Effects of losartan versus hydrochlorothiazide on indices of endothelial damage/dysfunction, angiogenesis and tissue factor in essential hypertension

BACKGROUND: Abnormalities in endothelial function, angiogenesis and thrombogenesis are found in essential hypertension. Angiotensin II has been postulated as an agent involved in these processes. We hypothesized that the treatment of essential hypertension with the angiotensin II receptor antagonist, losartan, would affect endothelial damage/dysfunction, angiogenesis and coagulation, when compared to treatment with a diuretic. METHODS: Forty hypertensive patients (28 male, mean age 56 +/- 11.8 years) were randomized to treatment with losartan 50-100 mg o.d. or hydrochlorothiazide 12.5-25 mg o.d. over a 12-week period. Patients were assessed at week 0, 4 and 12. Endothelial damage/dysfunction was assessed using plasma levels of von Willebrand factor (vWf) and changes in flow-mediated dilation of the brachial artery (FMD). Vascular endothelial growth factor (VEGF) and its soluble receptor Flt-1 (sFlt-1) were measured as indices of angiogenesis, and plasma tissue factor (TF) as an index of coagulation. Baseline results in hypertensives were compared to 20 healthy controls (13 male, mean age 61.1 +/- 10.1 years). Results: Mean patient BP was 161/95 +/- 21/18 mmHg compared to 134/81 +/- 11/7 mmHg in controls (p<0.002). Plasma levels of TF (p=0.023) were significantly higher in patients compared to controls, and FMD was significantly lower (p<0.001). There were no significant differences in baseline blood pressures, plasma indices or FMD between patients randomized to losartan and hydrochlorothiazide. There were no significant changes in levels of plasma indices or FMD over 12 weeks of treatment in either patient group. Significant correlations between levels of VEGF with sFlt-1 (Spearman p<0.001) and TF (p=0.009) and sFlt-1 and TF (p=0.035) were seen in the untreated state, amongst the patient group only. CONCLUSION: We have confirmed previous observations of increased levels of TF and decreased FMD in hypertensive patients compared to healthy controls. Contrary to previous observations in higher-risk hypertensive patient groups, the treatment of essential hypertension with either losartan or hydrochlorothiazide did not affect indices of endothelial damage/dysfunction, angiogenesis or coagulation.     

Assessment of endothelial damage in atherosclerotic vascular disease by quantification of circulating endothelial cells. Relationship with von Willebrand factor and tissue factor.

BACKGROUND: Increased numbers of CD146-defined circulating endothelial cells (CECs), as are present in the peripheral blood of patients suffering acute coronary syndromes, imply injury to the endothelium. Endothelial damage can also be assessed by the measurement of plasma levels of von Willebrand factor (vWf). Increased levels of procoagulant plasma tissue factor (TF), arising from monocytes/macrophages and endothelial cells, is present in atherosclerosis. We hypothesised increased CECs in patients with ischaemic rest pain (IRP) of the lower limb due to peripheral atherosclerosis and comparable to that seen in patients with acute myocardial infarction (AMI), when compared to patients with intermittent claudication (IC) or healthy controls that would correlate with vWf and TF. PATIENTS AND METHODS: We recruited 20 patients in each of four groups: (i) IRP of the lower limb; (ii) AMI; (iii) 'stable' IC; and (iv) healthy controls. CD146-expressing CECs were measured by immumomagnetic separation and counting under a fluorescence microscope; plasma vWf and TF by ELISA. RESULTS: In IRP, median (IQR) CEC levels were 3.5 (2.0-5.8) cells/ml, in IC were 1.1 (0.6-2.9) cells/ml, and in healthy controls were 1.0 (0.5-1.7) cells/ml (p<0.001). The levels of vWf (p=0.034) and TF (p=0.007) were also significantly different between the groups, with the highest levels in patients with IRP. Levels of CECs correlated with vWf (rs=0.4, p=0.002) and TF ( rs=0.296, p=0.021 ). In AMI, CEC levels were higher than those in IRP at 4.9 (3.6-8.4) cells/ml (p=0.0385). CONCLUSION: This study demonstrates evidence of direct endothelial cell injury (i.e. raised CECs) in patients with IRP that correlated with vWf and TF, but that this is less severe than in AMI.     

