Enhanced tyrosine sulfation is associated with chronic kidney disease-related atherosclerosis.

BACKGROUND: Chronic kidney disease (CKD) accelerates atherosclerosis, but the mechanisms remain unclear. Tyrosine sulfation has been recognized as a key post-translational modification (PTM) in regulation of various cellular processes, and the sulfated adhesion molecules and chemokine receptors have been shown to participate in the pathogenesis of atherosclerosis via enhancement of monocyte/macrophage function. The levels of inorganic sulfate, the essential substrate for the sulfation reaction, are dramatically increased in patients with CKD, which indicates a change of sulfation status in CKD patients. Thus, in the present study, we detected the sulfation status in CKD patients and probed into the impact of sulfation on CKD-related atherosclerosis by targeting tyrosine sulfation function. RESULTS: PBMCs from individuals with CKD showed higher amounts of total sulfotyrosine and tyrosylprotein sulfotransferase (TPST) type 1 and 2 protein levels. The plasma level of O-sulfotyrosine, the metabolic end product of tyrosine sulfation, increased significantly in CKD patients. Statistically, O-sulfotyrosine and the coronary atherosclerosis severity SYNTAX score positively correlated. Mechanically, more sulfate-positive nucleated cells in peripheral blood and more abundant infiltration of sulfated macrophages in deteriorated vascular plaques in CKD ApoE null mice were noted. Knockout of TPST1 and TPST2 decreased atherosclerosis and peritoneal macrophage adherence and migration in CKD condition. The sulfation of the chemokine receptors, CCR2 and CCR5, was increased in PBMCs from CKD patients. CONCLUSIONS: CKD is associated with increased sulfation status. Increased sulfation contributes to monocyte/macrophage activation and might be involved in CKD-related atherosclerosis. Inhibition of sulfation may suppress CKD-related atherosclerosis and is worthy of further study.

Quantitative Data-Independent Acquisition Mass Spectrometry Proteomics and Weighted Correlation Network Analysis of Plasma Samples for the Discovery of Chronic Kidney Disease-Specific Atherosclerosis Risk Factors.

Chronic kidney disease (CKD) accelerates atherosclerosis. The mechanism of CKD-related atherosclerosis is complex, and CKD-specific risk factors may contribute to this process in addition to traditional risk factors such as hypertension, diabetes, and hypercholesterolemia. In the present study, to discover CKD-specific atherosclerosis risk factors, a total of 62 patients with different stages of kidney function were enrolled. All patients underwent coronary angiographies and the severity of coronary atherosclerosis was defined by the SYNTAX score. Patients were divided into different groups according to their kidney function levels and coronary atherosclerosis severity. Data-independent acquisition mass spectrometry was used to identify differentially expressed proteins (DEPs) in the plasma samples, and weighted correlation network analysis (WGCNA) was employed to identify significant protein modules and hub proteins related to CKD-specific atherosclerosis. The results showed that 10 DEPs associated with atherosclerosis were found in the comparative groups with modest and severe CKD. Through WGCNA, 1768 proteins were identified and 8 protein modules were established. Enrichment analyses of protein modules revealed functional clusters mainly associated with inflammation and the complement and coagulation cascade as atherosclerosis developed under CKD conditions. The results may help to better understand the mechanisms of CKD-related atherosclerosis and guide future research on developing treatments for CKD-related atherosclerosis.

Oncostatin M promotes infarct repair and improves cardiac function after myocardial infarction.

