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Poor coronary collateral circulation is associated with higher concentrations of soluble adhesion molecules in patients with single-vessel disease
Abstract
As the endothelium and inflammatory cells play a crucial role in the development of collaterals after a sudden or slowly progressing stenosis of coronary arteries, the levels of soluble endothelial adhesion molecules (CAMs) including vascular cell adhesion molecule (VCAM-1) intercellular adhesion molecule-1 (ICAM-1) and E-selectin were compared between patients with poor coronary collaterals and patients with well-developed collaterals.
In the study, 97 non-diabetic subjects with single-vessel disease were included. Collateral supply to the stenotic coronary artery was determined by angiographic grading system of 0-3 (Rentrop et al. J Am Coll Cardiol 1985; 5:587-592). Serum levels of adhesion molecules were measured by enzyme-linked immunosorbent assay.
Patients were divided into two groups according to the collateral degree (group A: 50 patients with grade 0 and 1; group B: 47 patients with grade 2 and 3 collaterals). The groups were well matched with respect to baseline clinical and angiographic characteristics. Levels of soluble VCAM-1 (mean+/-SEM; 875+/-26.6 versus 742.7+/-35.1 ng/ml; P=0.004), ICAM-1 (322.4+/-12.4 versus 269.4+/-13.3 ng/ml; P=0.005), and E-selectin (43.6+/-2.6 versus 33+/-2.4 ng/ml; P=0.004) were found to be significantly higher in group A in comparison with group B. In addition, when patients were divided into four groups according to the collateral degree, patients with grade 0 collaterals had the highest values and those with grade 3 collaterals had the lowest values for all these molecules.
We concluded that poor collateral circulation is associated with increased levels of soluble CAMs in patients with obstructive coronary artery disease. However, further studies are needed to elucidate the exact role of these inflammatory markers in the setting of poor collateral circulation.
... We found that old age, female gender, traditional risk factors for coronary artery disease, and reduced renal function were associated with poor collateralization, whereas hypertension, especially elevated diastolic blood pressure, correlated with well-formed coronary collaterals. Several studies have suggested that poorly developed coronary collaterals may be related to chronic inflammation of low degree, as evidenced by elevated serum levels of cytokines such as hsCRP [28], tumor necrosis factor (TNF)-α [29], soluble endothelial adhesion molecules [30], monocyte chemoattractant protein-1 [31], and C1q/TNF-related protein-1 [8], which inhibit key components of angiogenesis particularly endothelial progenitor cell differentiation, survival and function. Recently, apelin has been shown to promote angiogenesis, and its serum levels were associated with coronary collateral development [32]. ...
... Nevertheless, these results may reflect true associations in the real world setting as prescription data were captured from a standard database. Another limitation is that our study did not include other possible factors influencing collateral development in patients with coronary artery disease especially inflammatory cytokines [8][9][10][11][12][28][29][30][31], although the effects of the established clinical variables were evaluated by multivariate analysis. The relative strength of a model by incorporating all potential biomarkers for predicting poor coronary collateralization deserves further investigations. ...
Objective:
We investigated whether and to what extent cystatin C was associated with angiographic coronary collateralization in patients with stable coronary artery disease and chronic total occlusion.
Methods:
Serum levels of cystatin C and high-sensitive C-reactive protein (hsCRP) and glomerular filtration rate (GFR) were determined in 866 patients with stable angina and angiographic total occlusion of at least one major coronary artery. The degree of collaterals supplying the distal aspect of a total occlusion from the contra-lateral vessel was graded as poor (Rentrop score of 0 or 1) or good coronary collateralization (Rentrop score of 2 or 3).
Results:
In total, serum cystatin C was higher in patients with poor collateralization than in those with good collateralization (1.08 ± 0.32 mg/L vs. 0.90 ± 0.34 mg/L, P < 0.001), and correlated inversely with Rentrop score (adjusted Spearmen's r = -0.145, P < 0.001). The prevalence of poor coronary collateralization increased stepwise with increasing cystatin C quartiles (P for trend < 0.001). After adjusting for age, gender, risk factors for coronary artery disease, GFR and hsCRP, serum cystatin C ≥ 0.97 mg/L remained independently associated with poor collateralization (OR 2.374, 95% CI 1.660 ~ 3.396, P < 0.001). The diagnostic value of cystatin C levels for detecting poor coronary collateralization persisted regardless of age, gender, presence or absence of diabetes, hypertension or renal dysfunction.
Conclusions:
Serum cystatin C reflects angiographic coronary collateralization in patients with stable coronary artery disease, and cystatin C ≥ 0.97 mg/L indicates a great risk of poor coronary collaterals.
... Atherosclerosis in obesity, the metabolic syndrome, and T2DM is initiated by damage/activation of the endothelium. [14][15][16] Plasma ICAM, VCAM, and ET-1 levels are reliable markers of endothelial dysfunction that predict future CVD and are elevated in obese children 17,18 and adults [19][20][21][22][23][24][25][26][27] and in patients with hypertension, 3 chronic renal disease, 28 and T2DM. 2,7,[29][30][31][32] Lean FH + patients are insulin-resistant and at increased risk for T2DM and CVD. ...
... Although fasting plasma VCAM and ICAM levels showed a modest inverse correlation with insulin sensitivity, both groups had similar baseline ICAM-1 and VCAM-1 levels, indicating that preexisting severe insulin resistance (as observed in the FH + group) per se is not sufficient to increase markers of endothelial activation in the absence of obesity. In the literature, obesity and the metabolic syndrome are common denominators for the elevation in plasma sCAM concentrations in children 17,18 and adults in different settings, [19][20][21][22][23][24] such as hypertension, 3 chronic renal disease, 28 and T2DM. 2,7,29,30 This also appears to be the case even in insulin-resistant individuals with a family history of T2DM. ...
Elevated plasma triglyceride/free fatty acid (FFA) levels and insulin resistance may promote atherosclerosis through endothelial activation (ie, increased expression of intercellular adhesion molecule 1 [ICAM-1]/vascular adhesion molecule 1 [VCAM-1], and endothelin-1 [ET-1]) in patients with the metabolic syndrome, but this has never been directly tested. The authors measured endothelial activation and insulin sensitivity (euglycemic insulin clamp with [3-(3)H]-glucose) after a 4-day low-dose lipid infusion that elevated plasma FFA to levels observed in the metabolic syndrome in 20 lean, non-diabetic insulin-resistant subjects with a strong family history of type 2 diabetes mellitus (FH(+)) and 10 insulin-sensitive volunteers without a family history of type 2 diabetes mellitus (FH(-)). Low-dose lipid infusion reduced insulin sensitivity by approximately 25% in insulin-sensitive FH(-)controls but did not worsen preexisting insulin resistance in FH(+). Low-dose lipid infusion elevated plasma ICAM and VCAM levels similarly in both groups (approximately 12%-18%; P<.01 vs baseline), while plasma ET-1 levels increased more in FH(+)vs FH(-)(46% vs 10%; P=.005). Increased plasma FFA levels closely correlated with elevated ICAM (r=0.60; P<.01), VCAM, and ET-1 levels (r=0.39 and r=0.42, respectively; P<.05). Low-dose lipid infusion induces endothelial activation in both lean insulin-resistant (FH(+)) and insulin-sensitive (FH(-)) healthy patients, regardless of changes in insulin sensitivity. These results prove that even a modest lipid oversupply may be sufficient to trigger a deleterious endothelial response.
