Coronary Collateral Development Research Articles

The relationship between L-arginine/ADMA ratio and coronary collateral development in patients with low glomerular filtration rate

It is yet to be established which factors are responsible for differences among patients with the same degree of coronary artery disease in terms of coronary collateral development (CCD). Patients who had a greater than or equal to 95% stenosis in at least one epicardial coronary artery were classified into two groups according to their glomerular filtration rate (GFR) level. Afterwards, the degree of CCD was evaluated according to their plasma concentration of asymmetric dimethylarginine (ADMA) and GFR levels. Rentrop grade 2-3 was found more frequently in patients with GFR > 60 mL/min than in patients with GFR < 60 mL/min (68.6% vs 41.4%, p = 0.032). Then we divided patients into four groups according to their GFR levels and Rentrop grades; whereas we did not find any significant difference for L-arginine or ADMA levels (respectively p = 0.629 and p = 0.076), we did find a statistically significant difference between groups for L-arginine/ /ADMA ratio (p = 0.003) and this statistically significant difference was evident between patients with GFR < 60 mL/min and Rentrop 0-1 and patients with GFR > 60 mL/min and Rentrop 2-3 (1.23 vs 1.69, p < 0.001). Multivariate logistic regression analysis revealed that L-arginine/ADMA ratio was the only variable which had a significant effect on CCD (OR = 1.016; 95% CI 1.001-1.031, Wald = 4.565; p = 0.033). These results showed that CCD was poor in patients with GFR < 60 mL/min, presumably because of the adverse effect of decreased L-arginine/ADMA ratio on endothelial cells and angiogenesis.

Overfed Ossabaw swine with early stage metabolic syndrome have normal coronary collateral development in response to chronic ischemia

Ossabaw miniswine have been naturally selected to efficiently store large amounts of lipids offering them a survival advantage. Our goal was to evaluate the myocardial response to chronic ischemia of the Ossabaw consuming a hypercaloric, high-fat/cholesterol diet with and without metformin supplementation. At 6weeks of age animals were fed either a regular diet (OC, n=9), a hypercaloric high-fat/cholesterol diet (OHC, n=9), or a hypercaloric high-fat/cholesterol diet supplemented with metformin (OHCM, n=8). At 9weeks, all animals underwent ameroid constrictor placement to the left circumflex coronary artery to simulate chronic ischemia. Seven weeks after ameroid placement, all animals underwent hemodynamic and functional measurements followed by cardiac harvest. Both OHC and OHCM animals developed significantly greater weight gain, total cholesterol, and LDL:HDL ratio compared to OC controls. Metformin administration reversed diet-induced hypertension and glucose intolerance. There were no differences in global and regional contractility, myocardial perfusion, capillary and arteriolar density, or total protein oxidation between groups. Myocardial protein expression of VEGF, PPAR-α, γ, and δ was significantly increased in the OHC and OHCM groups. Microvessel reactivity was improved in the OHC and OHCM groups compared to controls, and correlated with increased p-eNOS expression. Overfed Ossabaw miniswine develop several components of metabolic syndrome. However, impairments of myocardial function, neovascularization and perfusion were not present, and microvessel reactivity was paradoxically improved in hypercholesterolemic animals. The observed cardioprotection despite metabolic derangements may be due to lipid-dependant upregulation of the PPAR pathway which is anti-inflammatory and governs myocardial fatty acid metabolism.

The association between different monocyte subsets and coronary collateral development

An increased circulating monocyte count has been found to be related to good collateral development in patients with stable coronary artery disease. Our aim in this study was to determine any possible relationship between the levels of circulating monocyte subsets and coronary collateral development. Patients who had greater than 95% stenosis of at least one major coronary artery in their first coronary angiogram were included consecutively in this study. Collateral development was graded as good and poor according to the Cohen-Rentrop method. Blood samples were subjected to cytometric analysis for the determination of monocyte subsets, CD14++CD16- and CD14+CD16+ monocytes. Out of 105 patients, 55 had good and 50 had poor coronary collateral development. When the baseline characteristics were compared, the monocyte count was significantly higher in the good collateral group (517±151 vs. 396±109/mm3, P<0.001). Cytometric analysis indicated that CD14++CD16- levels were significantly higher in the good collateral group (422±147 vs. 298±105/mm3, P<0.001). CD14+CD16+ cells did not differ between groups (80±29 vs. 84±29/mm3, P=0.41). When multivariate analysis was performed, increased CD14++CD16- levels were still significantly associated with good collateral development [odds ratio: 1.009 (1.005-1.014), P<0.001]. Our present results are the first to show a significant association between increased circulating CD14++CD16- monocyte levels and good coronary collateral development. Further studies are needed to better understand the relationship between different subsets of monocytes and collateralization.

