Von Willebrand factor,soluble P-selectin,and target organ damage in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

To investigate the relationship between soluble markers of platelet, endothelial and rheological function, and target organ damage and their response to intensified management in a population of middle-age hypertensive patients at high risk of cardiovascular complications, we studied 382 consecutive patients (308 men; mean age, 63 years, SD 8) along with 60 normotensive controls free of cardiovascular disease. Patients were divided into those with target organ damage (TOD; n=107) and those free of end-organ damage. Plasma levels of soluble P-selectin (sP-sel), a marker of platelet activation, and von Willebrand factor (vWF), an index of endothelial damage/dysfunction (both enzyme-linked immunosorbent assay), and the rheological indices fibrinogen, plasma viscosity, hematocrit, platelet, and white cell count were measured. In 53 patients, variables were further measured after 6 months of intensified cardiovascular risk management. Patients with TOD had significantly higher vWF, 137 (SD 33) versus 125 (SD 33) IU/dL (P=0.002,) and a greater proportion of smokers, 31% versus 16% (P=0.002). There were no statistically significant differences in plasma viscosity, fibrinogen, hematocrit, white blood cell count, platelet count, or sP-sel between the 2 subgroups. In multivariate analysis, vWF was a significant independent predictor for TOD. After 6 months of intensified management in 53 patients who entered the trial, there were significant reductions in systolic blood pressure, total cholesterol, hematocrit, plasma viscosity, sP-sel, and vWF (all P<0.01) but no significant change in fibrinogen. In conclusion, there is a relationship between TOD and endothelial damage/dysfunction in hypertension. Intensified management results in improvements in hemorheology, endothelial and platelet function.     

Platelet and haemorheological markers in 'high risk' hypertensives are improved by tighter blood pressure control and cardiovascular risk management: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

OBJECTIVE: To investigate the impact of intensified cardiovascular risk management on soluble markers of platelet, endothelial and rheological function in a population of middle-aged hypertensive patients at high risk of cardiovascular complications. DESIGN: Prospective follow-up study. SUBJECTS AND METHODS: A total of 159 hypertensive patients [138 male, mean age 64 (+/-8) years] and 80 healthy controls were studied. Plasma levels of soluble P-selectin (sP-sel, a marker of platelet function), von Willebrand factor (vWF, an index of endothelial damage/dysfunction) and rheological indices [fibrinogen (Fib), plasma viscosity (PV), haematocrit (HCT), white blood count (WBC) and platelet count] were measured at baseline and again (in the patients) after 6 months' treatment. RESULTS: As expected, 6 months of intensified cardiovascular risk management resulted in a significant fall in mean blood pressure (BP) and total cholesterol. It also resulted in reduced haematocrit, vWF, sP-sel, WBC and PV levels (all P < 0.001), but not plasma fibrinogen. There were no correlations between the fall in BP and the improvement in any of the research indices. CONCLUSIONS: Intensified cardiovascular risk management results in significant improvements in indices of endothelial, platelet and rheological function in a population of hypertensives at high risk of cardiovascular events. These improvements appear to be independent of the degree of change in BP. Given the fundamental role of interactions between the endothelium and circulating blood components in the pathogenesis of hypertensive complications this may be of importance in preventing adverse cardiovascular outcomes.     

Platelet indexes in relation to target organ damage in high-risk hypertensive patients: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

