Association of high alpha2-Heremans-Schmid glycoprotein/fetuin concentration in serum and intima-media thickness in patients with atherosclerotic vascular disease and low bone mass.

OBJECTIVE: Alpha2-Heremans-Schmid glycoprotein (AHSG; fetuin), a member of the cystatin superfamily of cysteine protease inhibitors involved in vascular pathology and bone metabolism, has been reported to be reduced in patients with atherosclerosis and medial calcification related to end stage renal disease or dialysis. No data on fetuin in patients with peripheral artery disease associated with low bone mass and normal renal function are available in the literature. In the present study we evaluated serum fetuin concentrations, bone mass, and markers of bone turnover in patients with atherosclerosis of peripheral vessels and normal kidney function. PATIENTS AND METHODS: Ninety consecutive patients with evidence of atherosclerotic plaques at the common carotid or femoral artery were studied. Severity grade of disease was documented by ultrasound measurement of intima-media thickness (IMT). Fasting serum levels of fetuin were measured by sandwich enzyme immunoassay. MAIN RESULTS: The mean patient serum concentration of fetuin was 57.68+/-13.6 ng/ml, significantly higher than that of control subjects (41.6+/-7.6 ng/ml; p<0.001). The mean serum concentration of bone-specific alkaline phosphatase (BAP) were 8.4+/-2.3 microg/l, significantly lower than controls (13.6+/-1.6 microg/l; p<0.001). Fetuin was correlated with IMT (r=0.8530; p<0.0001) and inversely correlated with BAP (r=-0.5503; p<0.0001). Patients had a vertebral and femoral bone mass significantly lower than controls. CONCLUSION: This study documented for the first time that, in patients with atherosclerosis of peripheral vessels, serum fetuin levels were higher than in healthy subjects, and correlated with the severity of disease; further studies are required to analyse the role of AHSG as an independent predictor of atherosclerotic disease and low bone mass in patients with normal renal function.

Propionyl-L-carnitine therapy: effects on endothelin-1 and homocysteine levels in patients with peripheral arterial disease and end-stage renal disease.

BACKGROUND/AIMS: Recent data have addressed the issue of higher levels of homocysteine (Hcy) and endothelin-1 (ET-1) in end-stage renal disease (ESRD) that may be considered an independent predictor for cardiovascular disease. The prevalence of peripheral arterial disease (PAD) in patients with ESRD has been reported to be relevant, highlighting its clinical importance. We aimed to explore the therapeutic role of propionyl-L-carnitine (PLC) in hemodialysis patients with PAD by measuring ankle/brachial index (ABI), ET-1 and Hcy. DESIGN: Randomized, double-blind, placebo-controlled trial. METHODS: Sixty-four patients on hemodialysis with chronic renal insufficiency and PAD were assigned to receive either intravenous PLC (600 mg) or placebo 3 times weekly for 12 months. The ABI and plasma levels of ET-1 and Hcy were measured at baseline, 6 and 12 months. RESULTS: In the PLC-treated group, progressive increases in ABI were observed, while in the placebo group the reverse trend was seen. Highly significant and progressive reductions in plasma levels of ET-1 and Hcy, compared to baseline, were also seen in the PLC-treated group. CONCLUSIONS: Hemodynamic flow, endothelial profile and Hcy levels were ameliorated by the administration of PLC in hemodialysis patients with ESRD and PAD.

A randomised, controlled clinical trial evaluating changes in therapeutic efficacy and oxidative parameters after treatment with propionyl L-carnitine in patients with peripheral arterial disease requiring haemodialysis.