Myocardial infarction (MI) is one of the leading causes of morbidity and mortality worldwide. The immune response plays a central role in post-MI cardiac repair. A growing body of evidence suggests that oncostatin M (OSM), a pleiomorphic cytokine of the interleukin (IL)-6 family, participates in the cardiac healing and remodeling process. However, previous studies have shown inconsistent results, and the exact mechanisms underlying this process have not yet been fully elucidated. We verified whether OSM is involved in the healing process and cardiac remodeling after MI and sought to explore its potential mechanisms. Our data implied OSM's role in facilitating the post-MI healing process in mice, manifested by improved cardiac functional performance and a reduction in fibrotic changes. Furthermore, our flow cytometry analysis revealed that OSM influences the dynamics of cardiac monocytes and macrophages. In mice with a blunted C-X-C motif receptor (CCR)2 signaling pathway, OSM reserved its protective roles and polarized cardiac macrophages toward a reparative phenotype. Moreover, OSM reduced the number of matrix metalloproteinase (MMP)-9+ immune cells and increased the number of tissue inhibitor of metalloproteinase (TIMP)-1+ immune cells in the infarct area, mitigating the maladaptive remodeling following MI. These findings demonstrate that OSM favorably modulates cardiac remodeling, partially by accelerating the shift in the cardiac macrophage phenotype from M1 to M2 and by correcting the MMP-9 and TIMP-1 balance.

Biosafety and efficacy evaluation of a biodegradable magnesium-based drug-eluting stent in porcine coronary artery.

Although the drug-eluting stent (DES) has become the standard for percutaneous coronary intervention (PCI)-based revascularization, concerns remain regarding the use of DES, mainly due to its permanent rigid constraint to vessels. A drug-eluting bioresorbable stent (BRS) was thus developed as an alternative to DES, which can be absorbed entirely after its therapeutic period. Magnesium (Mg)-based BRSs have attracted a great deal of attention due to their suitable mechanical properties, innovative chemical features, and well-proven biocompatibility. However, the primary disadvantage of Mg-based BRSs is the rapid degradation rate, resulting in the early loss of structural support long before the recovery of vascular function. Recently, a new type of patented Mg-Nd-Zn-Zr alloy (JDBM) was developed at Shanghai Jiao Tong University to reduce the degradation rate compared to commercial Mg alloys. In the present investigation, a poly(D,L-lactic acid)-coated and rapamycin eluting (PDLLA/RAPA) JDBM BRS was prepared, and its biosafety and efficacy for coronary artery stenosis were evaluated via in vitro and in vivo experiments. The degree of smooth muscle cell adhesion to the PDLLA/RAPA coated alloy and the rapamycin pharmacokinetics of JDBM BRS were first assessed in vitro. JDBM BRS and commercial DES FIREHAWK were then implanted in the coronary arteries of a porcine model. Neointimal hyperplasia was evaluated at 30, 90, and 180 days, and re-endothelialization was evaluated at 30 days. Furthermore, Micro-CT and optical coherence tomography (OCT) analyses were performed 180 days after stent implantation to evaluate the technical feasibility, biocompatibility, and degradation characteristics of JDBM BRS in vivo. The results show the ability of a PDLLA/RAPA coated JDBM to inhibit smooth muscle cell adhesion and moderate the drug release rate of JDBM BRS in vitro. In vivo, low local and systemic risks of JDBM BRS were demonstrated in the porcine model, with preserved mechanical integrity after 6 months of implantation. We also showed that this novel BRS was associated with a similar efficacy profile compared with standard DES and high anti-restenosis performance. These findings may confer long term advantages for using this BRS over a traditional DES.

