[Show abstract][Hide abstract] ABSTRACT: Introduction: Peroxiredoxin (PRDX) and Thioredoxin (TRX) are antioxidant proteins that control cellular signalling and redox balance, although their response to exercise is unknown. This study aimed to assess key aspects of the PRDX-TRX redox cycle in response to three different modes of exercise.
Methods: Healthy males (n=10, mean ± SD: age 22 ± 3 yrs) undertook three exercise trials on separate days: two steady-state cycling trials at a moderate (60% MAX; 27 min, MOD) and high (80% MAX; 20 min, HIGH) intensity, and a low volume high intensity interval training trial (10×1 min 90% MAX, LV-HIIT). Peripheral blood mononuclear cells (PBMCs) were assessed for TRX-1 and over-oxidised PRDX (isoforms I-IV) protein expression before, during and 30 minutes following exercise (post+30). The activities of TRX reductase (TRX-R) and the NF-κB p65 subunit were also assessed.
Results: TRX-1 increased during exercise in all trials (MOD +84.5%; HIGH +64.1%; LV-HIIT +205.7%; p<.05), whereas over-oxidised PRDX increased during HIGH only (MOD -28.7%; HIGH +202.9%; LV-HIIT -22.7%; p<.05). TRX-R and NF-κB p65 activity increased during exercise in all trials, with the greatest response in TRX-R activity seen in HIGH (p<.05).
Discussion: All trials stimulated a transient increase in TRX-1 protein expression during exercise. Only HIGH induced a transient over-oxidation of PRDX, alongside the greatest change in TRX-R activity. Future studies are needed to clarify the significance of heightened peroxide exposure during continuous high intensity exercise and the mechanisms of PRDX-regulatory control.
Free Radical Research 12/2014; · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study sought to investigate the relative efficacy and safety of non-vitamin K oral anticoagulants (NOACs) for the treatment of venous thromboembolism (VTE) in cancer patients.
A systematic search of the PubMed, EMBASE, and ClinicalTrials.gov databases identified all multicentre, randomised phase III trials investigating the initial use of NOAC against a vitamin K antagonist (VKA) together with subcutaneous heparin or low molecular weight heparin (upstart) for treatment of VTE. Outcomes of interest were recurrent VTE (deep venous thrombosis or pulmonary embolism), and clinically relevant bleeding.
Four randomised controlled phase III trials were included, comprising a total of 19,060 patients randomised to either NOAC or VKA. For patients with active cancer (N = 759), the analysis on the efficacy outcomes demonstrated a trend in favour of NOAC (OR 0.56, 95% CI 0.28-1.13). Similar, analyses on the safety outcomes comparing NOAC to VKA and enoxaparin demonstrated a trend in favour of NOAC (OR 0.88, 95% CI 0.57-1.35).
Point estimates of the effect size suggest an important estimated beneficial effect of NOAC in the treatment of VTE in cancer, in terms of efficacy and safety, but given the small numbers of patients with cancer in the randomised trials, statistical significance was not achieved.
PLoS ONE 12/2014; 9(12):e114445. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives
Rheumatoid arthritis (RA) is a chronic inflammatory condition with increased all-cause and cardiovascular mortality. Accumulating evidence indicates that the immune and autonomic nervous systems (ANS) are major contributors to the pathogenesis of cardiovascular disease. We performed the first systematic literature review to determine the prevalence and nature of ANS dysfunction in RA and whether there is a causal relationship between inflammation and ANS function.
Electronic databases (Medline, Central and Cochrane Library) were searched for studies of RA patients where autonomic function was assessed.
Forty studies in total were included. ANS function was assessed by clinical cardiovascular reflex tests (CCTs)(n=18), heart rate variability (HRV)(n=15), catecholamines (n=5), biomarkers of sympathetic activity (n=5), sympathetic skin responses (n=5), cardiac baroreflex sensitivity (cBRS) (n=2) and pupillary light reflexes (n=2). 9 small studies reported a ~60% (median, range 20-86%) prevalence of ANS dysfunction (defined by abnormal CCTs) in RA. 73% of studies (n=27/37) reported at least one abnormality in ANS function: parasympathetic dysfunction (n=20/26, 77%), sympathetic dysfunction (n=16/30, 53%) or reduced cBRS (n=1/2, 50%). An association between increased inflammation and ANS dysfunction was found (n=7/19, 37%) although causal relationships could not be elucidated from the studies available to date.
ANS dysfunction is prevalent in ~60% of RA patients. The main pattern of dysfunction is impairment of cardiovascular reflexes and altered HRV indicative of reduced cardiac parasympathetic (strong evidence) and elevated cardiac sympathetic activity (limited evidence). The literature to date is underpowered to determine causal relationships between inflammation and ANS dysfunction in RA.