OBJECTIVES: We sought to investigate the relationship between target organ damage (TOD) in hypertension and a prothrombotic/hypercoagulable state, using a new technique of "platelet lysis" to quantify the amount of P-selectin per platelet (pP-sel), and to correlate it with other platelet markers (e.g., mass, volume and granularity, soluble P-selectin [sP-sel], and beta-thromboglobulin [beta-TG]). BACKGROUND: The increased risk of TOD in hypertension may be related to a prothrombotic/hypercoagulable state, with abnormalities in platelets, such as increased expression of P-selectin. METHODS: We studied 199 patients (mean age 68 years, 75% men) with hypertension. Of these, 125 had TOD (e.g., stroke, previous myocardial infarction, angina, left ventricular hypertrophy). Values obtained were compared with those from 59 healthy normotensive control subjects (mean age 68 years, 58% men). RESULTS: Hypertensive patients had a higher mean platelet volume, mass, pP-sel, sP-sel, and beta-TG and lower platelet granularity (all p < 0.01), but a similar platelet count, as compared with controls. Within the hypertensive group, those with evidence of TOD had significantly larger platelets with greater mass but had lower granularity, sP-sel, and pP-sel levels than those without TOD, possibly reflecting increased aspirin use. On multivariate analysis, aspirin use was a determinant of pP-sel (p = 0.03) and sP-sel (p = 0.01), but the use of other drugs or other co-morbidity (e.g., diabetes, smoking) did not influence either P-selectin value. CONCLUSIONS: Patients with hypertension have evidence of changes in platelet physiology, as reflected by a higher level of pP-sel. Patients with TOD also had larger platelets, with greater mass, and the use of aspirin lowered pP-sel and sP-sel levels. These changes may have implications for the pathophysiology of cardiovascular and cerebrovascular disease in hypertension.     

Haemorheological, platelet and endothelial indices in relation to global measures of cardiovascular risk in hypertensive patients: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

INTRODUCTION AND METHODS: We tested the hypothesis that there was a significant relationship between haemorheological markers [white blood cell count (WCC), plasma viscosity (PV), haematocrit (HCT) and fibrinogen], as well as plasma von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and soluble P-selectin (sP-sel, an index of platelet activation), to five global measures of cardiovascular risk [i.e. Framingham coronary heart disease (CHD), stroke and cardiovascular death score, the Pocock cardiovascular risk score and the sum of individual risk factors]. RESULTS: Men with a high (> or = median, n = 156) Framingham 10-year CHD risk score had higher levels of WBC (P = 0.027), fibrinogen (P = 0.012) and vWF (P = 0.002) than 153 men with results < median. Men with a high 10-year stroke risk score had significantly higher levels of fibrinogen (P = 0.01) and vWF (P < 0.0001). In stepwise linear regression analysis in men, vWF and fibrinogen were independent predictors of the number of risk factors (P < 0.0001), whilst WCC, vWF and fibrinogen emerged as independent predictors of Framingham CHD risk (P < 0.0001), and fibrinogen and vWF predicted Framingham stroke risk (R(2) = 0.089, P < 0.0001). vWF, PV and fibrinogen were predictors of Pocock cardiovascular death risk (P < 0.0001) but vWF was the only independent predictor of Framingham cardiovascular death risk (P = 0.001). CONCLUSIONS: Abnormal haemorheological factors (particularly high plasma fibrinogen levels) and endothelial damage/dysfunction (high vWF), but not platelet activation (sP-sel), are related to established cardiovascular and death risk scores. This relationship was most evident amongst male 'high-risk' hypertensive subjects.     

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.     

Effects of "newer" and "older" antihypertensive drugs on hemorrheological, platelet, and endothelial factors. A substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

BACKGROUND: Different antihypertensive therapies may exert benefits via not only a reduction in blood pressure but also in improving the risk of thrombosis. METHODS: We tested the hypothesis that a more modern antihypertensive drug regimen (ie, amlodipine +/- perindopril) would have a more beneficial effect on hemorheological markers (white blood-cell count [WCC], plasma viscosity [PV], hematocrit [HCT], and fibrinogen)--and on plasma von Willebrand factor (vWf, an index of endothelial damage and dysfunction) and soluble P-selectin (sP-sel, an index of platelet activation), compared with an older antihypertensive drug regimen (ie, atenolol +/- bendroflumethiazide). RESULTS: After 6 months, PV, sP-sel, and HCT fell in both groups (P < .01), while fibrinogen was unchanged. However, those 74 patients randomized to amlodipine +/- perindopril had significant reductions in WCC (P = .005), with no significant changes in vWF or platelet count. Conversely, in those 85 patients randomized to atenolol +/- bendroflumethiazide, there were significant reductions in vWF (P = .001) and platelet count (P = .011) but no significant reductions in WCC. There were no significant differences in the levels of any of the variables between the two arms of the trial, nor a significant difference in the magnitude of reduction between the two treatment arms. CONCLUSIONS: Within the constraints of this substudy design, there was no differential effect apparent of the two antihypertensive treatment arms on hemorheological parameters or endothelial and platelet function (as assessed by vWF and sP-sel), suggesting that other pathophysiological mechanisms may be involved.     

