Underuse and overuse of anticoagulation for atrial fibrillation: A study in Indigenous and non-Indigenous Australians.

BACKGROUND: Atrial fibrillation (AF) is a leading cause of preventable stroke in Australia. Given that anticoagulation therapy can significantly reduce this stroke risk, we sought to characterise anticoagulation use in Indigenous and non-Indigenous Australians with AF. METHODS: Administrative, clinical and prescription data from patients with AF were linked. Anticoagulation use was characterised according to guideline-recommended risk scores and Indigenous status. RESULTS: 19,613 individuals with AF were studied. Despite a greater prevalence of other risk factors, Indigenous Australians were significantly younger than their non-Indigenous counterparts (p<0.001) and thus had lower CHADS2- (1.19±0.32 vs 1.99±0.47, p<0.001) and CHA2DS2VASc-scores (1.47 ± 0.03 vs 2.82 ± 0.08, p<0.001). Correspondingly, the percentage of Indigenous Australians with CHADS2 ≥ 2 (39.6% vs 44.1%, p<0.001) and CHA2DS2VASc-scores ≥ 2 (62.9% vs 78.8%, p<0.001) was also lower. Indigenous Australians, however, had greater rates of under- and over-anticoagulation. Overall, 72.1% and 68.9% of Indigenous and non-Indigenous Australians with CHADS2 scores ≥2, and 76.3% and 71.3% with CHA2DS2VASc scores ≥2, were under-anticoagulated. Similarly, 27.4% and 24.1% of Indigenous and non-Indigenous Australians with CHADS2 scores=0, and 24.0% and 16.7% with CHA2DS2VASc-scores=0, were over-anticoagulated. In multivariate analyses, Indigenous Australians were more likely to receive under- or over-anticoagulation according to CHADS2- or CHA2DS2VASc-score (p=0.045 and p<0.001 respectively). CONCLUSION: Anticoagulation for AF is frequently not prescribed in accordance with guideline recommendations. Under-anticoagulation in those at high stroke risk, and over-anticoagulation in those at low risk, is common and more likely in Indigenous patients with AF. Improving adherence to guideline recommendations for anticoagulation in AF may reduce both ischaemic and haemorrhagic strokes in Indigenous and non-Indigenous Australians.

Thrombogenic Risk in Patients With Atrial Fibrillation: Importance of Comorbid Conditions and Intracardiac Changes.

OBJECTIVES: This study sought to determine the differences between the prothrombotic properties and chamber characteristics in patients with lone atrial fibrillation (AF) and those with AF and comorbidities. BACKGROUND: Thromboembolic risk is increased in patients with AF; however, whether this is due to AF per se or its comorbidities remains unclear. METHODS: A total of 87 patients undergoing ablation were prospectively recruited for the study, including 30 patients with lone AF, 30 patients with AF and comorbidities in sinus rhythm, and 27 patients with left-sided accessory pathways as controls. Blood samples were obtained from the left atrium (LA), right atrium (RA), and femoral vein (FV) after transseptal puncture. Platelet activation (P-selectin) was measured by flow cytometry. Thrombin generation (thrombin-antithrombin [TAT] complex), endothelial dysfunction (asymmetric-dimethylarginine [ADMA]), and platelet-derived inflammation (soluble CD40 ligand [sCD40L]) were measured using enzyme-linked immunosorbent assay. RESULTS: Platelet activation in the LA was significantly elevated compared to that in the FV in patients with lone AF and those with AF and comorbidities compared with that in the FV (p < 0.05 respectively). Thrombin generation was significantly elevated in the LA compared with RA in AF patients (p < 0.05). There were no significant differences in P-selectin, TAT, and sCD40L among the 3 groups. However, there was a significant stepwise increase in endothelial dysfunction measured by ADMA from controls to lone AF and then to patients with AF and comorbidities (p < 0.001 between the 2 groups). CONCLUSIONS: Patients with lone AF and those with AF and comorbidities had a greater propensity for atrial thrombogenesis than controls. Prothrombotic risk is greatest in those with comorbid conditions, in whom enhanced thrombogenesis occurs predominantly through increase in endothelial dysfunction.

Successful catheter ablation decreases platelet activation and improves endothelial function in patients with atrial fibrillation.

