Haemostatic and inflammatory biomarkers in advanced chronic heart failure: role of oral anticoagulants and successful heart transplantation

Advanced chronic heart failure (CHF) is associated with abnormal haemostasis and inflammation, but it is not known how these abnormalities are related, whether they are modified by oral anticoagulants (OAT), or if they persist after successful heart transplantation. We studied 25 patients with CHF (New York Heart Association class IV, 10 of whom underwent heart transplantation) and 25 age- and sex-matched healthy controls by measuring their plasma levels of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin (TAT) complexes, tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1), D-dimer, factor VII (FVII), fibrinogen, von Willebrand factor (VWF), tumour necrosis factor (TNF), soluble TNF receptor II (sTNFRII), interleukin 6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), endothelial-selectin (E-selectin) and thrombomodulin. CHF patients had higher plasma levels of TAT, D-dimer, t-PA, fibrinogen, VWF, TNF, IL-6, sTNFRII, sVCAM-1 (P = 0.0001), sICAM-1 (P = 0.003) and thrombomodulin (P = 0.007) than controls. There were significant correlations (r = 0.414-0.595) between coagulation, fibrinolysis, endothelial dysfunction and inflammation parameters, which were lower in those patients treated with OATs. Heart transplantation led to reductions in fibrinogen (P = 0.001), VWF (P = 0.05), D-dimer (P = 0.05) and IL-6 levels (P = 0.05), but all the parameters remained significantly higher (P = 0.01-0.0001) than in the controls. Advanced CHF is associated with coagulation activation, endothelial dysfunction and increased proinflammatory cytokine levels. Most of these abnormalities parallel each other, tend to normalize in patients treated with OATs and, although reduced, persist in patients undergoing successful heart transplantation, despite the absence of clinical signs of CHF.     

Circulating intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in patients with type 2 diabetes mellitus

Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in patients with type 2 diabetes mellitus (n = 64) and control subjects (n = 40) were studied. Serum ICAM-1 concentrations in diabetic patients were significantly higher than those of control subjects (378.2 +/- 70.0 versus 220.4 +/- 31.8 ng/ml, P < 0.01). By multiple regression analysis, hemoglobin A1c was independently associated with serum ICAM-1 concentration in patients with diabetes. The serum VCAM-1 concentration of diabetic patients with macroangiopathy was higher than those of patients without macroangiopathy and of control subjects (806.9 + 276.5 versus 639.0 +/- 146.0 (P < 0.01), and 652.1 +/- 146.9 ng/ml (P < 0.01), respectively). There was no difference in serum E-selectin concentration between diabetic patients with or without macroangiopathy and normal control subjects. These results suggest that adhesion molecules may contribute to the development of atherosclerosis in the diabetic state.     

Type 2 diabetes: assessment of endothelial lesion and fibrinolytic system markers.

This study aimed to investigate whether endothelial cells are damaged and to evaluate fibrinolytic system function in patients with type 2 diabetes. For this proposal, plasma levels of von Willebrand factor (an endothelial marker of injury), homocysteine (an inductor of endothelial injury), D-dimer (a marker of coagulation cascade activation) and plasminogen activator inhibitor-1 (a fibrinolysis marker) were measured in individuals with both type 2 diabetes and high blood pressure, with type 2 diabetes, with high blood pressure and in healthy control individuals. No significant differences among groups were observed for von Willebrand factor and homocysteine plasma levels. The type 2 diabetes and high blood pressure group presented a significant difference to the other groups for D-dimer and also presented high values for plasminogen activator inhibitor-1. The high blood pressure group and type 2 diabetes group presented separately higher values of plasminogen activator inhibitor-1 compared with the control group. High levels of D-dimer and plasminogen activator inhibitor-1 in patients with type 2 diabetes and high blood pressure with normoalbuminuria therefore indicate a state of hypercoagulability and hypofibrinolysis, despite no evident microvascular injury supported by normal levels of von Willebrand factor and homocysteine.     