Relationship of homocysteine to markers of platelet and endothelial activation in "high risk" hypertensives: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial

OBJECTIVE: To examine the relationship between plasma homocysteine (HCY) and rheological, endothelial and platelet markers in "high risk" hypertensive patients. DESIGN: Cross-sectional study. SUBJECTS AND METHODS: A total of 165 consecutive hypertensive patients (136 male; mean age 63 years (S.D. 8)) at high risk of cardiovascular disease who screened for inclusion in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) were studied along with 38 population normotensive healthy controls. We measured levels of plasma homocysteine [high pressure liquid chromatography (HPLC)], soluble P-selectin, a marker of platelet function, von Willebrand factor (vWF), an index of endothelial damage/dysfunction [both by ELISA] and fibrinogen (CLAUSS). The Framingham cardiovascular and cerebrovascular risk scores were calculated. RESULTS: Hypertensives had significantly higher blood pressure (BP) [165/90(16/10) vs. 138/82(12/8) mm Hg, p<0.0001], sP-sel [54(44-67) vs. 45(35-57) ng/ml, p=0.002], vWF [133(34) vs. 110(28) IU/dl, p<0.0001], and fibrinogen [2.98(2.52-3.47) vs. 2.43(2.20-2.83)g/l, p=<0.0001]. Homocysteine were lower in our hypertensives compared with controls [8.7(6.9-11.2) vs. 10.5(8.5-13.1) micromol/l, p=0.005], but there were significant correlations between homocysteine levels and both calculated 10-year coronary heart disease risk (Spearman r=0.197, p=0.026) and stroke risk (r=0.210, p=0.018), using the Framingham equation. There was a positive correlation between plasma homocysteine and soluble P-selectin (r=0.180, p=0.025), which persisted in multiple linear regression analysis. There was no significant relationship between homocysteine and HCT, PV, or the endothelial marker, vWF. CONCLUSION: Hypertensives demonstrate abnormalities of endothelial, platelet and rheological function. Homocysteine is related to both 10-year coronary heart disease risk and stroke risk, and is significantly correlated with soluble P-selectin, a marker of platelet activation, in hypertensives but only weakly or not at all to other thrombotic markers. Increased platelet activation as reflected by soluble P-selectin may be one mechanism by which hyperhomocysteinaemia confers an increased thrombotic risk in hypertension.     

高血压合并心房颤动患者内皮细胞及血小板功能的变化

目的探讨高血压合并心房颤动(简称房颤)患者血小板和内皮细胞功能的变化。方法选择轻、中度原发性高血压患者110例,其中伴房颤60例为房颤组,无房颤50例为对照组。测定两组血浆P-选择素、内皮素-1(ET-1)及血管性血友病因子(vWF)水平。结果房颤组血浆P-选择素、ET-1及vWF水平与对照组比较差异有统计学意义(P<0.01)。结论高血压合并房颤患者存在有血小板活性增高及内皮功能受损,临床工作中应重视内皮细胞功能的改善和血小板的抗凝治疗。     

Acute,short-term hyperglycemia enhances shear stress-induced platelet activation in patients with type II diabetes mellitus