Seminars in Arthritis and Rheumatism 12/2014; · 3.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Atrial fibrillation and heart failure often coexist, causing substantial cardiovascular morbidity and mortality. β blockers are indicated in patients with symptomatic heart failure with reduced ejection fraction; however, the efficacy of these drugs in patients with concomitant atrial fibrillation is uncertain. We therefore meta-analysed individual-patient data to assess the efficacy of β blockers in patients with heart failure and sinus rhythm compared with atrial fibrillation.
We extracted individual-patient data from ten randomised controlled trials of the comparison of β blockers versus placebo in heart failure. The presence of sinus rhythm or atrial fibrillation was ascertained from the baseline electrocardiograph. The primary outcome was all-cause mortality. Analysis was by intention to treat. Outcome data were meta-analysed with an adjusted Cox proportional hazards regression. The study is registered with Clinicaltrials.gov, number NCT0083244, and PROSPERO, number CRD42014010012.
18 254 patients were assessed, and of these 13 946 (76%) had sinus rhythm and 3066 (17%) had atrial fibrillation at baseline. Crude death rates over a mean follow-up of 1·5 years (SD 1·1) were 16% (2237 of 13 945) in patients with sinus rhythm and 21% (633 of 3064) in patients with atrial fibrillation. β-blocker therapy led to a significant reduction in all-cause mortality in patients with sinus rhythm (hazard ratio 0·73, 0·67–0·80; p<0·001), but not in patients with atrial fibrillation (0·97, 0·83–1·14; p=0·73), with a significant p value for interaction of baseline rhythm (p=0·002). The lack of efficacy for the primary outcome was noted in all subgroups of atrial fibrillation, including age, sex, left ventricular ejection fraction, New York Heart Association class, heart rate, and baseline medical therapy.
Based on our findings, β blockers should not be used preferentially over other rate-control medications and not regarded as standard therapy to improve prognosis in patients with concomitant heart failure and atrial fibrillation.
Menarini Farmaceutica Internazionale (administrative support grant).
[Show abstract][Hide abstract] ABSTRACT: Background
This register-based observational study compares dabigatran to warfarin for secondary stroke prevention in atrial fibrillation patients among both ‘new starters’ on dabigatran and ‘switchers’ to dabigatran from warfarin.
We identified in nationwide Danish registries 2,398 patients with atrial fibrillation and a history of stroke/TIA, making a first-time purchase of dabigatran 110mg bid (D110) and 150mg bid (D150). Patients were categorized as either vitamin K antagonist (VKA) naïve or experienced. Warfarin controls were identified using a complete (for VKA-naïve dabigatran patients) or matched sampling approach (for VKA-experienced dabigatran patients). Subjects were followed for an average of 12.6 months for stroke and transient ischemic attacks. Confounder-adjusted Cox regression models were used to compare event rates between treatments.
Among patients with a history of stroke/ transient ischemic attack and prior VKA experience, switching to dabigatran was associated with an increased stroke/ transient ischemic attack rate for both dabigatran doses compared to continuing on warfarin (D110 hazard ratio [HR] 1.99, 95% confidence interval [CI]: 1.42-2.78; D150 HR 2.34, 95% CI: 1.60-3.41).
Among prior stroke/ transient ischemic attack patients who were new starters on dabigatran or warfarin, the rate of stroke/ transient ischemic attack for both doses of dabigatran was similar to or lower than warfarin (D110 HR 0.64, 95% CI: 0.50-0.80; D150 HR 0.92, 95% CI: 0.73-1.15).
In this register-based study, VKA-experienced patients with a history of stroke or transient ischemic attack who switched to dabigatran therapy had an increased rate of stroke compared to patients persisting with warfarin therapy.
The American Journal of Medicine 12/2014; · 5.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New oral anticoagulants require dosing adjustment according to renal function. We aimed to determine discordance in hypothetical recommended dosing of these drugs using different estimated glomerular filtration rate equations in patients with atrial fibrillation.
Revista Espanola de Cardiologia 11/2014; · 3.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are limited prospective data evaluating the role of urinary F2-IsoP and NOX2 as predictive markers in 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 atrial fibrillation (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.
Thrombosis and Haemostasis 11/2014; 113(2). · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Catheter ablation (CA) of atrial fibrillation (AF) is associated with inflammatory response, endothelial damage and with increased risk of thrombosis. However, whether these processes differ in peripheral and cardiac circulation is unknown.
