Elevated soluble cellular adhesion molecules in subjects with low HDL-cholesterol

The purpose of this study was to investigate whether the expression of cellular adhesion molecules (CAMs) is enhanced in individuals with low HDL cholesterol (HDL-C). Plasma levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1), and E-selectin (sE-selectin) were measured in subjects with low (below the 10th percentile for the Italian population), average, or high (above the 90th percentile) HDL-C. Average sICAM-1 and sE-selectin levels were significantly higher in two groups of 65 individuals with low HDL levels, either hyperlipidemic (320.5+/-16.0 and 61.4+/-3.5 ng/mL) or normolipidemic (309.6+/-13.0 and 60.0+/-2.7 ng/mL), than in subjects with average HDL levels, either hyperlipidemic (267.0+/-10.1 and 50.4+/-2.8 ng/mL) or normolipidemic (257.9+/-5.4 and 51.1+/-2.4 ng/mL), or with high HDL levels (254.8+/-10.2 and 52.5+/-3.2 ng/mL). No significant difference was found in the plasma sVCAM-1 concentration. HDL-C was inversely correlated with sICAM-1 and sE-selectin in the low-HDL subjects (r(2)=0.087 and 0.035, P=0.0007 and 0.033, respectively), but not in individuals with normal or elevated HDL-C (r(2)=0.012 and 0.006). A fenofibrate-induced increase of HDL-C in 20 low-HDL subjects was associated with a significant reduction of plasma sICAM-1 and sE-selectin concentrations. An increased CAMs expression may be a mechanism by which a low plasma HDL level promotes atherogenesis and causes acute atherothrombotic events.     

Lack of association between dietary alcohol and HDL-cholesterol concentrations in obese women

The relationships of alcohol intake and corpulence to HDL-cholesterol were studied in 653 women taking medical advice about body weight. The body mass index (BMI) was positively correlated with triglyceride and negatively with HDL-cholesterol. The relation between BMI and HDL-cholesterol was discontinuous. Total cholesterol, triglycerides and diastolic blood pressure were increased for alcohol intakes greater than 10 g/d regardless of body weight. Alcohol intake was associated with higher concentrations of HDL-cholesterol (P = 0.006) in non obese (BMI = 25.2 +/- 1.5 kg/m2) subjects, but not in mildly (27.3 less than or equal to BMI less than 32.3) or massively (BMI greater than or equal to 32.3) obese subjects. The fact that HDL concentrations were not associated with alcohol intake in obese patients suggests that (1) alcohol acts on the HDL pool through one of the pathways which are perturbed in obesity, possibly lipolysis, (2) obesity is one of the reasons for the differences in individual responses of HDL-cholesterol to alcohol, (3) myocardial infarction might not be inversely correlated with alcohol intake in the obese as it is in the non-obese population.     

Genotype-specific association between circulating soluble cellular adhesion molecules and carotid intima-media thickness in community residents: J-SHIPP study. Shimanami Health Promoting Program.

Plasma levels of soluble forms of cellular adhesion molecules (CAMs) and their relationships with carotid intima-media thickness (IMT) were investigated in community residents. Plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) were measured by ELISA in 200 community residents in Japan. Carotid IMT showed a weak but significant positive correlation with the plasma levels of both sICAM-1 (r=0.175, p=0.013) and sVCAM-1 (r=0.19, p=0.0075). Gene polymorphisms of angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M235T, angiotensin II type 1 receptor (AT1R) A1166C and apolipoprotein E (apoE) were determined for each subject. The plasma level of sVCAM-1 tended to be lower in subjects with the ACE DD genotype than in those with the ACE ID and II genotypes (373+/-94, 421+/-133, 443+/-135 ng/ml, respectively, p=0.056). However, there were no genotype-specific differences in the plasma levels of soluble forms of CAMs for the other genes examined. In a separate analysis, the plasma level of sICAM-1 was significantly associated with carotid IMT in ACE D carriers (ID + DD) (r=0.28, p=0.002), AGT M carriers (MT + MM) (r=0.32, p=0.0045), and subjects with apoE4 (r=0.35, p=0.036). In contrast, the plasma level of sVCAM-1 showed significant positive correlations with carotid IMT in subjects with the ACE II genotype (r=0.33, p=0.0027) or AGT TT genotype (r= 0.22, p=0.015), and subjects with apoE E2/E3 or E3/E3 (r=0.16, p=0.043). Stepwise regression analysis showed that plasma sVCAM-1 was independently associated with carotid IMT in subjects with the ACE II genotype or apoE4 genotype. Similarly, the plasma level of sICAM-1 was independently associated with carotid IMT in AGT M carriers. These findings suggest that genetic background could be involved in the association between plasma CAMs and atherosclerosis.     