Blood coagulation,fibrinolysis, and markers of endothelial dysfunction in systemic sclerosis

OBJECTIVE: To evaluate the coagulative/fibrinolytic cascade and the circulating markers of the endothelial injury in systemic sclerosis (SSc). METHOD: Plasma was obtained from 29 patients with SSc and tested for thrombin-antithrombin (TAT), fragments 1+2 (F1+2), dermatansulphate (DS), thrombomodulin (TM), lipoprotein (a) [Lp(a)], von Willebrand factor (vWF), tissue type plasminogen activator (tPA), plasminogen activator inhibitor (PAI), D-dimers, intercellular adhesion molecole-1 (ICAM-1), vascular cell adhesion molecule (VCAM), and E-selectin. The data were correlated with lung (forced vital capacity, diffusing lung capacity for carbon monoxide, vital capacity) and skin (skin score) involvement. RESULTS: Coagulation was significantly activated (increase in F1+2, P <.001; TAT, P <.01; and Lp(a), P <.05). TM was not significantly different from controls. vWF was significantly increased (P <.01), and its supranormal multimers increased in more than 50% of patients. DS was significantly increased in diffuse cutaneous SSc (P <.01). Fibrinolysis was impaired as shown by reduced D-dimers (P <.01) and decreased levels of PAI (P < 0.01). The markers of endothelial injury were also significantly elevated. DS correlated significantly with forced vital capacity (P <.01) and forced vital capacity ratio (P <.01). CONCLUSION: Injury to the endothelium reduces endothelial function, as suggested by impairment of fibrinolysis and activation of the coagulative pathway. The loss of the balance between fibrinolysis and coagulation contributes to vessel engulfment with fibrin and breakdown of vessel patency. The increase of circulating DS suggests that this factor may be a new marker of endothelial injury.     

Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes

OBJECTIVE: To investigate the relationship of inflammation and endothelial activation with insulin resistance and adiposity in type 2 diabetes. METHODS AND RESULTS: Hundred and thirty-four (45 female) type 2 diabetic subjects aged 50-75 in the Fenofibrate Intervention and Event Lowering in Diabetes Study in Helsinki were examined before fenofibrate intervention. Fasting levels of circulating intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) (vascular cell adhesion molecule), ultra-sensitive C-reactive protein (CRP), human serum amyloid A (hSAA), interleukin-6 (IL-6), macrophage colony-stimulating factor (M-CSF), secretory phospholipase A(2) IIA (PLA(2)), total, HDL and LDL cholesterol, triglycerides, P-glucose, HbA1c, and serum free insulin were determined. Insulin resistance was assessed by the homeostasis model. HOMA IR correlated significantly with all measures of adiposity and markers of inflammation and endothelial dysfunction. BMI was significantly associated with inflammation and endothelial activation, but with neither lipoproteins nor glycaemic control. After controlling for age, gender and BMI, HbA1c correlated significantly with CRP, hSAA, ICAM-1, E-selectin, and HOMA IR. HDL cholesterol correlated inversely with IL-6, M-CSF, E-selectin, and HOMA IR. HbA1c, phospholipase A(2), VCAM-1, and HDL cholesterol remained independent determinants of HOMA IR in the linear regression analysis controlled for age, gender, and BMI. CONCLUSION: Endothelial activation and acute-phase reaction correlate with insulin resistance and obesity in type 2 diabetic patients.     

High serum concentrations of soluble E-selectin correlate with obesity but not fat distribution in patients with type 2 diabetes mellitus

Serum concentrations of soluble adhesion molecules, eg, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin are elevated in patients with type 2 diabetes. However, little is known about the role of obesity or abnormal fat distribution in inducing upregulation of adhesion molecules. To investigate this issue, soluble ICAM-1, VCAM-1, and E-selectin levels were evaluated in 40 obese and 30 nonobese patients with type 2 diabetes. Both groups were matched for age, sex, and glycosylated hemoglobin (HbA(1c)) levels. Computed tomography (CT) was used to measure the abdominal subcutaneous and visceral fat areas. Soluble ICAM-1 and VCAM-1 levels did not differ significantly between obese and nonobese patients. However, serum concentrations of soluble E-selectin were significantly higher in obese than in nonobese patients (90 +/- 7 v 56 +/- 4 ng/mL, P <.01). Soluble E-selectin levels significantly correlated with body mass index, subcutaneous fat area, and visceral fat area (Rho = 0.48, 0.37, and 0.30, respectively). Stepwise multiple regression analysis showed that body mass index (F = 16.7), but not subcutaneous and visceral fat areas (F = 0.29 and 0.01, respectively), significantly and independently correlated with soluble E-selectin levels. Our results suggest that obesity may induce endothelial activation or increased shedding of cell surface E-selectin that leads to subsequent increase in soluble E-selectin levels. The high serum concentrations of E-selectin closely correlated with increased total fat volume, but not with regional fat distribution.     

