Several previous studies have suggested a relation of plasma fibrinogen to the severity of coronary artery disease (CAD) [
More interestingly, few investigations suggested that glycohemoglobin might affect plasma fibrinogen concentrations in both genders and circulating high-sensitivity C-reactive protein (hs-CRP) in man [
Based on these studies, plasma fibrinogen appears to be not only an inflammatory marker linking to thrombotic disease but also a predictor connecting with the cardiovascular events. However, whether fibrinogen level has a causal relation to the diseases or reflects genetic variability and residual confounding by other risk factors has been controversial [
The study complied with the Declaration of Helsinki and was approved by the hospital ethnic review board (Fu Wai Hospital & National Center for Cardiovascular Diseases, Beijing, China). Informed written consent was obtained from all patients enrolled in this analysis.
From June 2011 to March 2012, we prospectively enrolled 373 consecutive women and men (70.2%) who aged from 31 to 79 years (average age 58.7 years) type 2 DM patients with typical stable exertional angina pectoris were referred for selective coronary angiography at our center. Patients with active cardiopulmonary diseases and serious systematic disease such as type 1 DM, acute coronary syndrome, significant hematologic disorders (white blood cell count ≤3.5 × 109/L or ≥20 × 109/L) and/or thrombosis, infectious or inflammatory disease, severe liver and/or renal insufficiency, and various cancers were excluded from the current study. In this study, the detailed demographic, clinical, hematologic, and angiographic data were collected from all subjects.
Hypertension was defined as repeated (at least two times in different peaceful circumstances) blood pressure measurements ≥140/90 mmHg or currently taking antihypertensive drugs. DM was diagnosed in patients with fasting serum glucose level of ≥6.99 mmol/L by multiple determinations or under active treatment with insulin or oral hypoglycemic agents. The hyperlipidemia was defined as low-density lipoprotein cholesterol ≥160 mg/dL and/or triglyceride (TG) ≥200 mg/dL. CAD was defined as the presence of significant obstructive stenosis, at least 50% of the vessel lumen diameters, in any of the main coronary arteries by at least two independent senior interventional cardiologists based on quantity coronary angiography. The severity of CAD was assessed by Gensini score system, which was old but still useful and popular in cardiovascular medicine [
Venous blood samples were obtained from each patient at baseline upon admission. Plasma concentrations of fibrinogen were measured by using of the Clauss method as previously reported [
Quantitative variables were expressed as mean ± standard deviation (SD), and qualitative variables were expressed as numbers and percentages. Continuous variables and categorical variables were analyzed by the Kruskal-Wallis test, chi-squared statistic tests, or Student’s
The study population of current observation consisted of 373 diabetic patients referred to coronary angiography with an average age of
Baseline demographic, clinical, and laboratory characteristics based on the tertiles of Gensini scores.
