sNOX2-dp and urinary isoprostanes were independently associated with the type of AF (paroxysmal/persistent vs permanent; β=−224, p=0.007 and β=−231, p=0.005, respectively). A significant correlation between sNOX2-dp levels and urinary excretion of isoprostanes was also detected (R=0.707, p<0.001). Conclusions This study provides evidence that NOX2 is upregulated only in patients with paroxysmal/persistent AF and is responsible for overproduction of isoprostanes. This finding warrants further study to see if inhibition of NOX2 may reduce the risk of paroxysmal/persistent 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.

Mediterranean diet reduces thromboxane A2 production in atrial fibrillation patients

BACKGROUND & AIMS Platelet activation plays a major role in cardiovascular events (CVEs). Mediterranean diet (Med-Diet) reduces the incidence of stroke and myocardial infarction but it is still unclear if it affects platelet activation. Aim of the study was to evaluate the effect of Med-Diet on the urinary excretion of 11-dehydro-thromboxane (Tx) B2, a marker of in vivo platelet activation, in patients with atrial fibrillation (AF). METHODS Prospective observational cohort study including 801 non-valvular AF patients on chronic treatment with warfarin/acenocumarol referring to I Medical Clinic - Atherothrombosis Center of Sapienza University of Rome, Italy, from February 2008 to December 2013. Adherence to Med-Diet was evaluated by a short nine-items dietary questionnaire. Urinary excretion of 11-dehydro-TxB2 was measured in all patients. RESULTS Mean follow-up was 33.9 (±19.8) months, yielding 2223 patient/year of observation. Mean age of patients was 73.3 (±8.9) years, 43.7% were female. Median value of urinary TxB2 was 105.5 [60.0-190.0] ng/mg creatinine. We found a significant inverse correlation between total Med-Diet score and 11-dehydro-TxB2 values (Rs: -0.356, p < 0.001). In a multivariable stepwise linear regression analysis, history of stroke/TIA (β = 0.146, p = 0.003), olive oil (β = -0.130, p = 0.007), wine (β = -0.102, p = 0.036) and antiplatelet drugs (β = -0.098, p = 0.045) were independently associated to 11-dehydro-TxB2. We found no differences in the rate of ischemic or bleeding events across tertiles of Med-Diet score during follow-up. CONCLUSIONS Med-Diet adherence is inversely associated to urinary excretion of 11-dehydro-TxB2, suggesting that Med-Diet may favorably affect platelet function in AF patients. Clinical Trial Registration: ClinicalTrials.gov NCT01882114.

Vitamin E Serum Levels and Bleeding Risk in Patients Receiving Oral Anticoagulant Therapy: a Retrospective Cohort Study

Background Hemorrhagic risk assessment is a crucial issue in patients with nonvalvular atrial fibrillation (NVAF) who are receiving oral anticoagulant therapy (OAT). Our aim was to analyze the relationship between vitamin E, which possesses anticoagulant properties, and bleeding events in NVAF patients. Methods and Results In this retrospective observational study we analyzed baseline serum cholesterol‐adjusted vitamin E (vit E/chol) levels in 566 consecutive patients (59% males, mean age 73.6 years) receiving OAT followed up for a mean time of 22 months. Mean time in therapeutic INR range (TTR) was 64%. The overall incidence rate of any bleeding event was 9.2/100 person‐years. Compared to patients who did not bleed, those who experienced bleeding events (n=92, 73 minor and 15 major bleedings and 4 cerebral hemorrhages according to International Society on Thrombosis and Haemostasis [ISTH] ) classification) showed a significant difference for history of coronary heart disease (P=0.039), HAS‐BLED score (P=0.002), and vit E/chol levels (P<0.001). Higher vit E/chol serum levels were found in patients who bled compared to those who did not (5.27±1.93 versus 4.48±1.97 μmol/cholesterol; P<0.001), with a progressive increase from minor (5.16±1.91 μmol/mmol cholesterol, P=0.006) to major bleedings (5.72±2.0 μmol/mmol cholesterol, P=0.008). A Cox proportional hazard model demonstrated that serum vit E/chol quartiles (global P=0.0189) and HAS‐BLED scores (P=0.005) predicted bleeding events. Conclusions In a NVAF population being treated with warfarin, serum vitamin E predicted hemorrhagic events. Further study is necessary to see if the relationship between serum levels of vitamin E and bleeding is still maintained with the use of new anticoagulants. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier NCT01882114.

Relationship between Mediterranean diet and time in therapeutic range in atrial fibrillation patients taking Vitamin K antagonists

AIMS It is unclear if atrial fibrillation (AF) patients treated with oral vitamin K antagonists (VKAs) must follow a specific diet to avoid interference with anticoagulation. The aim of this study was to assess if Mediterranean diet (Med-Diet) may affect quality of anticoagulation, as expressed by the time in therapeutic range (TTR). METHODS AND RESULTS A prospective observational study including 553 non-valvular AF patients. Time in therapeutic range was calculated for all patients treated with VKAs, and adherence to Med-Diet was evaluated with a validated nine-item dietary questionnaire. Cardiovascular events (CVEs), such as cardiovascular death and fatal/non-fatal stroke or myocardial infarction, and bleedings were recorded. The median follow-up was 31.6 months. The median number of international normalized ratios for each patient was 63.0 (35.0-98.0) and 38 730 blood samples were analysed. In the whole cohort, the mean TTR was 65.5 ± 17.8%. The mean Med-Diet score was 5.19 ± 1.6, with frequent use of olive oil (90.1%), fruits (88.4%), and vegetables (69.3%) and low meat intake (71.2%). There were no differences among tertiles of Med-Diet score regarding TTR. A multivariable linear regression analysis showed that diabetes (β: -0.105, P = 0.015) and the use of angiotensin converting enzyme inhibitor/angiotensin receptor blockers (β: 0.153, P < 0.001) were associated with TTR. Compared with those without, AF patients with a CVE had significantly lower TTR (65.9 ± 17.9 vs. 59.6 ± 15.9, P = 0.029) and Med-Diet score (5.2 ± 1.5 vs. 4.4 ± 1.9, P = 0.004). A reduction of CVE was observed for each point of the Med-Diet score (hazard ratio 0.790, P = 0.017). CONCLUSION In our cohort of AF patients, Med-Diet is not associated with changes in TTR, and thus can be recommended for AF patients who are taking VKAs.