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.     

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.     

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.     

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.     

Prognostic value of plasma soluble P-selectin and von Willebrand factor as indices of platelet activation and endothelial damage/dysfunction in high-risk patients with hypertension: a sub-study of the Anglo-Scandinavian Cardiac Outcomes Trial

BACKGROUND: Abnormal levels of prothrombotic markers have been described in hypertension, but no such marker has yet been shown to reliably predict cardiovascular outcomes in hypertension. We hypothesized that raised circulating levels of soluble P-selectin (sP-sel, an index of platelet activation) and/or von Willebrand factor (vWF, an index of endothelial damage/dysfunction) would predict vascular events in patients treated for cardiovascular risk. METHODS: We measured vWF and sP-sel levels by an ELISA in 234 hypertensive participants with no prior cardiovascular events who were participating in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Plasma vWF and sP-sel levels were related to the subsequent cardiovascular events over a mean (SD) follow-up period of 59.6 (19) months. RESULTS: Plasma sP-sel was a significant predictor of myocardial infarction (P = 0.03), with the greatest risk amongst those with the highest sP-sel levels. sP-sel did not predict cerebrovascular events (P = 0.53) or composite cardiovascular events (P = 0.06). No significant relationships were found between vWF levels and outcomes. There was no relationship to the presence or absence of diabetes mellitus (DM) at baseline or subsequent development of DM during the follow-up period. CONCLUSIONS: Among 'high-risk' patients with hypertension, raised levels of sP-sel (platelet activation) were predictive of myocardial infarction. Levels of vWF (endothelial damage/dysfunction) were not associated with coronary events and neither marker predicted cerebrovascular or composite cardiovascular endpoints. Platelets (or P-selectin) might represent a target for novel therapies or an adjunctive aid to risk stratification in the setting of hypertension.     

Cardiovascular disease risk prediction in type 1 diabetes: accounting for the differences

Present analyses used data from the Pittsburgh Epidemiology of Diabetes Complications Study, a prospective study of subjects with childhood type 1 diabetes (T1D), diagnosed between 1950 and 1980. Baseline exams took place 1986-1988 with biennial exams since. The Framingham risk equation was applied to generate the probability of risk for coronary heart disease (CHD) (MI, CHD death, or Q-waves) in 552 CHD free subjects who experienced 42 events over the 10-year follow-up period. Probabilities were split in to deciles. Expected and observed events were compared and demonstrated poor prediction. Risk factors previously found to be associated with CHD in T1D other than those in the Framingham risk function (age, smoking, cholesterol/HDLc, systolic blood pressure) were compared within the highest risk deciles. In men, elevated fibrinogen (p=0.007), white blood cell count (WBC) (p=0.037), albumin excretion rate (AER) (p=0.0001), and lower HDLc (p=0.048) were predictive. In females, higher Beck Depression Inventory (p=0.008), HbA1 (p=0.008), AER (p=0.01), LDLc (p=0.007), fibrinogen (p=0.006), WBC (p=0.005), non-HDLc (p=0.0005), WHR (p=0.003), and estimated glucose disposal rate (p=0.002) were associated. Risk factors not considered by the Framingham risk equation may account for the lack of fit and should be examined further.     

Performance of Framingham cardiovascular disease (CVD) predictions in the Rotterdam Study taking into account competing risks and disentangling CVD into coronary heart disease (CHD) and stroke

Background

To evaluate the performance of Framingham predictions of cardiovascular disease (CVD) risk corrected for the competing risk of non-CVD death, in an independent European cohort of older individuals and subsequently extend the predictions by disentangling CVD into coronary heart disease (CHD) and stroke separately.

Methods

We used the Rotterdam Study data, a prospective cohort study of individuals aged 55 years and older (N = 6004), to validate the Framingham predictions of CVD, defined as first occurrence of myocardial infarction, coronary death or stroke during 15 years of follow-up, corrected for the competing risk of non-CVD death. We subsequently estimated the risks of CHD and stroke separately, and used the sum as a predictor for the total CVD risk. Calibration plots and c-statistics were used to evaluate the performance of the models.

Results

Performance of the Framingham predictions was good in the low- to intermediate risk (≤ 30%, 15-year CVD risk) (17.5% observed vs. 16.6% expected) but poorer in the higher risk (> 30%) categories (36.3% observed vs. 44.1% expected). The c-statistic increased from 0.66 to 0.69 after refitting. Separately estimating CHD and stroke revealed considerable heterogeneity with regard to the contribution of CHD and stroke to total CVD risk.