Optimal timing of coronary angiograms for patients with chronic kidney disease: association between the duration of kidney dysfunction and SYNTAX scores.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of the progression of coronary artery disease (CAD). However, there are few data on the relationship between CAD severity and the duration of CKD. This study assessed the predictive value of the duration of kidney dysfunction in CKD patients with CAD severity. METHODS: In 145 patients (63.4% male, n = 92; mean age, 68.8 ± 12.8 years) with CKD, severity of CAD was assessed by coronary angiography and quantified by SYNTAX scores, and duration of kidney dysfunction was either assessed by checking historical biochemical parameters of individuals or was based on enquiries. RESULTS: Patients with high SYNTAX scores (≥ 22) had a greater prevalence of cardiovascular risk factors including age, gender, history of heart failure and smoking. In CKD patients, SYNTAX scores were positively correlated to duration of CKD and serum uric acid (UA), and negatively correlated to high-density lipoprotein-cholesterol (HDL-C) and ApoA1 levels. Univariate binary logistic regression and multivariate logistic analyses showed that SYNTAX scores correlated significantly with CKD duration, UA, and HDL-C. Receiver-operating characteristic analysis was used to explore a time point when coronary angiography application was economical and effective and yielded a Youden index of 6.5 years. CONCLUSIONS: Together, our results demonstrated that the duration of kidney dysfunction was an independent correlate of the severity of CAD in patients with CKD. Our findings suggest that coronary angiography should be considered for CKD patients with renal insufficiency having lasted for more than 6.5 years.

Using circulating O-sulfotyrosine in the differential diagnosis of acute kidney injury and chronic kidney disease.

BACKGROUND: Sulfation of tyrosine, yielding O-sulfotyrosine, is a common but fixed post-translational modification in eukaryotes. Patients with increased circulating O-sulfotyrosine levels experience a faster decline in renal function with progression to end-stage renal disease (ESRD). In the present study, we measured serum O-sulfotyrosine levels in individuals with chronic kidney disease (CKD) and acute kidney injury (AKI) to explore its ability to differentiate AKI from CKD. METHODS: A total of 135 patients (20 with AKI and 115 with CKD) were recruited prospectively for liquid chromatography-mass spectrometry assessment of circulating O-sulfotyrosine. We also studied C57BL/6 mice with CKD after 5/6 nephrectomy (Nx). Blood samples were drawn from the tail vein on Day 1, 3, 5, 7, 14, 30, 60, and 90 after CKD. Serum separation and characterization of creatinine, blood urea nitrogen (BUN), and O-sulfotyrosine was performed. Thus, the time-concentration curves of the O-sulfotyrosine level demonstrate the variation of kidney dysfunction. RESULTS: The serum levels of O-sulfotyrosine were markedly increased in patients with CKD compared with AKI. Median O-sulfotyrosine levels in CKD patients versus AKI, respectively, were as follows:243.61 ng/mL(interquartile range [IQR] = 171.90-553.86) versus 126.55 ng/mL (IQR = 48.19-185.03, P = 0.004). In patients with CKD, O-sulfotyrosine levels were positively correlated with creatinine, BUN, and Cystatin C (r = 0.63, P < 0.001; r = 0.49, P < 0.001; r = 0.61, P < 0.001, respectively) by the multivariate linear regression analysis (ß = 0.71, P < 0.001; ß = 0.40, P = 0.002; ß = 0.73, P < 0.001, respectively). However, this association was not statistically significant in patients with AKI (r = - 0.17, P = 0.472; r = 0.11, P = 0.655; r = 0.09, P = 0.716, respectively). The receiver operating characteristic (ROC) analysis illustrated that the area under the curve was 0.80 (95% confidence interval [CI] 0.71-0.89; P < 0.001) and the optimal cut-off value of serum O-sulfotyrosine suggesting AKI was < 147.40 ng/mL with a sensitivity and specificity of 80.90 and 70.00% respectively. In animal experiments, serum levels of O-sulfotyrosine in mice were elevated on Day 7 after 5/6 nephrectomy (14.89 ± 1.05 vs. 8.88 ± 2.62 ng/mL, P < 0.001) until Day 90 (32.65 ± 5.59 vs. 8.88 ± 2.62 ng/mL, P < 0.001). CONCLUSION: Serum O-sulfotyrosine levels were observed correlated with degrading renal function and in CKD patients substantially higher than those in AKI patients. Thus serum O-sulfotyrosine facilitated the differential diagnosis of AKI from CKD.

Lgr4 Governs a Pro-Inflammatory Program in Macrophages to Antagonize Post-Infarction Cardiac Repair.