PLoS ONE 11/2014; 9(11):e111760. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A meta-analysis was performed to evaluate the risk of major bleeding with the use of New Oral Anticoagulants (NOACs).Methods
Randomized controlled trials (RCTs) comparing NOACs (rivaroxaban, dabigatran, apixaban, edoxaban and darexaban) with comparators were selected.ResultsFifty trials included 155,537 patients. Pooled analysis of all NOACs for all indications together demonstrated no significant difference between NOACs and comparators for risk of major bleeding (odds ratio [OR] 0.93, 95% CI 0.79–1.09). Pooled analysis also showed that NOACs caused significantly less major bleeding compared to vitamin K antagonists (VKA) (0.77, 0.64–0.91). The analysis for individual NOACs showed risk of major bleeding were not different with rivaroxaban, apixaban or dabigatran compared to pharmacologically active comparators or VKA. Indication specific analysis showed that NOACs were associated with significantly higher major bleeding after hip surgery (1.43, 1.02–1.99), in patients with acute coronary syndrome (ACS), (compared against placebo) (2.89, 2.01–4.14), and for medically ill patients (2.79, 1.69–4.60). For the treatment of acute venous thromboembolism (VTE) or pulmonary embolism (PE), NOACs were associated with significantly less bleeding (0.63, 0.44–0.90). No significant difference was found between NOACs and comparators in treatment of atrial fibrillation and for extended treatment of VTE.Conclusions
Risk of major bleeding with new oral anticoagulants varies with their indication for use. New agents may be associated with comparatively less major bleeding compared to VKA. NOAC may increase the risk of major bleeding after hip surgery, ACS and acute medically ill patients; but may be associated with less bleeding in treatment of acute VTE/PE.
International Journal of Cardiology 11/2014; · 6.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Atrial fibrillation (AF) confers increased risk of stroke and other thromboembolic events, and oral anticoagulation therefore is the essential part of AF management to reduce the risk of this complication. Until recently, the vitamin K antagonists (VKAs, e.g. warfarin) were the only oral anticoagulants available, acting by decreased synthesis of vitamin K-dependent coagulation factors (II, VI, IX, and X). The VKAs had many limitations: delayed onset and prolonged offset of action, variability of anticoagulant effect among patients, multiple food and drug interactions affecting pharmacological properties of warfarin, narrow therapeutic window, obligatory regular laboratory control, which all made warfarin ‘inconvenient’ both for patients and clinicians. The limitations of VKAs led to development of new class of drugs collectively defined as non-VKA oral anticoagulants (NOACs), which included direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (rivaroxaban, apixaban, edoxaban). The NOACs avoid many of the VKA drawbacks. In this review, we will focus on the current evidence justifying use of NOACs in non-valvular AF.
Trends in Cardiovascular Medicine 10/2014; · 2.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A new scoring system, the anticoagulation and risk factors in atrial fibrillation (ATRIA) score, was proposed for risk stratification in patients with atrial fibrillation (AF). Whether the ATRIA scheme can adequately identify patients who are at low risk of ischemic stroke remains unknown.
Journal of the American College of Cardiology 10/2014; 64(16):1658-65. · 15.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Even 10 years after the first appearance in the literature of articles reporting on the management of patients on oral anticoagulation (OAC) undergoing percutaneous coronary intervention with stent (PCI-S), this issue is still controversial. Nonetheless, some guidance for the everyday management of this patient subset, accounting for about 5-8 % of all patients referred for PCI-S, has been developed. In general, a period of triple therapy (TT) of OAC, with either vitamin K-antagonists (VKA) or non-vitamin K-antagonist oral anticoagulants (NOAC), aspirin, and clopidogrel is warranted, followed by the combination of OAC, and a single antiplatelet agent for up to 12 months, and then OAC alone. The duration of the initial period of TT is dependent on the individual risk of thromboembolism, and bleeding, as well as the clinical context in which PCI-S is performed (elective vs acute coronary syndrome), and the type of stent implanted (bare-metal vs drug-eluting). In this article, we aim to provide a comprehensive, at-a-glance, overview of the management strategies, which are currently suggested for the peri-procedural, medium-term, and long-term periods following PCI-S in OAC patients. While acknowledging that most of the evidence has been obtained from patients on OAC because of atrial fibrillation, and with warfarin being the most frequently used VKA, we refer in this overview to the whole population of OAC patients undergoing PCI-S. We refer to the whole population of patients on OAC undergoing PCI-S also when OAC is carried out with NOAC rather than VKA, pointing out, when appropriate, the particular management issues.
Thrombosis and Haemostasis 10/2014; 112(6). · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Renal impairment is associated with poor prognosis in the setting of atrial fibrillation (AF). While AF catheter ablation is an effective treatment modality for AF burden reduction and improvement of symptoms, changes in renal function after catheter ablation and their association with rhythm outcome have not been studied in a large contemporary AF ablation cohort.
[Show abstract][Hide abstract] ABSTRACT: In atrial fibrillation (AF), oral anticoagulant(OAC) is the mainstay treatment in prevention of stroke. However, the various OAC confers one with different level of protection against thrombosis and bleeding risk, possibly due to different effect on fibrin clot structure. Coagulation and clot lysis can be assessed by Thrombelastography(TEG).
[Show abstract][Hide abstract] ABSTRACT: Atrial tachyarrhythmias (ATA) are associated with increased risk of stroke. Implantable cardiac devices (ICDs) can detect and store these arrhythmias. This study investigated the role of stroke risk stratification tools, CHADS2 and CHA2DS2-VASc, in predicting new-onset ATAs in the ICD population.