OBJECTIVES: The aim of our study was to assess whether acute, short-term hyperglycemia affects platelet reactivity in patients with Type II diabetes mellitus (T2DM). BACKGROUND: Hyperglycemic spikes are thought to precipitate ischemic events in T2DM. Previous studies have shown in vivo platelet activation in diabetes; however, no studies have assessed whether acute in vivo hyperglycemia induces further activation of platelets. METHODS: In a cross-over, randomized, double-blind study, 12 patients with T2DM underwent 4 h of either acute hyperglycemia (13.9 mmol/l, 250 mg/dl) or euglycemia (5.5 mmol/l, 100 mg/dl). Shear stress-induced platelet activation, P-selectin and lysosomal integral membrane protein (LIMP) expression on platelets in the bleeding-time blood, urinary 11-dehydro-thromboxane B(2) (TxB(2)) excretion, von Willebrand factor:antigen (vWF:Ag), and von Willebrand factor:activity (vWF:activity) were measured before and after hyperglycemia or euglycemia. RESULTS: Shear stress-induced platelet activation, P-selectin and LIMP expression on platelets in the bleeding-time blood, and urinary 11-dehydro-TxB(2) excretion increased significantly after hyperglycemic clamping, whereas no changes were observed after euglycemic clamping. Plasma vWF:Ag and vWF:activity increased strikingly in parallel fashion after hyperglycemic clamping, whereas no changes were observed after euglycemic clamping. CONCLUSIONS: Our data demonstrate that acute, short-term hyperglycemia induces an increased activation of platelets exposed to high shear stress conditions in vitro (filtration method) or in vivo (bleeding time). In vivo platelet activation is reflected by an increased urinary excretion of 11-dehydro-TxB(2). The increased levels of vWF in the circulation correlate with the increase in platelet activation markers and may indicate some degree of causation. Acute, short-term hyperglycemia in T2DM may precipitate vascular occlusions by facilitating platelet activation.     

抗血小板药物对脑梗死患者血小板-白细胞聚集体的影响

目的观察急性脑梗死患者血小板一白细胞聚集体（PLA）的变化以及阿司匹林和氯吡格雷对其的影响。方法对急性脑梗死和对照组患者血小板聚集率（PAR）、可溶性P选择素（sP—sel）、C-反应蛋白（CRP）和PLA进行检测。同时将急性脑梗死患者随机分为阿司匹林组和氯吡格雷组,观察两组患者治疗前后斯堪的纳维亚神经卒中量表（SNSS）评分、PAR、sP—sel、CRP和PLA的变化。结果急性脑梗死患者血小板单核细胞聚集体（PMA）显著高于对照组（P〈0．001）;PMA水平与PAR、sP-sel、CRP、血糖、胆固醇和纤维蛋白原正相关（P〈0．05）;与SNSS评分负相关（P〈0．05）。脑梗死患者治疗后PMA、PAR明显下降（P≤0．001）,且治疗后氯吡格雷组PMA和PAR（ADP）降低较阿司匹林组更明显（P〈0．05）,但PAR（AA）两组间差异无统计学意义;sP-sel在氯吡格雷组治疗后显著下降（P〈0．001）。结论急性脑梗死患者反映血小板活化的敏感指标PMA明显增高,阿司匹林和氯吡格雷可以降低PMA水平,其中氯吡格雷作用较阿司匹林更为明显。     

非瓣膜性心房颤动患者内皮和血小板功能及β受体阻滞剂干预的临床意义

目的 探讨非瓣膜性心房颤动(房颤)与内皮细胞功能及血小板功能的关系,观察β受体阻滞剂治疗对房颤患者内皮功能及血小板功能的影响.方法 非瓣膜性持续性房颤患者(房颤组)25例,窦性心律组(窦律组)35例,通过竞争性酶联免疫(ELASA)分析定量测定两组血清血管性血友病因子(von Willebrand Factor,vWF)和可溶性P选择素水平,及房颤组β受体阻滞剂治疗后上述指标的变化.结果 房颤组血清vWF水平(1945.2±111.3)g/L高于窦律组(1862.3±101.6)g/L,差异有统计学意义(P＜0.05).房颤组患者服用β受体阻滞剂(阿替洛尔)后,血清vWF水平下降至(1758.3±152.4)g/L,与服药前比较差异有统计学意义(P＜0.01).血清可溶性P选择素水平房颤组与窦律组[分别为(24.32±9.21)g/L与(24.68±11.70)g/L]比较,差异无统计学意义(P＞0.05),服用β受体阻滞剂后血清可溶性P选择素水平下降至(21.05±8.94)g/L,但与服药前相比差异无统计学意义(P＞0.05).vWF与可溶性P选择素无相关性(Pearson相关系数为-0.008,P＞0.05).结论 房颤患者血清vWF水平较窦性心律者升高,提示存在心血管内皮损伤.服用阿替洛尔后,房颤患者血清vWF水平下降,提示阿替洛尔用于房颤患者除能有效控制心室率外,还可能具有内皮保护功能.