Increased circulating endothelial cells in acute heart failure: comparison with von Willebrand factor and soluble E-selectin

BACKGROUND: Circulating endothelial cells (CECs) in the peripheral blood, probably representing the most direct evidence of endothelial cell damage, are increased in myocardial infarction, unstable angina and critical limb ischaemia. As chronic heart failure is also associated with endothelial abnormalities, we hypothesised that CECs are raised in acute heart failure and that they would correlate with plasma indices of endothelial perturbation, that is, von Willebrand factor (vWf) and soluble E-selectin. METHODS: We studied 30 patients with acute heart failure (venesected within 24 h of emergency hospital admission), 30 patients with chronic stable heart failure (venesected as out-patients, all patients in sinus rhythm with ejection fraction < or = 40%) and 20 healthy controls. CECs were quantified using epifluorescence microscopy after CD146-immunomagnetic separation and phenotyped by streptavidin/biotin immunocytochemistry. Citrated plasma was analysed for soluble E-selectin and vWf by ELISA. RESULTS: Levels of CECs, vWf and soluble E-selectin were significantly higher (all p<0.01) in patients with heart failure compared to controls, with no significant differences between acute and chronic heart failure. CECs correlated with plasma vWf (p<0.0001) and soluble E-selectin (p = 0.022) but not ejection fraction or NYHA class. In multiple regression analysis, heart failure was the only independent predictor of raised CECs (p<0.0001). Immunoperoxidase-defined surface expression of CD34, CD45 and CD36 by CECs was <2%, 0% and 8%, respectively. CONCLUSION: CECs, a possibly heterologous population, may be used as a novel measure of endothelial damage in acute heart failure and may have implications for the thrombotic risk associated with acute and chronic heart failure and prognosis in this condition.     

Circulating endothelial cells, von Willebrand factor, interleukin-6, and prognosis in patients with acute coronary syndromes

Markers of inflammation (eg, interleukin-6 [IL-6]), and endothelial perturbation (von Willebrand factor [VWF], circulating endothelial cells [CECs]) are altered in acute coronary syndromes (ACS). We hypothesized that CECs and IL-6 levels during the first 48 hours of ACS would predict 30-day and 1-year major cardiovascular end points (MACE). A total of 156 patients with ACS were included. Blood was drawn on admission (baseline) and 48 hours later for plasma VWF, IL-6 (both enzyme-linked immunosorbent assay [ELISA]), and CECs (CD146 immunomagnetic separation). CEC phenotyping was performed by indirect immunoperoxidase staining. At 30 days, 48 patients had a MACE, a predicted by baseline and 48-hour CECs and IL-6 levels, 48-hour VWF levels, and by the "admission-48 hour change" (Delta) in CECs, VWF, and IL-6 (all P = .002). On multivariate analysis, 48-hour CECs (P < .001) were the strongest predictor of MACE, followed by DeltaIL-6 (P = .01) and DeltaVWF (P = .048); 48-hour CECs were the only predictor of death (P = .007). At 1 year, 65 patients had MACE, predicted by 48-hour CECs and DeltaIL-6 levels (P < .001); age (P = .046) and 48-hour CECs (P < .001) were the only predictors of death. CECs stained 93% positive for endothelial nitric oxide synthase (eNOS) but were less than 1% positive for CD34, CD36, and CD45 and less than 3% for CD31. Like raised VWF, abnormal CECs and IL-6 levels during the first 48 hours of ACS were strongly associated with 30-day MACE. CECs at 48 hours were the only independent predictor of both death and MACE at 30 days and 1 year, indicating the crucial role of endothelial/vascular damage in ACS pathophysiology.     

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.     

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.     

Evaluation of coronary calcium score by multidetector computed tomography in relation to endothelial function and inflammatory markers in asymptomatic individuals.