RATIONALE: Macrophages are critically involved in wound healing following myocardial infarction (MI). Lgr4, a member of LGR (leucine-rich repeat-containing G protein-coupled receptor) family, is emerging as a regulator of macrophage-associated immune responses. However, the contribution of Lgr4 to macrophage phenotype and function in the context of MI remains unclear. OBJECTIVE: To determine the role of macrophage Lgr4 in MI and to dissect the underlying mechanisms. METHODS AND RESULTS: During early inflammatory phase of MI, infarct macrophages rather than neutrophils expressed high level of Lgr4. Macrophage-specific Lgr4 knockout mice had no baseline cardiovascular defects but manifested improved heart function, modestly reduced infarct size, decreased early mortality due to cardiac rupture, and ameliorated adverse remodeling after MI. Improved outcomes in macrophage-specific Lgr4 knockout mice subjected to MI were associated with mitigated ischemic injury and optimal infarct healing, as determined by reduction of cardiac apoptosis in the peri-infarct zone, attenuation of local myocardial inflammatory response, decrease of matrix metalloproteinase expression in the infarct, enhancement of angiogenesis, myofibroblast proliferation, and collagen I deposition in reparative granulation tissue as well as formation of collagen-rich scar. More importantly, macrophage-specific Lgr4 knockout infarcts had reduced numbers of infiltrating leukocytes and inflammatory macrophages but harbored abundant reparative macrophage subsets. Lgr4-null infarct macrophages exhibited a less inflammatory transcriptional signature. These findings were further supported by transcriptomic profiling data showing repression of multiple pathways and broad-spectrum genes associated with proinflammatory responses in macrophage-specific Lgr4 knockout infarcts. Notably, we discovered that Lgr4-mediated functional phenotype programing in infarct macrophages was at least partly attributed to regulation of AP (activator protein)-1 activity. We further demonstrated that the synergistic effects of Lgr4 on AP-1 activation in inflammatory macrophages occurred via enhancing CREB (cAMP response element-binding protein)-mediated c-Fos, Fosl1, and Fosb transactivation. CONCLUSIONS: Together, our data highlight the significance of Lgr4 in governing proinflammatory phenotype of infarct macrophages and postinfarction repair.

Dexmedetomidine improves cardiac function and protects against maladaptive remodeling following myocardial infarction.

Dexmedetomidine (DEX), a highly specific and selective α2 adrenergic receptor agonist, has been demonstrated to possess potential cardioprotective effects. However, the mechanisms underlying this process remain to be fully illuminated. In the present study, a myocardial infarction (MI) animal model was generated by permanently ligating the left anterior descending coronary artery in mice. Cardiac function and collagen content were evaluated by transthoracic echocardiography and picrosirius red staining, respectively. Apoptosis was determined by the relative expression levels of Bax and Bcl­2 and the myocardial caspase­3 activity. Additionally, nicotinamide adenine dinucleotide phosphate oxidase (NOX)­derived oxidative stress was evaluated by the relative expression of Nox2 and Nox4, along with the myocardial contents of malondialdehyde (MDA) and superoxide dismutase (SOD) activity. It was demonstrated that intraperitoneal DEX treatment (20 µg/kg/day) improved the systolic function of the left ventricle, and decreased the fibrotic changes in post­myocardial infarction mice, which was paralleled by a decrease in the levels of apoptosis. Subsequent experiments indicated that the restoration of redox signaling was achieved by DEX administration, and the over­activation of NOXs, including Nox2 and Nox4, was markedly inhibited. In conclusion, this present study suggested that DEX was cardioprotective and limited the excess production of NOX­derived ROS in ischemic heart disease, implying that DEX is a promising novel drug, especially for patients who have suffered MI.

Serum sLYVE-1 is not associated with coronary disease but with renal dysfunction: a retrospective study.