... Drugs (nitrate, calcium channel blockers, statin), endothelial dysfunction and the coronary vasomotor tone are important in CCC formation. In addition, it is known that high levels of sensitive C-reactive protein (CRP), lipoprotein (a), adhesion molecules (e.g., vascular adhesion molecule-1), intercellular adhesion molecule-1, various serum markers (e.g., E-selectin and tumor necrosis factor-a), and antioxidant capacity are associated with the degree of CCC development [5][6][7][8][9][10][11][12][13]. ...
Our aim was to investigate the relationship between thiol, which is the main component of the antioxidant system, and coronary collateral circulation (CCC). Our patients consisted of people with stable coronary artery disease (sCAD) and total occlusion in at least one vessel (n = 249). We divided the patients into two groups, good and poor, according to their CCC degree. We determined that DM, total thiol, and disulfide are independent predictors of poor CCC in multivariate logistic regression analysis (OR: 1.012, 95% CI: 1.008–1.017, p < 0.001; OR: 1.022, 95% CI: 1.000–1.044, p = 0.044; OR: 2.671, 95% CI: 1.238–5.761, p = 0.012, respectively). The ROC analysis showed a cut-off value of 328.7 for native thiol regarding the prediction of poor CCC, with 67.4% specificity and 78% sensitivity. For disulfide, it revealed a cut-off value of 15.1 regarding the prediction of poor CCC, with 57.9% specificity and 69.5% sensitivity. In this study, we detected that the patients with sCAD who developed poor CCC had lower levels of native thiol, total thiol, and disulfide compared to those with good CCC. The most interesting finding of our study is that CCC formation is an effective predictor of the antioxidant cascade rather than the inflammation cascade in sCAD patients.
... Despite the severity of coronary stenosis, duration of angina has a positive effect for developing CCC and a marked variety of collateral vessel development exists between similar stenosis [14,15] . Increased concentrations of tumor necrosis factor (TNF)-alfa, interleukin-6, soluble adhesion molecules, and high-sensitivity C-reactive protein (hs-CRP) were found to be related to poor CCC [16][17][18][19][20] . Alteration of white blood cells and differentials was associated with the inflammatory condition, and a relationship with cardiovascular disease has been demonstrated [21,22] . ...
... This finding is compatible with the literature. In addition, there are publications indicating that the inflammatory markers tumor necrosis factor alpha and soluble adhesion molecules negatively affect coronary collateral circulation [29,30]. ...
Objective Non high density lipoprotein cholesterol (non HDL-C) covers all aterojenic lipoproteins and correlates with C reactive protein (CRP) which is reliable marker of inflammation. CRP is related to poor angiographic coronary collateral circulation (CCC). We aimed to show whether non HDL-C is associated with CCC.
Methods Patients who underwent coronary angiography for stable coronary artery disease and at least one epicardial coronary artery occluded in the proximal or middle region were included in the study. Accrording to the Rentrop scoring system Rentrop 0 and 1 were considered to be poor CCC, and Rentrop 2 and 3 were considered to be good CCC. Non-HDL-C was calculated by subtracting HDL-C from total cholesterol (TC).
Results 84 patients were included in the study. While 44 patients (52%) had good CCC, 40 patients (48%) had poor CCC. TC was found to be higher in the poor CCC group than in the good CCC group (224.3 ± 35.6 vs 179.2 ± 25.5 p = 0.000). HDL-C levels were found to be lower in the poor CCC group than in the good CCC group (37.3 ± 9.8 vs 44.1 ± 8.6 p = 0.001). Non-HDL-C cholesterol levels were higher in the group with poor CCC (185.7 ± 39.2 vs 132.8 ± 28.1 p = 0.000). CRP levels were found to be higher in the poor CCC group (3.73 ± 2.5 vs 1.67 ± 1.4 p = 0,000).
Conclusion Non-HDL-C is independent predictors of poor CCC.
... In the original risk model, presence of diabetes mellitus, elevated WBC and neutrophil counts and NLR on admission were independent predictors of poor CCC in patients with acute NSTEMI, whereas older age emerged as a negative indicator. Previous data have clearly shown that poor collateralization in coronary artery disease was related to a low grade inflammation [6][7][8][9]. White blood cells and its subtypes play a major role in modulating this inflammatory response. In the case of acute infarction, leukocytosis is a common finding that reflects the infiltration of WBCs into damaged tissue in response to ischemia and reperfusion. ...
... We also found increased serum VCAM-1 levels in the well-developed coronary collateral group. Interestingly, our result for serum VCAM-1 levels was different from a previous study by Guray et al. [23] The authors found increased VCAM-1 levels in patients with poor coronary collateral circulation. However, they were unable to provide a clear explanation for this result, but speculated Table 4 Backward stepwise logistic regression analysis to predict independent variables for good collateral development disease who had at least one totally occluded coronary artery. ...
Angiogenesis and arteriogenesis have a crucial role in the formation of coronary collateral vessels. It has been shown that endocan and vascular cell adhesion molecule-1 (VCAM-1) are potential angiogenetic factors. We investigated the relationship between serum endocan levels and grade of coronary collaterals, and also the correlation of endocan levels with serum VCAM-1 levels. Patients with stable angina and at least one total coronary occlusion at invasive coronary angiography were included in our study. Collateral degree was graded according to Rentrop and Cohen’s classification. Patients who had grade 0 or 1 collateral vessels were included in the poorly-developed collateral group, and those with grade 2 or 3 coronary collateral vessels were included in the well-developed collateral group. Serum endocan and VCAM-1 levels were significantly higher in the well-developed collateral group (436.6 ± 213.3 ng/mL vs. 216.1 ± 78.5 ng/mL, p < .001; 11.02 ± 6.58 ng/mL vs. 6.78 ± 1.14 ng/mL, p < .001, respectively). In a logistic regression analysis, only serum endocan level remained as an independent predictor for good collateral development. In the ROC curve analysis, 282 ng/mL endocan level had an a 82 % sensitivity and 86 % specificity for prediction of the well-developed collateral group. Higher endocan level was related to better coronary collateral development. In the event that these results are confirmed in further studies, endocan may be considered as an anti-ischemic treatment strategy in order to improve collateral development.
... Acute-phase reactants and inflammatory cytokines such as tumor necrosis factor-a and interleukin-6 have been found to be the predictors of insufficient coronary collaterals [11]. Some investigators also reported an association between poorly developed collateral vessels and an elevated concentration of soluble adhesion molecules [12]. These data have clearly demonstrated that increased inflammatory activity was associated with poor collateralization. ...
