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1.  C-Peptide Levels Are Associated With Mortality and Cardiovascular Mortality in Patients Undergoing Angiography 
Diabetes Care  2013;36(3):708-714.
OBJECTIVE
C-peptide is a proinsulin cleavage product released from the pancreas in amounts equimolar to insulin, and elevated levels of C-peptide have been found in patients with insulin resistance and early type 2 diabetes mellitus. Recent data suggest that C-peptide could play a causal role in the pathophysiology of vascular disease, but nothing is known about the prognostic value of C-peptide concentrations in the circulation.
RESEARCH DESIGN AND METHODS
We examined whether C-peptide is associated with cardiovascular and total mortality in 2,306 patients from the Ludwigshafen Risk and Cardiovascular Health Study who underwent coronary angiography at baseline (1997–2000).
RESULTS
During a mean follow-up of 7.6 years, 440 deaths (19.1%) occurred, 252 (10.9%) of which were due to cardiovascular causes. Age- and sex-adjusted hazard ratios (HRs) in the third compared with the first tertile of C-peptide were 1.46 (95% CI 1.15–1.85; P = 0.002) for all cause and 1.58 (1.15–2.18; P = 0.005) for cardiovascular mortality. After further adjustment for common risk factors as well as markers of glucose metabolism, these HRs remained significant at 1.46 (1.10–1.93; P = 0.008) and 1.55 (1.07–2.24; P = 0.022), respectively. Moreover, patients in higher tertiles of C-peptide exhibited higher levels of markers of endothelial dysfunction and atherosclerosis as well as a more severe extent of coronary lesions.
CONCLUSIONS
In patients undergoing coronary angiography, C-peptide levels are independently associated with all cause and cardiovascular mortality as well as presence and severity of coronary artery disease. Further studies are needed to examine a potential causal role of C-peptide in atherogenesis in humans.
doi:10.2337/dc12-1211
PMCID: PMC3579368  PMID: 23204248
2.  Relationship between sclerostin and cardiovascular calcification in hemodialysis patients: a cross-sectional study 
BMC Nephrology  2013;14:219.
Background
Sclerostin is a Wnt pathway antagonist regulating osteoblast activity and bone turnover. Here, we assessed the potential association of sclerostin with the development of coronary artery (CAC) and aortic valve calcifications (AVC) in haemodialysis (HD) patients.
Methods
We conducted a cross-sectional multi-slice computed tomography (MS-CT) scanning study in 67 chronic HD patients (59.4 ± 14.8 yrs) for measurement of CAC and AVC. We tested established biomarkers as well as serum sclerostin (ELISA) regarding their association to the presence of calcification. Fifty-four adults without relevant renal disease served as controls for serum sclerostin levels. Additionally, sclerostin expression in explanted aortic valves from 15 dialysis patients was analysed ex vivo by immunohistochemistry and mRNA quantification (Qt-RT-PCR).
Results
CAC (Agatston score > 100) and any AVC were present in 65% and in 40% of the MS-CT patient group, respectively. Serum sclerostin levels (1.53 ± 0.81 vs 0.76 ± 0.31 ng/mL, p < 0.001) were significantly elevated in HD compared to controls and more so in HD patients with AVC versus those without AVC (1.78 ± 0.84 vs 1.35 ± 0.73 ng/mL, p = 0.02). Multivariable regression analysis for AVC revealed significant associations with higher serum sclerostin. Ex vivo analysis of uraemic calcified aortic valves (n = 10) revealed a strong sclerostin expression very close to calcified regions (no sclerostin staining in non-calcified valves). Correspondingly, we observed a highly significant upregulation of sclerostin mRNA in calcified valves compared to non-calcified control valves.
Conclusion
We found a strong association of sclerostin with calcifying aortic heart valve disease in haemodialysis patients. Sclerostin is locally produced in aortic valve tissue adjacent to areas of calcification.
doi:10.1186/1471-2369-14-219
PMCID: PMC3851854  PMID: 24112318
Aortic valve disease; Cardiovascular disease; Coronary calcification; Hemodialysis; Mineral metabolism; Vascular calcification; Renal osteodystrophy; Sclerostin
3.  The Associations of Fibroblast Growth Factor 23 and Uncarboxylated Matrix Gla Protein With Mortality in Coronary Artery Disease: The Heart and Soul Study 
Annals of internal medicine  2010;152(10):640-648.
Background
Fibroblast growth factor 23 (FGF23), uncarboxylated matrix Gla protein (ucMGP), and fetuin-A are regulators of mineral metabolism and inhibitors of vascular calcification. Whether circulating levels of each are associated with cardiovascular disease (CVD) events or mortality in populations without end-stage renal disease is unknown.
Objective
To evaluate the associations of FGF23, ucMGP, and fetuin-A with mortality and CVD events.
Design
Observational study.
Setting
12 outpatient clinics in the San Francisco Bay area.