The Metabolic Syndrome, Oxidative Stress, Environment, and Cardiovascular Disease: The Great Exploration

The metabolic syndrome affects 30% of the US population with increasing prevalence. In this paper, we explore the relationship between the metabolic syndrome and the incidence and severity of cardiovascular disease in general and coronary artery disease (CAD) in particular. Furthermore, we look at the impact of metabolic syndrome on outcomes of coronary revascularization therapies including CABG, PTCA, and coronary collateral development. We also examine the association between the metabolic syndrome and its individual component pathologies and oxidative stress. Related, we explore the interaction between the main external sources of oxidative stress, cigarette smoke and air pollution, and metabolic syndrome and the effect of this interaction on CAD. We discuss the apparent lack of positive effect of antioxidants on cardiovascular outcomes in large clinical trials with emphasis on some of the limitations of these trials. Finally, we present evidence for successful use of antioxidant properties of pharmacological agents, including metformin, statins, angiotensin II type I receptor blockers (ARBs), and angiotensin II converting enzyme (ACE) inhibitors, for prevention and treatment of the cardiovascular complications of the metabolic syndrome.

Increased Serum Bilirubin Level is Related to Good Collateral Development in Patients with Chronic Total Coronary Occlusion

Bilirubin is a bile pigment with potent anti-oxidant properties; in previous studies it has been reported to be negatively associated with coronary artery disease (CAD). Although elevated serum bilirubin concentrations may protect against endothelial dysfunction, it is not clear whether higher serum bilirubin levels (SBLs) in physiological ranges may work in favor of good collateral development in patients with chronic total coronary occlusion (CTO). The study population consisted of patients who underwent coronary angiography with a suspicion of CAD. Patients who had CTO in at least one major coronary artery were included. Coronary angiograms of 179 eligible patients from our database were reanalyzed and 110 of them had good collateral development and 69 had poor collateral development according to the Cohen-Rentrop method. Patients with good collateral development had a lower fasting plasma glucose level (FPG) (p=0.024) and higher SBLs in comparison to patients with poor collateral development (p<0.001). The number of CTO vessels (p=0.013) and left ventricular ejection fraction (EF%) were higher in good collateral group than poor collateral group (p=0.017). In multivariate analysis, FPG negatively (odds ratio [OR]: 0.981, p=0.003) and SBL (OR for per 0.1-mg/dL increase: 1.832, p<0.001) and the number of CTO vessels (OR: 5.642, p=0.007) were positively related to coronary collateral development. This study suggests that higher bilirubin levels within relatively normal ranges were related with favorable coronary collateral growth in patients with CTO. SBL may be responsible for the difference in coronary collateral vessel development among different patients with coronary artery disease. The anti-inflammatory and anti-oxidant properties of bilirubin may mediate this effect.

Abstract 18002: Coronary Collaterals Predict Improved Survival and Allograft Function in Patients with Coronary Allograft Vasculopathy

Coronary allograft vasculopathy (CAV) remains the most prevalent cause of allograft failure and cardiac mortality beyond the first year following heart transplantation. To date there are few proven therapies for this important disease. The presence of coronary collaterals has previously been demonstrated to impart a favorable prognosis in patients with ischemic heart disease. To determine whether the development of coronary collaterals is also associated with improved outcomes in patients with CAV, we performed a retrospective cohort study of all patients followed in the heart transplant clinic at Barnes Jewish Hospital between 1994 and 2008. The primary endpoint was the composite of all cause mortality, retransplantation, and inotrope dependence. LV end diastolic pressure and NYHA class served as surrogate measures of allograft function and heart failure symptoms. We screened 493 patients and identified 60 (13%) with moderate to severe CAV as defined by the International Society of Heart and Lung Transplantation. Coronary collaterals were present in 34 (57%) subjects. Patients with collaterals had a significantly lower risk of death, retransplanation, or inotrope dependence compared to patients without collaterals (OR 0.15, 95% CI 0.05-0.48, p= 0.002). In addition, patients with collaterals had lower LV end diastolic pressures and NYHA class. Multivariate analysis confirmed that the presence of collaterals independently predicted each of these outcomes. Immunohistochemical staining of biopsy specimens collected from patients with CAV revealed alterations in microvascular density that correlated with the presence of angiographically visible collaterals. Together these data demonstrate that the development of coronary collaterals predicts a favorable prognosis in patients with CAV and suggests that interventions aimed at promoting collateral growth may serve as effective therapies for this disease.