Background: We aimed to investigate the clinical features associated with development of coronary collateral circulation (CCC) in patients with acute non-ST elevation myocardial infarction (NSTEMI) and to develop a scoring model for predicting poor collateralization at hospital admission.
Methods: The study enrolled 224 consecutive patients with NSTEMI admitted to our coronary care unit. Patients were divided into poor (grade 0 and 1) and good (grade 2 and 3) CCC groups.
Results: In logistic regression analysis, presence of diabetes mellitus, total white blood cell (WBC) and neutrophil counts and neutrophil to lymphocyte ratio (NLR) were found as independent positive predictors of poor CCC, whereas older age (≥70 years) emerged as a negative indicator. The final scoring model was based on five variables which were significant at P˂0.05 level following multivariate analysis. Presence of diabetes mellitus, and elevated total WBC (≥7.85 X10³/µL ) and neutrophil counts (≥6.25 X10³/ µL) were assigned with 2 points; high NLR (≥4.5) with 1 point and older age (≥70 years old) with -1 point. Among 30 patients with risk score ≤1, 29 had good CCC (with a %97 negative predictive value). On the other hand, 139 patients had risk score ≥4; out of whom, 130 (with a % 93.5 positive predictive value) had poor collateralization. Sensitivity and specificity of the model in predicting poor collateralization in patients with scores ≤1 and ≥4 were %99.2 (130/131) and +76.3 (29/38), respectively.
Conclusions: This study represents the first prediction model for degree of coronary collateralization in patients with acute NSTEMI.
... These findings are in line with previous reports emphasizing the relation between inflammation and development of coronary collaterals. [34][35][36] Since there was no significant difference in the cardiovascular risk profiles (eg, diabetes and blood cholesterol levels) between the 2 subgroups, the present study may suggest that the subclinical inflammation rather than other metabolic factors may be the dominant characteristic leading to poor collateral development. In the subgroup analysis, we showed that the effect of PLR on coronary collateral development was independent of platelet or lymphocyte counts alone. ...
Objectives
We aimed to investigate the relationship between the platelet-lymphocyte ratio (PLR) and coronary collateral circulation (CCC) in patients with stable angina pectoris (SAP) and chronic total occlusion (CTO).
Methods
A total of 294 patients with both SAP and CTO were classified according to their Rentrop collateral grades as either poor (Rentrop grades/0-1) or good (Rentrop grades/2-3).
Results
The PLR values were significantly higher in patients with poor CCC than in those with good CCC (156.8 + 30.7 vs 132.1 + 24.4, P < 0.001). In regression analysis, PLR (unit = 10) [odds ratio 1.48, 95% confidence interval (CI) 1.33 -1.65; P < 0.001] and high-sensitivity C-reactive protein were found to be the independent predictors of poor CCC. In receiver operator characteristic curve analysis, optimal cut-off value of PLR to predict poor CCC was found as 138.1, with 76% sensitivity and 65% specificity.
Conclusion
PLR may be an important, simple, and cost effective tool predicting the degree of collateralization in patients with SAP and CTO.
... Seiler (2010) demonstrated that tumor necrosis factor-α was detectable more often in patients with insufficient coronary collateral. Guray et al. (2004) reported an association between poor collateral circulation and an elevated concentration of soluble adhesion molecules, a marker of cytokine-induced endothelial activation. ...
Objective:
Coronary collateral circulation is an alternative source of blood supply to myocardium in the presence of advanced coronary artery disease. We sought to determine which clinical and angiographic variables are associated with collateral development in patients with stable angina and chronic total coronary occlusion.
Methods:
Demographic variables, biochemical measurements, and angiographic findings were collected from 478 patients with stable angina and chronic total coronary occlusion. The presence and extent of collaterals supplying the distal aspect of a total coronary occlusion from the contra-lateral vessel were graded from 0 to 3 according to the Rentrop scoring system.
Results:
Low (Rentrop score of 0 or 1) and high (Rentrop score of 2 or 3) coronary collateralizations were detected in 186 and 292 patients, respectively. Despite similar age, cigarette smoking, and medical treatment, patients with low collateralization were female in a higher proportion and less hypertensive, and had higher rates of type 2 diabetes and dyslipidemia than those with high collateralization (for all comparisons, P<0.05). In addition, patients with low collateralization exhibited more single-vessel disease, less right coronary artery occlusion, more impaired renal function, and higher serum levels of high-sensitivity C-reactive protein (hsCRP) compared with those with high collateralization. Multivariate analysis revealed that age of ≥65 years, female gender, diabetes, no history of hypertension, dyslipidemia, moderate to severe renal dysfunction, single-vessel disease, and elevated hsCRP levels were independently associated with low coronary collateralization.
Conclusions:
Coronary collateralization was reduced in almost 40% of stable angina patients with chronic total occlusion, which was related to clinical and angiographic factors. The impact of coronary collateralization on outcomes after revascularization needs further investigation.
... In a recent study by Guray et al, a negative correlation was found between the coronary collateral development and inflammation. 9 On the other hand, Yilmaz et al demonstrated that metabolic syndrome is associated with poor coronary collaterals in patients with occluded right coronary artery. 10 In the Kadi et al study, 1 although coronary collateral circulation was evaluated noninvasively, mildly decreased GFR was found to impair the coronary collateral circulation in patients with coronary artery disease. ...
... Several serum markers such as high sensitive C-reactive protein [9], lipoprotein (a), [10], adhesion molecules like vascular adhesion molecule-1, intercellular adhesion molecule-1 and E-selectin [11], tumor necrosis factor-a [12] and, total antioxidant capacity [13] have been reported to be associated with the degree of collateral development as well. ...
Paraoxonase is a high-density lipoprotein-bound antioxidant enzyme that inhibits atherosclerosis and endothelial dysfunction. Coronary collateral flow is a crucial clinical entity with significant impact on the cardiovascular morbidity and mortality. This study sought to determine the relationship between the degree of angiographically visible coronary collateral circulation and serum paraoxonase activity.
The study population included 98 patients (mean age=57.9+/-10.1 years, 65 men) with angiographically documented total occlusion in one of the major coronary arteries. Development of collaterals was classified by Rentrop's method. Patients were defined as having poorly developed collaterals for Rentrop grades 0 and 1 or well-developed collaterals for Rentrop grades 2 and 3. Serum paraoxonase and arylesterase activities were measured spectrophotometrically.
Statistically significant differences between well and poorly developed collateral groups in respect to serum low-density lipoprotein cholesterol level (P=0.046), and serum paraoxonase (P=0.001), and arylesterase (P=0.014) activities were present. Serum low-density lipoprotein cholesterol level (chi=4.15, beta=-0.347, P=0.032) and serum paraoxonase activity (chi=10.43, beta=0.008, P=0.022) were independent predictors of well-developed coronary collateral flow. Serum paraoxonase activity gradually increased from collateral grade 0 to collateral grade 3 (analysis of variance P=0.003). Serum paraoxonase (r=0.362 and P<0.001) and arylesterase (r=0.245 and P=0.015) activities were both correlated with collateral flow grade.
