A cross-sectional and diurnal study of thrombogenesis among patients with chronic atrial fibrillation

OBJECTIVES

First, we sought to determine whether there is diurnal variation in hemostatic factors related to thrombogenesis and hypercoagulability among patients with chronic atrial fibrillation (AF). Second, we sought to determine whether levels of soluble thrombomodulin (sTM), a marker of endothelial function, or soluble P-selectin (sP-sel), an index of platelet activation, are altered in patients with AF as compared with subjects in sinus rhythm.

BACKGROUND

Atrial fibrillation is associated with an increased risk of stroke and thromboembolism and is known to confer a hypercoagulable state, with abnormalities of thrombosis, platelet activation and endothelial cell function. Many cardiovascular events, such as acute myocardial infarction, have thrombosis as an underlying process, and they undergo diurnal variation.

METHODS

Fifty-two patients (45 men, mean [±SD] age 66 ± 6 years) with chronic AF, none of whom received antithrombotic therapy, were studied. Baseline levels of fibrinogen, sP-sel, sTM and von Willebrand factor (vWF) were compared to those levels in matched healthy control subjects in sinus rhythm. In a subgroup of 20 patients, five venous blood samples were collected through an indwelling cannula at 6-h intervals from 12 to 12 the following day and were analyzed for the same markers.

RESULTS

Patients with chronic AF had higher plasma sP-sel, sTM, vWF and fibrinogen levels as compared with control subjects in sinus rhythm. Significant correlations were found between fibrinogen and sP-sel in patients with AF (r = 0.567 [Spearman], p < 0.001) and in control subjects (r = 0.334, p = 0.016). There was no significant diurnal variation in plasma levels of sP-sel, sTM, vWF or fibrinogen over the 24-h study period (repeated measures analysis of variance, p = NS).

CONCLUSIONS

There is no circadian or diurnal variation in the hypercoagulable state seen in AF, as assessed by plasma fibrinogen and markers of platelet (sP-sel) and endothelial function (vWF and sTM). The persistent hypercoagulable state, together with the loss of diurnal variation in various hemostatic markers, in chronic AF may contribute to the high risk of stroke and thromboembolic complications in these patients.     

Influence of atrial fibrillation on plasma von willebrand factor, soluble E-selectin, and N-terminal pro B-type natriuretic peptide levels in systolic heart failure

BACKGROUND: Endothelial dysfunction is present in patients with heart failure (HF) due to left ventricular systolic dysfunction, as well as in patients with atrial fibrillation (AF) who have normal cardiac function. It is unknown whether AF influences the degree of endothelial dysfunction in patients with systolic HF. METHODS: We measured levels of plasma von Willebrand factor (vWF) and E-selectin (as indexes of endothelial damage/dysfunction and endothelial activation, respectively; both enzyme-linked immunosorbent assay) in patients with AF and HF (AF-HF), who were compared to patients with sinus rhythm and HF (SR-HF), as well as in age-matched, healthy, control subjects. We also assessed the relationship of vWF and E-selectin to plasma N-terminal pro B-type natriuretic peptide (NTpro-BNP), a marker for HF severity and prognosis. RESULTS: One hundred ninety patients (73% men; mean age, 69.0 +/- 10.1 years [+/- SD]) with systolic HF were studied, who were compared to 117 healthy control subjects: 52 subjects (27%) were in AF, while 138 subjects (73%) were in sinus rhythm. AF-HF patients were older than SR-HF patients (p = 0.046), but left ventricular ejection fraction and New York Heart Association class were similar. There were significant differences in NT-proBNP (p < 0.0001) and plasma vWF (p = 0.003) between patients and control subjects. On Tukey post hoc analysis, AF-HF patients had significantly increased NT-proBNP (p < 0.001) and vWF (p = 0.0183) but not E-selectin (p = 0.071) levels when compared to SR-HF patients. On multivariate analysis, the presence of AF was related to plasma vWF levels (p = 0.018). Plasma vWF was also significantly correlated with NT-proBNP levels (Spearman r = 0.139; p = 0.017). CONCLUSIONS: There is evidence of greater endothelial damage/dysfunction in AF-HF patients when compared to SR-HF patients. The clinical significance of this is unclear but may have prognostic value.     

