Methods

We conducted a longitudinal study with long-term follow-up in patients undergoing inpatient rehabilitation after an acute coronary event. The study design has been described in detail elsewhere. Briefly, all patients 30 to 70 years old participating in a 3-week inpatient rehabilitation program after an acute manifestation of CHD ( International Classification of Diseases, Ninth Revision , codes 410 to 414) from January 1999 to May 2000 in 2 participating rehabilitation clinics in Germany (Schwabenland Klinik Isny-Neutrauchburg and Klinik am Südpark, Bad Nauheim) were considered for inclusion in the study. Only patients who were admitted within 3 months after an acute manifestation of CHD were included in this study. Most participants were on a calorie-restricted and/or low-cholesterol diet during the rehabilitation program. As reported in detail elsewhere, this rehabilitation program routinely administered in Germany was efficient in improving parameters such as body mass index, diastolic and systolic blood pressures, total cholesterol, and low-density lipoprotein and high-density lipoprotein cholesterol levels during the rehabilitation period. At the beginning of the rehabilitation program, all participants filled out a standardized questionnaire providing information on health-related behavior and medical history (including history of physician-diagnosed diabetes and hypertension). In addition, information was obtained from patients’ hospital charts, which included information from the acute care hospital. The study complied with the Declaration of Helsinki and all subjects gave written informed consent. The study was approved by the ethics boards of the universities of Ulm and Heidelberg and of the physicians’ chamber of the states of Baden-Wuerttemberg and Hessen (Germany). At the end of the rehabilitation period, we obtained blood samples under standardized conditions from patients in a fasting state and stored the samples at −80°C until analysis. Fetuin-A was measured using an enzyme-linked immunosorbent assay kit (BioVendor Laboratory Medicine, GmbH, Heidelberg, Germany) according to instructions of the manufacturer. Intra- and interassay coefficients of variation were <5.0%. We measured C-reactive protein with a high-sensitivity assay (hs-CRP; N Latex CRP mono), interleukin-6 with a high-sensitivity enzyme-linked immunosorbent assay (R&D Systems, Wiesbaden-Nordenstadt, Germany), and N-terminal pro–brain natriuretic peptide with a 1-step electrochemiluminescence enzyme immunoassay (Roche Diagnostics, Berlin, Germany). Total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol in blood samples from the Isny clinic were quantified on an Olympus AU2700 Chemistry-Immuno Analyzer and an Olympus AU4500 analyzer with cholesterol reagents from Olympus Europe, Hamburg, Germany, and high-density lipoprotein and low-density lipoprotein reagents from Wako Chemicals, Neuss, Germany. Fasting glucose was measured with a glucose oxidase method. Diagnosis of MetS was made according to criteria of the National Cholesterol Education Program Adult Treatment Panel III, with body mass index used as a surrogate for waist circumference.

We carried out all statistical procedures with SAS 9.1 (SAS Institute, Cary, North Carolina). Relations of fetuin-A levels with sociodemographic characteristics and various cardiovascular risk factors were analyzed by nonparametric methods due to deviations from normality in fetuin-A and several other factors (Spearman rank correlation, Kruskal–Wallis test). Likewise, differences in risk factors and fetuin-A baseline levels between subjects with and without a secondary event during the study period were assessed by Kruskal–Wallis test (continuous variables) or chi-square test (categorical variables). The association of fetuin-A levels and prevalent MetS was examined through logistic regression (adjusted for age and gender), in which the presence of ≥3 of the factors defining MetS (see introduction) served as the dependent variable. Furthermore, distribution of fetuin-A over the number of present MetS factors was examined by box plot and Kruskal-Wallis testing. Analyses were also performed using fetuin-A quartiles instead of quintiles and stratifying the analysis set by gender. The prognostic value of fetuin-A concentrations was examined by Kaplan–Meier plots and Cox regression models. Observation time was defined as the time from study inclusion to occurrence of a fatal cardiovascular event (CVD as major cause of death on the official death certificate) or of a nonfatal MI or nonfatal stroke as reported by a patient’s physician, whichever occurred first. The models were fit with various levels of adjustment; model 1 included fetuin-A quintiles and age and gender; model 2 also included traditional risk factors, such as smoking status (current/former/never smoker), history of hypertension and diabetes mellitus, and low-density lipoprotein cholesterol levels; and model 3, which included triglyceride levels, high-density lipoprotein cholesterol concentrations, fasting glucose levels, an impaired renal function indicator (creatinine clearance <60 ml/min), hs-CRP, interleukin-6, and N-terminal pro–brain natriuretic peptide levels, in addition to all variables in model 2. For trend modeling, subjects were assigned the median fetuin-A concentration of their respective quintile. Proportionality of hazards assumption was visually assessed by log(-log) survival plots. A 2-sided p value <0.05 was considered statistically significant.

Results

Of the 1,206 included subjects with a diagnosis of CHD at baseline, 6-year follow-up information (median 73.4 months, interquartile range 57.4 to 74.3) and serum fetuin-A levels were available for 1,049 patients (87.0%). During this period a total of 119 (11.3%) fatal and nonfatal events occurred (42 cardiovascular deaths, 40 nonfatal MIs, and 37 nonfatal strokes).

