Dwayne S.G. Conway

Prognostic Value of Plasma von Willebrand Factor and Soluble P-Selectin as Indices of Endothelial Damage and Platelet Activation in 994 Patients With Nonvalvular Atrial Fibrillation

Background—Abnormal plasma markers of a prothrombotic state have been described in atrial fibrillation (AF), but no such marker has yet been shown to reliably predict future stroke or cardiovascular outcome in AF. We hypothesized that raised plasma levels of von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and/or soluble P-selectin (sP-sel, an index of platelet activation) might predict vascular events in AF. Methods and Results—We measured vWf and sP-sel levels by ELISA in 994 participants receiving aspirin in the Stroke Prevention in Atrial Fibrillation III trial, at study entry or after 3 months, and related these indices to the subsequent incidence of stroke and vascular events. Plasma vWf levels were a significant predictor of both stroke (P =0.03) and vascular events (P <0.001), with the greatest risk for those with the highest levels of vWf. After adjustment for other clinical predictors, the relationship between vWf and stroke became nonsignificant, but vWf remained an independent predictor of vascular events (relative risk, 1.2 [95% CI, 1.0–1.4] per 20 IU/dL increase in vWf; P =0.02). No significant relationships were found between sP-sel levels and outcome. Conclusion—Among patients with AF who received aspirin, raised levels of vWf (endothelial damage/dysfunction) were predictive of stroke and vascular events, but raised sP-sel levels (platelet activation) were not associated with increased cardiovascular risk. Endothelial damage/dysfunction (or vWf itself) may play an important role in the mechanisms behind stroke and cardiovascular outcome among aspirin-treated AF patients and might represent a target for novel therapies or an adjunctive aid to risk stratification in AF.

Plasma von Willebrand Factor and Soluble P-Selectin as Indices of Endothelial Damage and Platelet Activation in 1321 Patients With Nonvalvular Atrial Fibrillation Relationship to Stroke Risk Factors

Background—Epidemiological studies have identified clinical and echocardiographic factors associated with increased stroke risk in atrial fibrillation (AF), but mechanisms linking these factors to stroke in AF are incompletely understood. We hypothesized that stroke risk factors may be associated with increased endothelial damage/dysfunction and platelet activation among patients with AF. Methods and Results—We measured plasma levels of von Willebrand factor (vWF, a marker of endothelial damage/dysfunction) and soluble P-selectin (sP-sel, a marker of platelet activation) by ELISA in 1321 participants in the Stroke Prevention in Atrial Fibrillation (SPAF) III study and related these indices to the presence of stroke risk factors and cardiovascular disease. Age (P <0.001), prior cerebral ischemia (P <0.01), recent heart failure (P <0.001), diabetes (P <0.001), and body mass index (P <0.001) were independently associated with increased vWF (r2 adjusted=9%). Independent associates of increased sP-sel were diabetes (P =0.01), peripheral vascular disease (P <0.001), and current smoking (P =0.01), whereas prior cerebral ischemia (P =0.002) and female sex (P <0.001) were associated with reduced sP-sel (r2 adjusted=4%). Using prospectively validated stroke risk stratification criteria, we observed a significant stepwise increase in vWF from low- to moderate- to high-risk groups (r2 adjusted=3%, P <0.001), whereas sP-sel remained constant (P = 0.24). Conclusions—Four recognized risk factors for stroke in AF (advancing age, prior cerebral ischemia, recent heart failure, and diabetes) were independently associated with raised plasma vWF (or endothelial damage/dysfunction), whereas only 1 (diabetes) was associated with increased sP-sel (platelet activation). Further longitudinal studies are now needed to confirm relationships between endothelial damage/dysfunction, platelet activation, and stroke in AF.