Patients
833 outpatients with stable coronary artery disease (CAD), recruited from 11 September 2000 to 20 December 2002.
Measurements
Fibroblast growth factor 23, ucMGP, and fetuin-A concentrations were measured at baseline. Participants were followed until 1 December 2008 for mortality and CVD events.
Results
During a median follow-up of 6.0 years, 220 participants died and 182 had CVD events. Compared with participants with FGF-23 levels in the lowest tertile, those in the highest tertile had 2-fold greater risk for mortality (hazard ratio [HR], 2.15 [95% CI, 1.43 to 3.24]) and CVD events (HR, 1.83 [CI, 1.15 to 2.91]) after adjustment for traditional CVD risk factors, C-reactive protein levels, and kidney function. The highest ucMGP tertile was associated with lower mortality risk (HR, 0.48 [CI, 0.31 to 0.75]) and showed a nonsignificant trend toward lower CVD event risk by tertile analysis (HR, 0.65 [CI, 0.40 to 1.05])—an association that was significant when modeled continuously (P = 0.029). No significant association of fetuin-A with mortality (HR, 0.84 [CI, 0.55 to 1.27]) or CVD events (HR, 0.99 [CI, 0.64 to 1.55]) was observed.
Limitation
Participants had prevalent CAD.
Conclusion
In outpatients with stable CAD, higher FGF23 and lower ucMGP levels are independently associated with mortality and CVD events.
Primary Funding Source
American Heart Association.
doi:10.1059/0003-4819-152-10-201005180-00004
PMCID: PMC3079370  PMID: 20479029
4.  Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients 
European Heart Journal  2010;31(18):2253-2261.
Aims
Dialysis patients experience an excess mortality, predominantly of sudden cardiac death (SCD). Accumulating evidence suggests a role of vitamin D for myocardial and overall health. This study investigated the impact of vitamin D status on cardiovascular outcomes and fatal infections in haemodialysis patients.
Methods and results
25-hydroxyvitamin D [25(OH)D] was measured in 1108 diabetic haemodialysis patients who participated in the German Diabetes and Dialysis Study and were followed up for a median of 4 years. By Cox regression analyses, we determined hazard ratios (HR) for pre-specified, adjudicated endpoints according to baseline 25(OH)D levels: SCD (n = 146), myocardial infarction (MI, n = 174), stroke (n = 89), cardiovascular events (CVE, n = 414), death due to heart failure (n = 37), fatal infection (n = 111), and all-cause mortality (n = 545). Patients had a mean age of 66 ± 8 years (54% male) and median 25(OH)D of 39 nmol/L (interquartile range: 28–55). Patients with severe vitamin D deficiency [25(OH)D of≤ 25 nmol/L] had a 3-fold higher risk of SCD compared with those with sufficient 25(OH)D levels >75 nmol/L [HR: 2.99, 95% confidence interval (CI): 1.39–6.40]. Furthermore, CVE and all-cause mortality were strongly increased (HR: 1.78, 95% CI: 1.18–2.69, and HR: 1.74, 95% CI: 1.22–2.47, respectively), all persisting in multivariate models. There were borderline non-significant associations with stroke and fatal infection while MI and deaths due to heart failure were not meaningfully affected.
Conclusion
Severe vitamin D deficiency was strongly associated with SCD, CVE, and mortality, and there were borderline associations with stroke and fatal infection. Whether vitamin D supplementation decreases adverse outcomes requires further evaluation.
doi:10.1093/eurheartj/ehq246
PMCID: PMC2938469  PMID: 20688781
Vitamin D; Sudden cardiac death; Mortality; Dialysis; Kidney; Cardiovascular
5.  Fetuin-A and kidney function in persons with coronary artery disease—data from the heart and soul study 
Background
Fetuin-A is a serum protein that inhibits ectopic vascular calcification and is present in lower concentrations in end-stage renal disease than in healthy controls. Whether fetuin-A concentrations are also lower in the setting of mild-to-moderate chronic kidney disease (CKD) is unknown.
Methods
We evaluated the associations of several parameters of kidney function including measured 24 h urinary creatinine clearance (CrCl), estimated glomerular filtration rate (GFR) by the Mayo Clinic quadratic GFR equation (qGFR), serum cystatin-C concentrations, and urinary albumin-to-creatinine ratio with serum fetuin-A concentrations in 970 outpatients with coronary artery disease. We used general linear models to determine the adjusted mean fetuin-A concentrations within each kidney function category.
Results
The mean age of the study sample was 67 years, 82% were male, 71% had hypertension and 26% had diabetes mellitus. In adjusted analysis, we observed no significant differences in mean fetuin-A concentrations across groups defined by CrCl, qGFR, or albumin-to-creatinine ratio groups. For example, adjusted mean fetuin-A concentrations were 0.66 g/l in participants with CrCl > 90, 60–90 and 45–60 ml/min/1.73 m2, and 0.65 g/l in participants with CrCl < 45 ml/min/1.73 m2. Higher serum cystatin-C (indicating worse kidney function) was associated with higher adjusted mean serum fetuin-A concentrations (lowest quartile 0.62 g/l, highest quartile 0.68 g/l; P for trend <0.001).