Findings of this study suggest that serum paraoxonase activity is independently associated with the degree of coronary collateral flow and reduced serum paraoxonase activity might represent a biochemical marker of impaired coronary collateral flow.
Aim:
Inflammation plays an important role in development of coronary collateral circulation (CCC). The aim of this study is to determine whether the inflammation-related miRNA miR-155 and the inflammation marker VCAM-1 could be a biomarker for CCC.
Patients & methods:
We measured levels of plasma VCAM-1 and miR-155 in patients with CCC according to Rentrop grade by ELISA or real-time polymerase chain reaction, respectively (n = 112).
Results:
Plasma miR-155 was negatively correlated with VCAM-1 in the poor CCC group and with Rentrop grade in all patients with CCC. In addition, plasma VCAM-1 was significantly decreased in CAD patients with CCC.
Conclusion:
Plasma miR-155 might be a potent independent predictor of collateral formation.
Objectives: In the presence of a chronically occluded coronary artery, the collateral circulation matures by a process of arteriogenesis; however, there is considerable variation between individuals in the functional capacity of that collateral network. This could be explained by differences in endothelial health and function. We aimed to examine the relationship between the functional extent of collateralization and levels of biomarkers that have been shown to relate to endothelial health. Methods: We measured four potential biomarkers of endothelial health in 34 patients with mature collateral networks who underwent a successful percutaneous coronary intervention (PCI) for a chronic total coronary occlusion (CTO) before PCI and 6-8 weeks after PCI, and examined the relationship of biomarker levels with physiological measures of collateralization. Results: We did not find a significant change in the systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor 6-8 weeks after PCI. We did find an association between estimated retrograde collateral flow before CTO recanalization and lower levels of sICAM-1 (r=0.39, P=0.026), sE-selectin (r=0.48, P=0.005) and microparticles (r=0.38, P=0.03). Conclusion: Recanalization of a CTO and resultant regression of a mature collateral circulation do not alter systemic levels of sICAM-1, sE-selectin, microparticles or tissue factor. The identified relationship of retrograde collateral flow with sICAM-1, sE-selectin and microparticles is likely to represent an association with an ability to develop collaterals rather than their presence and extent. Copyright
The heterogeneity in the degree of collateralization among patients with coronary artery disease (CAD) remains incompletely understood. We evaluated the predictors of poorly developed coronary collateral circulation (CCC) in patients with stable coronary artery disease.
Current study is a retrospective study, consisting of 118 patients with poor CCC and 130 patients with good CCC. We investigated predictors of poor coronary collaterals in a cohort of 248 patients who had high-grade coronary stenosis or occlusion on their angiograms. To classify CCC, we used the Rentrop classification.
Patients with poorly developed CCC had significantly higher neutrophil-to-lymphocyte ratio (N/L) compared with those with well-developed CCC, (4.2±2.8 vs. 3±3.1, p=0.001), whereas mean platelet volume, red cell distribution width and uric acid were not significantly different. Logistic regression analysis showed that N/L ratio (odds ratio 1.199, 95% confidence interval 1.045-1.375) and serum triglyceride levels [odds ratio (OR)=1.006, 95% confidence interval (CI)=1.001-1.010] were independent predictors of poorly developed CCC.
An elevated level of N/L ratio is independently associated with a significant impairment in coronary collateralization. Our findings suggest that N/L ratio is an inexpensive, universally available hematological marker for sufficiency of CCC in patients with stable coronary artery disease.
Objectives:Previous studies showed the association between the major adverse cardiovascular outcomes and both higher neutrophil and lower lymphocyte counts. We aimed to investigate whether there is an association between the neutrophil-lymphocyte ratio (NLR) value and the development of coronary collateral circulation (CCC) in patients with coronary chronic total occlusion (CTO).
A total of 274 patients with CTO were included in this study. Patients were then classified according to their Rentrop collateral grades as either poor (Rentrop grades 0-1) or good (Rentrop grades 2-3). Clinical information and analyses of blood samples were obtained from a review of the patients' charts.
Although there was no difference between the two groups with regard to cardiovascular risk profiles, the NLR values were significantly higher in the patients who had poorly developed CCC (2.6 ± 0.5 vs 2.2 ± 0.4, p<0.001). NLR, high-sensitivity C-reactive protein (hs-CRP), white blood cell count (WBC), age, diabetes, fasting glucose levels and body mass index were found to have univariate association with poorly developed CCC (p<0.1). In a multivariate logistic regression model, NLR (odds ratio 1.88, 95% confidence interval (CI) 1.37-2.74; p<0.001), high-sensitivity C-reactive protein and WBC were found to be the independent predictors of poor CCC. In receiver operator characteristic curve analysis, the optimal cut-off value of NLR to predict poor CCC was found as 2.17, with 77% sensitivity and 65% specificity.
NLR, as a novel cardiovascular risk marker, is an important, simple and inexpensive method which can be used by the cardiologist as a screening inflammation tool to estimate the development of CCC in patients with CTO.
Platelets are important in the pathogenesis of atherosclerotic complications. Higher mean platelet volume (MPV) levels are related to greater in vitro aggregation, and have been identified as an independent risk factor for myocardial infarction, and for death or recurrent vascular events.
To determine the relationship between MPV and the coronary collateral circulation.
The sample consisted of 96 patients with coronary artery disease, and patients were separated into two groups according to their poorly developed or well-developed collateral circulation. Coronary collateral vessels were analyzed according to the Cohen and Rentrop grading system of 0-3.
All analyses were conducted using SPSS 11.5 (SPSS for Windows 11.5, Chicago, IL, USA). Continuous variables were expressed as mean ± SD, and categorical variables were expressed as percentages. Comparison of categorical and continuous variables between the group with well-developed coronary collateral vessels and the group with poorly developed vessels was performed using the chi-squared test and independent samples t-test, respectively. Platelet count and MPV values were similar between the two groups.
Our study found that MPV levels are not related to coronary collateral circulation.
The heterogeneity in the degree of collateralization among patients with coronary artery disease (CAD) is poorly understood. We sought to determine whether chronic subclinical inflammation is related to coronary collateral development in patients with chronic stable angina pectoris and obstructive CAD. High-sensitivity C-reactive protein (CRP) levels were measured in 177 patients with stable angina pectoris before coronary angiography. Multivariable logistic regression revealed an inverse graded association between CRP and the presence of coronary collaterals (Rentrop grade 1 to 3). Compared with patients in the first CRP tertile, the adjusted odds ratio for the presence of coronary collaterals was 0.70 (95% confidence interval, 0.33 to 1.52; p = 0.45) for patients in the second CRP tertile and 0.33 (95% confidence interval, 0.15 to 0.75; p = 0.008) for patients in the third CRP tertile (p for trend = 0.008). In conclusion, an inverse graded association exists between CRP and the presence of coronary collaterals in patients with stable angina pectoris.