Conclusions

Framingham CVD risk predictions perform well in the low- to intermediate risk categories in the Rotterdam Study. Disentangling CVD into CHD and stroke separately provides additional information about the individual contribution of CHD and stroke to total individual CVD risk.     

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.     

A comparison of three different methods to determine arterial compliance in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study

BACKGROUND: Several different techniques to evaluate arterial compliance have been described but have not been simultaneously tested in a large-scale, population-based setting. This study aimed to evaluate the feasibility and relation to cardiac risk of three of these techniques in the Prospective Study of the Vasculature in Uppsala Seniors (PIVUS) study. METHODS AND RESULTS: In the population-based PIVUS study (1016 participants aged 70), assessment of arterial distensibility by ultrasound in the carotid artery, by pulse wave analysis (augmentation index) and the stroke volume to pulse pressure ratio by echocardiography were successfully employed in 86, 92, 91 and 77% of the sample, respectively. All three indices of arterial compliance were inter-related (r = 0.19-0.34, P < 0.0001 for all). Although all three indices were significantly related to the Framingham risk score (r = 0.12-0.32, P = 0.0005-0.0001), only carotid artery distensibility and the stroke volume to pulse pressure ratio were independently associated with the Framingham score in multiple regression analysis (P < 0.0001 for both). CONCLUSIONS: All three indices to evaluate arterial compliance were feasible to obtain in a general elderly population and were inter-related. Although all of the techniques were correlated to Framingham risk score, only carotid artery distensibility and the stroke volume to pulse pressure ratio were independently related to coronary risk, suggesting complementary use of these two indices of arterial compliance in the future.     

Predictive value of waist-to-hip ratio on cardiovascular risk events

BACKGROUND: A central distribution of adipose tissue is frequently associated with cardiovascular disease (CVD) and its risk factors. METHODS: Clinical usefulness of waist-to-hip ratio (WHR) for predicting the risk of cardiovascular events, estimated with models based on data from the Framingham and Prospective Cardiovascular Münster (PROCAM) studies was evaluated. SUBJECTS: These were 552 men and 160 women, asymptomatic and at risk for CVD, aged 30-74 y, recruited from an ongoing risk factor screening program conducted at worksites. RESULTS: Abdominal fatness was a strong predictor of cardiovascular complications in subjects whose WHR was in the top quintile (> 0.98 for men and > 0.91 for women). The estimated percentage rate of coronary heart disease (CHD, P <0.01) and death (P < 0.01), myocardial infarction (P < 0.01), stroke (P < 0.01), total CVD (P < 0.001) and death (P < 0.01) increased with increasing quintile of WHR in men and women. In the highest WHR, the number of subjects exceeding a 15% risk of developing a coronary event over the next 10 y was more than two-fold greater (odds ratio (OR) 2.60 (confidence intervals (CI) 1.09-6.54) than in the lowest WHR quintiles. Similar six-year myocardial infarction (MI) risks at each quintile of WHR were observed in men in both Framingham and PROCAM models. In the overall population, CHD estimates increased with increasing quintiles of WHR with the Framingham model and an adapted model for estimating probabilities of disease in the French population of the Prevention Cardiovasculaire en Médecine du Travail (PCV-METRA) group. CONCLUSION: Abdominal deposition of fat assessed by WHR may be of strong clinical value for predicting high risk of cardiovascular events.     

Risk of coronary heart disease and stroke in a large British cohort of patients with systemic lupus erythematosus