Relation between low serum cholesteryl-ester transfer activity and abdominal aortic calcification in normolipidemic elderly subjects

We studied the relation between cholesteryl-ester transfer activity (CETA) and abdominal aortic calcification in elderly subjects. Compared with 10 young healthy subjects (mean +/- S.D. age, 27 +/-2 years) and to 26 elderly subjects without abdominal aortic calcification (79 +/- 7 years), 16 elderly patients with abdominal aortic calcification (82 +/- 6 years) had significantly lower levels of serum CETA. However, there were no differences in the levels of serum lipids and apolipoproteins, including total cholesterol, triglycerides, high density lipoprotein cholesterol, low density lipoprotein cholesterol and apolipoproteins A-I, A-II, B, C-II and E, between the two elderly groups. When the two groups of elderly subjects were considered together, the level of serum CETA did not correlate significantly with any lipids and apolipoproteins. These results provide evidence that CETA may prevent the development of aortic calcification in normolipidemic elderly people.     

Influence of n-3 polyunsaturated fatty acids on soluble cellular adhesion molecules as biomarkers of cardiovascular risk in young healthy subjects

Background and aimSerum levels of soluble cellular adhesion molecules (CAMs) and blood lipid parameters have been used as markers of inflammatory processes associated with cardiovascular disease (CVD) events. The present study evaluated the effects of the intake of n-3 polyunsaturated fatty acids (PUFAs) in fish and fish oil within energy-restricted diets, on soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1).Methods and resultsTwo hundred and seventy-five healthy European subjects aged between 20 and 40 years, were randomized to one of four hypocaloric dietary groups: control (sunflower oil capsules, no seafood), lean fish (3 × 150 g portions of cod/week), fatty fish (3 × 150 g portions of salmon/week), fish oil ((docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) capsules, no seafood)). Diets rich in lean fish significantly decreased ICAM-1 levels, around 5% from baseline to endpoint (p < 0.05), and had no effect on VCAM-1 levels. No significant differences were observed in sICAM-1 levels after the intervention with fatty fish or fish oils. On the other hand, these two seafood based diets were responsible for a significant increase of VCAM-1 levels [fatty fish; 16.1% and fish oil; 21.9%] respectively (p < 0.05).ConclusionsCAMs as inflammatory biomarkers in young and healthy subjects are not conclusive for the evaluation of CVD risk. Hypocaloric fish diets had a different effect on CAMs, being lean fish responsible for the highest decrease in ICAM-1. On the other hand, VCAM-1 results allow speculation that a low dose of n-3 PUFA may be anti-inflammatory contrarily to a high dose which can have a pro-inflammatory effect. CAMs mechanism is complex and affected by multiple factors such as lifestyle, gender, and n-3 dose and source.     

Inverse relationship between circulating oxidized low density lipoprotein (oxLDL) and anti-oxLDL antibody levels in healthy subjects

Oxidized low density lipoprotein (oxLDL) has been implicated in the pathogenesis of atherosclerosis. Recent studies have shown that immunization of animals with oxLDL results in suppression of atherogenesis. Antibody against oxLDL (oxLDL Ab) is detectable in human sera, although its biological significance is not well established. We examined the relationship between oxLDL Ab titer and circulating oxLDL level in 130 healthy Japanese subjects. OxLDL was measured as apolipoprotein (apo) B-containing lipoproteins carrying oxidized phosphatidylcholines by a sensitive ELISA. IgG class oxLDL Ab titer was measured by ELISA. Plasma oxLDL concentration was very low and it corresponded on average to one to two out of 1000 apoB-containing lipoproteins in plasma. Plasma oxLDL correlated positively with LDL cholesterol and inversely with oxLDL Ab titer. These associations remained significant and independent in multiple regression analysis including age, gender, smoking, and high-density lipoprotein cholesterol. These data indicate that healthy subjects have a very low concentration of oxLDL in the circulation, and that oxLDL Ab titer is in an inverse relationship with plasma oxLDL concentration in this population. Although these results suggest that oxLDL Ab may play a role in maintaining the low level of plasma oxLDL, its role in atherogenesis awaits further studies.     