The focal distribution of atherosclerotic lesions in the arterial tree is related to the local shear stress generated by blood flow, but the molecular basis of the atherogenic response of endothelial cells in these lesion-prone areas is still unclear. We report that shear stress mediates a biphasic response of monocyte chemotactic protein 1 (MCP-1) gene expression in vascular endothelial cells (EC). Northern blot analysis indicated that the level of MCP-1 mRNA in human umbilical vein EC (HUVEC) subjected to a shear stress of 16 dynes/cm2 (1 dyne = 10 microN) for 1.5 hr increased by 2- to 3-fold when compared with static cells. The MCP-1 gene expression decreased to the basal level at 4 hr and then declined further to become completely quiescent at 5 hr after the onset of shear. Once the gene expression was fully suppressed, it remained quiescent even after static incubation for 1.5 hr and would not respond to reshearing after this static incubation. However, if the postshearing incubation extended from 1.5 to 24 hr, the MCP-1 mRNA returned to the basal level and was then able to increase after the reapplication of shear stress. Nuclear run-on experiments showed that the shear-induced increased MCP-1 mRNA in HUVEC was regulated at the transcriptional level. By using cycloheximide, it was shown that de novo protein synthesis was not necessary for the induction of MCP-1 by shear stress. The biphasic response of MCP-1 gene expression was found in experiments in which the applied shear stress was 6, 16, or 32 dynes/cm2, and it was observed not only in HUVEC but also in HeLa cells, glioma cell lines, and skin fibroblasts. This in vitro study demonstrates that the response of MCP-1 gene to shear stress represents an immediate early gene activation and suggests that this gene is probably suppressed in EC that have been exposed to a constant shear stress.
We have previously shown that monocytes adhere to the vascular wall during collateral vessel growth (arteriogenesis) and capillary sprouting (angiogenesis). In this study we investigated the association of monocyte accumulation with both the production of the cytokines-basic fibroblast growth factor (bFGF) and TNF-alpha-and vessel proliferation in the rabbit after femoral artery occlusion. In particular, we studied the effects of an increase in monocyte recruitment by LPS on capillary density as well as collateral and peripheral conductance after 7 d of occlusion. Monocytes accumulated around day 3 in collateral arteries when maximal proliferation was observed, and stained strongly for bFGF and TNF-alpha. In the lower limb where angiogenesis was shown to be predominant, macrophage accumulation was also closely associated with maximal proliferation (around day 7). LPS treatment significantly increased capillary density (424+/-26.1 n/mm2 vs. 312+/-20.7 n/mm2; P < 0.05) and peripheral conductance (109+/-33.8 ml/min/100 mmHg vs. 45+/-6.8 ml/min/100 mmHg; P < 0.05) as compared with untreated animals after 7 d of occlusion. These results indicate that monocyte activation plays a major role in angiogenesis and collateral artery growth.
To investigate the metabolic and genetic associations of levels of soluble adhesion molecules, plasma levels of soluble E-selectin and vascular cell adhesion molecule-1 were measured in 60 non-insulin-dependent diabetes mellitus (NIDDM) patients, 60 first-degree relatives of NIDDM patients and 60 control subjects, none of whom displayed clinical features of vascular disease. In addition, E-selectin A561C genotype, coding for a serine to arginine change, was determined. E-selectin levels were elevated in the patient group; 57 [52-63] (mean [95% confidence intervals]) ng/ml, compared with both relatives; 44 [39-50] ng/ml p = 0.001 and controls 39.5 [36-43] ng/ml p = 0.0001. E-selectin levels correlated with triglycerides, tissue-plasminogen activator and plasminogen activator inhibitor-1 activity in all groups. Levels of E-selectin were related to E-selectin genotype, being higher in subjects possessing the arginine allele (51.4 vs 44.5 ng/ml p < 0.05). E-selectin levels were higher in males than females in controls (female 35 [32-39] vs male 45 [40-51] ng/ml p = 0.004), and NIDDM relatives (female 38 [33-44] vs male 52 [45-61] ng/ml p = 0.004) but not in NIDDM patients where levels were similar (female 58 [49-69] vs male 56 [50-62] ng/ml, ns). There was no difference in soluble vascular cell adhesion molecule-1 levels between the three groups (control 640 [598-686] ng/ml, NIDDM relatives 634 [593-678] ng/ml and NIDDM patients 664 [608-725] ng/ml). In controls and patients vascular cell adhesion molecule-1 levels correlated with von Willebrand factor (vWF). The results indicate that levels of E-selectin relate to vascular risk factors in control subjects, NIDDM relatives and NIDDM patients.
Increased expression of tumour necrosis factor α (TNFα) has been found in cardiac tissue of patients with chronic heart failure, and the failing heart has been suggested as the cause of immune activation.1
Another, less frequently reported facet of the macrophage derived mediator TNFα is its function as an angiogenic factor2 which may be induced by myocardial ischaemia. This pleiotropic cytokine appears to act also as an angioinhibitory factor depending on the concentration, location, and duration of its action.3 So far, there have been no studies in patients with coronary artery disease (CAD) investigating the relation between the potentially angiogenic TNFα and directly measured collateral flow, the latter representing a variable in the course of CAD with considerable impact on its outcome.
The purpose of this study was to test the hypothesis that there is an association between TNFα and collateral flow in patients with CAD and normal systolic ventricular function.
Low and oscillatory shear stresses are major features of the hemodynamic environment of sites opposite arterial flow dividers that are predisposed to atherosclerosis. Atherosclerosis is a focal inflammatory disease characterized initially by the recruitment of mononuclear cells into the arterial wall. The specific characteristics of the hemodynamic environment that facilitate the generation of arterial inflammatory responses in the presence of, for example, hyperlipidemia are unknown. We show here that prolonged oscillatory shear stress induces expression of endothelial cell leukocyte adhesion molecules, which are centrally important in mediating leukocyte localization into the arterial wall. Vascular cell adhesion molecule-1 was upregulated an average 9-fold relative to endothelial monolayers in static culture. Intercellular adhesion molecule-1 and E-selectin exhibited 11-fold and 7.5-fold increases, respectively. Upregulation of these adhesion molecules was associated with enhanced monocyte adherence. Cytokine stimulation of surface vascular cell adhesion molecule-1 was maximally induced after 6 and 8 hours of cytokine incubation. Oscillatory shear stress for these time periods elicited respective vascular cell adhesion molecule-1 levels of 16% and 30% relative to those observed for cytokine stimulation. Surface intercellular adhesion molecule-1 induction by cytokine stimulation for 24 hours was found to be approximately five times the level detected after 24 hours of oscillatory shear stress. Experiments performed in the presence of the antioxidant N-acetylcysteine demonstrated that the expression of vascular cell adhesion molecule-1 could be almost totally abolished, whereas that of intercellular adhesion molecule-1 was typically reduced by approximately 70%. These results imply that oscillatory shear stress per se is sufficient to stimulate mononuclear leukocyte adhesion and, presumptively, migration into the arterial wall. These results further indicate that atherosclerotic lesion initiation is likely related, at least in part, to unique signals generated by oscillatory shear stress and that the mechanism of upregulation is, to some extent, redox sensitive.