High Levels of Serum Uric Acid Impair Development of Coronary Collaterals in Patients With Acute Coronary Syndrome

We evaluated the association of serum uric acid (SUA) level and development of coronary collateral vessels (CCVs) in patients with acute coronary syndrome (ACS). Patients (n = 224) with ACS were included in the study. Coronary collateral vessels were graded according to the Rentrop scoring system. Rentrop grade 0 was accepted as absence of CCV (group 1; n = 117) and Rentrop grade ≥1 was accepted as presence of CCV (group 2; n = 107). Rentrop 0-1 (poor CCV) were determined in 167 patients and Rentrop 2-3 (good CCV) were determined in 57 patients. Both presence of CCV (P < .001) and development of good CCV (P = .003) were significantly associated with low levels of SUA. We suggest that high levels of SUA affect the CCV development negatively in nondiabetic and nonhypertensive patients with ACS.

Relationship between serum thymosin β4 levels and coronary collateral development

Thymosin β4 was recently demonstrated to be a potential stimulator of angiogenesis and arteriogenesis in both in-vivo and in-vitro studies. Little is known about the relationship between serum thymosin β4 levels and the extent of coronary collaterals in patients with coronary artery disease. Serum thymosin β4 independently predicts the formation of coronary collaterals in patients with coronary artery disease. A total of 190 consecutive patients who underwent coronary angiography were divided into two groups according to coronary angiograms and collateral formation: the poor collateral group consisting of 103 patients with at least more than or equal to one coronary stenosis of greater than or equal to 75% without visible collateral circulation, and the good collateral group consisting of 87 patients with at least more than or equal to one coronary stenosis of greater than or equal to 75% with well-developed collateral circulation. Collateral score was analyzed using the Cohen-Rentrop classification. Serum thymosin β4 levels were 1024.50 ± 516.92 ng/ml and 1373.00 ± 1082.88 ng/ml for patients in the poor collateral group and the good collateral group, respectively. Serum thymosin β4 levels in the good collateral group were significantly higher than those in the poor collateral group (P<0.01). After adjustment in the multiple ordinal logistic regression model, serum thymosin β4 levels showed a strong independent association with the collateral Cohen-Rentrop score (χ(2)=4.45, odds ratio=1.00, 95% confidence interval: 1.000-1.002, P=0.035). Elevated serum thymosin β4 level is independently associated with a significant enhancement in coronary collateralization and patients in the good collateral tend to have a higher thymosin β4 level.

The Relationship of Serum Erythropoietin Level With Coronary Collateral Grade

Background Erythropoietin has been shown to induce neovascularization and protect against ischemic vascular injury. We investigated whether a higher serum erythropoietin (EPO) level is related to better coronary collateral vessel grade. Methods Ninety-nine patients with stable angina pectoris who have at least 1 coronary stenosis of equal to or greater than 70% at coronary angiography were prospectively enrolled. Serum EPO and vascular endothelial growth factor (VEGF) levels were studied. Coronary collateral degree was graded according to the Rentrop method. Patients with grade 2-3 collateral degree were included in the good collateral group and formed Group I. The patients with grade 0-1 collateral degree were included in the poor collateral group and formed Group II. Results The serum EPO level was significantly higher in the good collateral group (17.3 ± 9.3 mU/mL vs 11.7 ± 5.0 mU/mL; P < 0.001). There was also a positive correlation between serum EPO level and Rentrop score ( r = 0.39; P < 0.001). In multivariate analysis, serum EPO level (odds ratio [OR] 1.336; 95% confidence interval [CI], 1.120-1.593; P = 0.001), oxygen saturation (OR 0.638; 95% CI, 0.422–0.963; P = 0.033) and presence of chronic total occlusion (CTO) (OR 26.7; 95% CI, 3.874-184.6; P = 0.001) were independently related to well-developed coronary collaterals. Conclusions Higher serum EPO level is related to better coronary collateral development. Erythropoietin may have a positive effect on the development of collaterals and may provide a new agent for the treatment strategies to enhance coronary collateral vessel development.

