Valerio Fiore

Inflammation and peripheral arterial disease: The value of circulating biomarkers (Review)

Peripheral arterial disease (PAD) is a manifestation of atherosclerotic vascular disease and is often associated with other comorbidities, such as hypertension, diabetes and dyslipidemia. An increasing body of evidence supports the notion that inflammation plays an important role in the development and progression of PAD. A number of studies have investigated the association of various acute phase proteins, particularly C-reactive protein (CRP), with PAD. Apart from CRP, other circulating biomarkers, such as matrix metalloproteinases (MMPs), selectins and interleukin (IL)-1, IL-2, IL-6, IL-8 and IL-10 have been considered to play a role in the development of PAD. In this review, the role of these circulating biomarkers in PAD is discussed. Current data indicate that the appropriate use of biomarkers in patients with PAD may contribute to an early diagnosis, an enhanced knowledge of the developmental process of the disease, as well as to the subsequent improvement of current therapies and to the development of new ones.

Study on unrecognized peripheral arterial disease (PAD) by ankle/brachial index and arterial comorbidity in Catania, Sicily, Italy.

Peripheral arterial disease (PAD) is under diagnosed and early diagnosis decreases consequences. We screened unrecognized PAD focusing on arterial co-morbidities. In the 3412 subjects, screened from 10 general practices in the city of Catania (Sicily, Italy), ankle brachial index (ABI) measurements were performed. An ABI ≤0.9 was considered as valid in diagnosing PAD. ABI value ≤0.9 was found in 2.3%, and a significant rate of carotid stenosis was also found Echocardiographic markers left ventricular diameter (LVD) >55 mm, interventricular septum (IVS) >11 mm, left ventricular diastolic volume (LVDV) was found > 100 ml), and ejection fraction (EF) was <50% were found with high frequency in those with ABI ≤0.9. Unrecognized PAD is lower compared with other findings but our prevalence resulted higher than other prevalence previously found by other study performed in Italy. Unrecognized PAD shows significant arterial co-morbidities and the ABI is a useful method to screen asymptomatic PAD.

Patients with unrecognized peripheral arterial disease (PAD) assessed by ankle-brachial index (ABI) present a defined profile of proinflammatory markers compared to healthy subjects

BACKGROUND Many studies have postulated that atherosclerosis should be considered as an inflammatory disease. In addition, some studies have focused on the relationship between inflammation and peripheral arterial disease (PAD). OBJECTIVE Define the plasma levels of soluble markers, including the proinflammatory cytokine interleukin-6 (IL-6), the anti-inflammatory cytokine transforming growth factor-β1 (TGF-β1), the endothelial-specific adhesion factor (E-selectin) and two proteinases involved in extracellular matrix degradation (matrix metalloproteinases-2 and -9, MMP-2, and MMP-9) in previously unrecognized patients with peripheral artery disease (PAD) and non-PAD controls. RESULTS Significantly higher levels of IL-6, E-selectin and MMP-2/MMP-9 and significantly reduced levels of TGF-β1 were found in PAD patients (ankle-brachial index, ABI⩽0.9) compared to non-PAD control subjects (1.4>ABI>0.9). CONCLUSION The results demonstrated the subjects with unrecognized PAD (ABI⩽0.9) show a characteristic phlogistic pattern differently from healthy subjects and it strongly supports the pivotal role played by inflammatory and immunological mechanisms in the initiation and progression of the atherosclerotic process in peripheral arteries. These biomarkers could be helpful to screen the susceptibility for the diseases in peripheral arteries.