Elevated soluble cell adhesion molecules E-selectin and intercellular cell adhesion molecule-1 in type-2 diabetic patients with and without asymptomatic peripheral arterial disease.

AIM: Cell adhesion molecules may serve as markers of endothelial cell activation, and they may well have a role in the pathogenesis of atherosclerotic vascular disease in diabetes mellitus. METHODS: Experimental design: a cross sectional, comparative study. Setting: a teaching University Hospital. Patients and controls. A cohort of diabetic patients with absent peripheral arterial pulses but no history of cardiovascular or cerebrovascular disease i.e. asymptomatic (n=29), median age 68 (36-80) years, (range), diabetes duration 10 (1-43) years and HbA1c 7.7% (4.8-9.6). They were compared to 12 age and sex matched normal non-diabetic controls. Intervention: none. Measures: soluble cell adhesion molecules intercellular cell adhesion molecule-1 (ICAM-1) and E-selectin levels measured by ELISA methods. RESULTS: The 29 patients with diabetes, as a whole, were found to have significantly higher median plasma sICAM-1 and sE-selectin of 283 ng/ml (154-1000) (range), and 65.8 ng/ml (20.6-145) vs 237 (147-312.4) and 37.7 (19.8-46.6) respectively, Mann Whitney U test p<0.02, and p<0.002. In the diabetic group, E-selectin correlated with ICAM-1, age and HbA1c: r=0.524 p<0.01, r=0.385 p<0.05 and r=0.393 p<0.05 respectively (Spearman correlation coefficient). CONCLUSION: These results confirm that elevated levels of adhesion molecules, E-selectin and ICAM-1 occur in Type-2 diabetes early in the course of asymptomatic peripheral arterial occlusive disease, and this is related to glycemic control. This suggests that adhesion molecules may have a role in the pathogenesis of atherosclerotic vascular disease in diabetes.     

Circulating intercellular cell adhesion molecule-1, endothelin-1 and von Willebrand factor-markers of endothelial dysfunction in uncomplicated essential hypertension: the effect of treatment with ACE inhibitors

The aim of the study was to examine whether the circulating cell adhesion molecules, von Willebrand factor (vWf) and endothelin-1, are elevated in patients with essential hypertension with no other risk factors for atherosclerosis and thus may serve as a markers of endothelial dysfunction in uncomplicated hypertension. Furthermore, the effect of treatment with the ACE inhibitor, quinapril, on levels of endothelial dysfunction markers were studied. The levels of adhesion molecules (intercellular cell adhesion molecule-1 [ICAM-1], E-selectin, P-selectin), von Willebrand factor (vWf) and endothelin-1 were measured in patients with hypertension without any other risk factors of atherosclerosis before and after treatment with quinapril (n = 22) and in normotensive controls (n = 22). Compared with normotensive subjects, the hypertensive patients had significantly higher levels of ICAM-1 (238 vs 208 ng/ml, P = 0.02), vWf (119 vs 105 IU/dl, P < 0.05) and endothelin-1 (5.76 vs 5.14 fmol/ml, P < 0.05). Three-month treatment of hypertensive patients with quinapril led to a significant decrease in the levels of endothelin-1 (5.76 vs 5.28 fmol/ml, P < 0.01). We did not observe significant changes in the levels of adhesion molecules and vWf after ACE inhibitor treatment, although a trend toward a decrease was apparent with all these parameters. Patients with uncomplicated hypertension with no other risk factors of atherosclerosis had significantly elevated levels of ICAM-1, vWf, and endothelin-1. Our data suggest that these factors may serve as markers of endothelial damage even in uncomplicated hypertension. In hypertensive patients, treatment with the ACE inhibitor quinapril resulted in a significant decrease in endothelin-1 levels. These findings indicate a beneficial effect of ACE inhibitors on endothelial dysfunction in hypertensive patients.     