Mean age was 59.7 years, and 84.0% of the patients were men. Serum fetuin-A levels showed a left skewed distribution with a median of 0.70 g/L (interquartile range 0.5 to 40.78). Median fetuin-A levels according to categories of various sociodemographic variables and cardiovascular risk factors are listed in Table 1 . Spearman correlations were generally very low and significant only for triglyceride levels (r = 0.065, p = 0.036). Correspondingly, we found significantly increased fetuin-A levels in patients with prevalent hypertriglyceridemia (p = 0.013). Other metabolic parameters or MetS were not significantly associated with fetuin-A levels. Education, marital status, cystatin C, lipoprotein-associated phospholipase A2, history of MI, disease severity indicated by the number of affected vessels, type of cardiovascular acute intervention, and intake of β-blocking agents, angiotensin-converting enzyme inhibitors, or diuretics at rehabilitation discharge were not associated with fetuin-A (data not shown).

We also studied the relation between serum fetuin-A and MetS at baseline and performed logistic regression analysis to evaluate the predictive value of fetuin-A for the presence of MetS. As presented in Table 2 , serum fetuin-A levels were not associated with prevalent MetS (highest vs lowest fetuin-A quintile, odds ratio 0.95, 95% confidence interval [CI] 0.59 to 1.53, p = NS). To further explore the relation between fetuin-A and MetS in patients with CHD, we stratified median concentrations of serum fetuin-A by the number of MetS components in each subject ( Figure 1 ). Patients presenting with 4 (n = 67) and 5 (n = 7) individual components, respectively, were merged in 1 category. We found no statistically significant difference among categories of MetS and serum fetuin-A levels (0 component, fetuin-A 0.67 g/L; 1 component, 0.69 g/L; 2 components, 0.70 g/L; 3 components, 0.69 g/L; 4 to 5 components, 0.73 g/L, p = 0.36 by Kruskal–Wallis test).

Box plot diagram of fetuin-A by components of MetS with numbers known to be present for MetS components body mass index ≥30 kg/m ² , triglycerides ≥1.7 mmol/L, high-density lipoprotein cholesterol levels <1.03 mmol/L in men and <1.29 mmol/L in women, systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg, and fasting glucose level ≥6.1 mmol/L.

Table 3 lists baseline characteristics of patients with and without recurrent CVD during follow-up. Fetuin-A levels did not differ significantly between patients with and without secondary CVD events (0.69 vs 0.70 g/L, p = 0.38).

Table 3

Characteristics of patients without versus with secondary event after long-term follow-up

Variable	Without	With	p Value ⁎
	(n = 930)	(n = 119)
Age (years)	58.7 ± 8.1	60.7 ± 6.9	0.014
Men	785 (84%)	103 (87%)	0.54
Body mass index (kg/m 2 )	26.9 ± 3.3	27.0 ± 3.4	0.99
Total cholesterol			0.50
mmol/L	4.36 ± 0.84	4.42 ± 0.88
mg/dl	169.1 ± 32.7	171.5 ± 34.3
High-density lipoprotein cholesterol			0.011
mmol/L	1.02 ± 0.27	0.95 ± 0.23
mg/dl	39.7 ± 10.6	36.88 ± 9.1
Low-density lipoprotein cholesterol			0.57
mmol/L	2.60 ± 0.76	2.67 ± 0.79
mg/dl	100.8 ± 29.4	103.3 ± 30.8
Non–high-density lipoprotein cholesterol			0.16
mmol/L	3.34 ± 0.84	3.47 ± 0.88
mg/dl	129.3 ± 32.4	134.6 ± 34.0
Triglycerides			0.003
mmol/L	1.41 (1.09–1.90)	1.60 (1.25–2.13)
mg/dl	124 (96–167)	140 (110–187)
Fasting glucose			0.13
mmol/L	5.61 ± 1.33	5.87 ± 1.52
mg/dl	101.0 ± 24.0	105.7 ± 27.3
High-sensitivity C-reactive protein (mg/L)	3.38 (1.2–8.2)	3.83 (1.38–9.69)	0.061
Creatinine (mg/dl)	0.9 ± 0.3	1.0 ± 0.3	0.056
Creatinine clearance (ml/min)	100.3 ± 27.5	95.7 ± 33.6	0.0098
Adiponectin (μg/ml)	6.8 (4.7–10.7)	7.1 (4.7–11.5)	0.72
Interleukin-6 (pg/ml)	3.4 (2.2–7.1)	4 (2.2–7.9)	0.22
N-terminal pro–brain natriuretic peptide (ng/ml)	536.2 (267.4–1,027.5)	970.2 (476–2,228)	<0.0001
Systolic blood pressure (mm Hg)	119.8 ± 15.5	120.9 ± 16.1	0.29
RR diastolic blood pressure (mm Hg)	73.0 ± 9.0	72.9 ± 9.0	0.83
Serum fetuin-A (g/L)	0.70 (0.55–0.78)	0.69 (0.49–0.78)	0.38

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