OBJECTIVES: Patients with systemic lupus erythematosus (SLE) are at increased risk of myocardial infarction and stroke. We sought to determine how much of this risk was dependent on recognized cardiovascular risk factors. METHODS: Initially a software package 'Cardio-Risk-Manager', which utilizes Framingham data, was used to calculate a 10-yr risk of coronary heart disease (CHD) and stroke for 202 patients with SLE (Group 1) in comparison with hypothetical age- and sex-matched comparators. Subsequently 47 patients who had been followed since 1991 (Group 2) were studied to compare their predicted risks in 1991 with the actual number of cardiovascular events that occurred during the subsequent decade. RESULTS: Patients in Group 1 had a higher predicted 10-yr risk of stroke (P<0.0001), but not of CHD, than their comparators. However, following age stratification, traditional risk factors predicted a higher risk of CHD (P<0.0001) and of stroke (P<0.0001) in patients under 40 with SLE compared with age-matched comparators. The predicted 10-yr risks of CHD and stroke for patients aged 40 and above were not significantly different from those of their comparators. Predicted risks, however, were lower than the true 10-yr event rate for CHD and stroke in patients in Group 2. In this group, during the 10 yr of follow-up four patients (8.5%) suffered a CHD event and five patients (10.6%) had a stroke, significantly more than were predicted by the presence of conventional risk factors (P<0.001 for CHD and P<0.001 for stroke, respectively). CONCLUSIONS: Conventional risk factors predicted an increased risk of stroke and CHD in younger patients. They do not, however, fully explain the high risk of cardiovascular disease in patients with SLE. Although it is important to address the management of orthodox risk factors for cardiovascular disease in patients with SLE, other causes must be sought to explain the increased incidence of CHD and stroke, especially in those aged over 40.     

Relationship between plasma markers of endothelial cell integrity and the Framingham cardiovascular disease risk-factor scores in apparently healthy individuals.

Separate reports have identified differences in plasma levels of the endothelial markers soluble E-selectin, von Willebrand factor (vWf) and soluble thrombomodulin in each of the major modifiable risk factors for atherosclerosis (smoking, hypertension and hypercholesterolaemia), and abnormal levels of some plasma markers predict various adverse cardiovascular events. However, it is unclear whether there is an increasing effect on the endothelium with a worsening risk-factor profile. We measured the three endothelial cell markers by enzyme-linked immunosorbent assay in the plasma of 200 subjects (mean age, 54 years; 58% men) free of the symptoms and clinical signs of atherosclerosis. Levels of the markers were then correlated with the Framingham coronary heart disease (CHD) and cerebrovascular disease (CVD) scores to help determine which (if any) may be useful as good laboratory predictors of future cardiovascular events in prospective epidemiological studies. vWf correlated with CHD (r(s) = 0.269, < 0.001) and CVD risk (r(s) = 0.331, P < 0.001), but soluble E-selectin correlated only with CHD risk (r(s) = 0.163, P = 0.021). We conclude that, of the three specific endothelial markers, vWf correlates most closely with the Framingham risk-factor prediction scores and therefore may be the better plasma endothelial marker of the future development of an atherothrombotic event.     

Haemostasis in ischaemic stroke and vascular dementia.

Abnormalities of coagulation and fibrinolysis may play an important role in the pathogenesis of ischaemic stroke and vascular dementia. We aimed to determine whether haemostatic function is altered in acute recent-onset or chronic ischaemic cerebrovascular disease. We studied consecutive patients with ischaemic stroke (n = 74) and vascular dementia (n = 42) compared with healthy controls (n = 40) in a case-control study. The ischaemic stroke group was assessed twice, 3-10 days after the acute stroke and at 1-3 months. Fibrinogen, fibrin D-dimer (marker of fibrin turnover) and von Willebrand factor (vWF) (marker of endothelial disturbance) were elevated acutely (P < 0.0001) and in the convalescent phase after ischaemic stroke (P < 0.0001, P < 0.0001, and P < 0.01 respectively, compared with controls). Similar results were seen in the vascular dementia group. Stepwise multivariate regression analyses showed that cerebrovascular disease correlated independently with fibrinogen (P < 0.001) and fibrin D-dimer levels (P < 0.001), while vWF correlated independently with electrocardiograph evidence of ischaemic heart disease (P = 0.004). Changes between acute and convalescent phases in ischaemic stroke were slightly inconsistent. However, in the acute stage there were tendencies for fibrinogen, D-dimer and vWF to be increased, and factor VIII was significantly higher. Abnormalities of haemostasis, including increased fibrin turnover and endothelial disturbance, are found in both acute and chronic cerebral ischaemia. Many of these patients have co-existent ischaemic heart disease and this may contribute to some of these changes. Acute ischaemic stroke is associated with transient changes in haemostatic factors; however, most abnormalities persist into the convalescent phase, and are also demonstrable in subjects with vascular dementia.     