Elevated levels of circulating adhesion molecules in patients with active pulmonary tuberculosis

OBJECTIVE: Recent studies have indicated the importance of cell adhesion molecules in the pathogenesis of various inflammatory lung diseases. Our study was designed to determine whether five soluble adhesion molecules including soluble L-, E- and P-selectin (sL-, sE- and sP-selectin), intercellular adhesion molecule-1 (sICAM-1), and vascular cell adhesion molecule-1 (sVCAM-1) in serum reflect the severity of active pulmonary tuberculosis (TB), and whether there is a distinct profile of these soluble molecules in this disease. METHODOLOGY: Using enzyme-linked immunosorbent assays, we measured the serum levels of these five soluble adhesion molecules in 31 patients with active TB and 11 healthy volunteers. RESULTS: Serum levels of sE-selectin, sP-selectin and sICAM-1, but not sL-selectin or sVCAM-1, were significantly higher in patients with active TB than in the control subjects (P < 0.001, each). Significant correlations were detected only between serum levels of sE-selectin and sP-selectin, sE-selectin and sICAM-1, and sP-selectin and sICAM-1. There was a significant correlation between the Gaffky scale result (a scale assessing the number of mycobacteria bacilli present) and all of the above adhesion molecules, except for sL-selectin. Serum levels of sE-selectin, sL-selectin and sICAM-1 also correlated with the CXR radiological score. Higher levels of sL-selectin and sICAM-1 were detected in the serum of patients with radiological cavity formation compared to those without. The ESR, C-reactive protein and circulating neutrophil counts all correlated significantly with sE-selectin, sP-selectin, sICAM-1 and sVCAM-1. CONCLUSION: The results suggest that there is a distinct profile of soluble adhesion molecules in active pulmonary TB and that sE-selectin, sP-selectin, and especially sICAM-1 appear to be the most sensitive clinical measures of disease severity.     

The relationship between oxidative stress and the levels of serum circulating adhesion molecules in patients with hyperglycemia crises

ObjectiveTo investigate the relationship between oxidative stress and the levels of serum circulating adhesion molecules in patients with hyperglycemia crises.MethodsA total of 73 patients with diabetic ketoacidosis and nonketotic hyperglycemia were treated on a low-dose insulin protocol using intravenous infusion of insulin with the established rate of 0.1 U·kg^? 1·h^? 1. The patients received intravenous fluids and nutrition orally and intravenously. The levels of serum ICAM-1, E-selectin, and 8-iso-prostaglandin F_2α (8-iso-PGF_2α); the activities of superoxide dismutase (SOD); the total antioxidant capacity (TAC) and the contents of malondialdehyde (MDA) in 68 patients with hyperglycemia crisis on admission and after insulin therapy with resolution of hyperglycemia and ketoacidosis (72 h after resolution) were measured. Another 33 healthy individuals served as normal controls.ResultsThe activities of SOD and TAC at admission were lower in patients with hyperglycemia crisis than in normal controls, and the levels of MDA, 8-iso-PGF_2α, ICAM-1 and E-selectin were higher in patients with hyperglycemia crisis than in normal controls (all p < 0.05). The activities of SOD and TAC in patients at resolution were significantly lower than in patients at admission and were significantly higher than in controls (p < 0.05). The levels of MDA, 8-iso-PGF_2α, ICAM-1 and E-selectin in patients at resolution were markedly lower than in patients at admission (all p < 0.05) and were significantly higher than in normal controls (p < 0.05). There was a significant positive correlation between ICAM-1 and SOD (r = 0.32, p < 0.05) and between E-selectin and MDA (r = 0.30, p < 0.05) in patients at admission, and the level of E-selectin was positively correlated with MDA and 8-iso-PGF_2α in patients at resolution (r = 0.33, 0.36, p < 0.05). In stepwise regression analysis, MDA and 8-iso-PGF_2α showed a significant association with E-selectin, and 8-iso-PGF_2α showed a significant association with ICAM-1.ConclusionThe oxidative stress and the levels of serum circulating adhesion molecules are significantly changed in patients with hyperglycemia crisis. Intensive insulin therapy can attenuate the abnormity of oxidative stress and the levels of serum circulating adhesion molecules in patients with hyperglycemia crisis.     