OBJECTIVE: We explored the efficacy of intravenous therapy with propionyl L-carnitine in patients with both peripheral arterial disease (PAD) and chronic renal insufficiency requiring haemodialysis. METHODS: The trial was a randomised, double-blind, placebo-controlled trial. Sixty-four patients on haemodialysis (32 per treatment arm) with chronic renal insufficiency and PAD were assigned to receive either intravenous propionyl L-carnitine 600 mg or placebo 3 times weekly for 12 months. The main outcome measures were the ankle/brachial index (ABI), plasma malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations, and the plasma nitrite/nitrate ratio (NO(2)/NO(3)); these were measured at baseline and at 6 and 12 months. RESULTS: Significant increases in ABI were observed in the propionyl L-carnitine group, whereas in the placebo group the reverse trend was seen. In patients treated with propionyl L-carnitine, significant progressive decreases were seen in plasma MDA, 4-HNE and the NO(2)/NO(3) ratio from baseline. In the placebo-treated group, only weakly significant or no differences were seen. CONCLUSION: Intravenous administration of propionyl L-carnitine to haemodialysis patients with PAD improves both haemodynamic flow and the oxidative profile.

Behaviour of some indicators of oxidative stress in postmenopausal and fertile women.

OBJECTIVE: Unsaturated fatty acids are known to have a crucial role in the pathogenesis of atherosclerosis. They are very sensitive to oxidation caused by excess free oxygen radicals and the consequent oxidative status, and it is well known that lipid and lipoprotein metabolism is markedly altered in postmenopausal women. Oxidative stress is involved in the pathophysiology of atherosclerosis and our study aim was to assess the presence of such stress in postmenopausal women. DESIGN: One hundred and one women were enrolled in the study. Fifty were fertile (32.5+/-1.1 years) with regular menses and fifty-one were postmenopausal women (52.1+/-1.3 years). None of the study cohort had ever used hormone replacement therapy. Malonaldehyde (MDA), 4-hydroxynenal (4-HNE), oxidized lipoproteins (ox LDL) and glutathione peroxidase (GSH-PX) values were determined as we believe they reveal oxidative stress. RESULTS: MDA, 4-HNE and ox LDL concentrations were higher in postmenopausal than fertile women (p<0.001), while GSH-PX concentrations were significantly higher in fertile women than in postmenopausal subjects (p<0.001). CONCLUSIONS: Our data revealed the presence of oxidative stress in postmenopausal women.

Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease.

Deregulation of matrix metalloproteinases (MMPs) is an important factor contributing to the development of vascular lesions. Plasma levels and zymographic activities of MMP-2 and MMP-9 were investigated in type II diabetics with (n = 51) or without (n = 42) peripheral artery disease (PAD) and in normal volunteers (n = 23). Plasma MMP-2 levels were higher in type II diabetics with (p < 0.01) or without (p > 0.05) PAD in comparison with normal volunteers. Similarly, type II diabetics with (p < 0.0001) or without (p > 0.05) PAD had higher plasma MMP-9 levels than normal volunteers. Plasma zymographic activities of both MMP-2 and MMP-9 were positively correlated with their plasma levels. Plasma MMP-2 zymographic activity was higher in type II diabetics with PAD than type II diabetics without PAD (p > 0.05). Plasma MMP-9 zymographic activity was higher in type II diabetics with (p < 0.0001) or without (p < 0.0001) PAD in comparision with normal volunteers. Together, these results indicate that increased plasma levels and zymographic activities of MMP-2 and MMP-9 may contribute to PAD in type II diabetics. In particular, plasma MMP-9 may be a useful marker for the development of vascular disease in type II diabetics.

Early carotid atherosclerosis in women: results of an ultrasonographic study measuring carotid artery intima-media thickness.