Abstract：

Objective To examine the serum von Willebrand factor (vWF) and soluble Pselectin levels in patients with non-valvular atrial fibrillation (NVAF), and to observe the influence of beta-blocker treatment on endothelial function and platelet activation in NVAF patients. Methods The 25 subjects, 17 males and 8 females, with persistent NVAF and left ventricular ejection fraction (LVEF)≥50%, were enrolled in NVAF group. Those with myocardial infarction, cardiomyopathy or hyperthyroidism were excluded. Another 35 subjects with sinus rhythm were as control (age,gender and LVEF matched with NVAF group, and with similar cardiovascular diseases). Serum vWF and soluble P-selectin levels were tested by enzyme-linked immunosorbent assay. Results The serum vWF level was significantly higher in NVAF group than in control group [(1945.2±111.3) g/L vs. (1862.3±101.6) g/L, P＜0.05]. However, there was no significant difference in serum soluble P-selectin level between NVAF group and control group [(24.32±9.21) g/L vs. (24.68±11.70) g/L, P＞0. 05]. After administration of beta-blocker, a down-regulation was found in serum vWF level [(1758. 3±152. 4) g/L, P＜0. 01], but not in soluble P-selectin level [(21.05±8. 94) g/L, P＞0. 05]. There was no relationship between serum level of vWF and soluble P-selectin (r=-0.008,P＞0. 05). Conclusions High serum level of vWF is found in patients with persistent NVAF as compared with control, indicating endothelial damage/dysfunction in those patients. After administration of beta-blocker, serum level of vWF drops dramatically in NVAF patients, indicating possible endothelial function protection of beta-blocker.     

老年急性冠状动脉综合征患者血小板P选择素、血管性血友病因子的变化及氯吡格雷干预的临床研究

目的观察老年急性冠状动脉综合征(ACS)患者血小板P选择素和血管性血友病因子(vWF)的变化,及抗血小板聚集药物氯吡格雷干预后的临床相关研究,探讨它们在ACS发病机制中的作用和相互联系。方法选取60例老年ACS患者,其中急性心肌梗死(AMI)患者30例,不稳定型心绞痛(UAP)患者30例,另设对照组30例。随机将UAP分为常规治疗组和氯吡格雷(75mg/d)组,AMI组应用抗血小板聚集药物(氯吡格雷300mg+阿司匹林)联合治疗,采用全血法流式细胞术及血浆酶联免疫吸附法测定各组治疗前后血小板P选择素、vWF水平变化,同时探讨P选择素与vWF的相关关系。结果老年ACS患者P选择素、vWF水平[AMI组P选择素(9.74±1.97)%,vWF(272.24±28.62)%;UAP组P选择素(8.87±1.78)%,vWF(215.81±22.01)%]显著高于正常对照组[P选择素(2.27±1.30)%,vWF(112.45±13.22)%](P<0.001)。常规治疗组和氯吡格雷组均可降低UAP患者P选择素与vWF水平[常规治疗组P选择素治疗前(8.60±1.39)%,治疗后(5.60±2.18)%,降低(2.97±1.82)%,vWF治疗前(217.52±25.68)%,治疗后(170.17±20.88)%,降低(47.34±24.31)%;氯吡格雷组P选择素治疗前(9.15±2.11)%,治疗后(4.24±1.73)%,降低(4.89±2.02)%,vWF治疗前(214.10±18.35)%,治疗后(151.72±12.66)%,降低(62.38±21.58)%],但氯吡格雷组较常规治疗组降低的程度更明显(P<0.05),AMI组联合治疗后P选择素与vWF水平均低于治疗前[P选择素(2.27±1.30)%,vWF(112.45±13.22)%](P<0.001),但仍高于对照组(P<0.001)。老年ACS患者P选择素水平与vWF水平成正相关(r=0.365,P<0.05)。结论P选择素、vWF与ACS的发病过程有关,可能是老年ACS不稳定斑块的识别和预测指标。     

A comparison of flow-mediated dilatation and von Willebrand factor as markers of endothelial cell function in health and in hypertension: relationship to cardiovascular risk and effects of treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial.

