[Hyperhomocysteinemia, oxidative stress, endothelial dysfunction in postmenopausal women]. / Iperomocisteinemia, stress ossidativo, danno endoteliale e menopausa.

AIM: Menopause seems to accelerate the development of atherosclerosis and cardiovascular diseases. Several studies show a significant correlation between elevated homocysteine serum levels and increased cardiovascular risk. Oxidative stress is involved in the pathophysiology of endothelial dysfunction and atherosclerosis. Our study aim was to assess the correlations between intima-media thickness, homocysteine serum levels and oxidative stress both in fertile and postmenopausal women. MATERIALS AND METHODS: We have investigated 34 fertile women (mean age = 42 +/- 2 yrs; BMI = 21 kg/m2 and 34 postmenopausal women (48 +/- 3 yrs; BMI = 22 +/- 2 kg/m2). RESULTS: Results show increased levels of homocysteine, oxidative stress and intima-media tickness (IMT) in postmenopausal women. having a positive correlation with IMT. CONCLUSIONS: The positive correlations between serum levels of homocysteine and IMT in postmenopausal women reinforce the idea that a hyperhomocysteinemia may play a role in the progression of atherosclerosis. The lack of estrogens could be a pathophysiologic risk factor for endothelial damage via an augmented oxidative stress. Clin

Chronic peripheral arteriopathy is associated with seropositivity to Chlamydia pneumoniae.

The study was carried out to clarify the correlation between Chlamydia pneumoniae infection and peripheral arterial disease (PAD). The level of specific antibodies of the 133 consecutive patients suffering from PAD at 2nd stage of Leriche's classification were compared with 60 healthy controls by using a commercial Micro-IF Test. A higher incidence of serological evidence of C. pneumoniae infection was found in the patients (106/133) than in controls (6/60). These results are in agreement with other findings that measured the infection in atheromasic plaques. A strong cause-effect relationship between bacterial infection and peripheral arterial disease was not found, but the raised seropositivity level could be considered as a target for medical therapy of PAD.

Peak systolic velocity in patients with arterial erectile dysfunction and peripheral arterial disease.

The aim of this study is to evaluate whether penile peak systolic velocity (PSV) varies in patients with erectile dysfunction (ED) due to artery insufficiency associated with abnormalities in other arterial districts or not. To accomplish this, cavernous artery PSV was determined 10, 20 and 30 min after intracavernously administering alprostadil by means of echo-color Doppler to a total of 65 consecutive patients (age range 52-78 years). In all, 18 patients had ED alone (group A) and served as controls, 15 had ED plus atheroma plaques and/or marked intima-media thickness of the common carotid artery (group B); 17 had ED plus lower limb artery abnormalities; 17 had ED plus carotid and lower limb artery abnormalities (group D). Group B and C patients had a similar PSV, which turned out to be significantly lower than that in group A. Group D patients had the lowest PSV, which proved to be significantly lower than that in groups A, B and C. This study shows that a more generalized peripheral atherosclerotic process is associated with a severer penile artery insufficiency. Therefore, ED patients with a severe arterial insufficiency should undergo an extensive echo-duplex examination.

Incidence of extragenital vascular disease in patients with erectile dysfunction of arterial origin.

This research was carried out to evaluate the prevalence of carotid and/or lower limb artery abnormalities in patients with arterial erectile dysfunction (ED). To this end, patients with ED (Andrology Unit) or suspected peripheral atherosclerosis (Angiology Unit) underwent an independent and parallel echo-Duplex examination. The Andrology Unit examined 167 patients with ED of different etiologies: 52 of them had penile artery insufficiency and consequently their carotids and lower limb arteries had to be evaluated by means of echo-Doppler. In all, 36 out of the 46 patients with nonarterial organic ED and 22 out of the 69 patients with nonorganic ED underwent the same evaluation and served as controls. The Angiology Unit enrolled 457 ED patients who initially underwent echo-Doppler for suspected carotid and/or arterial leg atherosclerosis and subsequently dynamic echo-Doppler. Isolated penile artery insufficiency was found in 23.1 and 25% of the patients evaluated in the Angiology and Andrology Units, respectively. The remaining patients were shown to have ED associated with an atheroma or marked intima-media thickness of the carotid vessels and/or of leg arteries. The frequency of penile arterial insufficiency and of carotid and/or lower limb artery abnormalities was significantly higher (P < 0.01) compared to that found in patients with ED of nonarterial organic or psychogenic origin. Both Units found that the frequency of penile artery insufficiency and carotid or lower limb artery abnormalities was significantly higher than that of penile artery insufficiency alone or plus both carotid and lower limb artery abnormalities. This study showed that penile artery insufficiency is associated with carotid and/or lower limb artery ultrasound abnormalities in about 75% of the cases. Therefore, arterial ED may be regarded as a sign of a more generalized atherosclerosis.