Effects of prediabetes on coronary collateral circulation in patients with coronary artery disease

The risk for cardiovascular disease almost increases in patients with impaired glucose tolerance compared with those with normal glucose tolerance. In experimental studies, it has been shown that impaired fasting glucose has negative effect of coronary collateral circulation (CCC). The aim of this study is to investigate the effects of prediabetes on coronary collateral development in patients with coronary artery disease. We retrospectively enrolled 230 patients who underwent coronary angiography. All study participants had at least one occluded major coronary artery. Prediabetes was defined according to the American Diabetes Association definition and patients were then classified into having prediabetes group and control group. To classify CCC we used Rentrop's scoring system. Rentrop grades of 0 and 1 indicate poor CCC whereas 2 and 3 indicate good CCC. Groups were compared using the χ, the Student t or the Mann-Whitney U-tests. To identify predictors of CCC, multivariable logistics regression analysis was performed. The prediabetes group consisted of 104 patients and the control group consisted of 126 patients. Both groups were comparable for basal characteristics. Poor CCC was higher in the patients with prediabetes (P < 0.001). Multivariable logistic regression analysis showed that fasting glucose level was the only independent predictor of CCC (B = -0.124; odds ratio = 0.883; 95% confidence interval = 0.85-0.92; P < 0.001). Our study showed that coronary collateral development was impaired in patients with prediabetes when compared with patients with coronary artery disease who had normal fasting glucose level.

The relation of serum monocyte chemoattractant protein-1 level with coronary atherosclerotic burden and collateral degree in stable coronary artery disease

We investigated whether serum monocyte chemoattractant protein-1 (MCP-1) level predicted coronary atherosclerotic burden in patients with stable coronary artery disease and its relationship with coronary collateral grade. We prospectively included 196 patients (103 males, 93 females; mean age 59 ± 11 years) who underwent coronary angiography for stable angina pectoris. Serum MCP-1 levels were determined before coronary angiography. Coronary atherosclerotic burden was measured by the Gensini score, and coronary collateral development was assessed by the Rentrop classification. The patients were divided into four groups: those with normal coronary arteries (NCA); those with coronary lesions of <70% luminal obstruction; and those with coronary lesions of ≥ 70% luminal obstruction accompanied by a good or poor collateral grade. The mean serum MCP-1 level was higher in patients with coronary lesions compared to patients with NCA (129 ± 130 vs. 102 ± 55 pg/ml, p=0.048). Although there were no significant differences in the MCP-1 levels of patients with NCA, with <70% luminal obstruction, and those with a significant luminal obstruction and a poor collateral grade, patients with significant luminal obstruction and a good collateral grade had significantly higher MCP-1 levels compared to the remaining groups (p=0.016). However, in multivariate regression analysis, MCP-1 level was not independently associated with the Gensini score. Our findings suggest that serum MCP-1 level is higher in patients with coronary atherosclerosis, without a significant and independent association with coronary atherosclerotic burden. Significantly increased serum MCP-1 levels in patients with a good collateral grade may be an interesting issue of investigation.

Endothelial progenitor cells (CD34+KDR+) and monocytes may provide the development of good coronary collaterals despite the vascular risk factors and extensive atherosclerosis