Loss of adequate endothelial cell function (associated with various cardiovascular syndromes such as hypertension) is most widely quantified by assessing flow-mediated dilatation (FMD) or measuring plasma markers such as von Willebrand factor (vWF). However, the relationship between these two methods is unclear, as is their relationship to 10-year cardiovascular risk (defined by the Framingham equation) and their response to intensive cardiovascular risk factor management. We tested the hypothesis that there is an inverse relationship between vWF and FMD by measuring both in 132 subjects, of whom 89 were hypertensive (mean blood pressure, 167/91 mmHg) and 43 were healthy normotensive (mean blood pressure, 133/80 mmHg). High-resolution ultrasound assessed endothelium-dependent brachial artery FMD following reactive hyperaemia after occlusion. Plasma vWF was defined by enzyme-linked immunosorbent assay. These measurements were repeated in the patients after 6 months of intensive cardiovascular risk factor management. vWF and FMD correlated significantly (r = -0.517, P < 0.001), and both correlated with 10-year cardiovascular risk using the Framingham equation (vWF, r = 0.48, P < 0.001; FMD, r = -0.624, P < 0.001). Following 6 months intensive cardiovascular risk factor management, plasma vWF was significantly reduced whereas FMD significantly increased (both P < 0.002). We conclude that two fundamentally different methods for assessing endothelial function correlate well with each other, as well as with 10-year cardiovascular risk. Six months of intensive risk factor management is beneficial to the endothelium, as defined by improved vWF and FMD. These methods might therefore be useful indices to identify patients at risk of future cardiovascular events, and may also assist in the understanding of early developments in the pathogenesis of vascular risk in hypertension.     

Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention.

AIMS: We investigated the predictive value of plasma concentration of asymmetrical dimethylarginine (ADMA) on clinical outcome in patients undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: One-hundred and fifty-three consecutive patients with stable angina and undergoing PCI were prospectively enrolled for clinical follow-up. Plasma ADMA levels were determined before procedure by high performance liquid chromatography. The major adverse cardiovascular events included cardiovascular death, myocardial infarction, and repeat revascularization of target vessels. Patients were grouped into tertiles according to their plasma ADMA levels. Over a follow-up period of 16 months (median), cardiovascular events occurred in 6 patients of tertile I (<0.50microM), in 17 patients of tertile II (0.50-0.62microM), and in 28 patients of tertile III (>0.62microM), P<0.001. By multivariate analysis, tertiles of ADMA levels were independently associated with a higher risk of adverse cardiovascular events after PCI (relative risk: tertile II vs I: 3.0 [1.2-7.7], P=0.022; tertile III vs I: 5.3 [2.2-12.9], P<0.001). Moreover, plasma ADMA level in the highest tertile also appeared as a significant risk factor of subsequent death and non-fatal myocardial infarction after PCI (tertile III vs I, P=0.04). CONCLUSION: Pre-procedural plasma ADMA levels may independently predict subsequent adverse cardiovascular events in patients undergoing PCI. Measurement of plasma ADMA levels could provide a rationale for risk stratification of patients by measuring ADMA levels before intervention.     

Platelet activation in coronary artery disease: intracardiac vs peripheral venous levels and the effects of angioplasty