Endothelial markers and adhesion molecules in acute ischemic stroke--sequential change and differences in stroke subtype

The progress of a stroke concerns the activation of endothelial cells and platelets. We measured the plasma activities of von Willebrand factor (vWf) and the serum levels of soluble thrombomodulin (sTM) as endothelial markers, and the plasma concentrations of soluble P-selectin (sP-selectin) and soluble E-selectin (sE-selectin) as adhesion molecules during the acute (within 48 h from onset) and subacute (after 1 month from the onset) phases of 52 consecutive patients with acute ischemic stroke and 86 age-matched control subjects. The plasma vWf activities and levels of sP-and sE-selectins in stroke patients were significantly elevated compared with those in controls during both the acute and subacute phases. The serum levels of sTM in stroke patients were significantly higher than those in controls only during the subacute phase. In atherothrombotic infarction, the vWf activities and the levels of sP-selectin, markers for endothelial and platelet activation, remained higher until the subacute phase compared with controls, and the concentrations of sTM, a marker for endothelial injury, were increased during the subacute phase compared with during the acute phase. In lacunar infarction, the levels of sTM and sE-selectin of patients were higher only during the acute phase than controls. These findings suggest that the endothelial cell damage might be maintained until the subacute phase in atherothrombotic infarction, whereas it is remarkable only during the acute phase in lacunar infarction. The evaluation of endothelial markers and adhesion molecules would represent the pathophysiological states of stroke and may provide useful information for the treatment of the ischemic infarction.     

Effect of acute exercise on the raised plasma fibrinogen, soluble P-selectin and von Willebrand factor levels in chronic atrial fibrillation

BACKGROUND: There is increasing evidence that chronic atrial fibrillation (AF) is associated with a prothrombotic or hypercoagulable state. HYPOTHESIS: This study was undertaken to determine whether short-term exercise in patients with chronic AF would shift the overall hemostatic balance toward a more prothrombotic state with a reduction in fibrinolytic potential. METHODS: We recruited 20 patients (13 men; mean age 65 years +/- 11 standard deviation [SD]) with chronic AF who were not treated with antithrombotic therapy and exercised them to exhaustion using a multistage treadmill exercise (standard Bruce) protocol. Blood samples were taken pre exercise, immediately after cessation of exercise, and at 20 min post exercise. The prothrombotic state was quantified by fibrinogen (an index of hemorheology and a coagulation factor), soluble P-selectin (sP-sel, marking platelet activation), von Willebrand factor (vWF, an index of endothelial dysfunction), and plasminogen activator inhibitor-1 (PAI-1, a regulator of fibrinolytic activity) levels. There were two groups of age- and gender-matched controls in sinus rhythm: (1) healthy controls, and (2) "hospital controls" who were patients with vascular disease. RESULTS: Baseline levels of vWf (p = 0.034) and fibrinogen (p < 0.0001), but not sP-sel (p = 0.075) were significantly elevated in patients with AF compared with both control groups in sinus rhythm. The PAI-1 levels were highest in the hospital control patients, but not in chronic AF (p = 0.041). Following treadmill exercise, achieving a mean metabolic equivalent of 4.9 METS (+/- 1.75 SD) and total exercise duration of 4.9 min (+/- 2 SD), there was a significant rise in plasma fibrinogen (repeated measures analysis of variance [ANOVA] p = 0.047) and a reduction in PAI-1 levels (p = 0.025) in patients with AF. There were no significant changes seen in vWf (p = 0.308) or sP-sel (p = 0.071) levels. No significant changes in these indices were seen in hospital controls (all p = not significant), despite a much longer duration of exercise with greater workload. CONCLUSION: Patients with chronic AF have increased vWf and fibrinogen levels compared with sinus rhythm. Exercise to exhaustion influences the hypercoagulable state in chronic AF, with a rise in plasma fibrinogen and possible increase in fibrinolytic activity. Nevertheless, acute exercise does not appear to have a significant influence on endothelial dysfunction or platelet activation in patients with AF.     

系统性红斑狼疮患者血管内皮细胞损伤标志物检测及其临床意义

目的探讨血管内皮细胞损伤与系统性红斑狼疮(SLE)疾病活动、肾脏损伤的关系。方法应用酶联免疫吸附试验(ELISA)检测31例SLE患者和10例健康对照者血浆可溶性血栓调节蛋白(sTM)、血管假性血友病因子(vWF)水平。结果SLE组血浆sTM、vWF水平明显高于对照组;SLE组血浆sTM、vWF水平均与疾病活动指数(SLEDAI)呈显著正相关,与24小时尿蛋白定量呈正相关。结论血管内皮损伤可能在SLE发病机制中起重要作用,血浆sTM、vWF水平可作为判断SLE疾病活动性及肾脏损伤程度的指标。     

Persistent increase in plasma thrombomodulin in patients with a history of lupus nephritis: endothelial cell activation markers