Ultrasound imaging in diagnosis of superior mesenteric artery syndrome.

OBJECTIVES: We screened a cohort of subjects affected by various degree of dyspepsia to reveal if they presented a reduction of the aorto-mesenteric angle and to diagnose suspected cases of superior mesenteric artery (SMA) syndrome. DESIGN: Controlled, prospective, study. SETTING: Subjects were studied as outpatients. SUBJECTS: The study investigated a total of 3622 subjects referred to our department by their general practitioners for dyspepsia and/or abdominal pain. Interventions. Abdominal ultrasonography with power colour Doppler, gastroduodenoscopy, hypotonic duodenography, contrast-enhanced spiral computerized tomography were performed. MAIN OUTCOME MEASUREMENT AND RESULTS: Color Doppler revealed a significant reduction of the SMA angle in 29 of 950 subjects; gastroscopy showed duodenal compressive pulsation in 14 of 29 patients and X-ray revealed compression of the third segment of the duodenum in 28 of 29 patients. CT confirmed the presence of a reduced angle and various degrees of duodenal compression in all patients. Ultrasonography and CT examinations gave overlapping results (P > 0.05) in diagnosing pathological aorto-mesenteric angle. CONCLUSION: The authors believe that the incidence of reduced aorto-mesenteric angle and SMA syndrome might be underrated. Ultrasound power colour Doppler imaging is useful in epidemiological screening of reduced aorto-mesenteric angle to diagnose suspected cases of SMA syndrome.

Low bone density and abnormal bone turnover in patients with atherosclerosis of peripheral vessels.

Patients with vascular calcifications often have low bone mineral density (BMD), but it is still uncertain if osteoporosis and peripheral vascular disease (VD) are interrelated and linked by a common pathomechanism. Moreover, data on bone turnover in patients with advanced atherosclerosis are lacking. We measured BMD by dual-energy X-ray absorptiometry (DXA) and quantitative bone ultrasound (QUS), as well as the serum levels of osteocalcin (OC), bone-specific alkaline phosphatase (BAP), osteoprotegerin (OPG) and its ligand RANKL, and the urinary concentration of the C-terminal telopeptides of type I collagen (CrossLaps), in 36 patient (20 male and 16 female) with serious atherosclerotic involvement of the carotid and/or femoral artery to investigate the underlying mechanism of vascular and osseous disorders. Thirty age-matched and gender matched healthy individuals served as controls. After adjustment for age, BMD was significantly reduced at the lumbar spine in 23/36 (63%) patients (mean T score -1.71+/-1.42) and at the proximal femur in 34/36 (93%) patients (neck mean T score -2.5+/-0.88). Ten patients (27%) had abnormal QUS parameters. Gender and diabetes had no effect on the relationship between vascular calcification and bone density at any site measured. VD subjects had OC and BAP serum levels lower than controls (13.3+/-3.1 vs 27.7+/-3.3 ng/ml, P<0.01, and 8.4+/-2.3 vs 12.5+/-1.4 microg/l, P<0.01, respectively). Urinary CrossLaps excretion was not significantly different in patients with VD and in controls (257.9+/-138.9 vs 272.2+/-79.4 micro g/mmol Cr, respectively). Serum OPG and RANKL levels were similar in patients and in controls (3.5+/-1.07 vs 3.4+/-1.05 pmol/l, and 0.37+/-0.07 vs 0.36+/-0.06 pmol/l, respectively). We proved high occurrence of osteoporosis in VD, with evidence of age and gender independence. Negative bone remodelling balance would be a consequence of reduced bone formation, with no apparent increased activation of the OPG-RANKL system.

Effects of long-term hormone replacement therapy on arterial wall thickness, lipids and lipoproteins, fibrinogen and antithrombin III.