Antithrombotic therapy for atrial fibrillation

Atrial fibrillation is the commonest sustained disorder of cardiac rhythm. Although patients often present with symptoms caused by haemodynamic disturbance associated with the rhythm itself, the condition carries an increased risk of arterial thromboembolism and ischaemic stroke due to embolisation of thrombi that form within the left atrium of the heart. Presence of the arrhythmia confers about a fivefold increase in stroke risk, an absolute risk of about 4.5% a year, although the precise annual stroke risk ranges from 12%, according to the presence or absence of certain clinical and echocardiographically identifiable risk factors. ![][1] Severely damaged left atrial appendage endocardial surface with thrombotic mass in a patient with atrial fibrillation and mitral valve disease From trial data, patients with paroxysmal atrial fibrillation seem to carry the same risk as those with persistent atrial fibrillation. The same criteria can be used to identify high risk patients, although it is unclear whether the risk is dependent on the frequency and duration of the paroxysms. Randomised controlled trials have shown the benefit of warfarin and, to a lesser extent, aspirin in reducing the incidence of stroke in patients with atrial fibrillation without greatly increasing the risk of haemorrhagic stroke and extracranial haemorrhage. However, anticoagulant therapy is still underprescribed in patients with atrial fibrillation, particularly in elderly patients, who stand to benefit most It is well established that antithrombotic therapy confers thromboprophylaxis in patients with atrial fibrillation who are at risk of thromboembolism. A recent meta-analysis of antithrombotic therapy in atrial fibrillation showed that adjusted dose warfarin reduced stroke by about 60%, with absolute risk reductions of 3% a year for primary prevention and 8% a year for secondary prevention (numbers needed to treat for one year to prevent one stroke of 33 and 13, respectively). In contrast, aspirin reduced stroke by … [1]: /embed/graphic-1.gif

Is the Hypercoagulable State in Atrial Fibrillation Mediated by Vascular Endothelial Growth Factor

Background and Purpose— Tissue factor (TF; an initiator of coagulation) and vascular endothelial growth factor (VEGF; a marker of angiogenesis) are involved in the hypercoagulable state associated with malignancy. We investigated their roles in chronic atrial fibrillation (AF), a condition also associated with increased risk of stroke and thromboembolism, as well as a prothrombotic or hypercoagulable state. Methods— We studied 25 patients with AF (20 men; mean±SD age, 62±13 years) who were compared with 2 control groups in sinus rhythm: 30 healthy control subjects (17 men; mean age, 60±9 years) and 35 patient control subjects with coronary artery disease (CAD; 27 men; mean age, 60±12 years). Plasma levels of TF, VEGF, and the VEGF receptor sFlt-1 were measured by enzyme-linked immunosorbent assay. Results— VEGF, sFlt-1, and TF were significantly different between the 3 groups, with abnormal levels in AF and CAD patients compared with control subjects (P <0.001, P =0.022, and P =0.008, respectively). Among the AF patients, TF levels were significantly correlated with VEGF (Spearman’s r =0.65, P <0.001) and sFlt (r =0.54, P =0.006) levels. Only TF and VEGF levels were significantly correlated in CAD patients (r =0.39, P =0.02). There were no significant correlations among the healthy control subjects. Conclusions— Patients with chronic AF have high TF levels, in keeping with the prothrombotic state associated with this arrhythmia. The relationships between TF and VEGF and its receptor sFlt-1 in AF suggest a possible role for VEGF in the hypercoagulable state found in AF, as seen in malignancy and atherosclerosis.

Letters to the Editor: Atrial Fibrillation and Stroke: More Concepts and Controversies

Stroke welcomes Letters to the Editor and will publish them, if suitable, as space permits. They should not exceed 1000 words (excluding references) and may be subject to editing or abridgment. Please submit letters in duplicate, typed double-spaced. Include a fax number for the correspondling author and a completed copyright transfer agreement form (published in the January and July issues) . To the Editor: We wish to congratulate Hart and Halperin1 on their excellent overview of the current “concepts and controversies” surrounding atrial fibrillation (AF) and stroke. In discussing the formation of thrombus within the left atrial appendage (LAA), they focus a large part of their discussion on the issue of blood stasis in the LAA that occurs in AF, suggesting this mechanism of thrombogenesis to perhaps be of greatest importance, although conceding that “many questions remain about the formation and embolism of left atrial …

Increased von Willebrand factor in the endocardium as a local predisposing factor for thrombogenesis in overloaded human atrial appendage

We read with great interest the article by Fukuchi et al. [(1)][1], describing immunohistochemical evidence of increased expression of von Willebrand factor (vWF) in the endocardium of “overloaded” human atrial appendages, as a possible mechanism of intra-atrial thrombogenesis. They describe an

Risk for a major bleed was higher for women than men receiving warfarin in patients with atrial fibrillation

Source Citation Humphries KH, Kerr CR, Connolly SJ, et al. New-onset atrial fibrillation. Sex differences in presentation, treatment, and outcome. Circulation. 2001 May 15;103:2365-70. 11352885 (Al...