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      Serum Cystatin C Reflects Angiographic Coronary Collateralization in Stable Coronary Artery Disease Patients with Chronic Total Occlusion

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          Abstract

          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.

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          Most cited references42

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          Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus

          (2002)
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            Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects.

            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)
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              Collateral circulation

              Following an arterial occlusion outward remodeling of pre-existent inter-connecting arterioles occurs by proliferation of vascular smooth muscle and endothelial cells. This is initiated by deformation of the endothelial cells through increased pulsatile fluid shear stress (FSS) caused by the steep pressure gradient between the high pre-occlusive and the very low post-occlusive pressure regions that are interconnected by collateral vessels. Shear stress leads to the activation and expression of all NOS isoforms and NO production, followed by endothelial VEGF secretion, which induces MCP-1 synthesis in endothelium and in the smooth muscle of the media. This leads to attraction and activation of monocytes and T-cells into the adventitial space (peripheral collateral vessels) or attachment of these cells to the endothelium (coronary collaterals). Mononuclear cells produce proteases and growth factors to digest the extra-cellular scaffold and allow motility and provide space for the new cells. They also produce NO from iNOS, which is essential for arteriogenesis. The bulk of new tissue production is carried by the smooth muscles of the media, which transform their phenotype from a contractile into a synthetic and proliferative one. Important roles are played by actin binding proteins like ABRA, cofilin, and thymosin beta 4 which determine actin polymerization and maturation. Integrins and connexins are markedly up-regulated. A key role in this concerted action which leads to a 2-to-20 fold increase in vascular diameter, depending on species size (mouse versus human) are the transcription factors AP-1, egr-1, carp, ets, by the Rho pathway and by the Mitogen Activated Kinases ERK-1 and -2. In spite of the enormous increase in tissue mass (up to 50-fold) the degree of functional restoration of blood flow capacity is incomplete and ends at 30% of maximal conductance (coronary) and 40% in the vascular periphery. The process of arteriogenesis can be drastically stimulated by increases in FSS (arterio-venous fistulas) and can be completely blocked by inhibition of NO production, by pharmacological blockade of VEGF-A and by the inhibition of the Rho-pathway. Pharmacological stimulation of arteriogenesis, important for the treatment of arterial occlusive diseases, seems feasible with NO donors.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                24 September 2015
                2015
                : 10
                : 9
                : e0137253
                Affiliations
                [1 ]Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People’s Republic of China
                [2 ]Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People’s Republic of China
                Universitätsklinikum des Saarlandes, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: YS. Performed the experiments: RYZ QZ LL. Analyzed the data: FHD. Contributed reagents/materials/analysis tools: LL. Wrote the paper: WFS.

                Article
                PONE-D-15-26820
                10.1371/journal.pone.0137253
                4581619
                26402227
                ca218b8f-7093-4b08-8685-f327b0961487
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 22 June 2015
                : 13 August 2015
                Page count
                Figures: 3, Tables: 4, Pages: 14
                Funding
                The present work is supported by the National Natural Science Foundation of China (81400327) and Science Technology Committee of Shanghai Municipal Government (14ZR1425800). These funders support the basic and clinical researches in the field of cardiovascular diseases. However, no author received a salary from any of these funders, The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Custom metadata
                With respect to PLOS' data policy, we confirm that the ethically compliant dataset containing data of this study will be made upon request. The Ethics Committee of Rui Jin Hospital, Shanghai Jiaotong University School of Medcine is responsible for overseeing these restrictions. The contact and responsible person is Dr. Kang Chen, director, Research & Development Administration Department, Ruijin Hospital, Shanghai JiaoTong University School of Medicine. Address: 197, Ruijin Er Road, Shanghai 200025, China, Email: ck11208@ 123456rjh.com.cn ; chenkang1978@ 123456163.com .

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