BACKGROUND: Nonvalvular atrial fibrillation (AF) confers a five-fold increased risk of stroke. Whether catheter ablation (CA) subsequently decreases prothrombotic risk is unknown. OBJECTIVE: The purpose of this study was to assess the long-term effects of CA for AF on prothrombotic risk. METHODS: Fifty-seven patients undergoing CA for AF were prospectively studied. Platelet activation (CD62P [platelet P-selectin] and PAC-1 [glycoprotein IIb/IIIa] expression) and endothelial function (asymmetric dimethylarginine [ADMA] levels) were measured at baseline and 6-months postablation. RESULTS: Thirty-seven (65%) patients remained in sinus rhythm (SR group) and 20 (35%) sustained AF recurrence (AF recurrence group) at 6-months. Patients with AF-recurrence were older, had a higher proportion of hypertension and long-standing persistent AF. There were no significant differences in CD62P (P = .3), PAC-1 (P = .1) and ADMA (P = .7) levels at baseline between the two groups. In the SR group, markers of platelet activation decreased significantly at 6-month follow-up compared to baseline; log CD62P % 0.79 ± 0.28 vs 1.03 ± 0.27 (P <.05) and log PAC-1 % 0.22 ± 0.58 vs 0.89 ± 0.31 (P <.01). This was not significant in the AF-recurrence group (P = .8, log CD62P; P = .1, log PAC-1). For endothelial function, ADMA levels decreased significantly at 6-months compared to baseline in the SR group (log ADMA µM/L 0.15 ± 0.02 vs 0.17 ± 0.04; P <.05), but did not alter significantly in the AF-recurrence group (P = .4, log ADMA). CONCLUSION: Catheter ablation and successful maintenance of SR leads to a decrease in platelet activation and improvement in endothelial function in patients with AF. These findings suggest that AF is an important determinant of the prothrombotic state and that this may be reduced by successful catheter ablation.

Characterization of thrombogenic, endothelial and inflammatory markers in supraventricular tachycardia: a study in patients with structurally normal hearts.

Patients with atrial fibrillation (AF) are at an increased risk of thromboembolism and stroke primarily from the development of thrombi within the left atrium. Pathological changes in blood constituents and atrial endothelial damage promote left atrial thrombus formation. It is not known whether factors predisposing to left atrial thrombus formation in AF are disease specific or also evident within the normal heart. The present study examined whether there are differences in platelet reactivity, endothelial function and inflammation in blood samples obtained from intracardiac and peripheral sites in subjects within structurally normal hearts. Sixteen patients with diagnosed left-sided supraventricular tachycardia (SVT) undergoing a routine elective electrophysiological study and ablation were investigated. Blood samples were taken simultaneously from the femoral vein, right atrium and left atrium, immediately following trans-septal puncture and prior to heparin bolus administration. Between peripheral and atrial sample sites, patients with SVT showed no change in platelet reactivity or aggregation (P-selectin (CD62P) P = 0.91; platelet-derived soluble CD40 ligand P = 0.9), thrombus formation (thrombin-antithrombin complex; P = 0.55), endothelial function (von Willebrand factor P = 0.75; asymmetric dimethylarginine (ADMA) P = 0.97; nitric oxide P = 0.61), or inflammation (vascular cell adhesion molecule-1 P = 0.59; intercellular adhesion molecule-1 (ICAM-1) P = 0.69). However, SVT patients had lower ADMA and ICAM-1 levels than AF patients. The present study demonstrates, for the first time, that SVT subjects with structurally normal hearts have consistent haemostatic function between atrial and peripheral sites. These results suggest that the atria of SVT patients do not contain predisposing thrombogenic, endothelial or inflammatory factors that promote and/or initiate thrombus formation.

Clopidogrel improves microvascular endothelial function in subjects with stable coronary artery disease.

BACKGROUND: Clopidogrel therapy has recently been shown to reduce cardiovascular events in patients with stable vascular disease. This benefit may be due to effects not exclusively related to platelet aggregation. The aim of this study was to evaluate the effect of clopidogrel therapy on microvascular endothelial function in subjects with stable coronary artery disease (CAD). METHODS AND RESULTS: Forty subjects with stable CAD were randomised to clopidogrel therapy (75mg/day) or control. Blood and endothelial function testing occurred at baseline, one week and three months following randomisation. Microvascular endothelial function was assessed via reactive hyperaemic index (RHI). Platelet function was assessed by adenosine diphosphate (ADP)-induced whole blood aggregation and the VerifyNow™ system. Plasma markers of endothelial function (asymmetric dimethylarginine, ADMA) and oxidative stress (myeloperoxidase, MPO) were also tested. The primary endpoint was endothelial function assessment (RHI) at three months. At one week RHI increased by 20±10% in the clopidogrel group; this effect was maintained at three months (21±9% increase from baseline; P<0.01). A significant decrease in ADP-induced platelet aggregation and P2Y12 reaction units was observed in the clopidogrel therapy group (P<0.01). There was no correlation between endothelial function and platelet function testing in the clopidogrel therapy group. CONCLUSION: Clopidogrel therapy is associated with improved microvascular endothelial function in patients with stable CAD. This effect is independent of its effects on ADP-induced platelet reactivity.