Endothelial progenitor cells (EPC) have a regenerative role in the vascular system. In this study, we aimed to evaluate simultaneously the effects of EPC and inflammatory cells on the presence and the extent of coronary artery disease (CAD) and the grade of coronary collateral growth in patients with clinical suspicion of CAD. This study has a cross-sectional and observational design. We enrolled 112 eligible patients who underwent coronary angiography consecutively (mean age: 59±9 years). The association of circulating inflammatory cells and EPC (defined by CD34+KDR+ in the lymphocyte and monocyte gate) with the presence, severity and extent of CAD and the degree of collateral growth were investigated. Logistic regression analysis was used to define the predictors of collateral flow. Of 112 patients 30 had normal coronary arteries (NCA, 27%, 55±9 years) and 82 had CAD (73%, 61±8 years). Among the patients with CAD, the percent degree of luminal stenosis was <50% in 12 patients; 50-90% in 35 patients; and ≥90% in the other 35 patients. Circulating inflammatory cells were higher (leukocytes, 7150±1599 vs 8163±1588 mm(-3), p=0.001; neutrophils, 4239±1280 vs 4827±1273 mm(-3), p=0.021; monocytes, 512±111 vs 636±192 mm(-3), p=0.001) and EPCs were lower (0.27±0.15% vs 0.17±0.14%, p<0.001; 21±15 vs 13±12 mm(-3), p=0.004) in CAD group than NCA group. When we investigated the collateral growth in patients having ≥90% stenosis in at least one major coronary artery, we found that the patients with good collateral growth had significantly higher EPC (0.22±0.17% vs 0.10±0.05%, p=0.009; 18±15 vs 7±3 mm(-3), p=0.003) in comparison to patients with poor collateral growth. Presence of EPC was associated with reduced risk for coronary artery disease (OR: 0.934, 95%CI: 0.883-0.998, p=0.018) and was an independent predictor for good collateral growth (OR: 1.295, 95%CI: 1.039-1.615, p=0.022). A sum of CD34+KDR-, CD34+KDR+ and CD34-KDR+ cells (192±98 mm(-3)), and a CD34-KDR- cell subpopulation within monocyte gate (514±173 mm(-3)) reached to highest counts in good collateral group among all study population. Endothelial progenitor cells can be mobilized from bone marrow to induce the coronary collateral growth in case of myocardial ischemia even in presence of the vascular risk factors and extensive atherosclerosis. This finding may be supportive to investigate the molecules, which can specifically mobilize EPC without inflammatory cells.

Pitavastatin treatment normalizes VEGF signaling and cardiac function in STZ‐induced diabetic rat hearts

Abnormal alterations in cardiac expression of vascular endothelial growth factor (VEGF) as well as its receptors and impairment in the development of coronary collaterals have recently been reported in diabetic subjects. However, the effectiveness of pharmacological intervention on these diabetic defects remains unsettled. Here, we studied the effects of statin (pitavastatin) on cardiac VEGF signaling pathways and cardiac function in Sprague‐Dawley rats 5 wk after induction of type I diabetes with streptozotocin (65 mg/kg ip) in comparison with age‐matched control rats. After streptozotocin (1 wk), some diabetic rats were treated with pitavastatin (1 mg/day) for 4 wk. VEGF, its receptors, and its angiogenic signaling molecules [phosphorylated Akt and endothelial nitric‐oxide synthase (eNOS)] were analyzed by Western blot, ELISA, real‐time PCR, and immunohistochemistry, and cardiac function was evaluated by echocardiography. Coronary capillary morphology was assessed by lectin and enzymatic double staining. We found significant decreases in cardiac expression of VEGF, its receptors, phosphorylation of Akt and eNOS, and coronary capillary density in diabetic rats compared with controls. Treatment of diabetic rats with pitavastatin reversed these alterations to control levels and ameliorated impairment of cardiac function. The present study is the first to show the potential usefulness of a statin in the treatment of cardiac dysfunction in type I diabetes at the molecular level.

Porcine coronary collateral formation in the absence of a pressure gradient remote of the ischemic border zone

In the current paradigm on coronary collateral development, it is assumed that these vessels develop consequentially from increased fluid shear stress (FSS) through preexisting collateral arteries. The increased FSS follows from an increase in pressure gradient between the region at risk and well-perfused surroundings. The objective of this study was to test the hypothesis that, in the heart, collateral connections can form in the absence of an increased FFS and consequentially at any depth and region within the ventricular wall. In Yorkshire pigs, gradual left circumflex coronary artery occlusion was obtained over 6 wk by an ameroid constrictor, whereas the control group underwent a sham operation. Hearts were harvested and subsequently processed in an imaging cryomicrotome, resulting in 40-μm voxel resolution three-dimensional reconstructions of the intramural vascular vessels. Dedicated software segmented the intramural vessels and all continuous vascular pathways containing a collateral connection. In the ameroid group, 192 collaterals, 22-1,049 μm in diameter, were detected with 62% within the subendocardium. Sixty percent of collaterals bridged from the left anterior descending artery to left circumflex coronary artery. A novel result is that 25% (n = 48) of smaller-radius collaterals (P = 0.047) connected with both origin and terminus in the nontarget area where perfusion was assumed uncompromised. In the porcine heart, collateral vessels develop not only in ischemic border zones with increased FSS but also away from such border zones where increased FSS is unlikely. The majority of collaterals were located at the subendocardium, corresponding to the region with highest prevalence for ischemia.