We aimed to study the effects of hormone replacement therapy (HRT) in menopausal women on lipoproteins, blood coagulation, arterial blood pressure and markers of atherosclerosis. A total of 186 postmenopausal women were studied; 98 used HRT (0.625 mg 17 beta-estradiol plus 10 mg progestin) and were followed for 48 months, and were matched with 98 women without therapy. Low-density lipoproteins, high-density lipoproteins, triglycerides, antithrombin III, systolic and diastolic arterial pressure and intima-media thickness were measured at 6, 12, 24, 38 and 48 months. In users of HRT, we found a significant reduction of the lipoproteins, triglycerides, systolic and diastolic pressures and intima-media thickness; however, we found an increase in high-density lipoproteins and anthitrombin III in comparison with non-users. This study has shown a protective effect of HRT on such risk factors and on certain markers of atherosclerosis.

Effects of ischaemic stress on leukocyte activation processes in patients with chronic peripheral occlusive arterial disease: role of L-propionyl carnitine administration.

An open study was carried out to assess whether, in patients with occlusive peripheral arterial disease (PAD), ischaemic stress induced by maximal physical exercise is associated with leukocyte activation processes, and to evaluate the effects of L-propionyl carnitine (LPC) administration on such processes. Fifteen patients with occlusive PAD (stage II-A), with a mean pain-free walking distance (PWD) of 199 +/- 70.66 m were orally treated with 2000 mg/day LPC for 2 months. Serum levels of E-selectin, P-selectin, L-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-I (VCAM-1) were measured at rest and after the performance of a treadmill walking test (treadmill speed 3.5 km h(-1), inclination 12%) in the untreated condition, and again after treatment with LPC. Significant increases of these factors were observed after maximal exercise compared with resting values. Such increase was significantly reduced after LPC treatment compared with the untreated condition. This study shows that ischaemia induced by maximal stress is associated with leukocyte activation processes, and that LPC is capable of modulating these processes. LPC, therefore, may have a protecting role during ischaemia.

Duration of menopause and behavior of malondialdehyde, lipids, lipoproteins and carotid wall artery intima-media thickness.

AIM: our study assessed whether minor or major hormonal deficiency influenced oxidative status and vascular wall structure in menopausal women. METHODS: the study series was made up of 62 non hypertensive non diabetic menopausal women (mean age 52.3+/-4.7 years) divided into two groups depending on duration of menopause (group 1 duration 0-5 years; group 2 duration over 5 years). Total cholesterol (TC), LDL cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides (TG), malondialdehyde (MDA) and common carotid artery wall intima-media thickness (IMT) were determined in the entire series. RESULTS: mean TC, LDL-C, TG, MDA and IMT values were higher in group 2 than group 1. The intergroup difference between MDA (P<0.007) and IMT values (P<0.006) values was statistically significant. CONCLUSIONS: the study revealed a close temporal correlation between plasma oxidative stress and carotid wall IMT, jeopardizes vascular wall status as menopause proceeds.

Oxidative stress and endothelial damage in patients with asymptomatic carotid atherosclerosis.

It is known that oxidative stress can be able to induce cytotoxicity of blood cells, stimulate release of inflammatory cytokines, and induce the production of growth factors. The aim of this study was to investigate oxidative stress and endothelial dysfunction in patients with asymptomatic carotid artery disease and healthy controls. Native low-density lipoproteins, oxidised low-density lipoproteins, malondialdehyde, nitrates, glutathione peroxidase activity and endothelin-1 were determined in patients without severe (range between 30% and 50%) carotid artery stenosis. Native low-density lipoproteins, oxidized low-density lipoproteins, malondialdehyde, glutathione peroxydase, and endothelin-1 concentrations were higher in patients than in health controls (P<0.001). No difference was observed in nitrate values (P<0.8). Our results revealed oxidative stress in patients without severe carotid artery stenosis and clinical symptoms. This was shown by the elevated malondialdehyde and oxidized low-density lipoprotein levels.

Venous stasis causes release of interleukin 1beta (IL-1beta), interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFalpha) by monocyte-macrophage.

BACKGROUND: many studies have investigated between venous stasis, functions of the vascular and perivascular anastomotic structure, venous endothelium and circulating leukocytes. SETTING: patients with varicose veins (n = 15) and a healthy control group (n = 15). METHODS: the authors investigated some soluble mediators of monocytes-macrophages, which induce inflammation. They determined interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFalpha) levels at rest and after induced venous occlusion (using an inflated cuff to 60 mmHg for 25 minutes). RESULTS: their results revealed elevated baseline production in the former and that induced venous occlusion further augmented the levels of all cytokines in the study series, especially in patients with varicose veins. CONCLUSION: The authors believe that the study shows functional activation of monocyte-macrophages related to venous stasis as a consequence of venous hypertension. Cell response damages the endothelial structure and may represent an important element in the pathophysiology of chronic venous insufficiency.