纤维蛋白原与高敏C反应蛋白对稳定性冠心病患者心血管事件的预测价值

目的探讨高水平的纤维蛋白原（fibrinogen,FG）和高敏C反应蛋白（hs—CRP）对稳定性冠心病患者心血管事件的预测价值。方法对185例经冠状动脉造影检查证实的稳定性冠心病患者（2002年1月至11月入院患者）分别按FG、hs—CRP水平分组,随访3年,评估发生心血管事件（猝死、心肌梗死、慢性心力衰竭及其他心血管事件）。结果在3年的随访中,发生非致死性心血管事件21例和心血管原因导致的死亡10例。在调整了血脂、体重指数、吸烟、高血压等因素后,FG〉4．0g／L组与FG≤4．0g／L组比较,发生心血管事件的相对危险度为1．97,95％可信区间（CI）为1．68—2．40。hs—CRP〉3．0mg／L组与hs—CRP≤3．0mg／L比较,经调整后发生心血管事件的相对危险度为2．32,95％CI为1．76—2．89。FG〉4．0g／L伴hs—CRP〉3．0mg／L者与FG≤4．0g／L且hs—CRP≤3．0mg／L者比较,发生心血管事件的相对危险度为3．84（P〈0．05）,95％CI为2．80—4．99。结论FG和hs—CRP不仅均为冠心病患者心血管事件重要的独立预测因子,且FG联合hs—CRP检测可增加对冠心病患者心血管事件的预测价值。     

Relation of heart rate parameters during exercise test to sudden death and all-cause mortality in asymptomatic men

Heart rate (HR) profile during exercise predicts all-cause mortality. However, less is known about its relation to sudden (vs nonsudden) death in asymptomatic people. The relation of exercise HR parameters (HR at rest, target HR achievement, HR increase, and HR recovery) with sudden death, coronary heart disease (CHD) death, myocardial infarction, and all-cause mortality was assessed in 12,555 men who participated in MRFIT. Subjects were 35 to 57 years old without clinical CHD, but with higher than average Framingham risk. Trial follow-up was 7 years, and extended follow-up after the trial for all-cause mortality was 25 years. After adjusting for cardiac risk factors, having to stop exercise before achieving 85% of age-specific maximal HR was associated with increased risk of sudden death (hazard ratio 1.8, 95% confidence interval [CI] 1.3 to 2.5, p = 0.001), CHD death (hazard ratio 1.4, 95% CI 1.2 to 1.5, p <0.001), and all-cause mortality (hazard ratio 1.3, 95% CI 1.2 to 1.4, p <0.001). Increased HR at rest (p = 0.001), attenuated HR increase (p = 0.02), delayed HR recovery (p = 0.04), and exercise duration (p <0.0001) were independent predictors of all-cause death in the overall study population and also in the subgroup that achieved target HR. In conclusion, middle-aged men without clinical CHD who stopped exercise before reaching 85% of maximal HR had a higher risk of sudden death. Other exercise HR parameters and exercise duration predicted all-cause mortality.     

Assessment by cardiovascular magnetic resonance, electron beam computed tomography, and carotid ultrasonography of the distribution of subclinical atherosclerosis across Framingham risk strata

Screening for subclinical atherosclerosis has been advocated for individuals at intermediate global risk for coronary heart disease (CHD). However, the distribution of subclinical atherosclerosis test values across CHD risk strata is unknown. We studied a stratified random sample of 292 participants (mean age 59.5 years, 50% women) from the offspring cohort of the Framingham Heart Study who were free of clinically apparent cardiovascular disease. We assessed abdominal and thoracic aortic plaque burden by cardiovascular magnetic resonance (CMR), coronary artery calcification (CAC) and thoracic aortic calcification (TAC) by electron beam computed tomography, and common carotid intima-media thickness (C-IMT) by ultrasonography. We categorized the upper 20% of each measurement as a high level of atherosclerosis and evaluated these variables across clinically relevant Framingham CHD risk score strata (low, intermediate, and high risk). In age-adjusted analyses in men and women, correlations across CMR aortic plaque, CAC, TAC, and C-IMT were low (maximum r = 0.30 for CAC:TAC in women, p <0.005). In men and women, the proportion of subjects with high atherosclerosis test results for any of these measurements increased significantly across Framingham CHD risk score strata (Kruskal-Wallis test, p <0.0001). In the intermediate Framingham CHD risk score category, 14% of men and 25% of women had a high atherosclerosis result on >or=2 measurements. However, different participants were identified as having high atherosclerosis by each modality. For example, in a comparison of the overlap across CMR aortic plaque, CAC, and C-IMT, only 4% of men and 16% of women were classified as having high atherosclerosis on all 3 measurements. In conclusion, in a community-based sample, correlations among subclinical atherosclerosis test results are low, and a substantial proportion has high levels of subclinical atherosclerosis detected on >or=2 imaging tests.     