Up-regulation of circulating adhesion molecules in bronchiectasis.

Adhesion molecules are expressed on the surface of endothelial cells and leukocytes and are responsible for mediating the migration of intravascular leukocytes into inflamed tissue. Intensive recruitment of neutrophils into the airways occurs in bronchiectasis, although little is known about the role of adhesion molecules in this process. The authors, therefore, determined serum levels of E-selectin, intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 in stable bronchiectasis patients (n=37) and healthy control subjects (n=17), and evaluated their relationship with clinical markers of disease severity in bronchiectasis. Serum levels of E-selectin, ICAM-1 and VCAM-1 in bronchiectasis patients were significantly higher than those in control subjects (p=0.02, <0.0001 and 0.0002 respectively). Both E-selectin and ICAM-1 levels were inversely related to forced expiratory volume in one second (FEV1)% predicted (r=-0.57, p<0.001; and r=-0.53, p=0.001 respectively), and FVC% predicted (r=-0.52, p=0.002; and r=-0.46, p=0.005). This was not the case for VCAM-1 levels. There was a correlation between serum ICAM-1 levels and 24 h sputum volume (r=0.34, p= 0.04). Serum E-selectin and ICAM-1, but not VCAM-1, levels showed correlation with the number of lung lobes affected by bronchiectasis (r=0.35, p=0.04 and r=0.34, p=0.04 respectively). These original observations strongly suggest that E-selectin, intercellular adhesion molecule-1 and Vascular adhesion molecule-1 could play a significant role in the pathogenesis of bronchiectasis.     

Lack of difference in T wave variability between patients at risk of sudden cardiac death and healthy subjects

Background

T wave variability (Tvar) is a proposed method to predict sudden cardiac death (SCD). The purpose of this trial was to evaluate the reproducibility of Tvar measurements over time and demonstrate a difference in Tvar between patient populations at risk for ventricular arrhythmias and healthy subjects.

Methods

Sixty subjects were enrolled in into 3 groups: healthy subjects (Population I), patients at high risk of SCD (Population II), and patients with a recent ventricular tachyarrhythmia event (Population III). Recording and analysis of T wave amplitude variance (TAV) as a measure of Tvar was performed at baseline and 3 months.

Results

TAV could not be interpreted in 12 of 43 patients in Populations II and III due to PVCs or noise. No subject had a TAV value suggestive of high risk of SCD as per a previously defined cutoff of > 59 μV. Median (range) values of TAV in μV at baseline for Populations I, II and III were 26 (15–39), 21 (13–43), and 24 (18–41), respectively (p = 0.39). TAV was reproducible within population's from baseline to 3 months (p = 0.27, 0.53, 0.17 for Populations I, II and III, respectively). There was no significant difference between TAV values of high risk patients and healthy subjects.

Conclusion

Tvar was reproducible primarily in patients with left ventricular dysfunction. However, the role of Tvar as a risk stratifying tool remains inconclusive.     