Variables |
Low |
Intermediate |
High |
|
|
---|---|---|---|---|---|
Risk factors | |||||
Age, years | 56.7 ± 9.9 | 60.0 ± 9.4 | 59.8 ± 8.9 | 0.008 | 0.121 |
Male gender | 94 (65.7) | 78 (71.6) | 90 (74.4) | 0.291 | 0.226 |
BMI (kg/m2) | 25.7 ± 3.3 | 24.9 ± 2.8 | 25.7 ± 3.0 | 0.120 | 0.447 |
Current smoking | 68 (47.6) | 59 (54.1) | 70 (57.9) | 0.235 | 0.121 |
Hypertension | 85 (59.4) | 77 (70.6) | 82 (67.8) | 0.145 | 0.508 |
Hyperlipidemia | 100 (69.9) | 88 (80.7) | 99 (81.8) | 0.039 | 0.177 |
PVD | 3 (2.1) | 3 (2.8) | 2 (1.7) | 0.847 | 0.650 |
Prior stroke | 6 (4.2) | 3 (2.8) | 6 (5.0) | 0.690 | 0.523 |
Family history of CAD | 7 (4.9) | 13 (11.9) | 17 (14.0) | 0.033 | 0.064 |
Laboratory test | |||||
LVEF (%) | 62.8 ± 7.7 | 63.1 ± 7.4 | 60.2 ± 9.5 | 0.014 | 0.003 |
NT-pro-BNP (fmol/mL) | 661.1 ± 486.8 | 667.9 ± 485.2 | 893.5 ± 764.8 | 0.305 | <0.001 |
hs-CRP (mg/L) | 3.1 ± 3.9 | 2.3 ± 3.5 | 4.0 ± 4.5 | 0.006 | 0.006 |
Leukocyte (109/L) | 6.3 ± 1.5 | 6.2 ± 1.6 | 6.8 ± 1.5 | 0.003 | 0.001 |
Platelet count (109/L) | 204.5 ± 60.4 | 192.0 ± 45.8 | 206.5 ± 55.4 | 0.098 | 0.224 |
Fibrinogen (g/L) | 3.0 ± 0.8 | 2.9 ± 0.7 | 3.3 ± 0.9 | 0.000 | <0.001 |
D-dimer (mg/dL) | 0.4 ± 0.5 | 0.4 ± 0.5 | 0.4 ± 0.6 | 0.075 | 0.487 |
Hemoglobin (g/L) | 139.4 ± 15.2 | 138.3 ± 15.6 | 137.1 ± 15.6 | 0.505 | 0.305 |
HbA1c (%) | 6.4 ± 1.2 | 6.9 ± 1.6 | 7.0 ± 1.3 | 0.000 | 0.004 |
FBG | 5.6 ± 1.6 | 6.4 ± 2.7 | 6.2 ± 1.9 | 0.009 | 0.253 |
Bilirubin (umol/L) | 15.3 ± 5.4 | 15.1 ± 5.6 | 15.4 ± 7.4 | 0.969 | 0.836 |
ALP (IU/L) | 64.2 ± 17.9 | 61.6 ± 19.1 | 62.6 ± 17.4 | 0.517 | 0.816 |
AST (IU/L) | 19.4 ± 13.3 | 18.5 ± 9.2 | 17.4 ± 10.0 | 0.342 | 0.185 |
ALT (IU/L) | 31.2 ± 33.3 | 29.7 ± 21.9 | 28.7 ± 25.1 | 0.772 | 0.554 |
Creatinine | 73.8 ± 15.0 | 75.6 ± 16.4 | 78.6 ± 14.9 | 0.041 | 0.019 |
Uric acid | 335.6 ± 75.6 | 323.3 ± 80.8 | 354.6 ± 77.4 | 0.009 | 0.005 |
Lipid profile | |||||
Triglycerides (mmol/L) | 1.7 ± 1.0 | 1.7 ± 0.8 | 1.8 ± 1.1 | 0.434 | 0.230 |
TC (mmol/L) | 4.0 ± 1.0 | 4.0 ± 0.9 | 4.1 ± 1.1 | 0.572 | 0.360 |
LDL-C (mmol/L) | 2.3 ± 0.9 | 2.4 ± 0.8 | 2.5 ± 0.9 | 0.292 | 0.121 |
HDL-C (mmol/L) | 1.1 ± 0.3 | 1.1 ± 0.3 | 1.0 ± 0.2 | 0.011 | 0.009 |
Lipoprotein (a) (mg/L) | 237.7 ± 217.5 | 190.9 ± 211.2 | 289.7 ± 283.6 | 0.008 | 0.007 |
apoA (g/L) | 1.4 ± 0.3 | 1.5 ± 0.3 | 1.4 ± 0.3 | 0.012 | 0.057 |
apoB (g/L) | 1.0 ± 0.3 | 1.0 ± 0.3 | 1.1 ± 0.3 | 0.045 | 0.015 |
Prior treatment | |||||
Aspirin | 136 (95.1) | 106 (97.2) | 118 (97.5) | 0.501 | 0.463 |
Beta-blocker | 103 (72.0) | 87 (79.8) | 109 (90.1) | 0.001 | 0.001 |
ACE-I/ARB | 27 (18.9) | 22 (20.2) | 44 (36.4) | 0.002 | <0.001 |
Statin | 125 (87.4) | 109 (100) | 116 (95.9) | 0.000 | 0.258 |
BMI: body mass index; PVD; peripheral vascular disease; CAD: coronary artery disease; LV-FE: left ventricular ejection fraction; NT-pro-BNP: N-terminal pro-brain natriuretic peptide; hs-CRP: high sensitivity C-reactive protein; HbA1c: glycosylated hemoglobin A1c; FBG: fasting blood glucose; ALP: alkaline phosphatase; AST: aspartate aminotransferase; ALT: alanine aminotransferase; TC: total cholesterol; LDL-C: low density lipoprotein cholesterol; HDL-C: high density lipoprotein cholesterol; ACE-I: angiotensin converting enzyme inhibitors; ARB: angiotensin receptor blocker.