Ultrasonography (US) is a useful diagnostic tool in detecting early vascular diseases in women and is particularly relevant in the elderly population. Increased carotid artery intima-media thickness (IMT) is a predictive marker of onset of atherosclerosis and is associated with vascular events. The objective of the present study was to determine carotid artery IMT in asymptomatic women of different age classes and to correlate the results with metabolic and coagulative parameters, age, and menopause. A total of 1200 women age 29-73 years selected from the electoral list of the city of Catania, Italy consented to participate in the US study to determine IMT. The percentage of IMT values exceeding an IMT cutoff value of < 1.3 mm observed in our study groups was significant. Correlations were observed between IMT and total cholesterol (r = .157), high-density lipoprotein (HDL) cholesterol (r = .87), low-density lipoprotein (LDL) cholesterol (r = .149), and fibrinogen (r = .140) values. Increased ultrasonographic markers showing onset of carotid artery remodeling can be observed in asymptomatic women of all ages. Some cardiovascular risk factors are linked to the initial stages of atherosclerosis. We recommend US screening in healthy populations to identify subjects who could develop vascular disease.

Correlation between some metabolic markers of vascular risk and carotid artery intima-media thickness in postmenopausal women.

UNLABELLED: AIM AND SETTING: This study investigated correlations between insulinemia, insulin sensitivity, body mass index, lipids and lipoproteins with intima-media thickness in a group of 25 (age range 40-55 years) postmenopausal women (minimum duration of menopause 2 years) not on hormone replacement treatment. METHODOLOGY: Uni and multivariate correlations showed a direct relationship between insulin pattern, insulin sensitivity, body mass index, low density lipoproteins and increased intima-media thickness. RESULTS: Our multivariate correlation results revealed that intima-media thickness is influenced by the associations of the different metabolic functions investigated. Therefore, carotid wall intima-media thickness represents a dependent variable in postmenopausal women for some metabolisms whose dysfunction leads to atherosclerosis. CONCLUSION: This multielement synergy is able to detect cardiovascular risk and may underlie cardiovascular mortality in postmenopausal women.

Ultrasound diagnosis of carotid artery lesions in a population of asymptomatic subjects presenting atherosclerosis risk factors.

Carotid artery atherosclerosis, age, family history, smoking, arterial hypertension, diabetes mellitus, and dyslipidemia represent risk factors of cerebrovascular events (stroke and transient ischemic attack). Hence, preventive treatment is vital for patients presenting these factors. Seven hundred and sixty-six patients (348 men and 418 women; age range 30-80 years) who were asymptomatic and attending a vascular unit for routine ultrasound (US) screening of the carotid arteries and with risk factors, intima-media thickness (IMT) of carotid artery > 1.3 mm, IMT associated with findings of atherosclerotic plaque creating stenosis > 20%, < or = 50%, and carotid plaque creating stenosis > 50% were considered. For patients with diabetes and hyperlipemia (35.8%)--or with hypertension, diabetes, and hyperlipemia (34.8%)--a higher prevalence of IMT > 1.3 mm was found. Higher prevalence of atherosclerotic plaque > 50% varied between 14.2% (in cases with diabetes mellitus and dyslipidemia) and 29.6% (in cases presenting 4 concomitant risk factors). Direct correlation was found between different risk factors and US findings. Our US findings revealed both a high incidence of carotid atherosclerosis, and that single and multiple correlation between US diagnosis of vascular damage and risk factors further enhanced risk. The study results confirmed the significance of vascular risk factors in patients with carotid artery atherosclerosis, and underlined the diagnostic validity of US.

High circulating levels of cytokines (IL-6 and TNFalpha), adhesion molecules (VCAM-1 and ICAM-1) and selectins in patients with peripheral arterial disease at rest and after a treadmill test.

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that is associated with systemic inflammation. The aim of our study was to assess whether plasma markers of inflammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group (mean age 68.4 +/- 5.09 years) was affected by PAD with claudication, while the other group consisted of healthy controls (66.9 +/- 6.1 years). Concentrations of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFalpha) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin (ES), L-selectin (LS) and P-selectin (PS) concentrations and plasma concentrations of VCAM-1 and ICAM-1 were also determined. All determinations were performed in patients at rest and after the treadmill exercise. Resting values of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if post-treadmill concentrations were significantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001). These results confirm that white blood cell activation is characteristic of systemic atherosclerosis and that these inflammation markers increase in conditions of hemodynamic stress.