Hypertens Res. 2013 Feb;36(2):129-33.

Subclinical atherosclerosis and fetuin-A plasma levels in essential hypertensive patients.

Marco Guarneri, Calogero Geraci, Francesca Incalcaterra, Rosalia Arsena, Giuseppe Mulè, Francesco Vaccaro, Clelia Luna, Giovanni Cerasola, and Santina Cottone

Nephrology Unit, Dipartimento di Medicina Interna e Specialistica (DIMIS)-University of Palermo, Palermo, Italy. santina.cottone@unipa.it



The intima-media thickness (IMT) is considered as a surrogate marker for atherosclerotic disease. The aim of this study was to analyze the relationship of carotid IMT with fetuin-A in patients with essential hypertension (EH) and normal renal function. The plasma levels of fetuin-A, interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α) and the biomarker of oxidative stress 8-iso-PGF2alpha were assayed in samples from 105 untreated EH patients. Carotid IMT measurements were also performed. EH was studied overall and after dividing in EH with IMT ≥ and <0.9 mm. All of the biomarkers were significantly different between the two subgroups, in particular, the fetuin-A level was lower in the patients with an IMT ≥0.9 mm. In the overall group, the linear analysis of correlation demonstrated that the IMT was significantly inversely correlated with the fetuin-A level (r=-0.40, P<0.0001) and directly with TNF-α (r=0.39, P<0.0001), IL-6 (r=0.38, P<0.0001) and 8-iso-PGF2alpha (r=0.356, P<0.0003). The multiple regression analysis performed that assigned IMT as a dependent variable showed that fetuin-A (β=-0.268, P<0.0001) was independently correlated with the IMT. Receiver-operator curves demonstrated that fetuin-A levels have a predictive power of IMT>0.9 mm (AUC (area under the curve) 0.738, P<0.0001). Our results suggest that in EH, fetuin-A is associated with the IMT independently of oxidative stress and renal function, thus predicting increases in the IMT.

PMID: 22972556



Human fetuin-A, (a2-Heremans Schmid glycoprotein ASHG) is a liver-derived plasma protein member of the cystatin superfamily.(1)

Fetuin-A is a potent inhibitor of ectopic calcification accounting for about 50% of serum capacity to prevent calcium and phosphate precipitation. Being a negative inflammatory protein circulating levels of fetuin-A are reduced in inflammatory states in patients on hemodialysis, and are inversely related to C-reactive protein levels.

Both experimental and clinical studies supported an adverse role of fetuin-A deficiency on cardiovascular system. Indeed diffuse extraosseous calcifications (including vessels and cardiac valves) have been evidenced in fetuin-A knockout mice. In dialysis patients, low fetuin-A levels have been associated to increased vascular calcification, to calcific uremic arteriolopathy, and to cardiovascular mortality.

First Ketteler et al. reported  a relationship between serum fetuin-A levels and mortality in a cohort of  hemodialysis patients  (2). Fetuin-A  concentrations in serum were significantly lower in patients on haemodialysis and, low concentrations of the glycoprotein were associated with raised amounts of CRP, and with enhanced cardiovascular (p=0.031) and all-cause mortality (p=0.0013). Moreover Authors tested the capacity of serum to inhibit CaxPO4 precipitation in patients on long-term dialysis (n=17) with apparent soft-tissue calcifications, and in those on short-term dialysis (n=8) without evidence of calcifications and cardiovascular disease. Sera from patients on long-term dialysis with low fetuin-A  concentrations showed impaired ex-vivo capacity to inhibit CaxPO4 precipitation. Reconstitution of sera with purified fetuin-A  returned this impairment to normal.

In patients with pathologically low fetuin-A concentrations, the circulating levels of C-reactive protein were significantly increased and the inverse relationship between these compounds was highly significant. Interpretation of fetuin-A  deficiency is associated with inflammation and links vascular calcification to mortality in patients on dialysis. Activated acute-phase response and fetuin-A  deficiency might account for accelerated atherosclerosis in uraemia. Subsequently, Stenvinkel et al. showed  an association between fetuin-A concentrations and incident mortality in a group of 258 patients starting renal replacement therapy (3). During the 3.5 year follow up period , all-cause and cardiovascular mortality were both significantly (P<0.001) associated with low fetuin-A levels independently of age, smoking, diabetes, serum albumin, cardiovascular disease and inflammation state (including C-reactive protein > 10mg/L). Interestingly, a logistic regression model in a subgroup of 101 patients showed that fetuin-A was significantly (P<0.05) associated with the presence of carotid plaques independently of several confounders, including C-reactive protein.

Notably, patients having all components of malnutrition–inflammation–atherosclerosis calcification syndrome had the lowest fetuin-A levels. This finding suggests that the assessment of fetuin-A concentration in this setting may be useful in identifying subjects at very high cardiovascular risk.

Indeed we previously carried out a study aimed at evaluating whether fetuin-A plasma levels are decreased in patients with moderate chronic kidney disease and their linkage to plasma concentrations of hs-C-reactive protein (CRP), and to LVH. Fetuin A was reduced in CKD when compared with EH. The comparison between CKD having LVH with those without LVH showed significant differences in plasma levels of  fetuin-A (p < 0.002), and hs-CRP (p < 0.001). CKD with LVH had lower values of fetuin-A (p < 0.001), and higher values of hs-CRP (p < 0.001)  than EH with LVH. The linear analysis correlation demonstrated that Fetuin-A was significantly correlated with LVMI. The multivariate analysis of correlation demonstrated that in CKD patients hs-CRP (beta 0.42, p<0.00006), and systolic blood pressure (beta 0.29, p < 0.02) were independent predictors of LV mass index. The relationship between LV mass index and fetuin-A did not reach statistical significance.