BACKGROUND: Coronary calcification has been correlated with the presence and extent of coronary artery disease (CAD), so in the present study the associations between coronary artery calcification score (CACS) and endothelial dysfunction, as well as the important inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and oxidized low-density lipoprotein (OxLDL), were studied in asymptomatic individuals at intermediate risk for CAD. METHODS AND RESULTS: The study group comprised 177 subjects (103 males) aged 50.6+/-5.9 years. CACS was measured by multidetector computed tomography using the Agatston method. Endothelium-dependent flow-mediated dilatation (FMD) and endothelium-independent nitroglycerin-mediated dilatation (NMD) were measured by high-resolution external brachial ultrasound. Coronary artery calcification (CAC) was detected in 82 subjects (52 males), and the median CACS was 143 [31-311.25] units. After adjusting for gender and body mass index, log (CACS +1) correlated positively with age (r=0.401, p<0.001) and IL-6 levels (r=0.442, p<0.001), and negatively with FMD (r=-0.511, p<0.001). The correlations of log (CACS +1) with CRP and OxLDL levels, and with NMD, were non-significant. In a multivariate-adjusted logistic regression model, age (odds ratio (OR) =1.083 [1.014-1.156]), serum IL-6 level (OR=3.837 [2.166-6.798]) and FMD (OR=0.851 [0.793-0.913]) were significantly and independently associated with CAC. CONCLUSIONS: Peripheral endothelial function inversely correlated with CACS, whereas IL-6 level was associated with CACS. Testing for endothelial function and IL-6 level may improve cardiovascular risk assessment and help target the therapeutic strategies in asymptomatic patients at intermediate CAD risk.     

Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis

We explored the role of asymmetrical dimethylarginine (ADMA) as a cause of endothelial dysfunction induced by systemic inflammation. In vitro data suggest that ADMA bioavailability is regulated by proinflammatory stimuli, but it is unclear whether ADMA is a link between inflammation and endothelial dysfunction in humans. In study 1 we recruited 351 patients with coronary artery disease (CAD) and 87 healthy controls. In study 2 we recruited 69 CAD, 69 healthy, and 10 patients with rheumatoid arthritis, whereas in study 3, 22 healthy and 70 CAD subjects were randomly assigned to Salmonella typhii vaccination (n=11 healthy and n=60 CAD) or placebo (n=11 healthy and n=10 CAD). Circulating interleukin 6/ADMA and flow-mediated dilation (FMD) were measured at 0 and 8 hours. In study 1, ADMA was inversely correlated with FMD in healthy individuals and CAD patients (P<0.0001 for both). However, interleukin 6 was inversely correlated with FMD (P<0.0001) in healthy subjects but not in CAD patients. The positive correlation between ADMA and interleukin 6 was stronger in healthy (r=0.515; P<0.0001) compared with CAD (r=0.289; P=0.0001) subjects. In study 2, both patients with rheumatoid arthritis and CAD had higher interleukin 6 (P<0.0001) and ADMA (P=0.004) but lower FMD (P=0.001) versus healthy subjects. In study 3, vaccination increased interleukin 6 in healthy (P<0.001) and CAD (P<0.001) subjects. FMD was reduced in healthy subjects (P<0.05), but its reduction in CAD was borderline. Vaccination increased ADMA only in healthy subjects (P<0.001). Systemic, low-grade inflammation leads to increased ADMA that may induce endothelial dysfunction. This study demonstrated that ADMA may be a link between inflammation and endothelial dysfunction in humans.     

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.     

Relationships between brachial artery flow mediated dilation and carotid artery intima-media thickness in patients with suspected coronary artery disease

The correlation of peripheral endothelial dysfunction and intima-media thickness (IMT) in patients with suspected coronary artery disease (CAD) has been unclear. Inflammation and thrombosis may play a role at early stages of atherosclerosis. Thus, early atherosclerosis was noninvasively examined morphologically by IMT of carotid arteries, and functionally by flow mediated dilation (FMD) of brachial arteries in patients who were suspected of CAD and had undergone coronary angiography. Plasma antigen levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, representative atherogenic cytokines, tissue factor (TF) and tissue factor pathway inhibitor (TFPI), markers of coagulation, and plasma activity level of plasminogen activator inhibitor type-1 (PAI-1), a marker of defective fibrinolysis, were measured. Patients with coronary atherosclerosis in one or more vessels with lesion > or = 50% had significantly reduced FMD compared with those with angiographically normal coronary arteries. Carotid artery IMT increased significantly only in patients with advanced coronary atherosclerosis in one or more vessels with lesion > or = 90%. Plasma antigen levels of IL-6 were significantly increased in patients with reduced FMD (< 5%) compared to those in patients with FMD between 10 and 15%. Plasma antigen levels of TF, total and free TFPI, and PAI-1 activity tended to increase with a reduction in FMD. Thus, (1) FMD was reduced at early stages of CAD while IMT was increased in advanced CAD, and (2) inflammation and thrombosis may play a role in the early stages of the atherosclerotic process.     