OBJECTIVE: To investigate the presence of continuing endothelial cell activation in patients with systemic lupus erythematosus (SLE) and its relationship with lupus nephritis. METHODS: We measured plasma concentrations of soluble thrombomodulin (sTM), vascular cellular adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWf), sP-selectin, and ED1-fibronectin in 75 SLE patients with a median SLE disease activity index (SLEDAI) of 4. Forty patients with a history of lupus nephritis, confirmed by renal biopsy in 33, were compared with 35 patients without lupus nephritis and 25 controls. For subgroup analysis in patients with clinically stable remission we excluded patients with a SLEDAI > 6 or with evidence of renal disease activity. RESULTS: In the total SLE patient group sTM, sVCAM-1, vWf, and sP-selectin were significantly elevated compared with controls. In patients with a history of lupus nephritis plasma levels of sTM and vWf were significantly increased compared with SLE patients without nephritis. After adjustment for significantly associated variables, especially creatinine clearance and age, in a multivariate linear regression analysis, sTM remained significantly elevated in patients with a history of lupus nephritis (difference 28.9 ng/ml, 95% CI 11.5-46.4). In the subgroup analysis of 57 patients, the results remained unchanged. CONCLUSION: The increase of sVCAM-1, sP-selectin, sTM, and vWf reflects a state of persistent endothelial cell activation. Multivariate regression analysis shows that the elevated sTM levels are strongly associated with a history of lupus nephritis, independent of creatinine clearance or disease activity, suggesting endothelial cell activation specifically localized in the kidneys.     

Indexes of hypercoagulability measured in peripheral blood reflect levels in intracardiac blood in patients with atrial fibrillation secondary to mitral stenosis

Systemic thromboembolism is a major complication in patients with mitral stenosis, especially in those who have atrial fibrillation (AF). It has been suggested that there may be increased regional left atrial coagulation activity in such patients, despite normal systemic coagulation activity on peripheral blood sampling. Our aim was to investigate whether there were significant differences between intracardiac versus peripheral indexes of hypercoagulability in 25 patients (5 men; mean age 60 years) with mitral stenosis who were undergoing percutaneous balloon mitral valvuloplasty and who were all in chronic AF. Two days after halting warfarin therapy, intracardiac (right and left atria) and peripheral (venous and arterial) blood samples from patients were obtained and compared with levels in matched healthy controls in sinus rhythm. Thrombogenicity was assessed by levels of fibrin D-dimer, fibrinogen, indexes of platelet activation (soluble P-selectin and beta thromboglobulin [betaTG]) and indexes of endothelial dysfunction (soluble thrombomodulin [sTM] and von Willebrand factor [vWF]). There were no statistically significant differences in the various markers between the femoral vein and artery, left and right atria, and between the femoral vein and both atria (all p = NS). Plasma fibrinogen, vWf (both p <0.005), and D-dimer (p = 0.011) were significantly higher and levels of sP-selectin and sTM were lower (both p <0.005) in patients when compared with controls. There was no significant difference in plasma betaTG levels. Our results suggest that there is no significant variation in indexes of thrombogenesis, platelet activation, and endothelial dysfunction between left atrium, right atrium, and the peripheral artery or vein. Peripheral samples therefore do reflect atrial coagulation, platelet, and endothelial activities.     

Atrial Fibrillation and Hypercoagulability: Dependent on Clinical Factors or/and on Genetic Alterations?