Increased plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are related to good collateral development in patients with isolated left coronary artery disease

Development of coronary collaterals (CCs) is a time-dependent adaptive response to an ischemic process arising from the gradient between obstructed arteries and myocardial ischemia. It is a complex inter-relationship among various factors [1]. A complex interaction exists between new blood vessel formation and inflammation. However, little data are available on the relation between inflammation and the development of CCs [2,3]. Inflammation has emerged as central to the initiation and progression of atherosclerosis. The mechanism(s) underlining collateral artery growth closely resemble those of atherosclerosis. Lipoprotein-associated phospholipase A2(Lp-PLA2) is actively secreted by monocyte-derived macrophages in atherosclerotic plaque. Lp-PLA2 is a unique inflammatory biomarker, as it is highly vascular specific, has low biologic variability, and is directly related to the propensity of plaque rupture and the degree of inflammation present in the walls of coronary arteries [4]. The inflammatory process is also associatedwith an increased oxidant environment. In a recent study, it was indicated that oxidative stress may also play an important role in the development of CCs [5]. Ischemia modified albumin (IMA), the earliest ischemic marker, in atherosclerosis has been extensively studied, but, there is no data on the possible involvement of Lp-PLA2 and IMA in the development of coronary collaterals. In this prospective preliminary study, it was aimed to investigate the possible role and involvement of plasma Lp-PLA2, IMA and oxidant stress status in patients with isolated left coronary artery disease (CAD). This prospective study was conducted between January 2007 and September 2009 in our university hospital setting. Clinical indications were considered in all patients undergoing coronary angiography by using the standard femoral approach by the Judkins technique. Because the multi-vessel coronary disease has a significant influence on the development of collaterals, we mainly evaluated the single-vessel disease group, with ≥90% narrowing or total occlusion of the left anterior descending (LAD) and nonsignificant (b30%) narrowing of the non-LAD (5). The study was approved by the local Ethics Committee. Coronary collateral development was graded according to the Cohen– Rentrop method [6]. Classification of the patients according to the Rentrop's score yielded 24 of patients with poor developed CCs, (Rentrop's score of 0 to 1), and 21 had good developed CCs (Rentrop's score of 2 to 3). The Gensini score was computed for each patient from the coronary arteriogram by assigning a severity score to each coronary stenosis [7]. The levels of serum total cholesterol (TC), triglyceride (TG), LDL cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDLC) were determined by enzymaticmethods using a ROCHE autoanalyzer (Modular System,GmbH,Mannheim,Germany). hs-CRPwas assessed by the latex enhanced immunonephelometric method (DADE BEHRING, GmbH, Marburg, Germany). Lp-PLA2 concentration (mass) was measured by a turbidimetric immunoassay method (PLAC® test, diaDexus). Lp-PLA2 activity was measured in an autoanalyzer (Roche, Cobas-6000). The inter-assay coefficient of variation (CV) was 6.2%. Serum total antioxidative capacity (TAC), total oxidant status (TOS) and Oxidative Stress Index (OSI) were assayed as described previously [8]. Inter-assay CVswere 2.5% and 3.1% respectively. The IMA level was assayed by using Bar-Or et al.'s method [9]. The results were reported as absorbance units (AbsUs). Inter-assay CV was 4.2%. Of the inflammation markers, Lp-PLA2 was found to be significantly higher in patients with good CCs thanwith poor CCs (pb0.020) while hs-CRP was lower in patients with good CCs thanwith poor CCs. The results of the present prospective study demonstrated that Lp-PLA2 has an independent association with good coronary collateral development andwithGensini score in patientswith isolated left coroner artery involvement. This is the first report investigating the plasma Lp-PLA2 level in coronary collateral development. Lp-PLA2 plays a pivotal role for inflammatory progress of the atherosclerotic process [10]. Lp-PLA2 is a unique inflammatory biomarker, as it is highly vascular specific, and has low biologic variability compared to the hs-CRP (4). Little data are available on the relation between inflammation and the development of CCs [11]. In those studies, authors showed an inverse relationship between CRP and coronary collateral development. Similar distribution of the CRP level between poor and good CC groups was observed in the