2型糖尿病患者糖耐量正常一级亲属血管内皮功能及炎症因子的研究

目的研究2型糖尿病患者一级亲属糖耐量正常者(FDR)的血管内皮功能、炎症因子水平及其影响因素。方法测定31例正常人、57例FDR的血管内皮功能、血浆纤溶酶原激活物抑制物1(PAI1)及血清可溶性血管细胞黏附分子1(VCAM1)水平,同时测定胰岛素水平,计算胰岛素敏感性(IAI)。结果与正常对照组比较,FDR内皮依赖性血管舒张功能减低[(1245±337)%比(503±034)%],IAI降低[(-379±057)比(-411±046)],血浆PAI1水平升高[(3046±1228)μg/L比(3925±654)μg/L],血清VCAM1水平升高[(63731±10732)μg/L比(74239±12431)μg/L],差异均有统计学意义(P值均<005)。结论糖耐量正常的2型糖尿病患者一级亲属胰岛素敏感指数下降、血管内皮功能受损、纤溶活性降低,且血管内皮功能失调与胰岛素抵抗密切相关。     

Enhanced endothelial activation in diabetic patients with unstable angina and non-Q-wave myocardial infarction.

AIMS: Diabetes mellitus (DM) is associated with chronic endothelial dysfunction. Diabetic patients presenting with acute coronary syndromes have a worse prognosis than non-diabetics. An acute inflammatory reaction at the site of coronary plaque rupture and increased expression of surface and soluble cellular adhesion molecules (CAMs) are pathological features of acute coronary syndromes. We set out to characterize the expression of soluble CAMs in patients with and without diabetes presenting with unstable angina (UA) and non Q-wave myocardial infarction (NQMI). METHODS: Patients presenting with UA and NQMI had serum samples taken on presentation, after 72 h and then 3, 6 and 12 months after discharge. Levels of soluble intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin and P-selectin were measured using an ELISA technique. RESULTS: We studied 15 diabetic patients and 15 age- and sex-matched non-diabetic patients presenting with either UA or NQMI. Levels of soluble E-selectin were elevated in the diabetic patients in comparison with the non-diabetic patients at all measured time points: 74 +/- 10 ng/ml vs. 47 +/- 3 ng/ml, P < 0.03 at t = 0 h, 55 +/- 5 ng/ml vs. 38 +/- 2 ng/ml, P < 0.02 at t = 72 h. However, levels of soluble P-selectin were lower in the diabetic cohort during follow-up: 134 +/- 15 ng/ml vs. 225 +/- 32 ng/ml, P < 0.02 at t = 3/12 and 112 +/- 8 ng/ml vs. 197 +/- 23 ng/ml, P < 0.02 at t = 6/12. There was no significant difference in levels of soluble ICAM-1 and VCAM-1 between diabetic and non-diabetic patients. CONCLUSIONS: Levels of soluble E-selectin are significantly elevated in diabetic patients presenting with UA and NQMI in comparison with non-diabetics. This finding may reflect enhanced endothelial activation which may contribute to the adverse prognosis of diabetic patients with acute coronary syndromes.     

Endothelial dysfunction, ambulatory pulse pressure and albuminuria are associated in Type 2 diabetic subjects.