It is well known that atrial fibrillation is associated with high incidence of thromboembolic events, propably due to a prothrombotic or hypercoagulable state. However, it is unclear whether or not there is any difference of this prothrombotic state in the clinical subgroups of atrial fibrillation patients, that is, in those with paroxysmal, persistent or permanent atrial fibrillation. From the other side the role of the arrhythmia duration on the changes of coagulative variables in atrial fibrillation patients is not clearly enough.The contribution of genetic and functional alterations in factors of the coagulation and fibrinolytic pathways (that is hemostatic risk factors) to the development of hypercoagulation state in atrial fibrillation requires clarification. We investigated therefore (1) if there are differences in the prothrombotic state between patients with different clinical status of the arrhythmia, (2) if the arrhythmia duration per se could be an independent determinant of the prothrombotic state in all atrial fibrillation patients and (3) if coexistent genetic alterations in haemostatic risk factors in patients with atrial fibrillation could contribute to the development of prothrombotic abnormalities. METHODS: Over a period of 23 months, we studied 55 patients with chronic non-valvular atrial fibrillation. We recruited 18 consecutive patients (13 men, mean age 59 +/- 10 years) with paroxysmal atrial fibrillation 17 patients (11 men, mean age 61 +/- 7 years) with persistent atrial fibrillation who underwent elective successful DC and remained in sinus rhythm at the 3 month visit and 20 patients (14 men mean age 64 +/- 9) with permanent atrial fibrillation. Blood results were compared to 17 age-sex- and race-matched controls. The prothrombotic state was quantified by measurement of plasma levels of fibrinogen, soluble P -selectin (an index of platelet activation) and von Willebrand factor (a marker of endothelial dysfunction). We assessed the frequencies of factor V Leiden and prothrombin variant G20210A to determine whether particular inherited haemostatic risk factors may have contribution to the development of prothrombotic state in atrial fibrillation patients. RESULTS: Permanent atrial fibrillation was associated with significant raised levels of von Willebrand factor, fibrinogen levels and soluble P -selectin compared to matched controls (all p < 0.001) and matched patients with paroxysmal and permanent AF (all p ranged between <0.003 and <0.002). Patients with persistent atrial fibrillation had significantly elevated von Willebrand factor levels (p = 0.0064) and fibrinogen levels (p = 0.002), but not Soluble P -selectin (p = 0.509). when compared to controls. Patients with paroxysmal atrial fibrillation had significantly elevated levels of P -selectin (p = 0.005) and fibrinogen (p = 0.003), but not von Willebrand factor (p =.0.61) compared to controls. Stepwise multiple regression analyses demonstrated that the arrhythmia duration (approximately 3 years) was an independent predictor of abnormal von Willebrand factor, fibrinogen and soluble P -selectin levels. Restoration of sinus rhythm in paroxysmal atrial fibrillation subgroup and successful electrical cardioversion of patients with permanent fibrillation atrial fibrillation did not significantly alter levels of the affected factors. The frequency of factor V Leiden was 8.9 in all studied patients with atrial fibrillation, versus 2.4% in the control group (odds ratio [OR] 4.6 [95% confidence (CI) 1.4-17.5], p = 0.02). The frequency of the prothrombin variant G20210A was 6.4.% compared with control group 1.6% (OR 4.9 [95% confidence interval (CI) 1.2-2.9], p = 0.04).There was a trend towards an increased frequency of factor V Leiden and/or prothrombin variant G20210A in patients age <55 years and in patients living at a particular area of Thrace mountains. CONCLUSIONS: Our results showed that there were significant differences in the prothrombotic state when patients with paroxysmal, and persistent atrial fibrillation were compared to matched that there were significant differences in the prothrombotic state when patients with paroxysmal, and persistent atrial fibrillation were compared to matched patients with permanent atrial fibrillation and controls in sinus rhythm.The duration of the arrhythmia (about 3 years) was an independent predictor of abnormal measured factors. We found for the first time that some genetic alterations in haemostatic risk factors could be coexist in atrial fibrillation patients and may be a contributor to the development of hypercoagulability in atrial fibrillation patients.     

Plasma levels of tissue factor and soluble E-selectin in sickle cell disease: relationship to genotype and to inflammation.

BACKGROUND: Microvascular occlusion, the pathophysiological hallmark of sickle cell disease (SCD), is a complex multifactorial process with alterations in coagulation, endothelial function and inflammation. However, relationships between these process in the two most common genotypes, HbSS and HbSC, are unknown. We hypothesized differences in the hypercoagulable state [as assessed by tissue factor (TF), fibrinogen and D-dimer], endothelial function [markers soluble E-selectin (sE-sel) and von Willebrand factor (vWf)], and inflammation [markers interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP)] in these two SCD genotypes. Citrated plasma TF, sE-sel, vWf, fibrinogen and fibrin D-dimer, and serum IL-6 and hsCRP (enzyme-linked immunosorbent assay/Clauss) were measured in 64 patients with SCD (27 with HbSS disease) and 42 AA subjects matched for age and ethnic origin. TF (P = 0.0014), sE-sel (P = 0.001) and, as expected, vWf, D-dimer, and hsCRP (all P < or = 0.01), but not fibrinogen or IL-6, were raised in the SCD patients compared with the AA subjects. However, only vWf and, as expected, D-dimer (all P < or = 0.01) were higher in HbSS disease than in HbSC disease. Raised plasma TF and sE-sel in SCD compared with HbAA subjects may contribute to the increased risk of thrombotic disease in this group. Raised vWf in HbSS compared with HbSC may be important in determining pathophysiology in these two genotypes. Positive correlations between IL-6 and TF in both HbSC and HbSS disease leads us to speculate that inflammation may be important in coagulation activation in these patients, or vice versa. However, lack of correlation of sE-sel with inflammatory markers implies that other mechanisms are responsible for increased levels of this marker of endothelial activation.     

Endothelial damage and hemostatic markers in patients with uncomplicated mild-to-moderate hypertension and relationship with risk factors.