Vitamin E inhibits lipid peroxidation-induced adhesion molecule expression in endothelial cells and decreases soluble cell adhesion molecules in healthy subjects

OBJECTIVE: In a combination of in vivo and in vitro studies, we investigated mechanisms via which alpha-tocopherol, a lipid soluble form of vitamin E, can directly affect endothelial activation as induced by H(2)O(2) and TNFalpha. METHODS: We measured effects of alpha-tocopherol on H(2)O(2)-induced lipid peroxidation as determined with a fluorescent C-11 BODIPY(581/591) probe and on adhesion molecule expression in cultured endothelial cells. In 20 healthy volunteers treated with increasing doses of alpha-tocopherol up to 800 IU/ml for 12 weeks, plasma levels of soluble cell adhesion molecules (sCAMs) and C-reactive protein were measured. RESULTS: We showed that alpha-tocopherol protects cultured endothelial cells against H(2)O(2)-induced lipid peroxidation, while TNFalpha did not induce lipid peroxidation. Moreover, alpha-tocopherol attenuated H(2)O(2)-, but not TNFalpha-induced increases in adhesion molecule expression. In healthy persons, alpha-tocopherol decreased plasma levels of sE-selectin from 65+/-6 to 60+/-6 ng/ml (P=0.002), sVCAM from 893+/-31 to 853+/-23 ng/ml (P=0.022), and sICAM from 483+/-21 to 463+/-16 ng/ml (P=0.048). C-Reactive protein, as a sensitive marker of low grade inflammation, was not significantly affected. CONCLUSION: alpha-Tocopherol specifically inhibits lipid peroxidation-induced endothelial activation in vitro. The observed vitamin E-induced decrease in sCAMs in control subjects suggests that lipid peroxidation can take place in healthy individuals. Although vitamin E supplementation may be especially effective in specific groups of patients exposed to increased oxidative stress, our study suggests that vitamin E supplementation can be of benefit in healthy individuals as well.     

Soluble adhesion molecules in healthy subjects: a dose-response study using n-3 fatty acids

BACKGROUND AND AIM: Long-chain n-3 polyunsaturated fatty acids (PUFA) may protect against atherosclerotic disease, and serum levels of soluble cellular adhesion molecules (sCAMs) possibly reflect the inflammatory process underlying atherosclerosis. We studied the effect of n-3 PUFA dietary supplementation on the serum levels of sP-selectin, soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular adhesion molecule-1 (sVCAM-1), and the correlation between sCAMs and the fatty acid composition of granulocyte membranes. METHODS AND RESULTS: Sixty healthy volunteers were randomly assigned to receive a daily supplement of n-3 PUFA 6.6 g, n-3 PUFA 2.0 g, or olive oil for 12 weeks in a double blind design. A significant negative correlation was found between serum sICAM-1 levels and the DHA content of granulocyte membranes at entry. After supplementation with 6.6 g of n-3 PUFA, there was a significant decrease only in sP-selectin, which a gender subanalysis showed to be more marked in men. Among the women, there was a significant decrease in sICAM-1 in the PUFA 2.0 g group and a significant increase in sVCAM-1 in the PUFA 6.6 g group. CONCLUSIONS: The results indicate that high-dose supplementation with n-3 PUFA decreases sP-selectin levels in healthy subjects, thus suggesting a decrease in platelet reactivity or endothelial activation. However, the effect of n-3 PUFA on sCAMs is complex and may depend on gender and n-3 PUFA dose.     

Inverse association between pulmonary function and C-reactive protein in apparently healthy subjects

RATIONALE: Increased levels of systemic markers of inflammation have been reported in patients with impaired lung function due to obstructive or restrictive lung disease. OBJECTIVE: We tested the hypothesis that a decline in lung function within the normal range may be associated with a systemic subclinical inflammation. METHODS: Pulmonary function tests, cardiorespiratory fitness, components of the metabolic syndrome, and high-sensitivity C-reactive protein (CRP) were determined in 1,131 subjects without known pulmonary disease. MEASUREMENTS AND MAIN RESULTS: Ninety-six of the study participants (8.5%) had FEV(1) of less than 80% of predicted values. There was a strong inverse association between CRP levels and quartiles of FEV(1). The median CRP levels in nonsmoking participants were 2.5, 1.8, 1.7, and 1.3 mg/L in the first, second, third, and forth FEV(1) quartiles, respectively (p < 0.0001). A similar inverse association was present in smoking subjects (median CRP levels were 3.8, 2.3, 2.0, and 1.9 mg/L in the first, second, third, and fourth FEV(1) quartiles, respectively; p < 0.0001). These associations remained highly significant after adjustment for age, sex, components of the metabolic syndrome, and fitness level (p = 0.0005). CONCLUSIONS: An inverse linear relationship exists between CRP concentrations and measures of pulmonary function in subjects without pulmonary disease and in never-smokers. These results indicate that systemic inflammation may be linked to early perturbations of pulmonary function.     

