Diagnosis of coronary artery disease requires invasive procedures that are typically not implemented until clinical warning signs are apparent. The goal of this study was to determine the relation between the severity of coronary artery disease, as measured by the SYNTAX scoring system, with serum levels of fetuin-A and fibroblast growth factor 23 (FGF23) in the general population. We enrolled 165 patients who had stable angina and positive results on treadmill testing or abnormal results on thallium myocardial perfusion scanning showing perfusion defects or who had acute coronary syndromes. Patients were hospitalized for evaluation with angiography, with or without simultaneous percutaneous coronary intervention. SYNTAX Scores were calculated on the basis of the results of coronary angiography using a computer-based questionnaire of sequential and interactive self-guided questions. Univariate analysis was used to assess the significance of fetuin-A and FGF23, as well as gender, age, body mass index, waist circumference, diabetes, hypertension, creatinine, total cholesterol, cholesterol, triglycerides, and high-sensitivity C-reactive protein in relation to cardiovascular disease severity. Multivariate analysis with stepwise regression was used to assess the utility of fetuin-A and FGF23 as predictors of SYNTAX Score. Multivariate analysis showed log fetuin-A to be a significant predictor of SYNTAX Score (p <0.0001) after controlling for the significant factors gender, cholesterol levels, and log high-sensitivity C-reactive protein. Log FGF23 values were also shown by multivariate regression to significantly predict SYNTAX Score (p = 0.0137) after controlling for gender, creatinine, cholesterol, and log high-sensitivity C-reactive protein. In conclusion, fetuin-A and FGF23 can be considered in combination with noninvasive test results as patient selection criteria for performing angiography.
The relations of fetuin-A levels and fibroblast growth factor 23 (FGF23) with the severity of coronary artery disease (CAD) has rarely been investigated. The purpose of this study was to evaluate the relations between serum levels of fetuin-A and FGF23 and the severity of CAD using the SYNTAX scoring system, a tool that scores the complexity of CAD as assessed by coronary angiography.
Methods
Patients were enrolled in this cross-sectional observational study from January 2010 to December 2010. Patients who presented with stable angina and positive results on treadmill testing (≥1 mm of horizontal or downsloping ST-segment depression ≥80 ms after the J point, relative to the level of the PQ interval) or abnormal results on thallium myocardial perfusion scanning showing defects in perfusion were eligible for inclusion, as well as patients diagnosed with acute coronary syndromes (acute myocardial infarction or unstable angina pectoris). Patients who had undergone previous angioplasty or who did not meet the criteria for angiography (current infection, hypersensitivity to contrast media, etc.) were excluded from participation. Patients who were enrolled in the study were subsequently hospitalized in the cardiology department for further evaluation with angiography, with or without simultaneous percutaneous coronary intervention.
The following baseline characteristics were recorded for each participant: gender, age, previous diagnosis of diabetes, previous diagnosis of hypertension, current dialysis treatment, body mass index, and waist circumference. In addition, we obtained baseline measurements of serum glucose, serum creatinine, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, high-sensitivity C-reactive protein (hs-CRP), fetuin-A, and FGF23. Fetuin-A was measured using an enzyme-linked immunosorbent assay kit from Immunology Consultants Laboratory, Inc. (Newberg, Oregon) according to the manufacturer’s instructions, and FGF23 was measured using an enzyme-linked immunosorbent assay kit from EMD Millipore Corporation (Billerica, Massachusetts) according to the manufacturer’s instructions. The SYNTAX Score was calculated for each patient using a computer program consisting of sequential and interactive self-guided questions, on the basis of the results of coronary angiography. The calculations, described in detail by Sianos et al, were performed according to the SYNTAX calculation procedure detailed on the SYNTAX Web site ( http://www.syntaxscore.com/index.php ).