Factors associated with the presence of circulating active tissue factor and activated factor XI in stable angina patients

Circulating active tissue factor (TF) and activated factor XI (FXIa) have been detected in subgroups of acute coronary syndromes (ACSs) and stable angina patients. We sought to evaluate the determinants of active TF and FXIa in stable angina patients. We studied 124 consecutive stable angina patients. Recent ACS, atrial fibrillation, and anticoagulant therapy were the exclusion criteria. Plasma active TF and FXIa were determined by measuring the response to inhibitory antibodies. T helper 1 lymphocyte (Th1) and Th2 responses were assessed in plasma by interleukin (IL)-4, IL-6, IL-8, IL-10, IL-18, interferon-γ, and tumor necrosis factor-α, oxidative stress by 8-isoprostaglandin F(2α) (8-iso-PGF(2α)), and coagulation by prothrombin fragments F1+2 (F1+2) and free TF pathway inhibitor (f-TFPI). TF and FXIa activity were detected in 25 (20.2%) and 49 (39.5%) stable angina patients, respectively. Both factors were found in 23 (18.5%) patients. Patients with detectable TF or FXIa had higher F1+2, 8-iso-PGF(2α), IL-6, but not other cytokines, and lower f-TFPI (all P < 0.001) compared with the remainder. There were no intergroup differences with regard to cardiovascular risk factors or medication. Multivariate analysis showed that F1+2 and f-TFPI were the only independent predictors of the TF presence, whereas 8-iso-PGF(2α) and F1+2 predicted the presence of FXIa in stable angina patients. In stable angina patients, circulating active TF and FXIa are associated with enhanced thrombin formation, with a minor effect of inflammatory mediators. Moreover, FXIa is also related to oxidative stress, indicating additional links between coagulation and free radical generation in stable angina.     

Remnant lipoproteinemia is a risk factor for endothelial vasomotor dysfunction and coronary artery disease in metabolic syndrome

This study aimed to determine whether elevated levels of remnant lipoprotein, an atherogenic triglyceride-rich lipoprotein, might be associated with coronary artery disease (CAD) and endothelial vasomotor dysfunction in metabolic syndrome. The fasting serum levels of remnant lipoproteins (remnant-like lipoprotein particles cholesterol; RLP-C) were measured by an immunoseparation method in 210 patients with metabolic syndrome meeting ATP III criteria. Flow-mediated endothelium-dependent dilatation (FMD) in the brachial artery during reactive hyperemia was examined by high-resolution ultrasound technique. This study found that elevated RLP-C levels were a significant and independent risk factor for impaired FMD and angiographically proven coronary artery disease (CAD). Treatment with bezafibrate (n = 20) or atorvastatin (n = 20) for 4 weeks significantly reduced RLP-C levels, with a concomitant improvement in FMD. The % reduction in RLP-C levels from baseline after the treatment was independently correlated with the magnitude of improvement in FMD after adjustment for the % changes in levels of triglyceride, hsCRP, and IL-6, and HOMA index. Thus, elevated levels of RLP-C are a risk factor for CAD and endothelial vasomotor dysfunction, a predictor of coronary events, in metabolic syndrome. Measurement of RLP-C is useful for assessment of CAD risk and therapeutic effects in metabolic syndrome.     