MICROVASCULAR proliferation is essential to many biological processes,
such as wound healing, but the mechanisms underlying this vascular
response are poorly understood1. Neovascularisation can be
induced by extracts from various cell types, including malignant solid
tumour cells2, normal and viral-transformed (SV40) BALB/c 3T3
cells, and diploid human embryonic lung fibroblasts3, and
neutrophils4. Extracts of mouse salivary gland5
and skin6 have been reported to induce vascular growth, but
the relevance of these observations to the vascular proliferation that
occurs in wound healing and chronic inflammation is unclear.
Neovascularisation is also an important component of immunological
reactions. Sidky and Auerbach reported increased vessel density in the
skin during graft-versus-host reactions and attributed it to the
lymphocyte7. Herman and associates8 and Anderson
et al.9 found an increase in capillary density, and extensive
proliferation of postcapillary venular endothelium, respectively, in
lymph nodes undergoing strong immunological reactions. We have shown
significant endothelial proliferation in delayed hypersensitivity
reactions in the skin of guinea pigs at the time of maximal mononuclear
cell infiltration10 and so we have investigated whether
macrophages, an important component of immunological and
non-immunological inflammatory reactions, might be involved in this
vascular response. We report here that macrophages activated in vivo and
in vitro, and media conditioned by these cells, induce vascular
proliferation in the guinea pig cornea.
Soluble forms of the adhesion molecules ICAM-1, VCAM-1 and E-selectin have been detected in supernatants from cytokine activated cultured endothelial cells. The release has been quantified using two site enzyme immunoassays. The molecular weights of the released molecules have been determined by immunoprecipitation and are consistent with the generation of soluble forms by cleavage at a site close to the point of membrane insertion.
The influence of coronary collateral vessels on infarct size in humans remains controversial, partly because no previous study has examined the impact of collaterals present at the onset of acute myocardial infarction on infarct size.
The present study used the data base of the Thrombolysis in Myocardial Infarction (TIMI) Phase I trial to correlate the presence or absence of angiographically documented collaterals in the initial hours of myocardial infarct evolution with the size of the infarct as assessed by serial measurements of serum creatine kinase (CK). To avoid the confounding effects of reperfusion on enzymatic estimates of infarct size, this report is limited to those 125 patients who failed to recanalize at 90 minutes after administration of tissue plasminogen activator or streptokinase. Patients with angiographically documented collaterals (group A, n = 51) had significantly lower values of peak serum CK than patients without collaterals (group B, n = 74) (1,877 +/- 216 versus 2,661 +/- 212 IU/l, respectively [mean +/- SEM], p = 0.004). Similarly, CK-derived infarct size estimates were significantly lower in group A than in group B (20.6 +/- 2.5 versus 31.4 +/- 2.8 CK gram equivalents, p = 0.001). The infarct size observed in patients with collaterals was less for anterior infarctions as well as for infarctions of other locations; thus, the beneficial effects of collaterals were independent of the site of the infarct. In 65 of the 125 patients who failed to reperfuse, left ventricular ejection fraction (LVEF) was assessed by contrast ventriculography both at initial cardiac catheterization (before thrombolytic therapy) and at hospital discharge. Among the patients who had both studies, global LVEF tended to increase from pretreatment to hospital discharge in group A (from 50.6 +/- 1.8% to 53.4 +/- 1.8%, p = 0.10) but decreased in group B patients (from 50.3 +/- 1.8% to 47.8 +/- 1.7%, p = 0.02). At hospital discharge, global LVEF was greater in patients with coronary collaterals (53.5 +/- 1.7% versus 49.6 +/- 1.7%, p = 0.01).
The results demonstrate that, in patients in whom thrombolytic therapy fails to induce reperfusion, the presence of coronary collateral vessels at the onset of myocardial infarction is associated with limitation of infarct size as assessed enzymatically and with improved ventricular function on discharge as assessed by LVEF.
In vitro differentiation of human monocytes (Mo) provides large amounts of mature and functionally competent macrophages (M phi) which may be used as potentially powerful anticancer agents for adoptive immunotherapy. Granulocyte macrophage-colony stimulating factor (GM-CSF) was evaluated for its ability to influence long term cultures of Mo-derived M phi. Large quantities of Mo isolated by leukapheresis and elutriation were cultured in non-adherent cell culture bags or in plastic flasks with or without GM-CSF. At various stages of differentiation, GM-CSF treated M phi were recovered and assayed for survival, morphology, surface antigens, functional properties and proliferation in comparison with control M phi. In the present paper, we demonstrate that GM-CSF at a concentration of 50 U/ml (5 ng/ml) promotes better cell survival and the differentiation of Mo into M phi displaying certain morphological differences as compared to control M phi such as an increased expression of Max-1 antigen, CR3 and Fc gamma II receptors, higher phagocytic properties and increased capacities of cytotoxicity and TNF secretion when the cells are further activated by IFN-gamma. Furthermore, GM-CSF treated cells exhibit a low-grade proliferation although the nature of the proliferating cells has not been entirely elucidated. We conclude that the GM-CSF treated M phi would be particularly suitable for adoptive immunotherapy.
In a consecutive series of 96 patients with coronary artery occlusion, 67 had good and 29 had no or poor collateral circulation. Patients with good collaterals had the severest degree of coronary artery disease. Good collaterals are associated with a higher incidence of angina pectoris and normal electrocardiogram and with lower incidence of Q-waves, positive exercise tests, heart failure, previous myocardial infarction, and dyskinesia at ventriculography. Survival rates after 10 years were (1) 51.5% with good and 34.5% with poor collaterals (p less than 0.1), (2) 59.4% with angina pectoris and good collaterals and 41.2% with angina pectoris and poor collaterals (p less than 0.05), (3) 64.8% without and 24.4% with heart failure and good collaterals (p less than 0.001), and (4) 58.3% without and 16.1% with heart failure and poor collaterals (p less than 0.01). Good collaterals protect the myocardium by prevention of acute myocardial infarction and heart failure and thus improve survival.
The effect of preexistent coronary collateral perfusion on the prevention of left ventricular aneurysm formation was examined in 47 patients undergoing an intracoronary thrombolysis within 6 hours after the onset of a first acute anterior myocardial infarction. Left ventricular aneurysm formation and wall motion were analyzed with cineventriculography. A left ventricular aneurysm was determined as well-defined demarcation of the infarcted segment from normally contracting myocardium. In 25 patients with successful thrombolysis (group A), a left ventricular aneurysm was observed in one patient (4%) during the chronic stage of infarction. In 10 patients who had a significant collateral circulation to the infarct-related coronary artery and unsuccessful reperfusion (group B), the left ventricular aneurysm was observed in only one patient (10%). In the remaining 12 patients with unsuccessful recanalization in the absence of a significant collateral perfusion (group C), there was a higher incidence (seven of 12, 58%) of left ventricular aneurysm formation than in groups A and B (p less than 0.05). In group A, both the global ejection fraction and regional wall motion in the infarct areas improved significantly (p less than 0.05) between the acute and chronic stages of infarction. By contrast, in groups B and C, these indexes on the ventricular function did not change significantly during the convalescent period. Thus, although the collateral perfusion existing at the onset of acute myocardial infarction may not improve ventricular function, it exerts a beneficial effect on the prevention of left ventricular aneurysm formation.