Recent evidence has indicated that the lymphatic vessel endothelial hyaluronan receptor (LYVE-1) is implicated in chronic inflammation and the lymphatic immune response. The soluble form of LYVE-1 (sLYVE-1) is produced by ectodomain shedding of LYVE-1 under pathological conditions including cancer and chronic inflammation. In this study, 1014 consecutive patients who underwent coronary angiography from May 2015 to September 2015 were included to investigate whether serum sLYVE-1 is associated with coronary artery disease (CAD) and its concomitant diseases includes chronic kidney disease (CKD). Results showed that there was no significant difference in sLYVE-1 levels between patients with CAD and without. However, a significantly higher level of sLYVE-1 was seen in patients with renal dysfunction compared to those with a normal eGFR. Results were validated in a separate cohort of 259 patients who were divided into four groups based on their kidney function assessed by estimated glomerular filtration rate (eGFR). Simple bivariate correlation analysis revealed that Lg[sLYVE-1] was negatively correlated with eGFR (r = -0.358, p < 0.001) and cystatin C (r = 0.303, p < 0.001). Multivariable logistic regression analysis revealed that the increase in Lg[sLYVE-1] was an independent determinant of renal dysfunction (odds ratio = 1.633, p = 0.007). Therefore, renal function should be considered when serum sLYVE-1 is used as a biomarker for the detection of pathological conditions such as chronic inflammation and cancer. Further study is required to elucidate the exact role of sLYVE-1 in renal function.

Impact of serum levels of lipoprotein lipase, hepatic lipase, and endothelial lipase on the progression of coronary artery disease.

PURPOSE: The purpose of this study was to investigate the relationship between serum levels of lipoprotein lipase (LPL), hepatic lipase (HL), and endothelial lipase (EL) and the progression of coronary artery disease (CAD). MATERIALS AND METHODS: According to the inclusion criteria, exclusion criteria, diagnostic criteria, angiography results, and the random matching scheme, the enrolled patients were divided into the following two groups: the progression-free group (n = 47) and the progression group (n = 15). The baseline characteristics and various biochemical parameters were obtained from the medical records and medical history. Serum LPL, HL, and EL levels were detected by ELISA. The correlation between serum LPL, HL, and EL levels and coronary lesions was statistically analyzed with SPSS software. RESULTS: Significant differences were observed in serum levels of HL and EL between the progression-free group and the progression group (HL, 75.5 ±â€¯39.2 ng/mL vs. 125.1 ±â€¯42.1 ng/mL, P < 0.05; EL, 139.2 ±â€¯59.6 pg/mL vs. 175.1 ±â€¯40.1 pg/mL, P < 0.05), while the difference in the LPL level was not significant (P > 0.05). Receiver operating characteristic curve (ROC) analysis showed that the area under the curve (AUC) values of LPL, HL, and EL were 0.506 (95% CI: 0.369-0.642, P = 0.9470), 0.792 (95% CI: 0.664-0.888, P < 0.0001), and 0.693 (95% CI: 0.553-0.811, P = 0.0095), respectively. Additionally, logistic regression analysis showed that the serum level of HL was an independent risk factor for coronary artery lesion progression. CONCLUSION: Serum levels of EL and HL, but not the serum level of LPL, were positively correlated with the progression of CAD. The serum level of HL was an independent risk factor for the progression of CAD, while the serum level of EL or LPL was not an independent risk factor for the progression of CAD. For the diagnosis of CAD progression, the serum level of HL was better than the serum level of EL or LPL.

Recombinant human interleukin-1 receptor antagonist treatment protects rats from myocardial ischemia-reperfusion injury.

