In this study, in patients with a wide range of glucose tolerance (from NGT to newly diagnosed T2DM), we found that serum ferritin levels increase in parallel to the worsening of glycometabolic parameters (particularly insulin sensitivity), the raise of inflammation (as assessed by hs-CRP) and the reduction of serum iron and hemoglobin levels (Table 1). Furthermore, these observations go in close parallellism with the increase of central hemodynamic parameters and arterial stiffness indicators, in particular carotid-femoral PWV, across the same groups (from NGT to T2DM). In our study, in a multiple linear regression model, ferritin resulted to be the strongest determinant of PWV explaining a 14.9% of the variability of this biomarker and the ferritin-PWV relationship remained significant also after data adjustment for well-known modulators of arterial stiffness such as insulin sensitivity, hs-CRP and renal function. Age was not significantly associated with PWV, thus it did not represent a confounder in the ferritin-arterial stiffness link. Another novel hypothesis tested by us, was that serum ferritin could act as an effect modifier on the relationship between inflammation and arterial stiffness in the same patient-population. According to this hypothesis, we found that the estimated increase in PWV value promoted by 1 mg/l increase in hs-CRP was significantly more consistent across increasing values of serum ferritin. Thus, the present results suggest that serum ferritin levels are not only a risk factor of arterial stiffness but also an amplifier of the damage induced by inflammation on PWV.
The association between serum ferritin levels and arterial stiffness is in line with the hypothesis that elevated body iron stores are associated with the atherosclerosis process development and in keeping with previous studies reporting an association between higher serum ferritin levels with arterial hypertension and metabolic disorders incidence [5–9]. Moreover, a strong association between serum ferritin levels and atherosclerotic injury has been reported in different settings of patients [25, 26]. In particular, increased common carotid artery intima-media thickness and presence of carotid plaques has been associated with serum ferritin in haemodialysis patients [25] and patients with non-alcoholic fatty liver disease [26]. However, there is growing evidence demonstrating a strong association between higher serum ferritin levels and functional vascular damage. According with this, Ha et al reported, in a large cohort of healthy subjects, an association between ferritin and brachial-ankle PWV [18]. Moreover in haemodialysis patients, serum ferritin was associated with progressive arterial stiffness increase during a three years follow-up, but only for serum values > 500 ng/ml (19).
In hypertensive patients, only few data are reported in literature. In this regard, Valenti and co-authors [16] showed that hyperferritinemia (i.e. higher than 240 ng/ml in females and 320 ng/ml in males) was associated with high aortic stiffness measured as carotid-femoral PWV in patients with well-controlled hypertensives but with several comorbidities and already receiving drug treatment whereas data about the glycometabolic state were not available in this study. All these factors may explain why hs-CRP was not retained as an independent risk factor of PWV in the multiple regression analysis [16]. In respect to the study by Valenti et al, our study has the advantage to include younger naive hypertensive, without chronic conditions (in particular renal and liver diseases) and who received no pharmacological treatment thus avoiding/minimizing possible confounding factors. Moreover, all patients were evaluated by OGTT to define glucose tolerance and the effect of insulin sensitivity on vascular damage was assessed by Matsuda index, a strong surrogate of euglycemic clamp. Finally, the most important observation was that, in our study, serum ferritin levels were within the normal range value.
It’s plausible that in chronic conditions characterized by subclinical inflammation, such as arterial hypertension and T2DM, dysregulation of iron metabolism may lead to increased oxidative stress promoting arterial stiffening. According with this, exprimental and clinical studies demonstrated that increased ROS production during chronic iron overload plays an important role in the CV damage [1, 27, 28]. In fact, chronic iron overload can induce structural and functional changes in resistance arteries by reducing nitric oxide (NO) bioavailability resulting in an increase of O2− production through NADPH oxidase activity. These changes may involve local angiotensin 2 expression and ERK1/2 pathways, which may interfere with vascular remodelling and collagen deposition, thus favouring increased vascular stiffness [27]. Moreover, the same mechanisms facilitating endothelial dysfunction may also justify the increased vascular reactivity during chronic iron overload [1]. To prove this, iron restriction was able to attenuate vascular fibrosis and renal damage in renovascular hypertensive rats [2].
These pathophysiological aspects may strengthen the association between ferritin levels, an important biomarker of iron store, and arterial stiffness in patients with CV risk factors characterized by subclinical inflammation. In keeping with this observations, hs-CRP levels represent a significant predictor of PWV in the present study. Moreover serum ferritin acts as an effect modifier on the relationship between hs-CRP and arterial stiffness in the same population.
It is well known that serum ferritin is an acute-phase reactant, reflecting the degree of acute and chronic inflammation in several systemic diseases. However, emerging evidence suggests a potential causative role for ferritin in the inflammatory process [4]. At this regard, in vitro studies showed that ferritin may work as a local cytokine, activating Mitogen-Activated Protein Kinases (MAPK)-induced NF-kB in an iron-independent manner. This activity induces the increased expression of multiple pro-inflammatory mediators and a near 100-fold increase in inducible NO synthase that amplify oxidative stress [29, 30]. In addition, ferritin is also able to directly modulate the lymphocyte function thus acting as pathogenetic player in the innate immune response [31]. Considering that our study population presented a normal inflammation and iron status, it is clinically plausible that ferritin per se might affect the increase in oxidative stress promoting those mechanisms that lead to vascular remodeling and increased arterial stiffness. Clinical practice supports this hypothesis, because ferritin represents a biomarker of disease progress and an independent predictor of various clinical outcome in different settings of patients [32–34]. Since the increase in carotid femoral PWV is associated with a significant risk increase for CV morbidity and mortality, we can speculate that the association between serum ferritin levels and PWV may be responsible for the negative prognostic effect of ferritin.