BACKGROUND: Platelet activation and aggregation play a key role in coronary artery disease, with antiplatelet therapies leading to improved clinical outcomes. Limited data exist as to whether peripheral venous blood measurements of platelet physical indexes (eg, platelet count, volume, and granularity) and soluble markers of platelet activation (eg, P-selectin [sP-sel] and CD40 ligand [CD40L]) reflect the local (intracardiac) coronary environment. Furthermore, how percutaneous coronary interventions (PCIs) affect levels of peripheral/cardiac platelet indexes is unclear. METHODS: Blood samples were sequentially acquired from the coronary os, aortic root, coronary sinus, and the femoral vein, and where relevant, pre-PCI and post-PCI. Eighty-seven patients undergoing coronary angiography were recruited (mean [+/-SD] age, 59.8+/-10.8 years; 54 men [62%]), of whom 36 proceeded to PCI. Platelet physical indexes and plasma sP-sel and CD40L levels were measured (by enzyme-linked immunosorbent assay). RESULTS: At baseline, no intracardiac vs peripheral differences were noted in sP sel levels, while CD40L levels were elevated in the aorta compared to the coronary sinus and femoral venous. The mean platelet count (MPC) was similar at all four sites, but within the coronary sinus blood, mean platelet volume (MPV) was significantly lower and mean platelet granularity (MPG) was higher when compared to arterial levels. Though aortic and femoral levels of sP-sel were raised following PCI, transcardiac gradients of plasma sP-sel levels were unaffected. PCI was associated with lower CD40L, MPC, and MPV levels but with a higher MPG level in all sampling sites. CONCLUSIONS: sP-sel levels measured peripherally reflect the cardiac environment, unlike CD40L, MPC, MPV, and MPG. PCI leads to further platelet activation (raised sP-sel) despite aggressive antiplatelet therapy.     

Relation of thrombogenesis in systemic hypertension to angiogenesis and endothelial damage/dysfunction (a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT])

Increasing evidence points toward a prothrombotic state in hypertension and atherosclerosis, conditions associated with thrombosis-related complications, such as myocardial infarction and stroke. We hypothesized that this increased risk of thrombogenesis may be related to endothelial damage/dysfunction and abnormal angiogenesis, and thus, an increased risk of future cardiovascular disease. Thrombogenesis, endothelial damage/dysfunction, and angiogenesis can be assessed by measurement of tissue factor (TF), von Willebrand Factor (vWF), flow-mediated dilatation (FMD), and vascular endothelial growth factor (VEGF), respectively. To test this hypothesis, we measured TF, vWF, FMD, and VEGF in 76 patients with systemic hypertension (71 men; mean age 64; mean blood pressure 167/72 mm Hg), considered additional risk factors such as diabetes, and related them to the patient's 10-year cardiovascular and cerebrovascular risk score using the Framingham equation. Patients were compared with 48 healthy normotensive controls. In these patients, the effects of 6 months of intensified blood pressure and (where appropriate) lipid-lowering treatment were investigated. In our patients, TF, VEGF, and vWF levels were higher, but FMD was lower (all p <0.001) compared with the controls. All markers correlated with each other and with both cardiovascular and cerebrovascular risk scores (all p <0.001). After intensified blood pressure and hypercholesterolemia treatment, total cholesterol, blood pressure, TF, VEGF, and vWF levels all decreased, whereas FMD increased (all p <0.001). Thus, in subjects with hypertension and other risk factors, endothelial damage/dysfunction (and thus, atherogenesis), thrombogenesis, and angiogenesis are abnormal, correlate with overall cardiovascular risk, and importantly, can be related to each other in a "Birmingham Vascular Triangle." Furthermore, these processes are beneficially affected by intensive blood pressure and lipid treatment.     

Pro-coagulant state resulting from high levels of soluble P-selectin in blood

The plasma concentration of soluble adhesion receptors is increased under pathological circumstances, but their function remains enigmatic. Soluble P-selectin (sP-sel) is shed from activated platelets and endothelial cells. Mice genetically engineered to express P-selectin without the cytoplasmic tail (DeltaCT) constitutively show a 3- to 4-fold increase of sP-sel in plasma. We observed that the DeltaCT mice formed fibrin very readily. In an ex vivo perfusion chamber, there was more fibrin deposited at the site of platelet thrombus formation than in wild type (WT), whereas no fibrin deposits were detected using P-selectin-deficient blood during the same interval. Similarly, in vivo, the hemorrhage produced by local Shwartzman reaction was smaller in the DeltaCT mice than in WT. In contrast, we previously showed hemorrhage to be more prominent in P-selectin knock-out mice. Infusion of mouse P-sel-Ig chimera produced the same protective effect in WT mice as seen in the DeltaCT mice, indicating that the effect was due to increased levels of sP-sel. Mice infused with P-sel-Ig showed significantly more fibrin deposited on the luminal face of the injured vessels than control mice. Plasma from DeltaCT mice or mice infused with P-sel-Ig contained higher concentration of pro-coagulant microparticles and clotted one minute faster than WT. This pro-coagulant phenotype of DeltaCT mice could be reversed by a 4-day treatment with PSGL-Ig, a P-selectin inhibitor. We propose that sP-sel should no longer be considered only as a marker of inflammation or platelet activation, but also as a direct inducer of pro-coagulant activity associated with vascular and thrombotic diseases.     