Endothelial damage, high fibrinogen levels, and platelet activity are the important accelerating factors for the development of hypertension (HT). von Willebrand factor (vWF; endothelial damage marker), fibrinogen levels, and platelet aggregability were compared between patients with uncomplicated, mild-to-moderate hypertension and healthy subjects. The relationship between traditional cardiovascular risk factors and endothelial damage and prothrombotic state was evaluated. One hundred sixty-nine (54 males, 115 females) patients with untreated and uncomplicated mild-to-moderate HT, and age, gender, and body mass index-matched 124 (58 males, 83 females) healthy subjects were enrolled in this study. Plasma vWF, fibrinogen levels, adenosine diphosphate-induced platelet aggregability, insulin, glucose, serum lipids, and uric acid were measured. Patients with HT had significantly increased fibrinogen, vWF, platelet number and aggregability induced by adenosine diphosphate, triglycerides, total/HDL-C, glucose, uric acid levels, and insulin resistance than control group. vWF and hemostatic markers were comparable between smoker and nonsmoker subjects. Platelet aggregability was positively related to systolic and diastolic blood pressure, and vWF. Fibrinogen was positively associated with body mass index (BMI), systolic and diastolic blood pressure, total cholesterol (TC), uric acid, vWF, and insulin resistance. vWF was significantly related to age, systolic blood pressure, TC, LDL-C, and total/HDL-C. Systolic blood pressure was independently related to vWF. vWF and diastolic blood pressure were significant predictors for adenosine diphosphate-induced platelet aggregability. Systolic blood pressure and vWF were independent predictors for fibrinogen levels. Uncomplicated mild-to-moderate HT had endothelial damage and is associated with a prothrombotic state. Traditional cardiovascular risk factors such as age, BMI, dyslipidemia, and insulin resistance are important contributors to the development of endothelial damage and a prothrombotic state. Therefore, it is important to control these cardiovascular risk factors along with proper treatment of HT for preventing target organ damage in mild-to-moderate HT.     

Long-term rhythm control of drug-refractory atrial fibrillation with "hybrid therapy" incorporating dual-site right atrial pacing, antiarrhythmic drugs, and right atrial ablation

We evaluated the long-term efficacy, safety, and applicability of a "hybrid" therapy strategy for rhythm control in atrial fibrillation (AF), incorporating dual-site right atrial pacing, antiarrhythmic drugs, and right atrial ablation. One hundred thirteen patients (paroxysmal AF [n = 70], persistent/permanent AF [n = 43]) with refractory symptomatic AF were treated with this strategy and followed for 1 to 81 months (mean 30 +/- 23). All-cause mortality, AF recurrences, and progression to permanent AF were monitored and recorded by implanted device data logs. There was no procedural mortality. Rhythm control was achieved in 90% of all patients at 3 and 5 years, with comparable efficacy in subpopulations with paroxysmal (98%), persistent, or permanent AF (87%, p >2). Overall survival was 84% at 3 years and 80% at 5 years, and was higher in patients with paroxysmal AF than in patients with persistent or permanent AF (86% vs 67% at 4 years, p <0.001). Patients with persistent or permanent AF had a greater need for cardioversion (p <0.004) and right atrial ablation (p <0.04) than patients with paroxysmal AF to achieve comparable rhythm control. A hybrid therapy strategy can provide safe and effective long-term rhythm control in patients with drug-refractory AF, and can be implemented in subpopulations presenting with paroxysmal, persistent, or permanent AF.     

A study of platelet activation in paroxysmal, persistent and permanent atrial fibrillation.

We hypothesized that the 'residual' thromboembolic risk in therapeutically anticoagulated patients undergoing cardioversion could potentially be related to abnormal haemorheology and platelet activation. To test this hypothesis, we firstly investigated the role of haemorheology and platelet activation in patients with paroxysmal and persistent atrial fibrillation (AF), who were compared with healthy controls and patients with permanent AF. Second, we compared these indices in patients with persistent AF, before and after successful cardioversion. We measured indices of haemorheology (haematocrit, plasma viscosity, and fibrinogen), fibrin D-dimer (an index of thrombogenesis and fibrin turnover) and platelet activation (as assessed by platelet aggregation and plasma levels of beta-thromboglobulin, and soluble P-selectin) in 29 patients with paroxysmal AF, 87 patients with permanent AF and 29 healthy controls in sinus rhythm. The effects of cardioversion were studied in 20 patients with persistent AF, who maintained sinus rhythm at 2 months follow-up. Plasma levels of beta-thromboglobulin (P = 0.03) and fibrin D-dimer (P = 0.001) were higher in patients with AF, when compared with controls; the highest levels were seen in those with permanent AF (Tukey's test, < 0.05). Plasma viscosity was significantly higher in the patients with paroxysmal AF compared with healthy controls (P = 0.02). Plasma soluble P-selectin levels and platelet aggregation responses to all four platelet agonists (adenosine diphosphate, collagen, epinephrine and thrombin) in patients with paroxysmal AF and permanent AF were similar to controls. Plasma fibrinogen, viscosity and other markers of platelet activation (including platelet aggregation) were not significantly different in patients with paroxysmal AF, during episodes of AF and sinus rhythm (P = not significant), although mean haematocrit was significantly higher during the episodes of AF compared with episodes of sinus rhythm (P = 0.03). Among the patients with persistent AF who remained in sinus rhythm at 2 months following successful cardioversion, there was a significant decrease in the plasma levels of soluble P-selectin at 2 weeks and 2 months, when compared with baseline (pre-cardioversion) levels (P < 0.001). Haemorheology and platelet aggregation response to agonists did not change significantly, except for a transient increase in platelet aggregation response to collagen at 2 weeks (P = 0.045). In conclusion. abnormal haemostatic and platelet activation in patients with permanent AF are not consistently observed in patients with paroxysmal and persistent AF. Abnormal haemorheology appears to play an important role in patients with paroxysmal AF, especially during the paroxysms of AF. Cardioversion of persistent AF to sinus rhythm appears to decrease the platelet activation, but whether this translates into a beneficial reduction in thromboembolic risk requires further study.     