For the first time in moderate CKD patients, we demonstrate that fetuin-A is decreased and relates to LVH depending on C-reactive protein. (4)

CIMT (Carotid Intima Media Thickness) is a well-recognized marker of atherosclerosis; it has been associated with traditional cardiovascular risk factors and prevalent/incident cardiovascular disease.(5-6) Hundreds of cross-sectional studies using high-definition ultrasound scanning of carotid arteries have consistently shown a direct, independent relationship between CIMT and established risk factors such as age, blood pressure, diabetes, dyslipidemia and smoking. Further studies have provided a clear evidence of an association between CIMT and preclinical cardiac and extracardiac alterations, including left ventricular hypertrophy, coronary calcifications, cerebral white matter lesions, peripheral arterial atherosclerosis and microalbuminuria. A number of prospective trials, such as  the Atherosclerotic Risk in Communities (ARIC), the Rotterdam Study, the Cardiovascular Health Study (CHS), the European Lacidipine Study on Atherosclerosis (ELSA) and the Carotid Atherosclerosis Progression Study (CAPS) have reported that CIMT and/or plaques are strong predictors of coronary events and stroke.

Controversial data about the association between fetuin-A concentrations and the extent of vascular calcification, indices of atherosclerotic involvement (that is, CIMT, arterial stiffness and ankle- brachial index) and mortality are available in patients with preserved renal function or mild-to-moderate renal impairment, as well as in individuals with Type 2 diabetes mellitus. In the Rancho Bernardo Study, a population-based prospective study of 633 men and 1025 women, the association of fetuin-A with cardiovascular mortality differed according to diabetes status. (7)

Low fetuin-A levels predicted greater risk for cardiovascular mortality in subjects without diabetes, but were associated with a reduced risk of cardiovascular death in those withdiabetes. The magnitude of coronary artery calcification correlated with increased rather than decreased fetuin-A levels in a group of diabetic patients with chronic kidney disease spanning stages.

Considering tha only limited data are available in patients with normal kidney functions or moderate renal impairment and advanced atherosclerosis  we performed a  cross-sectional , observational study aimed to analyzing  the relationship of subclinical atherosclerosis evaluated by carotid IMT measurements, with fetuin-A, and some biomarkers of both oxidative stress and inflammation in patients having essential hypertension and normal renal function, free from CV disease.(8)

In 105 untreated EH plasma levels of fetuin-A, Interleukin 6(IL-6), Tumour Necrosis Factoralpha(TNFalpha), and the biomarker of oxidative stress 8iso-PGF2alpha were assayed along with carotid IMT measurements. EH were studied overall and after dividing in EH with IMT > and <0.9 mm. All biomarkers were significantly different between the two subgroups, in particular fetuin-A was lower in patients with IMT > 0.9 mm. In the overall group, the linear analysis of correlation demonstrated that IMT significantly correlated inversely with fetuin-A(r -0.40, p<0.0001), and directly to TNF-alpha (r 0.39, p< 0.0001) , IL-6(r 0.38, p<0.0001), and 8-iso-PGF2alpha(r 0.356, p<0.0003). The multiple regression analysis carried out considering IMT as a dependent variable showed that only fetuin-A(B -0.463, p<0.0001) was independently correlated to IMT. Receiver–operator curves(ROC) demonstrated that fetuin-A levels are endowed with a predictive power of IMT> 0.9mm(AUC 0.738, p<0.0001).

The main findings of our study can be summarized as follows:

  • mean plasma fetuin-A concentrations were significantly lower (18%, P<0.001) in hypertensive subjects than in controls;
  • hypertensives with thicker CIMT (X900 mm) had lower fetuin-A levels (11%, P<0.001) than their counterparts with normal CIMT (as defined according to the 2007 ESH/ESC guidelines);
  • in the whole study sample, a significant inverse correlation was found between fetuin-A and CIMT (r¼ 0.40, P<0.001);
  • in multiple regression analyses, older age, male gender and fetuin-A were independently correlated with CIMT (P<0.001 for all).

These results are in keeping with previous findings from patients on hemodialysis and patients with atherosclerotic aortic aneurysms; moreover, we extend previous observations to a sample of nondiabetic subjects with untreated hypertension, preserved renal function and free from overt cardiovascular disease. Our observations, however, are not in line with studies carried out in a population-based sample without prevalent hypertension, in subjects with nonalcoholic fatty liver disease and in patients with Type 2 diabetes mellitus or with atherosclerotic vascular disease. In fact, in these settings, a direct, rather than an inverse, correlation between fetuin-A levels and CIMT has been reported. These conflicting data may be related to the heterogeneity of patients examined in terms of clinical and demographic characteristics.

A few strengths and limitations of our study deserve to be mentioned. First, although crosssectional investigations do not allow any causal inference, thie results offer a new piece of information by suggesting that fetuin-A downregulation is a potential promoter of carotid atherosclerosis in the early phases of essential hypertension. Thus, the assessment of plasma fetuin-A could identify patients with subclinical carotid atherosclerosis over and beyond traditional risk factors. Second, a  strength of the study refers to the exclusion of patients taking antihypertensive or lipidlowering drugs that could have affected the relationship between CIMT and fetuin-A. A limitation of the study is due to the lack of information on the carotid atherosclerotic burden in terms of carotid plaques, in particular calcified plaques, and its relationship with fetuin-A levels. Actually, this was due to the poor number of patients having plaques who were not included in the statistical analysis.

In conclusion, fetuin-A seems to have an emerging role of n the pathophysiology of atherosclerosis and cardiovascular disease.


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