Categorical variables are presented as number (percentage) and continuous variables as mean ± SD (range). Correlations between outcomes and factors were assessed using Pearson’s correlation coefficient. Further analyses included univariate and multivariate regression, with stepwise regression to determine outcome predictors. Data were analyzed using SPSS version 15.0 statistical software (SPSS, Inc., Chicago, Illinois). A p value <0.05 was considered statistically significant.
Results
The study group included 165 patients (115 men and 50 women) with a mean age of 66.1 ± 11.8 years (range 35 to 90). Serum fetuin-A levels ranged from 46 to 453 μg/dl (mean 167.4 ± 96.9), and FGF23 ranged from 15 to 6,297 μg/dl (mean 385.7 ± 729 μg/dl). The baseline characteristics and measurements for all participants are listed in Table 1 .
| Variable | n | Value |
|---|---|---|
| Men | 165 | 115 (69.7%) |
| Diabetes mellitus | 165 | 53 (32.3%) |
| Hypertension | 165 | 96 (58.2%) |
| Positive exercise test results | 156 | 81 (51.9%) |
| Mild abnormality on perfusion scan | 156 | 39 (25.0%) |
| Moderate/severe abnormality on perfusion scan | 156 | 36 (23.1%) |
| Dialysis | 165 | 9 (5.5%) |
| Acute coronary syndromes | 165 | 10 (6.1%) |
| Body surface area (m 2 ) | 165 | 1.7 ± 0.2 |
| Body mass index (kg/m 2 ) | 165 | 26.1 ± 4.3 |
| Waist circumference (cm) | ||
| Men | 115 | 90.8 ± 10.1 |
| Women | 50 | 86.4 ± 10.9 |
| Age (yrs) | 165 | 66.1 ± 11.8 |
| Glucose (mg/dl) | 144 | 121.1 ± 55.2 |
| Serum creatinine (mg/dl) | 165 | 1.6 ± 1.7 |
| Total cholesterol (mg/dl) | 165 | 185.1 ± 38.2 |
| Triglycerides (mg/dl) | 162 | 134.4 ± 74.1 |
| Low-density lipoprotein cholesterol (mg/dl) | 144 | 111.3 ± 36.4 |
| High-density lipoprotein cholesterol (mg/dl) | 152 | 46.6 ± 12.4 |
| hs-CRP (mg/L) | 147 | 10.0 ± 21.6 |
| Log hs-CRP | 147 | 0.4 ± 0.7 |
| Fetuin-A (μg/ml) | 165 | 167.4 ± 96.9 |
| FGF23 (μg/ml) | 149 | 385.7 ± 729 |
| SYNTAX Score | 165 | 10.3 ± 7.8 |
Log-transformed values of serum fetuin-A (log fetuin-A) and FGF23 (log FGF23) were used for analysis. A significant negative correlation was identified between log fetuin-A and SYNTAX Score (r = −0.511, p <0.001; Figure 1 ). No correlation was found between log FGF23 and SYNTAX Score (r = −0.0925, p = 0.2621). Univariate linear regression showed that a 1-unit increase in SYNTAX Score was accompanied by a 5.69-unit decrease in log fetuin-A. In addition, male gender, creatinine, total cholesterol, and log hs-CRP were positively correlated with the severity score (p = 0.0105, p = 0.0078, p = 0.0125, and p = 0.0032, respectively).
Multivariate analysis showed log fetuin-A to be a significant predictor of SYNTAX Score (p <0.0001) after controlling for the significant factors gender (p = 0.0193), total cholesterol (p = 0.018), and log hs-CRP (p = 0.0017), with log fetuin-A decreasing by 5.87 units for each 1-unit increase in SYNTAX Score ( Table 2 ). Multivariate regression showed log FGF23 to also be a significant predictor of SYNTAX Score (p = 0.0137) after controlling for gender (marginally significant, p = 0.0854), creatinine (p = 0.0025), total cholesterol (p = 0.009), and log hs-CRP (p = 0.0018). Each 1-unit increase in SYNTAX Score was associated with a decrease of 1.28 units in log FGF23 ( Table 2 ).