The interleukin-1 (IL-1) signaling pathway plays a vital role in multiple mechanisms associated with myocardial ischemia-reperfusion (I/R) injury, including inflammation and apoptosis. An IL-1 receptor antagonist (IL-1Ra) can block IL-1 by competitive binding to the IL-1 receptor type I (IL-1RI) and thus may provide a cardioprotective effect. In the present investigation, we determined whether exogenous administration of recombinant human IL-1Ra (rhIL-1Ra) provides a protective role against myocardial I/R injury. Sprague-Dawley rats underwent surgical coronary artery ligation (or sham operation) by occlusion of the left anterior descending artery (LAD) for 30 min followed by reperfusion. After 30 min of reperfusion, a 2 mg/kg dose of rhIL-1Ra was injected subcutaneously. This was followed up with once daily injections for seven days. Echocardiography revealed that ejection fraction (EF) values were significantly greater in the rhIL-1Ra-treated animals. RhIL-1Ra was found to reduce the severity of myocardial injury and increase the viability of the cardiac tissue. There was found to be less IL-1ß expression in rhIL-1Ra-treated animals than in controls. These results provide compelling data to suggest administration of IL-1Ra could have a significant cardioprotective effect against myocardial I/R injury and thus IL-1Ra could emerge as a potential clinical drug for the treatment of myocardial I/R injury.

Tubular epithelial C1orf54 mediates protection and recovery from acute kidney injury.

Acute kidney injury (AKI) incidence among hospitalized patients is increasing steadily. Despite progress in prevention strategies and support measures, AKI remains correlated with high mortality, particularly among ICU patients, and no effective AKI therapy exists. Here, we investigated the function in kidney ischaemia-reperfusion injury (IRI) of C1orf54, a newly identified protein encoded by an open reading frame on chromosome 1. C1orf54 expression was high in kidney and low in heart, liver, spleen, lung and skeletal muscle in healthy mice, and in the kidney, C1orf54 was expressed in tubular epithelial cells (TECs), but not in glomeruli. C1orf54 expression was markedly decreased on Day 1 after kidney IRI and then gradually recovered to baseline levels by Day 7. Notably, relative to wild-type mice, C1orf54-knockout mice exhibited impaired TEC proliferation and delayed recovery after kidney IRI, which led to deteriorated renal function and increased mortality. Conversely, adenovirus-mediated C1orf54 overexpression promoted TEC proliferation and ameliorated kidney pathology, which resulted in accelerated renal repair and improved renal function. Mechanistically, C1orf54 was found to promote TEC proliferation through PI3K/AKT signalling. Thus, C1orf54 holds considerable potential as a therapeutic target in kidney IRI.

The anti-inflammatory vasostatin-2 attenuates atherosclerosis in ApoE-/- mice and inhibits monocyte/macrophage recruitment.

We showed previously that reduced level of vasostatin-2 (VS-2) correlates to the presence and severity of coronary artery disease. In this study, we aimed to figure out the role of chromogranin A (CGA) derived VS-2 in the development of atherosclerosis and monocyte/macrophage recruitment. Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet exhibited attenuated lesion size by 65 % and 41 % in En face and aortic root Oil red O staining, MOMA-2 positive area by 64 %, respectively, in VS-2 treatment group compared with PBS group. Proinflammatory cytokines tumour necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) were all remarkably reduced in aortic tissues after VS-2 treatment. Mechanistically, in adhesion assay using intravital microscopy in vivo, VS-2 suppressed the number of leukocytes adhering to the wall of apoE-/- mice mesenteric arteries. In chemotactic assay, flow cytometry analysis of peritoneal lavage exudate from C57BL/6 mice showed VS-2 significantly decreased the recruiment number of inflammatory monocytes/macrophages in a thioglycollate-induced peritonitis model. Furthermore, fewer fluorescent latex beads labelled Ly-6Chi monocytes accumulated in aortic sinus lesions of apoE-/- mice after VS-2 treatment. In addition, according to the microarray of human monocyte/macrophage, we found VS-2 stimulation caused a dose-dependent decrease of Rac1 expression and inactivation of Pak1 in mice primary monocytes as well as THP-1 cells and inhibited MCP-1/CCL-5 induced transmigration in vitro. In conclusion, the Chromogranin A-derived VS-2 attenuates atherosclerosis in apoE-/- mice and, in addition to its anti-inflammatory property, also acts as an inhibitor in monocyte/macrophage recruitment.