Prevalence of high ankle–brachial index (ABI) in general population of Southern Italy, risk factor profiles and systemic cardiovascular co-morbidity: An epidemiological study

Many studies have been carried out to assess the prevalence, risk factors and co-morbidities of peripheral artery disease (PAD). By contrast, to date there is a lack of data on patients with high-ABI. This study aimed at estimating the prevalence of increased ABI (ABI>1.4) and to evaluate the involvement of traditional cardiovascular (CV) risk factors and the atherosclerotic burden (peripheral and carotid arteries) of these patients in a population of Southern Italy. We invited 9647 subjects, age ranging from 30 to 80, by letters to undergo an ABI measurement. Consequently, in patients with ABI>1.4, an ultrasound evaluation of the peripheral and carotid arteries was performed. An ABI>1.4 was found in 260 of 3412 subjects (7.6%). Statistically significant differences were reported in age, diabetes and hypertension, body mass index (BMI) and waist circumference (WC). No differences in sex distribution, dyslipidemia and smoke prevalence were observed. Moreover, 67.9% of ABI>1.4 patients showed a peripheral intima-media thickness (IMT)>0.9 mm; at linear regression it was correlated with ABI values; 25% of patients showed peripheral plaques. A carotid IMT>0.9 mm was reported in 78.6% of high-ABI patients and 32.1% were affected by atherosclerotic plaques. The observed increased-ABI prevalence of 7.6% was higher than previously reported. This was more prevalent in an older population with diabetes, hypertension and obesity. Moreover, these patients are characterized by an extended atherosclerotic involvement. Further studies are needed to clarify this evidence, a longitudinal observation of this clinical outcome, as we are performing, could provide a number of interesting elements.

Circulating miR-130a, miR-27b, and miR-210 in Patients With Peripheral Artery Disease and Their Potential Relationship With Oxidative Stress A Pilot Study

Some emerging risk factors such as oxidative stress biomarkers and microRNAs (miRs) may add additional value to the established risk factors for peripheral artery disease (PAD). We enrolled 27 patients with PAD and 27 age-matched controls. We examined the levels of a series of miRs (miR-130a, miR-27b, and miR-210) in serum samples. The level of well-established oxidative stress biomarkers, such as lipid hydroperoxides, isoprostanes, hemeoxygenase-1 (HO-1) and reduced glutathione, was also measured in plasma and their relationship with the miRs was determined. Levels of miR-130a, miR-27b, and miR-210 were significantly increased in patients with PAD when compared to the controls. The level of miR-130 was positively correlated with body mass index, whereas miR-210 was inversely associated with pain-free walking distance (PfWD). None of the evaluated miRs was associated with lowered PfWD of patients with PAD (stage IIa > 250 m, IIb < 250 m) or oxidative stress parameters. In conclusion, our findings suggest the need for more research to assess if miRs can serve as useful markers for the early diagnosis and monitoring of PAD.

IL-6-174 G > C and MMP-9-1562 C > T polymorphisms are associated with increased risk of deep vein thrombosis in cancer patients.

BACKGROUND A growing body of evidence shows an increased risk of deep vein thrombosis (DVT) among cancer patients. Novel markers are needed to identify patients prone to develop DVT. The aim of the present study was to determine whether IL-6-174 G > C and MMP-9-1562 C > T polymorphisms may influence the development of DVT in cancer patients. METHODS Polymorphisms of IL-6 and MMP-9 were analyzed in 320 DNA samples from cancer patients (DVT+ and DVT-) and in 215 healthy donors. IL-6 and MMP-9 plasma levels were also measured by ELISA. RESULTS Distribution of -174 IL-6 genotype and -1562 MMP-9 were similar between healthy controls and DVT- cancer cases (OR = 0.98 and 1.04, respectively). Different results were obtained by compared healthy controls with DVT+ cancer patients. -174 IL-6 GG polymorphism was associated to DVT (OR = 2.07; 95% CI: 1.30-3.30), as well as -1562 MMP-9 CC polymorphism (OR = 2.60; 95% CI: 1.48-4.57). CONCLUSION The results of the present study support a model in which the GG and CC genotypes, respectively for IL-6-174 G > C and MMP-9-1562 C > T polymorphisms, are associated with a risk of DVT in cancer patients by inducing the release of IL-6 with subsequent increment of MMP-9. Overall, these findings may contribute to the management of DVT in cancer patients.