Coronary artery calcium as a measure of biologic age

BACKGROUND: Age is assigned a heavy weight in the calculation of the total cardiovascular risk score but often the atherosclerotic disease burden varies from a patient's chronological age. METHODS: We used measures of coronary artery calcium to estimate the number of life years lost (calcium-adjusted age) in 10,377 asymptomatic individuals referred for electron beam tomography (EBT) screening and followed for 5 years for all-cause mortality. Linear regression was used to calculate predicted age and time to death was estimated via a Cox proportional hazard model. RESULTS: There was a direct relationship between coronary artery calcium and observed age (r = 0.32, p < 0.0001). In linear prediction models, a calcium score < 10 resulted in a reduction in observed age by 10 years in subjects older than 70 years, while a calcium score > 400 added as much as 30 years of age to younger patients. Calcium-adjusted age was a better predictor of mortality (model chi2 = 373, p < 0.0001) than observed age (model chi2 = 355, p < 0.0001). Detectable calcium was noted in 16% of men and 12% of women with an unadjusted low risk Framingham score (p < 0.0001). For those with an intermediate Framingham risk score, calcium scores > 10 were noted in 31 and 43% of men and women (p < 0.0001). Using calcium-adjustments to age, 55% of previously low risk Framingham scores to intermediate risk (p < 0.0001). Similarly, 45% of the unadjusted intermediate Framingham risk scores were re-classified as high risk based upon calcium-adjusted ages (p < 0.0001). CONCLUSIONS: Measures of coronary artery calcium are related to survival and can be used to assess an individual's biological age. Undetected risk based upon current calculations of the Framingham risk may be improved based upon determination of a re-adjustment of a patient's age using the extent of coronary calcification.     

Insulin resistance is accompanied by increased von Willebrand factor levels in nondiabetic women: a study of offspring of type 2 diabetic subjects compared to offspring of nondiabetic subjects

OBJECTIVES: To examine whether levels of von Willebrand factor (vWF), fibrinogen and fibronectin are related to a parental history of type 2 diabetes and to determine possible explanatory factors for high versus low vWF and fibrinogen. DESIGN: Cross-sectional study. SUBJECTS, MAIN OUTCOME MEASURES: We compared vWF, fibrinogen and fibronectin in 88 nondiabetic offspring of type 2 diabetic subjects (relatives) and 103 offspring of nondiabetic subjects (controls). Other measurements included urinary albumin excretion rate, blood pressure, lipid profile and insulin resistance using homeostasis model assessment (HOMAIR). RESULTS: There were no significant differences in vWF (1.12 vs. 1.06 IU x mL(-1), P = 0.296), fibrinogen (3.2 vs. 3.1 g x L(-1); P = 0.263) or fibronectin (0.39 vs. 0.40 g x L(-1), P = 0.448) between relatives and controls. With multiple logistic regression we determined explanatory factors for high versus low vWF and fibrinogen. Age (P < 0.01), urinary albumin excretion rate (P < 0.05), ischaemic heart disease (IHD) (P < 0.05) were found to be significant explanatory factors for vWF above the median (1.10 IU x mL(-1)). Interaction between insulin resistance and sex was found. Odds ratio for high versus low insulin resistance was 18.39 (P < 0.001) for women and 1.92 (P = 0.32) for men. Body mass index (BMI) (P < 0.05), sex (P < 0.01), smoking status (P < 0.05) and IHD (P < 0.01) were significant explanatory factors for fibrinogen above the median (3.1 g x L(-1)). CONCLUSIONS: Levels of vWF, fibrinogen and fibronectin were not influenced by a parental history of type 2 diabetes. Insulin resistance was found to be a significant risk indicator for high vWF only in women. This may indicate that insulin resistance is a higher risk factor for women than for men, when the outcome is endothelial dysfunction possibly resulting in overt cardiovascular disease.     

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.