We have used the quantitative binding of murine monoclonal antibodies to the surface of cultured human umbilical vein endothelial (HUVE) cells to study the responses of HUVE cells to three different immune mediators: interleukin 1 (IL 1), tumor necrosis factor (TNF), and immune interferon (IFN-gamma). Antibody H4/18, reactive with an endothelial cell-specific activation antigen, does not bind to unstimulated HUVE cells but shows rapidly and transiently inducible binding (peak 4 to 6 hr) to cells stimulated by IL 1 or TNF that declines to basal levels by 24 hr, even in the continued presence of mediator. Binding of H4/18 is unaffected by IFN-gamma. Antibody RR1/1, reactive with intercellular adhesion molecule 1, binds to unstimulated HUVE cells, but binding is rapidly increased (plateau 24 hr) after stimulation by IL 1 or TNF and slowly increased (over several days) by IFN-gamma. In contrast to H4/18 binding, the increase in RR1/1 binding is sustained in the continued presence of mediator. Antibody W6/32, reactive with HLA-A,B antigens, binds to unstimulated HUVE cells and shows gradually progressive increases (over several days) in binding upon treatment with IFN-gamma or TNF. These observations demonstrate that HUVE cells show distinct but overlapping patterns of antigenic modulation in response to three different lymphokines, and suggest that the "activation" of endothelial cells observed in situ may represent a complex integration of several lymphokine-mediated signals.
Transluminal coronary angioplasty can serve as a model for controlled coronary artery occlusion and reperfusion which enables assessment of short-term changes in collateral vessel filling in patients with severe atherosclerotic coronary artery disease. In 16 patients with isolated left anterior descending or right coronary artery disease (greater than or equal to 75% stenosis) and normal left ventricular function, collateral filling to the artery being dilated was visualized by contrast injection into the contralateral artery using a second arterial catheter. During balloon inflation, contralateral dye injection was performed as soon as the patient developed angina or ST-T changes or at 90 seconds in those patients without symptoms or signs of ischemia. Grades of collateral filling from the contralateral vessel were: 0 = none; 1 = filling of side branches of the artery to be dilated via collateral channels without visualization of the epicardial segment; 2 = partial filling of the epicardial segment via collateral channels; 3 = complete filling of the epicardial segment of the artery being dilated via collateral channels. At baseline angiography, nine patients had grade 0 collateral filling, seven had grade 1 and none had grade 2 or 3. During coronary occlusion by balloon inflation, collateral filling improved by one grade in eight patients, two grades in five patients, three grades in two patients and remained the same in one patient.(ABSTRACT TRUNCATED AT 250 WORDS)
Increased expression of cell adhesion molecules (CAMs) on the vascular endothelium has been postulated to play an important role in atherogenesis. Both in vitro and in vivo studies have suggested that dyslipidemia may increase expression of CAMs.
To determine whether dyslipidemia is associated with increased expression of CAMs, we examined the levels of soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1), and soluble E-selectin (sE-selectin) in individuals with either hypercholesterolemia or hypertriglyceridemia and in control subjects matched for age and sex. Patients with hypertriglyceridemia had significantly higher levels of sVCAM-1 (739 +/- 69 ng/mL) compared with patients with hypercholesterolemia (552 +/- 63 ng/mL) and control subjects (480 +/- 56 ng/mL). Levels of sICAM-1 were significantly increased in both the hypercholesterolemic and hypertriglyceridemic groups (298 +/- 29 and 342 +/- 31 ng/mL, respectively) compared with the control group (198 +/- 14 ng/mL). Levels of sE-selectin were significantly increased in hypercholesterolemic patients (74 +/- 9 ng/mL) compared with control subjects (48 +/- 5 ng/mL). Ten hypercholesterolemic patients were treated aggressively with atorvastatin alone or a combination of colestipol and either atorvastatin or simvastatin for a mean of 42 weeks and had an average LDL cholesterol reduction of 51%. Comparison of soluble CAMs before and after treatment showed a significant reduction only in sE-selectin (77 +/- 11 versus 56 +/- 6 ng/mL, P < or = .03) but not for sVCAM-1 or sICAM-1.
Although severe hyperlipidemia is associated with increased levels of soluble CAMs, aggressive lipid-lowering treatment had only limited effects on the levels. Increased levels of soluble CAMs in patients with hyperlipidemia may be a marker for atherosclerosis.
Monocytes are activated during collateral artery growth in vivo, and monocyte chemotactic protein-1 (MCP-1) has been shown to be upregulated by shear stress in vitro. In order to investigate whether MCP-1 enhances collateral growth after femoral artery occlusion, 12 rabbits were randomly assigned to receive either MCP-1, PBS, or no local infusion via osmotic minipump. Seven days after occlusion, isolated hindlimbs were perfused with autologous blood at different pressures, measuring flows at maximal vasodilation via flow probe and radioactive microspheres, as well as peripheral pressures. This allowed the calculation of collateral (thigh) and peripheral (lower limb) conductances from pressure-flow tracings (slope of the curve). Collateral growth on postmortem angiograms was restricted to the thigh and was markedly enhanced with MCP-1 treatment. Both collateral and peripheral conductances were significantly elevated in animals with MCP-1 treatment compared with the control group, reaching values of nonoccluded hindlimbs after only 1 week of occlusion (collateral conductance, 70.6 +/- 19.23 versus 25.1 +/- 2.59 mL/min per 100 mm Hg; P < .01; peripheral conductance, 119.3 +/- 22.37 versus 45.4 +/- 6.80 mL/min per 100 mm Hg; P < .05). These results suggest that activation of monocytes plays an important role in collateral growth as well as in capillary sprouting.
Occlusive arterial disease stimulates compensatory growth of pre-existent and new arterial channels which help to maintain organ perfusion. Previous studies characterizing compensatory or collateral vascular growth have been performed in normocholesterolemic animals. Because hyperlipidemic states alter vascular regulation, it remains to be demonstrated that the capacity of the vasculature to undergo compensatory growth is preserved in the presence of dyslipidemic vascular injury. To assess effects of hypercholesterolemia on vascular growth, arterial supply to the ear of rabbits with (n = 13) or without hypercholesterolemia (n = 14) was surgically restricted. Compensatory growth of residual arteries and distal microvessels was evaluated using quantitative angiographic and microanatomic methods. Lumen-expanding hyperplasic arterial remodeling and distal microvascular proliferation induced by arterial restriction were assessed by independent techniques including in vivo microangiography, laser Doppler flowmetry, quantitative histometry, and thymidine incorporation. Compared with controls, hypercholesterolemic rabbits exhibited depressions in all arterial and capillary growth indexes. Microvascular proliferation in hypercholesterolemic rabbits was less than 20% of control. Results demonstrate for the first time that an atherogenic dyslipidemia may limit compensatory macro- and microvascular growth in response to arterial restriction, a phenomenon that could play an important role in the pathophysiology of atherosclerotic occlusive artery disease.