Association of decreased serum sTREM-1 level with the severity of coronary artery disease: Inhibitory effect of sTREM-1 on TNF-α- and oxLDL-induced inflammatory reactions in endothelial cells.

Soluble triggering receptor expressed on myeloid cells 1 (sTREM-1) is closely involved in autoimmune diseases and inflammatory reactions. We aimed to investigate whether serum sTREM-1 is related to coronary artery disease (CAD) and to evaluate the biological effects of sTREM-1 in cell experiments.This cross-sectional study included 263 consecutive patients with angiographically documented CAD, who were admitted for diagnosis and interventional treatment of CAD (CAD group), with 162 participants without CAD serving as controls (control group). Serum levels of sTREM-1 and high sensitivity C reactive protein (hsCRP) were determined in all participants. In cell experiments, the influence of sTREM-1 on tumor necrosis factor-α (TNF-α)- or oxidized low-density lipoprotein (oxLDL)-induced inflammatory reactions was evaluated in human umbilical vein endothelial cells (HUVECs).Serum level of sTREM-1 was significantly lower in CAD patients than in controls (P < 0.001). sTREM-1 values were related to the number of diseased coronary arteries (Spearman r = -0.413, P < 0.001) and the severity represented by Gensini score (Pearson r = -0.336, P < 0.001). Multivariable logistic regression analysis revealed that decreased sTREM-1 were independent determinants of CAD (OR = 0.428, P < 0.001). In cell experiments, recombinant sTREM-1 protein concentration-dependently inhibited the expression of IL-1ß, IL-6, TNF-α, VCAM-1, and ICAM-1 induced by TNF-α or oxLDL in HUVECs.This study demonstrates that decreased serum sTREM-1 level is significantly associated with the presence and severity of CAD. sTREM-1 restrains inflammatory reaction in endothelial cells, suggesting that it might be a potential vascular protective factor.

Clinical utility of the ratio between circulating fibrinogen and fibrin (ogen) degradation products for evaluating coronary artery disease in type 2 diabetic patients.

BACKGROUND: We investigated whether and to what extent the ratio between circulating fibrinogen (Fg) and its degradation products (FDP) reflects the severity of coronary artery disease (CAD) in type 2 diabetic patients. METHODS: Plasma levels of Fg and FDP were determined, and Fg/FDP ratio was calculated in 344 consecutive patients with type 2 diabetes and chest pain on exertion undergoing coronary angiography. The severity of CAD was evaluated by the number of significant CAD (>50% luminal diameter narrowing) and Gensini score. RESULTS: Plasma Fg was higher, but Fg/FDP ratio was lower in patients with significant CAD (n = 255) compared with those without (n = 89), due to a disproportionate increase in FDP. Fg and FDP correlated positively, while Fg/FDP ratio negatively, with the number of diseased coronary arteries and the tertile of Gensini score (all P values for trend < 0.01). After adjusting for age, sex, risk factors for CAD, lipid profiles, glycosylated hemoglobin A1c, creatinine, leukocyte count, and high-sensitivity C-reactive protein, Fg/FDP ratio remained an independent determinant for multivessel coronary disease (MVD) (odds ratio [OR], 0.869; 95% confidence interval [CI], 0.788-0.958, P = 0.005) and high tertile of Gensini score (OR, 0.797, 95% CI, 0.682-0.930, P = 0.004). The area under the curve of Fg/FDP ratio was larger than that of Fg for predicting the presence of MVD (0.647 vs. 0.563, P = 0.048) and Gensini score ≥ 30 (0.656 vs. 0.538, P = 0.026). CONCLUSIONS: Elevated plasma Fg and FDP level and reduced Fg/FDP ratio are associated with presence of CAD, and Fg/FDP ratio is superior to Fg in reflecting severe coronary atherosclerosis for patients with type 2 diabetes.