The Role of Osteoprotegrin/Nuclear Factor kB Ligand in Coronary Collateral Development

Osteoprotegrin (OPG), as a member of the TNF family is demonstrated to be a potential regulator of the endothelial function and angiogenesis by neutralization of nuclear factor kB ligand (RANKL). We investigated the OPG and RANKL gene expressions in circulating peripheral blood mononuclear cells (PBMCs) of Coronary artery disease (CAD) patients with different extents of coronary collateral development. In a cross-sectional study, 206 individuals with angiographically documented CAD were recruited. Severity of CAD was defined by the number of involved coronary vessels. The Rentrop scoring system was used to grade the extent of collateral development. Grade 0 or 1 collateralization was considered poor collateralization. RNA extraction and cDNA synthesis were performed. OPG and RANKL gene expressions were evaluated using quantitative real-time PCR. Among patients with CAD, 48.5% (100), 16.5%(34) and 35%(72) were considered to have one to three degrees of coronary artery involvement, respectively. The OPG and the ratio of OPG to RANKL expression were significantly elevated in patients with well-developed collateralization. In a logistic regression, severity of CAD was associated with a better collateral development, and OPG gene over expression was correlated with a better collateralization, independently of other variables. In conclusion, it seems that OPG might have an important role in prognosis of CAD; its up-regulation is parallel with CAD severity while it can enhance collateral development.

Relation between serum monocyte chemoattractant protein-1 and coronary collateral development

The degree of coronary collateral development is not same in every patient with similar degree of coronary stenosis. In animal studies monocyte chemoattractant protein-1 (MCP-1) has been found to be related to collateral vessel development. In this study we investigated whether a higher serum MCP-1 level is related to better coronary collateral vessel development in patients with stable coronary artery disease. Eighty-three patients with stable angina pectoris, who have at least one coronary stenosis equal to or greater than 70% at coronary angiography, were prospectively enrolled. Serum MCP-1 and vascular endothelial growth factor (VEGF) levels were studied. Coronary collateral development was graded according to the Rentrop method. Patients with grade 2-3 collateral developments were included in good collateral group and formed group I. The patients with grade 0-1 collateral developments were included in poor collateral group and formed group II. The serum MCP-1 level was significantly higher in good collateral group (288 ± 277 pg/ml vs. 132 ± 64 pg/ml; P<0.001). There was also a positive correlation between serum MCP-1 level and Rentrop score (r=0.39, P<0.001). The patients in the good collateral group also had a significantly higher number of coronary arteries with significant stenosis (1.7 ± 0.7 vs. 1.4 ± 0.6, P=0.049), and higher VEGF levels (322 ± 147 pg/ml vs. 225 ± 161 pg/ml, P=0.007). In multivariate analysis, only serum MCP-1 level (P=0.014, odds ratio: 1.01, 95% confidence interval: 1.002-1.019) was independently related to good coronary collateral development. Higher serum MCP-1 level is related to better coronary collateral development.

Poor coronary collateral vessel development in patients with mild to moderate renal insufficiency

The development of coronary collaterals is crucial to survival through acute ischemia. Mild to moderate loss of renal function has been suggested to play a role in this event, but evidential data are scarce. The aim of this study was to investigate the relationship between mild to moderate renal insufficiency and coronary collateral development in patients with chronic total coronary artery occlusion. A total of 83 patients with mild to moderate loss of renal function (30mL/min/1.73m(2)≤eGFR<90mL/min/1.73m(2)) with chronic total coronary artery occlusion were included in our study. The collateral circulation was graded according to Rentrop classification and the function of collateral circulation was graded according to Werner collateral connection (CC) grades. Compared to patients with good collateral circulation (Rentrop=2,3), eGFR was found to be lower in those patients with poor coronary collateral circulation (Rentrop=0,1) (63.30±10.51 vs. 54.13±10.56, P=0.02). eGFR was also found to be lower in poorly functioning coronary collateral circulation (CC=0,1) than in efficiently functioning coronary collateral circulation (CC=2) (55.22±9.98 vs. 66.28±9.16, P=0.03). Multiple logistic regression analysis showed that low eGFR was independently associated with poor coronary collateral circulation (Rentrop=0,1, 95% CI, 0.09-1.09, P=0.044) and poor function of coronary collateral circulation (CC=0,1, 95% CI, 0.02-0.17, P=0.02). Lower eGFR is associated with poorer coronary collateral vessel development in patients experiencing mild to moderate renal insufficiency. Moreover, eGFR represents an independent factor affecting coronary collateral vessel development.