Inflammation in Peripheral Arterial Disease (PAD)

Peripheral arterial disease (PAD) affects a large number of individuals over the age of 55 years old, and data from studies has shown a relationship between inflammation, and PAD. Many researchers have not only focused on the role played by inflammatory biomarkers and the progression of PAD, but also on the efficiency of biomarkers in monitoring medical, surgical and interventional strategies in PAD patients. In this review, Authors aim to demonstrate that biomarkers play a key role in the pathophysiology of PAD, and consequently they could be screened to highlight individuals showing these crucial pathophysiological signs. Based on a large debate about phlogosis, it is now considered to be a relevant objective in reducing the prevalence and consequences of atherosclerotic diseases such as PAD. Finally, efforts must be made towards addressing this very important objective, and consequently a greater number of studies need to be made in combatting phlogosis, especially among PAD patients.

Plasma Levels of Inflammatory Biomarkers in Peripheral Arterial Disease: Results of a Cohort Study.

Previous research analyzed the level of plasma inflammatory markers in patients with coronary disease, but very few studies have evaluated these markers in patients with peripheral arterial disease (PAD). The objective of this study was to investigate the plasma levels of inflammatory markers in patients with PAD and in healthy controls. The following plasma levels of biomarkers were measured in 80 patients with PAD (mean age 68 ± 5 years) and in 72 healthy participants (mean age 67 ± 6 years): interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), L-selectin (LS), neopterin (N), P-selectin (PS), E-selectin (ES), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and matrix metalloproteinase 2 (MMP-2), and 9 (MMP-9). Significantly higher levels of IL-6 (P < .001), TNF-α (P < .0001), ES (P < .0001), LS (P < .0001), PS (P < .0001), ICAM-1 (P < .001), VCAM-1 (P < .001), N (P < .001), MMP-2 (P < .001), and MMP-9 (P < .005) were found in the patients with PAD. Patients with PAD show a inflammation marker profile different from that of control participants. Reducing the high plasma levels of inflammatory markers could be a new therapeutic approach both for the prevention and the treatment of PAD.

Thrombophilia in Patients With Lower Limb Deep Veins Thrombosis (LDVT) Results of a Monocentric Survey on 103 Consecutive Outpatients

A debate concerns the utility of large screening for acquired or inherited thrombophilia. The study concerns relationship between inherited thrombophilic status and lower limb deep vein thrombosis (LDVT) and highlights the possible use of extensive thrombophilia screening to determine an emerging risk of LDVT. From January 2010 to January 2012, 103 consecutive patients with LDVT were considered. In all, 57 (55.3%) patients with LDVT showed inherited thrombophilia. The most frequent trombophilic alterations were deficiency of protein S (33 patients, 32.0%), methylentethrafolate reductase (MTHFR) gene C677T variant (22 patients, 21.4%), protrombin gene G20210A alteration (50, 14.6%), and deficiency of protein C (12, 11.6%). Age and MTHFR variant were found related to LDVT and thrombophilia was related to distal LDVT. A high frequency of thrombophylic factor was found in patients with LDVT, but we believe that a generic genetic screening should not be suggested for these patients.

Neopterin: A potential marker in chronic peripheral arterial disease

Neopterin is a marker of macrophage activation that has exhibited high plasma levels in atherosclerotic diseases including coronary heart disease and critical limb ischemia. The role of neopterin in chronic peripheral arterial disease (PAD) has yet to be elucidated. In the present study, neopterin (Ν) serum concentrations were analyzed in asymptomatic (AsP) and symptomatic (SyP) patients with PAD as well as controls (C). In total 120 subjects, 40 AsP [ankle brachial index (ABI) ≤0.90], 40 SyP (ABI ≤0.90 plus pain in legs) and 40 controls (ABI >0.9) were enrolled. The results of the present study showed that neopterin plasma levels were statistically different among the groups. These findings demonstrated that activation of N‑mediated monocyte‑macrophage, was also observed in chronic PAD.