Conclusions
Among ambulatory patients with coronary artery disease, there is no evidence that mild-to-moderate CKD is associated with lower concentrations of serum fetuin-A compared with persons with normal renal function. The mechanisms explaining the association between CKD and vascular calcification remain elusive.
doi:10.1093/ndt/gfl204
PMCID: PMC2776687  PMID: 16644775
calcium; chronic kidney disease; fetuin-A; alpha-2-Heremans-Schmid-glycoprotein; vascular calcification; phosphorus
6.  Association Between Human Fetuin-A and the Metabolic Syndrome Data From the Heart and Soul Study 
Circulation  2006;113(14):1760-1767.
Background
Fetuin-A is a multifunctional hepatic secretory protein that inhibits the action of insulin in experimental animals. We evaluated the association between human serum fetuin-A and the metabolic syndrome (MetS) in a cohort of persons with coronary artery disease.
Methods and Results
We defined MetS by the National Cholesterol Education Program criteria among 711 nondiabetic outpatients with coronary artery disease. The mean age was 67 years, and 82% were male. We divided participants into quartiles by serum fetuin-A concentrations. A total of 45% of participants (80 of 177) in the highest quartile of fetuin-A had MetS compared with 24% of participants (42 of 177) in the lowest quartile (odds ratio, 2.7; 95% confidence interval, 1.7 to 4.2; P<0.001). This association persisted after adjustment for potential confounding variables, including hypertension, body mass index, and inflammatory biomarkers (adjusted odds ratio, 2.0; 95% confidence interval, 1.1 to 3.5; P=0.02). Higher fetuin-A quartiles were also strongly and independently associated with higher low-density lipoprotein, non–high-density lipoprotein (HDL), and triglyceride concentrations and lower HDL concentrations (all P<0.01).
Conclusions
Higher human fetuin-A concentrations are strongly associated with MetS and an atherogenic lipid profile. Future studies should evaluate whether fetuin-A predicts coronary artery disease risk.
doi:10.1161/CIRCULATIONAHA.105.588723
PMCID: PMC2776669  PMID: 16567568
alpha2HS-glycoprotein; hypercholesterolemia; insulin; lipids; metabolism
7.  Association of Fetuin-A With Mitral Annular Calcification and Aortic Stenosis Among Persons With Coronary Heart Disease: Data From the Heart and Soul Study 
Circulation  2007;115(19):2533-2539.
Background
Fetuin-A is a multifunctional hepatic secretory protein that inhibits dystrophic vascular and valvular calcification. Lower serum fetuin-A concentrations are associated with valvular calcification in persons with end-stage renal disease. Whether fetuin-A is associated with valvular calcification in other patient populations is unknown.
Methods and Results
We evaluated the associations among serum fetuin-A concentrations, mitral annular calcification, and aortic stenosis in 970 ambulatory persons with coronary heart disease and without severe kidney disease. The presence or absence of mitral annular calcification and aortic stenosis was determined by transthoracic echocardiography. The subjects’ mean age was 66 years; 81% were men; 189 (20%) had mitral annular calcification; and 79 (8%) had aortic stenosis. Participants were categorized by tertiles of fetuin-A concentrations. Those within the highest fetuin-A tertile had significantly lower odds of mitral annular calcification compared with the lowest tertile (adjusted odds ratio, 0.47; 95% confidence interval, 0.29 to 0.77; P=0.002); this association was similar regardless of diabetes status (P for interaction=0.34). In contrast, the association of fetuin-A with aortic stenosis was modified by the presence or absence of diabetes mellitus (P for interaction=0.03). Among participants without diabetes, the highest fetuin-A tertile had a significantly lower odds of aortic stenosis compared with the lowest tertile (adjusted odds ratio, 0.37; 95% confidence interval, 0.15 to 0.92; P=0.03), whereas among participants with diabetes, no statistically significant association was observed between fetuin-A and aortic stenosis (adjusted odds ratio, 1.49; 95% confidence interval, 0.48 to 4.63; P=0.49).
Conclusions
Among persons with coronary heart disease, we observed an inverse association of fetuin-A and mitral annular calcification. An inverse association also was observed between fetuin-A and aortic stenosis among participants without diabetes mellitus. Fetuin-A may represent an important inhibitor of dystrophic calcification in persons with coronary heart disease.
doi:10.1161/CIRCULATIONAHA.106.682450
PMCID: PMC2771196  PMID: 17485576
alpha2HS-glycoprotein; calcium; diabetes mellitus; fetuin-A, human; valves

Results 1-7 (7)