Associations of big endothelin-1 and C-reactive protein in atrial fibrillation

Background Atrial fibrillation (AF) is associated with inflammation and endothelial dysfunction. However, the association between inflammation (as indexed by high-sensitivity C-reactive protein, hs-CRP) and endothelial function [as indexed by big endothelin-1 (ET-1)] in AF patients remains unclear. Methods We enrolled 128 patients with lone AF, among which 83 had paroxysmal AF, and 45 had persistent AF. Eighty-two age- and gender-matched controls of paroxysmal supraventricular tachycardia without AF history were evaluated. Plasma hs-CRP, big ET-1 levels and other clinical characteristics were compared among the groups. Results Patients with persistent AF had higher hs-CRP concentrations than those with paroxysmal AF (P < 0.05), both groups had higher hs-CRP level than controls (P < 0.05). Patients with persistent AF had higher big ET-1 level than those with paroxysmal AF, although the difference did not reach the statistical significance (P > 0.05), and both groups had higher big ET-1 levels than controls (P < 0.05). Multiple regression analyses revealed hs-CRP as an independent determinant of AF (P < 0.001). Further adjusted for big ET-1, both big ET-1 and hs-CRP were independent predictors for AF (P < 0.001), but the odds ratio for hs-CRP in predicting AF attenuated from 8.043 to 3.241. There was a positive relation between hs-CRP level and big ET-1 level in paroxysmal AF patients (r = 0.563, P < 0.05), however, the relationship in persistent AF patients was poor (r = 0.094, P < 0.05). Conclusions Both plasma hs-CRP and big ET-1 levels are elevated in lone AF patients, and are associated with AF. In paroxysmal lone AF patients, there were significant positive correlations between plasma hs-CRP level and big ET-1 level.     

Plasma von Willebrand factor, fibrinogen and soluble P-selectin levels in paroxysmal, persistent and permanent atrial fibrillation. Effects of cardioversion and return of left atrial function.

BACKGROUND: Atrial fibrillation is associated with increased risk of stroke and thromboembolism, possibly by conferring a prothrombotic or hypercoagulable state. However, it is unclear whether or not this differs in the clinical subgroups of chronic atrial fibrillation patients, that is, in those with paroxysmal, persistent or permanent atrial fibrillation. We therefore hypothesized that: (i) there are differences in the prothrombotic state between these patients; and (ii) reduction in indices of hypercoagulability would follow elective electrical cardioversion of persistent atrial fibrillation and the return of left atrial function. PATIENTS AND METHODS: We studied 69 patients with chronic atrial fibrillation: 23 with paroxysmal atrial fibrillation (16 males; mean age 65 years+/-SD 13); 23 with persistent atrial fibrillation (16 males; 65 years+/-13), with a mean duration of atrial fibrillation of 3 months (range 2 to 6 months); and 23 with permanent atrial fibrillation (16 males; 67 years+/-10). Blood results were compared to 20 age- and sex-matched healthy controls. The patients with persistent atrial fibrillation then underwent elective DC cardioversion, with Doppler echocardiographic examinations and bloods tests performed prior to cardioversion, and at 3 and 12 weeks afterwards. The prothrombotic state was quantified by measurement of plasma levels of fibrinogen, soluble P-selectin (an index of platelet activation) and von Willebrand factor (a marker of endothelial dysfunction). RESULTS: Permanent atrial fibrillation was associated with significantly raised levels of von Willebrand factor, soluble P-selectin and fibrinogen (all P<0.001); paroxysmal atrial fibrillation with significantly elevated levels of plasma von Willebrand factor (P=0.0067) and fibrinogen (P=0.0001) but not soluble P-selectin (P=0.472); and persistent atrial fibrillation with normal levels of fibrinogen, von Willebrand factor and soluble P-selectin when compared to healthy controls (all P=ns). Stepwise multiple regression analyses demonstrated that the presence of atrial fibrillation was an independent predictor of abnormal von Willebrand factor, fibrinogen and soluble P-selectin levels. Electrical cardioversion of the patients with persistent atrial fibrillation did not significantly alter levels of von Willebrand factor (P=0.766), soluble P-selectin (P=0.726) or fibrinogen (P=0.50) despite maintenance of sinus rhythm and a significant return of left atrial systolic function (as quantified by the presence of A wave on Doppler echocardiography) at 3 months. CONCLUSION: There were significant differences in the prothrombotic state when patients with paroxysmal and permanent atrial fibrillation are compared to matched patients with persistent atrial fibrillation or controls in sinus rhythm. Cardioversion of persistent atrial fibrillation did not significantly alter indices of hypercoagulability even after 3 months maintenance of sinus rhythm, despite the return of atrial systole.     