Although myocardial ischemia is known to be significantly related to the development of coronary collateral vessels (CCVs), there is considerable variation between patients with ischemic heart disease in the presence of collateral development. The nature of this variability is not well known. Likewise, it remains unclear whether diabetes mellitus (DM) has any effect on CCVs. The aim of this study was to evaluate the effect of DM on CCVs.
Of the patients who underwent coronary angiography during the interval between March 1, 1993, and June 20, 1998, in our institution, 306 were diabetic. Those patients in whom coronary angiography is normal or severity of coronary artery stenosis is thought not to be sufficient for the development of CCVs (<75%) were excluded from the study. A total of 205 patients (mean age, 59+/-8 years) met the criteria for the DM group. For case-control matching, 205 consecutive nondiabetic patients (mean age, 58+/-9 years) who had >/=1 diseased vessel with >75% stenosis were included in the control group. The CCVs were graded according to the Rentrop scoring system, and the collateral score was calculated by summing the Rentrop numbers of every patient. There was no statistical difference between patients with and without DM in clinical baseline characteristics. The mean number of diseased vessels in the DM group (1.58+/-0.68) was higher than that in the nondiabetic group (1.42+/-0.65, P=0.005). The mean collateral score was 2.41+/-2.20 in the DM group and 2.60+/-2.39 in the control group. After confounding variables were controlled for, the collateral score in the diabetic group was significantly different from that in the nondiabetic group (P=0.034).
Our findings suggest that CCV development is poorer in patients with than in patients without DM. Thus, we can speculate that DM is an important factor affecting CCV development.
The coronary artery collateral circulation may be beneficial in protecting against myocardial ischemia and necrosis. However, there is a tremendous interindividual variability in the degree of new collateral formation in patients with coronary artery disease. The basis for this interindividual heterogeneity is not understood. In this study we test the hypothesis that failure to generate collateral vessels is associated with a failure to appropriately induce with hypoxia or ischemia the angiogenic factor, vascular endothelial growth factor (VEGF).
We correlated the VEGF response to hypoxia in the monocytes harvested from patients with coronary artery disease with the presence of collaterals visualized during routine angiography. We found that there was a highly significant difference in the hypoxic induction of VEGF in patients with no collaterals compared with patients with some collaterals (mean fold induction 1.9+/-0.2 versus 3.2+/-0.3, P<0.0001). After subjecting the data to ANCOVA, using as covariates a number of factors that might influence the amount of collateral formation (ie, age, sex, diabetes, smoking, hypercholesterolemia), patients with no collaterals still have a significantly lower hypoxic induction of VEGF than patients with collaterals.
This study provides evidence in support of the hypothesis that the ability to respond to progressive coronary artery stenosis is strongly associated with the ability to induce VEGF in response to hypoxia. The observed interindividual heterogeneity in this response may be due to environmental, epigenetic, or genetic causes. This interindividual heterogeneity may also help to explain the variable angiogenic responses seen in other conditions such as diabetic retinopathy and solid tumors.
Endothelial and smooth muscle cells interact with each other to form new blood vessels. In this review, the cellular and molecular mechanisms underlying the formation of endothelium-lined channels (angiogenesis) and their maturation via recruitment of smooth muscle cells (arteriogenesis) during physiological and pathological conditions are summarized, alongside with possible therapeutic applications.
Background:
Vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, and E-selectin mediate adhesion and transmigration of leukocytes to the vascular endothelial wall and may promote plaque growth and instability. In a prospective study, we evaluated the effect of soluble adhesion molecules on the risk of future cardiovascular events among patients with angiographically documented coronary artery disease (CAD). Methods and Results- -We obtained baseline samples from a prospective cohort of 1246 patients with CAD. Besides various markers of inflammation, soluble VCAM-1 (sVCAM-1), sICAM-1, and sE-selectin were determined. Follow-up information on cardiovascular events was obtained (mean, 2.7; maximum, 4.1 years). Independently higher levels of sVCAM-1 (1932 versus 1128 ng/mL; P<0.0001), sICAM-1 (353 versus 287 ng/mL; P=0.015), and sE-selectin (81 versus 63 ng/mL; P=0.003) were observed in patients with future death from cardiovascular causes. In a multivariate model, fatal risk was 2.1-fold (1.1 to 4.0) higher in patients within the top quartile of baseline sVCAM-1 concentrations compared with lower quartiles. This association was present independent of general inflammatory response as reflected by low or high C-reactive protein (hs-CRP) levels. In a model that simultaneously controlled for all inflammatory and soluble adhesion markers determined, only sVCAM-1 remained independently significant for future fatal cardiovascular events, with a 2.8-fold increase in risk (P=0.003).
Conclusions:
Soluble adhesion molecules sVCAM-1, sICAM-1, and sE-selectin were significantly related to future death from cardiovascular causes among patients with documented CAD. Especially sVCAM-1 added to the predictive value of classic risk factors and hs-CRP in determining the risk of future cardiovascular death.
Experimentally, activated macrophages have been documented to induce vascular proliferation.
In 21 patients (age 74+/-9 years) with extensive coronary artery disease not eligible for coronary artery bypass surgery, the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF, Molgramostim) on quantitatively assessed collateral flow was tested in a randomized, double-blind, placebo-controlled fashion. The study protocol consisted of an invasive collateral flow index (CFI) measurement immediately before intracoronary injection of 40 microg of GM-CSF (n=10) or placebo (n=11) and after a 2-week period with subcutaneous GM-CSF (10 microg/kg) or placebo, respectively. CFI was determined by simultaneous measurement of mean aortic pressure (P(ao), mm Hg), distal coronary occlusive pressure (P(occl), mm Hg; using intracoronary sensor guidewires), and central venous pressure (CVP, mm Hg): CFI=(P(occl)-CVP)/(P(ao)-CVP). CFI, expressing collateral flow during coronary occlusion relative to normal antegrade flow during vessel patency, changed from 0.21+/-0.14 to 0.31+/-0.23 in the GM-CSF group (P<0.05) and from 0.30+/-0.16 to 0.23+/-0.11 in the placebo group (P=NS). The treatment-induced difference in CFI was +0.11+/-0.12 in the GM-CSF group and -0.07+/-0.12 in the placebo group (P=0.01). ECG signs of myocardial ischemia during coronary balloon occlusion occurred in 9 of 10 patients before and 5 of 10 patients after GM-CSF treatment (P=0.04), whereas they were observed in 5 of 11 patients before and 8 of 11 patients after placebo (P=NS).
This first clinical study investigating the potential of GM-CSF to improve collateral flow in patients with coronary artery disease documents its efficacy in a short-term administration protocol.
- Hackman