AIM: Elevated pulse pressure (PP) is associated with microvascular complications in Type 2 diabetic patients. In non-diabetic subjects, elevated PP has been associated with endothelial dysfunction. The relation between endothelial dysfunction and PP in diabetic subjects has not previously been examined. We examined the relation between PP, markers of endothelial activation and albuminuria in Type 2 diabetic patients. METHODS: In 46 Type 2 diabetic patients and 19 non-diabetic subjects, we performed 24-h ambulatory blood pressure (AMBP) monitoring. Urinary albumin excretion rate was measured as three urinary albumin/creatinine ratios. Von Willebrand factor (vWF), fibrinogen, E-selectin and soluble intercellular adhesion molecule 1 (ICAM-1) were measured in plasma. RESULTS: Thirty-four patients had normoalbuminuria (group N) and 12 had micro- or macroalbuminuria (group A). PP levels increased in a stepwise manner from the control group (group C) to group N and group A; night PP 43 +/- 5, 48 +/- 10 and 59 +/- 12 mmHg (groups C, N and A, respectively, P < 0.001). Likewise, plasma levels of vWF, fibrinogen, E-selectin and ICAM-1 increased from group C to group A; e.g. ICAM-1 [median (interquartile range)] 191 (160-217), 213 (189-262) and 316 (260-417) ng/ml, groups C, N and A, respectively, P < 0.001). In diabetic patients, night PP and plasma levels of E-selectin and ICAM-1 correlated (r = 0.38, P < 0.01 and r = 0.37, P = 0.01, night PP with E-selectin and ICAM-1, respectively). CONCLUSION: Increased PP is associated with endothelial activation and albuminuria in Type 2 diabetic patients. Thus, endothelial dysfunction may represent a pathophysiological link between an elevated PP and microvascular complications in these subjects. Prospective studies are needed to further elucidate these associations.     

5-HT2A receptor antagonist increases circulating adiponectin in patients with type 2 diabetes.

We compared the levels of plasma adiponectin, platelet activation markers (P-selectin, CD63, PAC-1, annexin V, and platelet-derived microparticles), and endothelial injury markers (soluble E-selectin and soluble vascular cell adhesion molecule-1) in 53 patients with type 2 diabetes mellitus to investigate potential contributions to diabetic vascular complications. In addition, we administered serotonin antagonist (sarpogrelate hydrochloride) to type 2 diabetes patients who had increased soluble E-selectin levels. The concentrations of platelet activation markers and endothelial injury markers in diabetic patients were significantly higher than those in normal subjects. However, levels of adiponectin were lower in type 2 diabetes patients than in control subjects. A total of 32 patients had high-soluble E-selectin levels (soluble E-selectin >or= 62 ng/ml); a subset of patients that also had significant elevation of platelet activation and endothelial injury markers compared with patients without high soluble E-selectin. In addition, both platelet-P-selectin and platelet-derived microparticle levels negatively correlated with the adiponectin level. Patients with high soluble E-selectin exhibited significant improvement of all markers after sarpogrelate hydrochloride treatment. These findings suggest that there is a link between vascular change in type 2 diabetes and activated platelets, endothelial dysfunction, and an adiponectin abnormality.     

Elevated levels of soluble E-selectin in patients with IDDM and NIDDM: relation to metabolic control

Summary The adhesion of leucocytes to the endothelium, an early step in atherogenesis, is mediated by cell adhesion molecules. In this study we evaluated the concentration of soluble adhesion molecules in patients with insulin-dependent (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) and studied its relation to glycaemic control. Soluble adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) were measured in 31 diabetic patients (18 with IDDM and 13 with NIDDM), 20 hyperlipoproteinaemic patients (10 with type IIa and 10 with type IIb) and 20 healthy subjects. Increased E-selectin concentrations were found in the patients with IDDM and NIDDM and in the hyperlipoproteinaemic patients when compared to the control subjects (p<0.01 for all the groups). ICAM-1 was found to be elevated only in the patients with NIDDM (p<0.01). No significant differences in VCAM-1 concentration were found in the different groups of subjects. The concentration of plasma E-selectin was positively correlated with the glycated haemoglobin (r=0.54, p<0.01) in patients with IDDM and NIDDM. In the same patients E-selectin was not related to the concentrations of plasma lipids in spite of the fact that it was found to be elevated in hyperlipoproteinaemic subjects. The results though preliminary suggest that in diabetic patients the concentration of soluble adhesion molecules and especially of E-selectin may be related to metabolic control.Abbreviations IDDM insulin-dependent diabetes mellitus - NIDDM non-insulin-dependent diabetes mellitus - ICAM-1 intercellular adhesion molecule-1 - VCAM-1 vascular adhesion molecule-1 - AGE advanced glycation end products     