Time course of inflammation, myocardial injury, and prothrombotic response after radiofrequency catheter ablation for atrial fibrillation.

BACKGROUND: Inflammation has been linked to the genesis of stroke in atrial fibrillation (AF) and is implicated in early recurrent arrhythmia after AF ablation. We aimed to define the time course of inflammation, myocardial injury, and prothrombotic markers after radiofrequency ablation for AF and its relation to AF recurrence. METHODS AND RESULTS: Ninety consecutive AF patients (53% paroxysmal) undergoing radiofrequency ablation were recruited. High-sensitivity C-reactive protein (hs-CRP), Troponin-T, creatine kinase-MB, fibrinogen, and D-Dimer concentrations were measured at baseline, at 1, 2, 3, 7 days, and at 1 month after ablation. AF recurrence was documented at 3 days and at 1, 3, and 6 months follow-up. Troponin-T and creatine kinase-MB peaked at day 1 after procedure (both P<0.05). Hs-CRP peaked at day 3 after procedure (P<0.05). Fibrinogen (P<0.05) and D-Dimer (P<0.05) concentrations were significantly elevated at 1 week after procedure. Ln hs-CRP elevation correlated with Ln Troponin-T and fibrinogen elevation. The extent of Ln hs-CRP, Ln Troponin-T, and fibrinogen elevation predicted early AF recurrence within 3 days after procedure (P<0.05, respectively), but not at 3 and 6 months. CONCLUSIONS: Patients undergoing radiofrequency ablation for AF exhibit an inflammatory response within 3 days. The extent of inflammatory response predicts early AF recurrence but not late recurrence. Prothrombotic markers are elevated at 1 week after ablation and may contribute to increased risk of early thrombotic events after AF ablation.

Effect of atrial fibrillation on atrial thrombogenesis in humans: impact of rate and rhythm.

OBJECTIVES: We sought to assess the effect of atrial fibrillation (AF) on atrial thrombogenesis in humans by determining the impact of rate and rhythm. BACKGROUND: Although AF is known to increase the risk of thromboembolic stroke from the left atrium (LA), the exact mechanisms remain poorly understood. METHODS: We studied 55 patients with AF who underwent catheter ablation while in sinus rhythm; 20 patients were induced into AF, 20 patients were atrial paced at 150 beats/min, and 15 were control patients. Blood samples were taken from the LA, right atrium, and femoral vein at baseline and at 15 min in all 3 groups. Platelet activation (P-selectin) was measured by flow cytometry. Thrombin generation (thrombin-antithrombin [TAT] complex), endothelial dysfunction (asymmetric dimethylarginine [ADMA]), and platelet-derived inflammation (soluble CD40 ligand [sCD40L]) were measured using enzyme-linked immunosorbent assay. RESULTS: Platelet activation increased significantly in both the AF (p < 0.001) and pacing (p < 0.05) groups, but decreased in control patients (p < 0.001). Thrombin generation increased specifically in the LA compared with the periphery in both the AF (p < 0.01) and pacing (p < 0.01) groups, but decreased in control patients (p < 0.001). With AF, ADMA (p < 0.01) and sCD40L (p < 0.001) levels increased significantly at all sites, but were unchanged with pacing (ADMA, p = 0.5; sCD40L, p = 0.8) or in control patients (ADMA, p = 0.6; sCD40L, p = 0.9). CONCLUSIONS: Rapid atrial rates and AF in humans both result in increased platelet activation and thrombin generation. Prothrombotic activation occurs to a greater extent in the human LA compared with systemic circulation. AF additionally induces endothelial dysfunction and inflammation. These findings suggest that although rapid atrial rates increase the thrombogenic risk, AF may further potentiate this risk.

Assessment of endothelial function in atrial fibrillation: utility of peripheral arterial tonometry.