The effect of multi-factorial intervention on plasma von Willebrand factor, soluble E-selectin and tissue factor in diabetes mellitus: implications for atherosclerotic vascular disease.

BACKGROUND: Endothelial abnormalities and a hypercoagulable state may contribute to increased cardiovascular risk in diabetes mellitus, particularly in patients with overt cardiovascular disease (CVD). We sought to determine the effect of intensified multi-factorial cardiovascular risk intervention on indices of endothelial abnormality and hypercoagulability in diabetes, and if patients with overt CVD would derive similar benefit as those without. PATIENTS AND METHODS: We measured plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction), soluble E-selectin (sE-sel, marking endothelial activation) and tissue factor (TF, an initiator of coagulation) by ELISA in 94 patients with diabetes mellitus (38 with CVD and 56 without overt CVD) and 34 comparable controls. Thirty-three patients with CVD and 31 without overt CVD then participated in multi-factorial cardiovascular risk intervention over 1 year. RESULTS: Plasma levels of vWf (P = 0.009), sE-sel (P < 0.001) and TF (P < 0.001) were significantly higher in diabetic patients compared with controls, with TF highest in patients with overt CVD. Intensive multi-factorial intervention resulted in reductions in glycated haemoglobin (HbA(1c)), total and LDL-cholesterol (all P < 0.05), but no significant weight change. This was associated with reductions in vWf in patients with (by 26%P = 0.003), and without (by 47%, P < 0.001), overt CVD. TF was reduced only in patients without overt CVD (by 45%, P < 0.001). There were no significant changes in sE-sel levels in either group. CONCLUSION: Endothelial abnormalities in diabetes are only partially influenced by contemporary intensified multi-factorial cardiovascular risk intervention. These data suggest the need for earlier and more aggressive risk factor intervention.     

左心房/肺静脉重构在孤立性心房颤动进展中的作用

目的 探讨孤立性心房颤动（房颤）进展过程中左心房/肺静脉重构的作用.方法 连续47例孤立性房颤患者在房颤心律下接受左心房/肺静脉CT检查,其中25例为阵发性房颤,22例为新发持续性房颤.通过对两组间有差异的CT指标进行Logistic回归分析,确定孤立性房颤进展的预测指标.结果 新发持续性房颤组的平均房颤持续时间为1～12（6.4±4.3）周.与阵发性房颤组比较,新发持续性房颤组呈现如下的左心房/肺静脉重构特征：（1）左心房非对称扩张;（2）左心房容积显著增大;（3）肺静脉开口扩张.经Logistic回归分析,左心房容积（P=0.003,OR=1.139,95%可信区间：1.046～1.240）是预测孤立性房颤进展最强的独立指标.左心房容积≥108 ml预测孤立性房颤由阵发性进展为持续性的敏感性为68.2%,特异性为88%.结论 孤立性房颤在由阵发性进展为持续性的过程中伴随有显著的左心房和肺静脉重构;左心房容积显著增加是该过程的独立预测指标.     

A pilot study of streptokinase-induced endothelial injury and platelet activation following acute myocardial infarction

OBJECTIVE: To relate the changes in serum vitamin E, an essential antioxidant, to changes in fibrinogen, as well as indices of endothelial damage [as indicated by plasma markers, soluble thrombomodulin (sTM) and von Willebrand factor (vWf), and an index of platelet activation (soluble P selectin (sPsel)], in myocardial infarction treated with thrombolytic therapy. DESIGN AND SETTING: Prospective longitudinal pilot study in a teaching hospital Coronary Care Unit. SUBJECTS AND INTERVENTION: Seventeen patients (12 men: mean age (62 years +/- SD 11 years) admitted with acute myocardial infarction (AMI), who were given thrombolytic therapy, and 59 healthy controls. RESULTS: Baseline levels of fibrinogen (Mann-Whitney test, P = 0.0055) and vWf (P < 0.001) were significantly higher than controls, but sPsel, sTM or vitamin E levels were not significantly different. Following thrombolysis, as expected, median concentrations of plasma fibrinogen fell profoundly (Friedman ANOVA P < 0.001) so that after 45 min, levels were undetectable in 13 patients. At 24-h median fibrinogen concentration had recovered to approximately 30% of baseline (P < 0.01) and was still undetectable in three patients. Levels of vWf and sPsel increased steadily, reaching significance after three hours (both P < 0.05). However, levels of sTM rose immediately after thrombolysis, peaking between 1 and 3 h, and remained elevated at 24 h. These increases corresponded to a simultaneous early fall in serum vitamin E concentrations. CONCLUSION: The present pilot study demonstrates significant endothelial damage and platelet activation in association with increased oxidative stress following streptokinase therapy for AMI.     