Physical activity in relation to indices of endothelial function and angiogenesis factors in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)

BACKGROUND: Hypertension is an important risk factor for cardiovascular disease. The latest guidelines recommend regular physical exercise as initial step or adjunct in the treatment of hypertension. We investigated the association between physical activity and the degree of hypertension, as well as the relation to indices of endothelial damage/dysfunction and angiogenesis. METHODS: We studied 234 patients with hypertension (198 males; mean age 64 years; mean blood pressure 166/90 mmHg), who were compared with 60 age and sex-matched healthy normotensive controls. We assessed the patient's physical activity using the validated Baecke physical activity questionnaire and measured flow-mediated dilatation (FMD) of the brachial artery and von Willebrand factor (vWf) as indices of endothelial damage/dysfunction, whilst angiogenesis was assessed by measurement of plasma vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1) both by ELISA. RESULTS: When hypertensive patients were compared with the controls, there was no statistically significant difference in total physical activity score using the Baecke questionnaire although plasma VEGF and vWf levels were higher, but sFlt-1 levels and FMD lower (all P < 0.001). Patients with high physical activity were younger, and had lower mean diastolic blood pressure and 10-year Framingham stroke risk, when compared with those with low physical activity; but indices of endothelial damage/dysfunction and angiogenesis were not significantly different. CONCLUSION: Physical activity scores in hypertensive patients are not significantly different from healthy normotensive controls, and there appears to be no relation to the abnormal processes of endothelial damage/dysfunction and angiogenesis seen in hypertensives.     

Relationship between endothelial function and coronary risk factors in patients with stable coronary artery disease.

BACKGROUND: Results of experimental and clinical studies suggest that both coronary artery disease (CAD) itself and its traditional risk factors lead to endothelial dysfunction. The aim of the present study was to determine which CAD risk factors sustain their contribution to endothelial dysfunction despite the presence of established CAD. METHODS AND RESULTS: The study group comprised 150 patients with CAD. Using a high-resolution ultrasound, the diameter of the brachial artery at rest and during reactive hyperemia (flow-mediated dilatation, FMD%: endothelial-dependent stimulus to vasodilatation), as well as after sublingual administration of nitroglycerin (NTG%: endothelium-independent vasodilatation), was measured. The relationship between FMD% and coronary risk factors [diabetes mellitus (DM), total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, age, family history of premature atherosclerosis, smoking, hypertension (HT), body mass index (BMI)] was investigated. In univariate analysis there was an inverse relationship between FMD% and age (r=-0.300, p<0.001), and BMI (r=-0.230, p<0.005) and FMD% was significantly lower in diabetic patients when compared to non-diabetic patients (p<0.001). In stepwise multivariate regression analysis; FMD still correlated with DM and advanced age, but not with BMI (beta=0.065, p<0.001, beta=-0.001 p=0.002, beta=-0.087, p<0.284, respectively). FMD% was found to be not associated with hypercholesterolemia, family history of premature atherosclerosis, HT and smoking. CONCLUSION: Only aging and DM were independently associated with endothelial dysfunction in patients with established CAD.     

急性冠状动脉综合征患者血浆组织因子和白细胞介素18水平的变化及意义

目的观察急性冠状动脉综合征(ACS)患者血浆组织因子和白细胞介素18水平的变化及其关系,探讨凝血与炎症的相关性及其在ACS发生、发展中的作用。方法选择冠心病患者118例,根据诊断分为ACS组67例和稳定性心绞痛组51例,2组患者测定血浆组织因子和白细胞介素18水平,并进行比较,采用Pearson相关分析法分析两变量的相关性。结果 ACS组血浆组织因子和白细胞介素18水平明显高于稳定性心绞痛组[(101.44±21.32)ng/L vs(90.01±19.44)ng/L,(311.73±113.00)ng/L vs(246.59±94.63)ng/L,P<0.01];ACS组血浆组织因子与白细胞介素18呈正相关(r=0.654,P<0.01),稳定性心绞痛组血浆组织因子与白细胞介素18无相关性(P>0.05)。结论 ACS患者体内炎症活动与凝血活动可能互相作用。     