Endothelial function is an independent predictor of adverse cardiovascular outcomes. The evaluation of endothelial function via changes in vessel diameter or blood flow may be inaccurate during atrial fibrillation (AF) because of non-uniform stroke volumes. Using peripheral arterial tonometry, 50 patients with AF (25 in AF, 25 in sinus rhythm) had digital pulse amplitudes assessed at baseline and during reactive hyperaemia. Hyperaemic responses were compared over varying measurement durations (5, 10 and 15beats; 30s; and 1-10min) to determine optimal measurement duration. Endothelial responses were significantly decreased (indicating endothelial dysfunction) in patients in AF compared with patients in sinus rhythm (1.48±0.60 vs 2.05±1.13, respectively; P=0.03). Beat-to-beat pulse amplitude was highly variable during AF; although coefficients of variation (CV) for short measurement durations were large, these decreased with longer measurement durations. Bland-Altman plots revealed that limits of agreement for short measurement durations were poor. Limits of agreement became consistently narrower when measurement durations of at least 1min were used. In contrast, limits of agreement and CV for short measurement durations during sinus rhythm were significantly narrower and smaller, respectively, than during AF over similar measurement durations. Pulse amplitudes are highly variable owing to the non-uniform stroke volumes in AF. Our results suggest that methods of determining endothelial function via vessel diameters or blood flow during reactive hyperaemia should use measurement durations of at least 1min to ensure accurate and reproducible results.

Atrial platelet reactivity in patients with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with an increased risk of thrombus formation in the left but not the right atrium. The mechanisms underlying this differential effect on the atria are unknown. OBJECTIVE: The purpose of this study was to examine whether atrial-specific differences in platelet activation are present in patients with AF. METHODS: Nineteen patients (13 men and 6 women; age 60 +/- 2 years) with AF undergoing ablation in sinus rhythm were studied. Blood samples from the left atrium, right atrium, and femoral vein were obtained at the start of the procedure and analyzed by whole-blood flow cytometry for expression of platelet P-selectin (CD62P), vitronectin receptor (CD51/61), and active glycoprotein IIb/IIIa receptor (PAC-1). Platelet aggregation was evaluated using adenosine diphosphate (ADP)-induced whole-blood impedance aggregometry. Seven patients with left-sided accessory pathway also were studies as a reference group for the effect of transseptal puncture on platelet reactivity. RESULTS: Platelet P-selectin levels were significantly elevated in the left atrium compared to the right atrium (10.2% +/- 2.5% vs 8.6% +/- 2.3%, P <.05). CD51/61 and PAC-1 levels did not differ between sampling sites. ADP-induced platelet aggregation was significantly higher in the left atrium compared to the right atrium and femoral vein (P <.05 for both). Platelet P-selectin levels and ADP-induced platelet aggregation did not differ between sampling site in the reference group. CONCLUSION: In patients with AF, left atrial platelet reactivity is increased compared to the right atria and peripheral circulation. The study data suggest that the presence of chamber-specific platelet activation may explain, in part, the propensity for left atrial thrombus formation in patients with AF.

Detrimental effects of energy drink consumption on platelet and endothelial function.

BACKGROUND: Energy drink consumption has been anecdotally linked with sudden cardiac death and, more recently, myocardial infarction. As myocardial infarction is strongly associated with both platelet and endothelial dysfunction, we tested the hypothesis that energy drink consumption alters platelet and endothelial function. METHODS: Fifty healthy volunteers (34 male, aged 22+/-2 years) participated in the study. Platelet aggregation and endothelial function were tested before, and 1 hour after, the consumption of 250 mL (1 can) of a sugar-free energy drink. Platelet function was assessed by adenosine diphosphate-induced (1 micromol/L) optical aggregometry in platelet-rich plasma. Endothelial function was assessed via changes in peripheral arterial tonometry and expressed as the reactive hyperemia index (RHI). RESULTS: Compared with baseline values, there was a significant increase in platelet aggregation following energy drink consumption, while no change was observed with control (13.7+/-3.7% vs 0.3+/-0.8% aggregation, respectively, P <.01). Similarly, RHI decreased following energy drink consumption (-0.33+/-0.13 vs 0.07+/-0.12 RHI [control], P <.05). Mean arterial pressure significantly increased following energy drink consumption, compared with control (P <.05). Heart rate was unaffected by energy drink consumption. CONCLUSION: Energy drink consumption acutely increases platelet aggregation and decreases endothelial function in healthy young adults.