Flow-mediated vasoactivity and circulating adhesion molecules in hypertriglyceridemia: association with small, dense LDL cholesterol particles

BACKGROUND: Endothelial dysfunction is considered one of the earliest events in the process of atherosclerosis, and an impaired vasodilatory response has been reported in patients with dyslipidemias. However, the independent association between hypertriglyceridemia and endothelial dysfunction is controversial, and the relation between endothelium-dependent vasodilation and circulating cell adhesion molecules as markers of endothelial dysfunction has not been fully determined. METHODS: Brachial artery flow mediated vasodilation (FMV) and the soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) were determined after overnight fasting in 16 men with hypertriglyceridemia (age 33 +/- 6 years) and in 16 age-matched healthy men with normal triglycerides and cholesterol. Subjects who smoked and those with known cardiovascular disease, diabetes, hypertension, recent or active infections, or any other disease that could affect leukocyte activation were excluded from the study. RESULTS: Compared with normal subjects, subjects with hypertriglyceridemia showed a higher level of sVCAM-1 and sICAM-1 (both P <.001), a reduced FMV (P <.01), and a smaller LDL particle size (P <.05). FMV had a significant inverse correlation with sVCAM-1 (r = -0.61, P <.001) and sICAM-1 (r = -0.38, P <.03). LDL particle size had a strong, direct association with FMV (r = 0.75, P <.001) and an inverse association with adhesion molecules. By multiple regression analysis, triglycerides (P <.001) and small LDL particle size (P <.002) predicted a reduced FMV. CONCLUSIONS: Serum level of cell adhesion molecules is increased and FMV is impaired in young healthy men with hypertriglyceridemia compared with age-matched men with normal lipid levels. Small, dense LDL particles may play a role in determining endothelial dysfunction in these subjects.     

Lack of association between intercellular adhesion molecule-1 gene polymorphisms and giant cell arteritis

OBJECTIVE: Studies have shown an association between HLA-DRB1*04 and giant cell arteritis (GCA). Intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms were reported to contribute susceptibility to GCA in Italian patients where susceptibility to GCA is not associated with HLA-DRB1*04 alleles. ICAM-1 is also highly expressed within inflammatory infiltrates of the blood vessels of GCA patients. To investigate the clinical implications of ICAM-1 polymorphisms in GCA, we examined their potential association and influence in the development of visual ischemic complications in a series of patients with GCA from Northwest Spain where GCA susceptibility is associated with HLA-DRB1*04. METHODS: Fifty-eight biopsy proven GCA and 129 ethnically matched controls were studied. Patients and controls were genotyped for ICAM-1 polymorphism at codons 241 and 469 by PCR-RFLP. RESULTS: The distribution of the alleles and genotypes for each ICAM- polymorphism did not show significant differences between GCA patients and controls. Although visual manifestations were significantly more likely to occur in men than women (OR 5.2, p = 0.018), allele and genotype frequencies of ICAM-1 polymorphisms in patients with GCA were not associated with development of visual complications or anemia. Visual complications in GCA were primarily associated with carriage of an HLA-DRB1*04 allele. No evidence was found for interaction between HLA-DRB1*04 and ICAM-1 polymorphism. CONCLUSION: ICAM-1 polymorphisms are not genetic risk factors for the susceptibility and severity of GCA in Northwest Spain.     

糖尿病患者循环内皮细胞的变化及其与微血管病变的关系

目的探讨糖尿病（ＤＭ）患者血管内皮细胞（ＶＥＣ）损伤及其与微血管病变的关系。方法测定６０例ＤＭ患者及３０例正常人外周血循环内皮细胞（ＣＥＣ）数。结果ＤＭ患者ＣＥＣ数明显高于正常人，伴微血管病变者增高更明显。ＣＥＣ数与糖化血红蛋白水平呈显著正相关。结论ＤＭ患者存在明显的ＶＥＣ损伤，其在糖尿病微血管病变发病机制中有重要作用。