Hemostatic implications of endothelial cell apoptosis in obstructive sleep apnea

Patients with obstructive sleep apnea (OSA) are at increased risk of atherothrombosis independent of the Framingham risk factors. Studies on hemostasis factors in OSA are scarce and inconsistent. We sought to understand the variation in atherothrombotic propensity as a function of apoptotic circulating endothelial cells (CECs) in OSA by investigating the relationship between CEC apoptosis and plasma levels of hemostatic factors tissue factor (TF) and von Willebrand Factor (vWF) in apneic subjects. Apoptotic CECs were detected by flow cytometry in 35 male subjects free of cardiovascular diseases (AHI range 8–43) and 12 healthy male controls (AHI range 2–5) before and after 8 weeks of nasal continuous positive airway pressure (nCPAP). Quantitative determination of TF and vWF was performed using an enzyme-linked immunosorbent assay (ELISA) kit. The mean levels of TF (66.78 ± 41.59 pg/ml) and vWF (189.70 ± 69.24 IU/dl) were significantly higher in OSA patients compared with those in healthy subjects (42.83 ± 14.18 pg/ml; and 124.48 ± 31.43 IU/dl). Apoptotic CECs were elevated in patients with OSA and correlated strongly with TF and vWF levels (p = 0.02 and p < 0.001; respectively). There were no correlations between TF, vWF and apnea hypopnea index, or arousal index. Only the percentage of time spent <90% oxygen saturation was inversely associated with TF (r = 0.38; p = 0.02). Following nCPAP therapy, there was significant decrease in TF levels that correlated with decrease in apoptotic CECs. In patients with OSA, increased prothrombotic factors are strongly determined by apoptotic CECs. Treatment with nCPAP may alleviate the coagulation propensity.     

High pulse pressure and nondipping circadian blood pressure in patients with coronary artery disease: Relationship to thrombogenesis and endothelial damage/dysfunction

BACKGROUND: Patients with high ambulatory pulse pressure (APP) or nondipping pattern of circadian BP (nondippers) are at increased risk of cardiovascular disease that may be due to abnormalities in coagulopathy and vascular function. We hypothesized that patients with high APP or nondipper status have an adverse hemostasis profile. Accordingly, we assessed hemorheology (by plasma viscosity and fibrinogen levels), endothelial damage/dysfunction (von Willebrand factor [vWf] and flow-mediated dilatation [FMD]), thrombogenesis (D-dimer), and platelet activation (soluble P-selectin). METHODS: Seventy-three patients (58 men, 59 +/- 11 years) with stable coronary artery disease completed 24-h ambulatory BP monitoring. Plasma viscosity was assessed on a Coulter viscometer, fibrinogen by Clauss, vWf, D-dimer and soluble P selectin by ELISA, and FMD by reactive hyperemia. RESULTS: High APP (median APP >/=51 mm Hg) and nondipping was associated with significantly higher levels of vWf, D-dimer, fibrinogen, and soluble P-selectin compared to patients with low APP and dippers, respectively (all P < .05), even after adjustment for ages, 24-h mean systolic, mean diastolic, and mean arterial BPs. After the same adjustments, as well as for dipping status, white coat effects, and left ventricular mass, patients with high APP also had more impaired FMD and still significantly higher levels of vWf and D-dimer, compared to patients with low APP (all P < .05). However, the highest levels of vWf, fibrinogen, and soluble P-selectin and the most impaired FMD were found in those nondipper patients with concurrent high APP. CONCLUSIONS: High ambulatory pulse pressure or nondipping pattern of circadian BP per se are important pathophysiologic factors that may influence cardiovascular risk by altering hemostasis or endothelial function.     

Association of cardiovascular risk factors and endothelial dysfunction in japanese hypertensive patients: implications for early atherosclerosis.