von Willebrand factor in CHD and stroke: Relationships and therapeutic implications

Opinion statement Atherosclerotic cardiovascular disease (CVD), which includes coronary heart disease (CHD) and stroke, is now the most common cause of death in the middle aged and elderly in all parts of the world except subSaharan Africa. The direct cause of death is frequently an acute thrombotic arterial occlusion. Because atherosclerosis is a diffuse disease, patients with CHD also have a high risk of ischemic stroke. The hemostatic process is a needed defense mechanism to control hemorrhage after injury but at same time, if overactive, may have the potential to precipitate diseases such as myocardial infarction or stroke in the setting of atherosclerosis. In approximately 1% of all patients with ischemic stroke, and in up to 4% of young adults with stroke, the major precipitant of brain ischemia is a hematologic disorder or coagulopathy that predisposes to thrombosis. von Willebrand factor (vWF) plays an important role in platelet adhesion to subendothelial structures and in the intrinsic pathway of coagulation. It is regarded as an indirect measure of endothelial dysfunction. Deficiency of vWF in von Willebrand’s disease is well established. However, much less is known regarding the pathophysiologic implications of an elevated level of vWF, particularly in relation to CVD and cerebrovascular disease. The importance of vWF in the pathogenesis of this disease is poorly defined and information is limited and inconsistent. Elevated levels of vWF have been variably linked with risk of CHD; causal criteria are not fully met. Relationships with stroke risk are even less well established. Measurement of vWF adds little to risk prediction after considering the major risk factors—age, sex, smoking, raised blood cholesterol, and hypertension. vWF may have a greater role in predicting outcome in subjects with acute coronary syndromes (ACS), stroke, and perhaps atrial fibrillation. Investigation of the use of vWF level to guide treatment of ACS or stroke is ongoing; however, there is no compelling evidence to date.     

心脑血管疾病患者阿司匹林抵抗的临床与实验研究

目的探讨心脑血管疾病患者阿司匹林抵抗(aspirin resistance,AR)的发生率、可能影响因素及其对预后的影响。方法采用光学法测定157例服用阿司匹林的心脑血管疾病患者的血小板聚集率,其中高血压76例、脑梗死56例、冠心病25例,将AR和阿司匹林半抵抗患者作为非阿司匹林敏感(aspirin sensitive,AS)组(59例),其余患者作为AS组(98例),并同时检测肝、肾功能、血脂、血糖等生化指标,分析该患者群中AR的发生、相关危险因素及预后。结果非AS组冠心病患者较AS组明显增多(P0.05)。糖尿病、高脂血症与AR发生相关(OR=4.438,OR=2.943,P0.01)。非AS组脑梗死和心肌梗死再发率明显高于AS组(15.05% vs 3.06%,P0.05;18.64% vs 7.14%,P0.01)。结论 AR对预后影响大,可使心脑血管事件再发风险显著升高,应及时调整药物剂量或者联合应用其他抗血小板药物。     

Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study

BACKGROUND: Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure. METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified. RESULTS: At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SBP was associated with total mortality. Importantly, SBP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SBP, DBP, and pulse pressure was associated with hazard ratios (95% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95% confidence intervals) were 1.34 (1.21-1.47) with SBP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SBP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension. CONCLUSION: In this population-based study of older adults, although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events, SBP was the best single predictor of cardiovascular events.