Relationship between intravascular ultrasound imaging features of coronary plaques and soluble CD105 level in patients with coronary heart disease

Plaque rupture with subsequent thrombus formation is the common pathophysiological substrate of acute coronary syndrome (ACS).1 Moreno et al2 reported that neovascularization as manifested by the localized appearance of microvessels is increased in ruptured plaques in the human aorta. Microvessel density is also increased in inflammatory lesions, with intraplaque hemorrhage and in thin-cap fibroatheromas. Microvessels at the base of the plaque are independently correlated with plaque rupture, suggesting a contributory role for neovascularization in the process of plaque rupture. Soluble CD 105, a sensitive serum marker of neovascularization, is thought to be associated with cardiovascular disease. The purpose of this study was to assess the relationship between the level of soluble CD 105 and the morphological plaques by intravascular ultrasound (IVUS) in patients with stable angina (SA) and those with unstable angina (UA) and whether soluble CD105 may serve as a non-invasive marker of coronary plaque destabilization. METHODS Patients From August 2004 to December 2006, a clinical study was conducted in 102 patients who were divided into 3 groups: 30 patients in control group, 25 patients in SA group, and 47 patients in UA group. Concentrations of soluble CD105 were measured in all of the patients examined by cardioangiography (CAG). The study protocol was approved by the local institutional review board and informed consents were obtained from each patient. IVUS imaging and analysis According to the results of CAG, 9 of the SA group and 31 of the UA group were examined by IVUS with a 2.9F, 30-MHz mechanical transducer (JOMED In-Vision R Gold V 4.01, Germany). Qualitative and quantitative analyses of IVUS images were performed by two independent experienced observers, according to the recommendations of the American College of Cardiology's Clinical Expert Consensus Document on IVUS.3 The parameters measured in the present study included external elastic membrane cross-sectional area (EEM CSA), minimal lumen cross-sectional area (MLA), plaque area (EEM CSA-MLA), plaque burden (plaque area/EEM CSA × 100), eccentric index (EI), lipid pool area, lipid pool burden (lipid pool area/plaque area × 100), thickness of fabric-cap, and remolding index (RI, positive remodeling: RI > 1.05; negative remodeling: RI < 0.95). According to the morphology of IVUS plaque, plaques were divided into two groups: unstable plaque group and stable plaque group. The former has the following characteristics: lipid pool area >1 mm2, lipid pool burden >20%, fibrous caps <0.7 mm, and strong inflammation reaction at the plaque cap (Fig.).4,5Fig. A:: Stable plaque (concentric lesion with thick fabric-cap and small lipid pool). B: Unstable plaque (eccentric lesion within fabric-cap and big lipid pool). C: ruptured plaque (eccentric lesion with fabric-cap dissection).Measurement of soluble CD105 Concentrations of soluble CD105 (Quantikine human soluble CD105, R&D, USA; minimum detectable dose (MMD) is 0.156 ng/ml) in stored serum were measured by enzyme-linked immunosorbent assay (ELISA). Statistical analysis Continuous variables are shown as mean ± standard deviation (SD) and categorical variables as frequencies (%). Continuous variables were compared using unpaired Student's t test or analysis of variance (ANOVA). Categorical variables were compared with the chi- square test. A P value <0.05 was considered statistically significant. Statistical analysis was performed with SPSS 11.5 (SPSS Inc., Chicago, IL, USA). RESULTS Characteristics of patients Unstable plaques were mainly observed in 22 UA patients (71%), whereas stable plaques were mainly observed in 8 SA patients (89%) (Table 1). No significant difference was found in baseline clinical characteristics among the 3 groups. Unstable plaque was more frequently found in UA patients (70.97%).Table 1: Clinical characteristics of the patientsIVUS findings IVUS found that patients in the SA group had stable and fibrous plaques, whereas those in the UA group had unstable and soft lipid plaques (P<0.01). But fibrous plaques were also found in the UA group (17/66, 26%), mainly in 10 patients of low risk or moderate risk subgroups. Calcified plaques were found in the SA group as well as in UA group with no significant difference (P>0.05). RI and EI were higher in the UA group than in the SA group (P<0.05), and coronary segments in the UA group were prone to positive remodeling (Table 2).Table 2: Pre-intervention IVUS findingsSoluble CD105 The soluble CD105 level was higher in the UA group than in the SA group ((4.06 ± 0.19) ng/ml vs (3.47±0.17) ng/ml, P<0.05) as well as in the SA group than in the control group ((3.47±0.17) ng/ml vs (2.57±0.54) ng/ml, P<0.05). The concentration of soluble CD105 was significantly higher in the unstable plaque group than in the stable plaque group ((4.01±0.18) ng/ml vs (3.22± 0.16) ng/ml, P<0.01). DISCUSSION Rupture at the site of a vulnerable atherosclerotic plaque is the most frequent cause of acute coronary syndrome. Typically, such plaque does not cause high-grade stenosis but has a large lipid core and a thin fibrous cap that is often infiltrated by inflammatory cells.6 Using IVUS imaging, we investigated the relationship between plaque characteristics and arterial remodeling. In comparison to the patients with negative remodeling, the patients with positive remodeling presented with more unstable angina pectoris. Both plaque area and vessel area were significantly larger in lesions with positive remodeling than in those with negative remodeling. The lesions with positive remodeling were predominantly soft compared with lesions with negative remodeling. Observational studies of necrotic core progression identified intraplaque hemorrhage as a critical factor in atherosclerotic plaque growth and destabilization.7,8 Neoangiogenesis is associated closely with plaque progression, and microvascular incompetence is a likely source of intraplaque hemorrhage. In the absence of disease, microvessels provide vessel wall nutrients to the tunica media, whereas the intima is fed by oxygen diffusion from the lumen. In addition, microvessels are also involved in stent restenosis and plaque regression. Therefore, they are a pivotal component of atherosclerosis, and proper patient risk-stratification in the near future may include the detection of increased neovascularization in atherosclerotic lesions, a “bench to bedside” approach to neovascularization in human atherosclerosis.9 Endoglin is a transmembrane protein that is found to be associated with transforming growth factor-beta (TGF-β) superfamily receptor complexes and has an expression pattern that appears to be restricted primarily to endothelial cells, activated macrophages, trophoblasts, and fibroblasts.10 According to previous reports, CD105 may be present in vascular endothelial cells, vascular smooth muscle cells and vascular fibroblast cells.11-14 Since CD105 can be detected in the presence of E-9 protein in tissue culture media of endothelial cells and soluble CD105 can be detected in serum samples of health people and cancer patients, soluble CD105 may be a dropping physiology phenomenon of CD105 in normal or abnormal state.15 In the present study, the soluble CD105 level was higher in the UA group than in the SA group, and in the unstable plaque group than in the stable plaque group. This finding shows that neovascularization is more increased in UA and unstable plaque patients. In conclusion, there is a close relationship between plaque morphology and clinical manifestations in patients with ACS. Positive remolding and bigger plaque area can be found in voluable plaque, and negative remodeling and smaller plaque area in stable plaque. The elevation of soluble CD105 is related to plaque characteristics and may serve as a predictor for soluble plaque. Large sample studies are needed to prove whether soluble CD105 can predict the ruptured plaque.