Atorvastatin therapy in hypercholesterolemic patients suppresses cellular uptake of oxidized-LDL by differentiating monocytes

The study was aimed at investigating the effects, after treatment for 1 year, of two different statins on the levels of circulating biochemical markers of endothelial function in patients with established coronary heart disease, with the hypothesis that statins might reduce these levels. Twenty-eight patients were randomized to treatment with atorvastatin and 30 to simvastatin for 1 year. The starting dose in both groups was 20 mg/day. Soluble forms of P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were determined to assess inflammatory activity of the endothelium, and tissue plasminogen activator antigen (tPAag), von Willebrand factor and thrombomodulin for evaluation of the haemostatic function. In the total study population there were significantly reduced levels after 1 year treatment in ICAM-1 (P<0.001), E-selectin (P=0.022) and P-selectin (P<0.001), whereas a significant increase was observed in VCAM-1 (P=0.003). Almost the same pattern was seen within both groups although the increase in VCAM-1 was only seen in the simvastatin group (P=0.017). An overall reduction in tPAag was further observed (P=0.048). The reduction in proinflammatory and to some extent haemostatic markers of endothelial function after 1 year treatment with either simvastatin or atorvastatin may be indicative of a less activated state of the endothelium which possibly may contribute to modulation of the progression of atherosclerosis.     

2型糖尿病纤溶系统变化与胰岛素抵抗的关系

目的探讨2型糖尿病患者纤溶活性变化与胰岛素抵抗之间的关系。方法采用酶联免疫吸附法测定63例2型糖尿病患者（包括无血管并发症组30例和有血管并发症组33例）和25例正常对照者血浆组织型纤溶酶原激活剂（t-PA）、纤溶酶原激活物抑制剂-1（PAI-1）含量,结合临床资料分析其变化趋势及影响因素。结果2型糖尿病患者血浆t-PA含量明显降低（P〈0．01）,而PAI-1含量明显升高（P〈0．01）,合并血管病变者,此变化更为显著（均P〈0．001）。多元逐步回归分析显示,HOMA模型胰岛素抵抗指数（HOMA—IR）是PAI-1升高的独立危险因素。结论2型糖尿病患者纤溶活性降低,胰岛素抵抗在降低其纤溶活性,并发血管病变中起了重要作用。     

Nicotine induced changes in gene expression by human coronary artery endothelial cells

The primary role of cigarette smoking in the development of coronary heart disease is to cause damage to the vascular endothelium, leading to endothelial cell dysfunction and initiating the pathogenesis of coronary atherosclerosis. We studied the response of human coronary artery endothelial cells to nicotine exposure by examining the expression of a panel of genes encoding molecules that have been shown to be involved in atherogenesis. Treatment of primary human coronary artery endothelial cells with nicotine for 24 h at concentrations (10(-5) and 10(-7) M) similar to those in the blood of smokers resulted in increased mRNA levels of endothelial nitric oxide synthase, angiotensin-I converting enzyme, tissue-type plasminogen activator, plasminogen activator inhibitor-1, von Willebrand factor, and vascular cell adhesion molecule-1. No change was detected in the expression levels of the genes encoding basic fibroblast growth factor, endothelin-1, endothelial leukocyte adhesion molecule-1 and matrix metalloproteinase-2 under these conditions. These data indicate that nicotine alters the expression of a number of endothelial genes whose products play major roles in regulating the vascular tone and thrombogenicity, making a contribution to the understanding of the effects of cigarette smoking on the development of coronary atherosclerosis.     

Postprandial thrombin activatable fibrinolysis inhibitor and markers of endothelial dysfunction in type 2 diabetic patients