Behaviour of the carotid wall in menopausal women with and without arterial hypertension.

OBJECTIVE: A study was conducted on the carotid vascular wall to evaluate its behaviour in postmenopausal women suffering from arterial hypertension compared to normotensive postmenopausal women. METHOD: Intima-media thickness(IMT) of carotid artery was determined by ecoduplex scanner in 182 postmenopausal women (age range 40-60 years) divided in four age classes (40-45, 46-50, 51-55, 55-60 years). Ninety-one women presented normal arterial blood pressure (SBP 136.6+/-11.7 and DBP 82.3+/-8.9 mmHg) and 91 were hypertensive (SBP 172.6+/-11.7 and DBP 97.4+/-6.6 mmHg). RESULTS: The normotensive women presented the following IMT values: 1.19+/-0.21 mm (40-45 years), 1.21+/-0.25 mm (46-50 years), 1.25+/-0.20 mm (51-55 years), 1.25+/-0.20 mm (55-60 years). IMT values in hypertensive women were: 1.75+/-0.25 mm (40-45 years), 1.77+/-0.30 mm (45-50 years), 1.91+/-0.28 mm (51-55 years), 2.02+/-0.33 mm (55-60 years). ANOVA test was performed in both groups of women and did not show any significant difference in the four age classes of normotensive women. On the other hand it revealed a statistical significance between 40-45 and 46-50-year-old hypertensive classes (P<0.001) and between 51-55 and 55-60-year-old hypertensive clases (P<0.02). CONCLUSIONS: There was a correlation between age and IMT in the arterial hypertensives, especially in two older classes, and between the duration of menopause and IMT values. The results indicated that carotid wall thickening was constantly higher in hypertensive women compared with normotensive ones.

Varicose symptoms without varicose veins: the hypotonic phlebopathy, epidemiology and pathophysiology. The Acireale project.

Ever since 1982 the authors have been interested in varicose symptoms without varicose veins. Carrying out several pilot studies with infrared photoplethysmography (PPG) and strain gauge plethysmography they suggest that the pathophysiology of this behaviour could be caused by the reduction of the venous wall tone. They propose the name of Hypotonic Phlebopathy (HP). The diagnosis criteria are focused by symptoms (heavy legs in upright position, restless leg syndrome, sub-oedema and/or evening oedema) and signs detected by PPG, s.g plethysmography and duplex scanning (reduction of the muscle-venous calf pump and increase of the venous wall compliance). Epidemiology, assessed between 1989 and 1992 (Acireale Project), showed a 15.90% morbidity, with higher prevalence in females; the most important risk factors are pregnancy and family history. HP is not rare in males; the principal risk factor is work involving standing for long periods. These behaviours have been independently confirmed by two studies carried out in France in 1992, which showed a 15% prevalence in a similar group of subjects with functional venous insufficiency. The authors suggest the introduction of the term of Hypotonic Phlebopathy, the symptoms of which are significantly improved by phlebotonic drugs, especially when they are stronger. CEAP classification: C(0-S); E(P); A(0); P(unclassifiable); Clinical score (1-2); Anatomical score (0); Disability score (1).

Postphlebitic syndrome: clinical activity and tolerability of desmin, new LMW dermatan sulfate.

One hundred patients suffering from postphlebitic syndrome of the lower limbs were enrolled in an open, randomized, and multicenter (six centers) trial for a period of eighteen months. Patients were randomly assigned to three treatment groups to receive (for ninety consecutive days) Desmin, a new low-molecular-weight dermatan sulfate, at the dose, respectively, of 100 mg once daily by subcutaneous (SC) route (36 patients), 100 mg twice a day by SC route (33 patients), and 200 mg once daily by intramuscular (IM) route (31 patients). The general and local tolerability and the clinical efficacy of the drug were evaluated by means of clinical, instrumental, and laboratory parameters. Desmin is effective in the decompensation stage of postphlebitic syndrome; this was demonstrated by a significant reduction in the severity of a number of typical symptoms as well as by the drug's positive effect on venous tone as confirmed by phlebotensiometric examination. The daily dose of 200 mg (either SC or IM) was more effective than the 100 mg dose. The results obtained at the end of the trial (ninety days) were statistically better than those obtained after thirty days of treatment. This trial demonstrated that both the systemic and the local (at the site of injection) tolerability of the drug, administered for three months, were good and without significant variations in the laboratory parameters monitored.