THE RELATION BETWEEN SERUM MONOCYTE CHEMOATTRACTANT PROTEIN-1 AND CORONARY COLLATERAL DEVELOPMENT

Background The degree of coronary collateral development is not same in every patient with similar degree of coronary stenosis. In animal studies monocyte chemoattractant protein-1 (MCP-1) has been found to be related to collateral vessel development. In this study we investigated whether a higher serum MCP-1 level is related to better coronary collateral vessel development in patients with stable coronary artery disease. Method Eighty-three patients with stable angina pectoris, who have at least one coronary stenosis equal to or greater than 70% at coronary angiography, were prospectively enrolled. Serum MCP-1 and vascular endothelial growth factor (VEGF) levels were studied. Coronary collateral development was graded according to the Rentrop method. Patients with grade 2–3 collateral developments were included in good collateral group and formed group I. The patients with grade 0–1 collateral developments were included in poor collateral group and formed group II. Results The serum MCP-1 level was significantly higher in good collateral group (288±277pg/ml vs. 132±64pg/ml; P<0.001). There was also a positive correlation between serum MCP-1 level and Rentrop score (r=0.39, P<0.001). The patients in the good collateral group also had a significantly higher number of coronary arteries with significant stenosis (1.7±0.7 vs. 1.4±0.6, P=0.049), and higher VEGF levels (322±147pg/ml vs. 225±161pg/ml, P=0.007). In multivariate analysis, only serum MCP-1 level (P=0.014, odds ratio: 1.01, 95% confidence interval: 1.002–1.019) was independently related to good coronary collateral development. Conclusion Higher serum MCP-1 level is related to better coronary collateral development. Coron Artery Dis 21:455–459 c 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins. Coronary Artery Disease 2010, 21:455–459

Growth Differentiation Factor 15 and Coronary Collateral Formation

The coronary collateral circulation can reduce sudden cardiac death,myocardial cell loss,and infarct size.Growth differentiation factor 15(GDF-15),a member of the transforming growth factor-beta (TGF-beta) superfamily,has been reported to have a prognostic predicting value in coronary artery disease. GDF-15 can be related with the extent of collateral formation. Growth differentiation factor 15 (GDF-15), a member of the transforming growth factor-beta (TGF-beta) superfamily, has been reported to have a prognostic predicting value in coronary artery disease. We sought to investigate whether GDF-15 is related to coronary collateral development in patients with coronary heart disease. A cross-sectional study was performed in 201 patients, who were admitted for selective coronary angiography. Patients were divided into 3 groups based on Rentrop's classification of coronary collaterals. Group 1: patients with coronary collateral presence, which was defined by Rentrop's grade 1-3 collateral development. Group 2: patients with grade 0 collateral development. Group 3: control group were patients with a normal coronary angiogram. The levels of plasma GDF-15, asymmetric dimethylarginine (ADMA), and soluble Fms-related tyrosine kinase-1 (sFLT-1) were compared among the 3 groups. There were significant statistical differences in plasma sFLT-1, ADMA, and GDF-15 concentrations among the different collateral groups. The correlations between Rentrop's grade and the cytokines were significant. A positive correlation was found between Rentrop's grade and GDF-15 (r = 0.187, P < 0.05). The correlations between the levels of plasma sFLT-1, ADMA, and Rentrop's grade were significant, with the correlation coefficient of r = 0.181, P < 0.05 (sFLT-1) and r = - 0.646, P < 0.001 (ADMA), respectively. Our findings suggest that GDF-15 levels increase with the extent of collateral formation. In that case, the patients with a higher level of GDF-15 may predict more severe coronary stenosis, which has a higher probability to develop collaterals.