The aim of this study was to assess postprandial changes in thrombin activatable fibrinolysis inhibitor (TAFI) antigen, a thrombin-dependent fibrinolysis inhibitor with anti-inflammatory properties, and soluble markers of endothelial dysfunction in normotriglyceridemic type 2 diabetic patients. Fasting and postprandial TAFI antigen, thrombomodulin, tissue factor pathway inhibitor (TFPI), and plasminogen activator inhibitor 1 were assessed in 12 normotriglyceridemic type 2 diabetic patients treated with diet (hemoglobin A1c, 6.80% +/- 0.67%) and 14 controls. Fasting low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, free fatty acids and apolipoprotein B, and fasting and postprandial triglyceride, glucose, and insulin were also measured. Fasting TAFI was higher in the control group (102% +/- 16.9% vs 72.9% +/- 15.9%; P < .0005) and was inversely correlated with glycemic control. It decreased 4 hours after the meal (31.8% reduction [P < .005] for controls and 12.6% [P < .05] for diabetic patients) and returned to fasting levels after 8 hours. This decrement was correlated with fasting TAFI, glucose and hemoglobin A1c, and the area under the curve of glucose. Thrombomodulin, TFPI, and plasminogen activator inhibitor 1 were similar in both groups, with thrombomodulin and TFPI showing a transient postprandial increase. A fat-rich meal produces a transient increase in markers of endothelial dysfunction and a temporary reduction in TAFI, an anti-inflammatory molecule whose concentration is low in type 2 diabetes mellitus.     

Intercellular adhesion molecule-1 (ICAM-1) polymorphism is associated with diabetic retinopathy in Type 2 diabetes mellitus.

AIMS: Leucocyte adhesion to the diabetic retinal vasculature has been implicated in the pathogenesis of diabetic retinopathy. We evaluated the relationship between genetic polymorphisms in leucocyte and endothelial cell adhesion molecules and diabetic retinopathy in Type 2 diabetes mellitus. METHODS: We determined ICAM-1, platelet endothelial cell adhesion molecule-1 (PECAM-1), and leucocyte endothelial adhesion molecule-1 (LECAM-1) genotypes in 81 patients with and 50 without diabetic retinopathy. RESULTS: The frequency of ICAM-1 469KK genotype and K allele were significantly higher in the patients with diabetic retinopathy than in those without retinopathy (genotype 42% vs. 20%, chi2 = 6.70, P = 0.035; allele 66% vs. 50%, chi2 = 6.49, P = 0.011). With regard to the PECAM-1 V125L and LECAM-1 P213S polymorphisms, there were no significant associations between the distribution of genotypes or allele frequencies and the presence of diabetic retinopathy. Independent of other risk factors, the ICAM-1 469KK genotype was associated with a 3.51-fold increased risk for retinopathy. CONCLUSIONS: These data suggest that the ICAM-1 469KK genotype could be a genetic risk factor for retinopathy in Type 2 diabetes mellitus.     

Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression

Pulmonary hypertension (PH), a risk factor for mortality in sickle cell disease (SCD), has pathologic features of both pulmonary arterial hypertension (PAH) and PH related to left-sided heart disease (LHD) suggesting a link between these two entities. We hypothesized that both are characterized by endothelial dysfunction and increased adhesion molecule expression. SCD patients and normal volunteers underwent a screening questionnaire, echocardiogram, and blood donation for preparation of platelet-poor plasma. PAH was defined as a tricuspid regurgitant jet (TRJ) velocity > or =2.5 m/sec and/or the presence of isolated right ventricular hypertrophy or decreased systolic function. LHD was defined as either left-sided systolic/diastolic dysfunction or significant valvular disease. Plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P- and E-selectin, nitric oxide (NO(x)), erythropoietin, and vascular endothelial growth factor (VEGF) levels were assayed by enzyme-linked immunoassay. Forty-three percent of sickle cell anemia (HbSS) and 28% of hemoglobin SC disease (HbSC) disease patients had PAH. Additionally, 10-15% of SCD patients had LHD. VCAM-1 levels were significantly increased in HbSS patients compared with HbSC patients and normal volunteers. VCAM-1 and P-selectin levels correlated positively with TRJ velocity in HbSS patients (r = 0.45, P = 0.03, r = 0.2, P = 0.05, respectively). ICAM-1, E-selectin, NO(x), erythropoietin, and VEGF levels were similar across subject groups. PH is common in SCD and, at times, due to LHD. Increased VCAM-1 and P-selectin expression was associated with TRJ elevation regardless of etiology suggesting a similar effect on endothelial gene expression and possibly providing a pathologic link between PAH and PH related to LHD in SCD.