[Changes in cerebral vasomotor reactivity in relation to respiratory and metabolic stimuli: an analysis of its behavior in hypertensive and normotensive subjects]. / Modificazioni della reattività vasomotoria cerebrale in relazione a stimoli respiratori e metabolici: analisi del comportamento in soggetti ipertesi e normotesi.

We know that increases in the arterial blood pressure determines changes in the behaviour of the cerebrovascular resistance and also the possible lack of vasomotor reactivity. In order to clarify the pathway of circulatory vasomotor reactivity in arterial hypertension, we carried out a study on a group of hypertensive subjects (20 patients) who were compared to a group of normotensive controls (18 patients). A transcranial doppler (TCD) study was performed with rebreathing tests (apnea and hyperventilation) and it was carried out in both groups of subjects. The TCD was repeated after an administration of sublingual pill of nitroglycerin. In both groups the hyperventilation caused a significant reduction in the velocity peak in the middle cerebral artery (norm.: 84.88 +/- 4.86 cm/sec 60 +/- 5.2 cm/sec; hyperten. 84.50 +/- 7.1 cm/sec 58.80 +/- 5.47 cm/sec) in contrast apnea induced a major increase in the velocities (norm.: 84.88 +/- 4.86 cm/sec 102.50 +/- 4.89 cm/sec; hyperten.: 84.50 +/- 7.1 cm/sec 101.59 +/- 10.6 cm/sec). We noticed a statistical significant difference between the velocities recorded in the different tests (Anova test p < 0.0001). The behaviour of the velocities in the rebreathing tests after nitroglycerin was similar when compared to the same test were performed without the drug. This study suggests that there is no difference in the behaviour of the cerebral reactivity between normotensives and the hypertensive subjects without vascular or cardiac compliance. Finally we would emphasize the role of TCD in the recording changes of cerebrovascular resistances due to pressure or metabolic causes.

Tolerability and clinical efficacy of desmin in the treatment of superficial thrombovaricophlebitis.

Fifty-six patients with superficial thrombovaricophlebitis of the lower limbs were enrolled in an open and multicenter (4 centers) trial for a period of thirty days. Patients were randomly allocated to three treatment groups to receive a new low-molecular-weight dermatan sulfate (Desmin) at the dose, respectively, of 100 mg once daily by subcutaneous (SC) route, 100 mg twice a day SC, and 200 mg once daily by intramuscular (IM) route. The general and local tolerability and the clinical efficacy of the drug were evaluated by means of clinical, instrumental, and laboratory parameters. Desmin proved capable of effectively improving the symptoms of patients affected by thrombovaricophlebitis, inducing rapid regression by the tenth day of treatment. The daily dose of 200 mg (either SC or IM) was more effective than the 100 mg dose. The systemic tolerability of the drug, administered for the first time for one month, was extremely good, without significant variations in the relevant laboratory tests. Local tolerance (at the site of injection) of the drug was also good.

Iloprost, stable analogue of the prostacyclin, is able to improve the tissue resistance to ischaemia.

On 10 patients, suffering from peripheral arterial disease, with critical limb ischaemia, the CO2 production during ischaemia has been evaluated at 1st and at 28th day of treatment with iloprost. The study demonstrated that the drug is able to improve the tissue resistance to ischaemia, with a significant (p < 0.05) reduction of the CO2 production. The authors underline that this study is one of the first confirmations, in vivo and on the man, of the previous experimental findings, made in isolated arterial tissue.

Three-month therapy with calcium-heparin in comparison with ticlopidine in patients with peripheral arterial occlusive disease at Leriche-Fontaine IIb class.

Forty patients with a mean age of 62.6 +/- 6 years, 36 men and 4 women, with peripheral arterial occlusive disease (PAOD) at Leriche-Fontaine IIb class, were randomly allocated to one of two treatment groups, receiving either 12,500 IU/day of subcutaneous (sc) calcium-heparin (CAE) or 250 mg/day of oral ticlopidine, each given for ninety days. The following parameters were evaluated before the start of the active treatment period and after thirty and ninety days of treatment: pain-free walking distance (PWD), maximum walking distance (WDmax), systolic and diastolic blood pressure (BP), posterior tibial arterial pressure and Winsor index at rest and after exercise (treadmill), transcutaneous oxygen and carbon dioxide pressures at rest (TcPO2 and TcPCO2 respectively), and time to 50% TcPO2 recovery after three-minute ischemia. Both treatments induced an improvement in PWD/WDmax, which, at the end of the study, were increased by 50.7/58.7% and 31.7/36.2%, respectively, for CAE and ticlopidine treatments, respectively.