To explore the relationship of plasma fibrinogen concentration and other biomarkers in patients with DM, a correlation evaluation was performed in the present study. Using the Spearman and Pearson correlation analysis, there was definitely correlation among plasma fibrinogen with HbA1c, hs-CRP, and GS (
(a) to (c) scatter diagram indicated correlation between plasma fibrinogen and other biomarkers based on Pearson’s correlation analysis ((a) hs-CRP; (b) hemoglobin A1c; (c) Gensini scores).
As shown in Figure
Univariate and multivariate logistic regression analysis to determine the independent predictor of high Gensini Score.
Variables | Univariate | Multivariate | |||
---|---|---|---|---|---|
O.R. (95% CI) |
|
O.R. (95% CI) |
|
|
|
Uric acid | 1.00 (1.00-1.01) | 0.006 | 1.00 (1.00-1.01) | 0.004 | 0.004 |
Leukocyte | 1.28 (1.10–1.47) | 0.001 | 1.17 (1.00–1.36) | 0.16 | 0.046 |
LVEF | 0.96 (0.93–0.99) | 0.004 | 0.97 (0.95–0.99) | −0.03 | 0.026 |
Lipoprotien (a) | 1.00 (1.00-1.00) | 0.008 | 1.00 (1.00-1.00) | 0.001 | 0.033 |
HbA1c | 1.24 (1.07–1.44) | 0.005 | 1.24 (1.05–1.46) | 0.22 | 0.009 |
Fibrinogen | 1.69 (1.28–2.23) | <0.001 | 1.40 (1.04–1.88) | 0.34 | 0.026 |
LVEF: left ventricular ejection fraction; HbA1c: hemoglobin A1c.
Plasma fibrinogen values according to the Gensini scores.
Receiver-operating characteristic (ROC) curves showed discriminatory power of plasma fibrinogen for high Gensini scores.
The present study prospectively examined the predictive value of plasma fibrinogen concentration with the severity of stable CAD in type 2 diabetic patients. To the best of our knowledge, the present study firstly demonstrated that the plasma fibrinogen concentrations were significantly different assessed by both trend analysis for the tertiles of GS and comparison test for the high and low-intermediate GS groups. In accordance with previous studies on nondiabetic patients, as shown in ROC curves and box bars, our data further suggested that elevated circulating fibrinogen might confer to not only the presence of CAD but also the severity of coronary lesions in diabetic patients with stable CAD. Besides, our findings confirmed that there was correlation of plasma fibrinogen with other systematic inflammatory biomarkers such as HbA1c and hs-CRP (
Up to date, numerous prospective and retrospective studies have validated the pivotal role of inflammation in the pathogenesis of atherosclerosis [
Meanwhile, previous studies have indicated that glycohemoglobin and aging were vital determinants of fibrinogen concentrations in type 2 diabetic patients [
The exact underlying mechanisms for the present study are unclear. However, the increased levels of plasma fibrinogen were implied not only with the long-term disorder of glycolipid metabolism but also with long time standing of low-grade systematic inflammatory reaction and atherosclerotic plaques progress in these settings [
A cross-sectional observational, single center study with a relatively small sample size may be a limitation. In addition, we did not directly examine the role of plasma fibrinogen in predicting CAD between patients with and without DM. Finally, we failed to track the outcome of study population in the present study.
Summarily, in the current prospective cohort study, the data clearly suggested that the elevated level of plasma fibrinogen was an independent indicator for the severity of CAD in type 2 diabetic patients. Future investigations may be needed using large sample size for revealing more causative information regarding the role of circulating fibrinogen superimposed on stable CAD of DM.
The authors report no conflict of interests for this paper. The authors alone are responsible for the content and writing of the paper.
Li-Feng Hong and Xiao-Lin Li contributed equally to this study.
This paper is partly supported by National Natural Scientific Foundation (Grants nos. 81070171, 81241121, and 81100118), Specialized Research Fund for the Doctoral Program of Higher Education of China (Grants nos. 2011 1106110013 and 20101106120007), Capital Special Foundation of Clinical Application Research (Grant no. Z121107001012015), Capital Health Development Fund (Grant no. 2011400302), and Beijing Natural Scientific Foundation (Grant no. 7131014).