Although hypertension, hyperlipidemia, diabetes and smoking are known risk factors of atherosclerosis in Caucasians, their relative contributions to early atherosclerosis among Japanese are unknown. Decrease in flow-mediated dilation (FMD) of the brachial artery is a useful marker of endothelial dysfunction and early atherosclerosis. To evaluate the relative contribution of hypertension to early atherogenesis, we determined FMD, as well as plasma levels of tissue-type plasminogen activator (t-PA; a sensitive index of endothelial damage) and tumor necrosis factor (TNF)-a and interleukin (IL)-6 (established markers of inflammation) in normotensive and hypertensive patients under treatment. FMD was significantly reduced as the number of risk factors increased, suggesting that accumulations of risk factors were related to endothelial dysfunction. FMD was reduced in hypertensives (9.9 +/- 5.8 (SD) %) compared to normotensives (14.6 +/- 7.6, p<0.01) despite good blood pressure control (139 +/- 20/80 +/- 14 mmHg in hypertensives). Nitroglycerine-induced endothelium-independent vasodilation was not altered in hypertensives (16.0 +/- 6.3%) as compared to normotensives (16.7 +/- 5.8). Plasma t-PA, TNF-alpha, and IL-6 levels were increased in hypertensives despite good blood pressure control. Thus, hypertension alone is a high risk for early atherosclerosis. Persistent endothelial damage and moderate inflammation may increase the risk of early atherosclerosis synergistically under the presence of hypertension in Japanese.     

Plasma von Willebrand factor and the development of the metabolic syndrome in patients with hypertension

Although the metabolic syndrome is associated with endothelial damage/dysfunction, the effect of risk factors and their relationship with the development of this condition are unclear. We hypothesized that plasma von Willebrand factor (vWf, marking endothelial damage/dysfunction) increases with the number of components of metabolic syndrome and that increased levels precede its development. To test this, fasting vWf, glucose and lipids were measured in 161 patients (mean age 63 +/- 7 yr, 85% males) with hypertension. Using World Health Organization (WHO) criteria, 32 (19.9%), and using National Cholesterol Education Program (NCEP) criteria, 70 (43.5%) had metabolic syndrome. Plasma vWf was higher in these patients regardless of defining criteria and increased with the number of the components of metabolic syndrome (both P < 0.001). After 4 yr, patients who did not have metabolic syndrome at baseline were reassessed for the development of this condition. Of the 129 patients who did not meet the WHO criteria at baseline, 38 (29.5%) subsequently developed the condition, whereas 36 of the 91 (39.6%) who did not meet the NCEP criteria at baseline subsequently developed metabolic syndrome. Baseline vWf levels did not predict development of metabolic syndrome, regardless of criteria (P = 0.071 for WHO and P = 0.639 for NCEP). Our data suggest more severe endothelial damage/dysfunction with cumulative metabolic syndrome-related risk factors. The failure of plasma vWf to predict the development of metabolic syndrome suggests that endothelial damage/dysfunction is a consequence, not a cause, of these risk factors.     

Circulating Endothelial Cells and Endothelial Function Predict Major Adverse Cardiac Events and Early Adverse Left Ventricular Remodeling in Patients With ST‐Segment Elevation Myocardial Infarction

Endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) are mobilized from the bone marrow and increase in the early phase after ST‐elevation myocardial infarction (STEMI). The aim of this study was to assess the prognostic significance of CECs and indices of endothelial dysfunction in patients with STEMI. In 78 patients with acute STEMI, characterization of CD34+/VEGFR2+CECs, and indices of endothelial damage/dysfunction such as brachial artery flow mediated dilatation (FMD) were determined. Blood samples for CECs assessment and quantification were obtained within 24 hours of admission and FMD was assessed during the index hospitalization. At 30 days follow up, the primary composite end point of major adverse cardiac events (MACE) consisting of all‐cause mortality, recurrent nonfatal MI, or heart failure and the secondary endpoint of early adverse left ventricular (LV) remodeling were analyzed. The 17 patients (22%) who developed MACE had significantly higher CEC level (P = 0.004), von Willebrand factor (vWF) level (P = 0.028), and significantly lower FMD (P = 0.006) compared to the remaining patients. Logistic regression analysis showed that CECs level and LV ejection fraction were independent predictors of MACE. The areas under the receiver operating characteristic curves (ROC) for CEC level, FMD, and the logistic model with both markers were 0.73, 0.75, and 0.82, respectively, for prediction of the MACE. The 16 patients who developed the secondary endpoint had significantly higher CEC level compared to remaining patients (P = 0.038). In conclusion, increased circulating endothelial cells and endothelial dysfunction predicted the occurrence of major adverse cardiac events and adverse cardiac remodeling in patients with STEMI. (J Interven Cardiol 2016;29:89–98)