In patients with deep-vein thrombosis elevated levels of factor VIII correlate only with von Willebrand factor but not other endothelial cell-derived coagulation and fibrinolysis proteins.

Several studies have shown that patients with venous thrombosis have elevated levels of factor VIII (FVIII) at an increased frequency. Most such patients also have high von Willebrand factor (vWF) levels. Since vWF is synthesized by the vascular endothelium, we hypothesized that elevated FVIII levels would also be associated with an increase of other endothelial cell-derived coagulation proteins suggesting perturbation of the endothelium. In 100 healthy individuals and 129 patients with venous thromboembolism, we have determined antigenic FVIII levels along with several endothelial proteins including vWF, soluble thrombomodulin (sTM), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor 1 (PAI-1). Levels of FVIII, vWF, PAI-1 and t-PA were significantly increased in patients compared with the controls (FVIII, vWF, and PAI-1,P < 0.001; t-PA, P < 0.05). Levels of sTM, however, were higher in the controls than in the patients (P < 0.001). Whereas the FVIII levels correlated well with the vWF levels in the patients (correlation, 0.61; P < 0.001) and the controls (correlation, 0.70; P < 0.001), there was neither a relevant correlation between FVIII and sTM, PAI-1, and t-PA, nor between vWF and sTM, PAI-1, and t-PA in the patients and the controls. In conclusion, although levels of PAI-1 and t-PA can be found, on average, at increased levels in patients with thrombosis, FVIII levels correlate only with vWF but not other endothelial cell-derived coagulation and fibrinolysis proteins including sTM, PAI-1, and t-PA.     

几丁质酶-3样蛋白-1在心房颤动发病机制中的作用

目的探讨几丁质酶-3样蛋白-1（ehitinase-3．1ike-1protein,YKL-40）在心房颤动（房颤）发病机制中的作用。方法选择在广州市番禺区何贤纪念医院心内科住院的房颤患者71例（其中阵发性房颤组22例,持续性房颤组30例．永久性房颤组19例）为研究对象。另外,选择同期年龄匹配的健康体检者20名为对照组。采用酶联免疫吸附试验（ELISA）方法检测各组血浆YKL-40浓度并进行比较。结果各组间基线资料比较,差异无统计学意义（P〉0。05）。永久性房颤组、持续性房颤组及阵发性房颤组血浆YKL-40浓度均显著高于对照组,差异有统计学意义[（4．21±0．62）μg／L、（3．72±0．63）μg／L、（3．29＋0．75）μg／Lus（2．79±0．56）μg／L,P〈0．05];持续性及永久性房颤组血浆YKL-40浓度高于阵发性房颤组,差异有统计学意义（P〈0．05）;永久性房颤组YKL-40浓度高于持续性房颤组．差异有统计学意义（P〈0．05）。结论YKL-40可能参与房颤的发生、发展。     

孤立性心房颤动患者血浆血小板α颗粒膜蛋白-140和血栓素B_2及6-酮-前列腺素F_(1α)浓度变化的研究

目的研究孤立性心房颤动(房颤)患者血小板功能改变,探讨房颤引起血栓前状态的原因。方法用放射免疫分析法对21例孤立性阵发性房颤(A组)、28例孤立性持续性房颤(B组)患者分别于房颤发作及终止后1周测定外周静脉血浆血小板а颗粒膜蛋白-140(GMP-140)、血栓素B2(TXB2)、6-酮-前列腺素F1α(6-K-PGF1α)浓度,并与27例风湿性心脏病二尖瓣狭窄伴持续性房颤(C组)、32例阵发性室上性心动过速患者(D组)及与20例健康体检者(对照组)相比较。结果A、B组患者房颤发作时及C组患者GMP-140、TXB2和TXB2/6-K-PGF1α比A组患者房颤终止后1周和D组及对照组明显上升。A组患者血浆GMP-140、TXB2浓度及TXB2/6-K-PGF1α与房颤发作时间呈正相关,而与患者年龄、性别及左心房内径等临床参数无关。结论无论是器质性心脏病房颤还是孤立性房颤,无论是阵发性房颤还是持续性房颤都存在血小板的激活和血管内皮细胞功能损伤。