Lifestyle intervention improves microvascular reactivity and increases serum adiponectin in overweight hypertensive patients.

BACKGROUND AND AIMS: Obesity and hypoadiponectinemia are often associated with high blood pressure. Moreover, microvascular dysfunction is reported to be an early event in patients with hypertension and may be involved in the pathogenesis of organ damage. METHODS AND RESULTS: We investigated the impact of 8-week moderate-intensity aerobic training on adiponectin plasma levels and skin microvascular reactivity in 24 overweight sedentary patients (18 men, age 44+/-6 years, body mass index 28+/-3 kg/m(2)) with never-treated grade 1 essential hypertension. Twenty-four age- and sex-matched hypertensive patients, who were examined twice at 8-week intervals in the absence of exercise training, served as controls. Exercise training was followed by a significant reduction in waist circumference (from 97+/-9 to 95+/-9 cm, p<0.05) and an increase in adiponectin plasma levels (from 11.9+/-3 to 12.5+/-4 mg/L, p<0.05). An inverse correlation was found between adiponectin change and waist circumference change (r=-0.43, p<0.05). The area under the curve after post-occlusive reactive hyperemia at skin laser-Doppler examination increased significantly after aerobic training (from 876+/-539 to 1468+/-925 PU/s, p<0.001). A positive correlation was found between exercise-induced variations of post-occlusive reactive hyperemia and adiponectin plasma levels (r=0.41, p<0.05). Office or 24-h blood pressure values did not change significantly. CONCLUSION: In sedentary overweight patients with mild hypertension, moderate aerobic training improves cutaneous microvascular reactivity and adiponectin plasma levels. These changes precede blood pressure reduction and may serve as biomarkers of the efficacy of non-drug treatment in hypertensive patients.

Renal dysfunction predicts long-term mortality in patients with lower extremity arterial disease.

BACKGROUND: Patients with renal insufficiency tend to suffer from advanced atherosclerosis and exhibit a reduced life expectancy. OBJECTIVES AND DESIGN: This prospective study investigated the relation between renal dysfunction and long-term all-cause and cardiovascular mortality in a population of nonsurgical patients with lower extremity arterial disease (LEAD). SUBJECTS AND METHODS: A total of 357 patients with symptomatic LEAD underwent baseline glomerular filtration rate (GFR) estimation by the 4-variable Modification Diet in Renal Diseases equation, and were then followed for 4.2 years (range: 1-17). RESULTS: During follow-up, 131 patients died (8.6 deaths per 100 patient-years), 79 of whom (60%) from cardiovascular causes. All-cause death rates were 3.8, 6.6, and 15.5 per 100 patient-years, respectively, in the groups with normal GFR, mild reduction in GFR (60-89 mL min(-1) per 1.73 m2) and chronic kidney disease (CKD; <60 mL min(-1) per 1.73 m2; P < 0.001 by log-rank test). Compared to patients with normal renal function, the risk of all-cause and cardiovascular death was significantly higher in patients with CKD [hazard ratio, respectively, 2.23, 95% confidence interval (CI): 1.16-4.34, P = 0.017; 2.15, 95% CI: 1.05-4.43, P = 0.03]. The association of CKD with all-cause and cardiovascular mortality were independent of age, LEAD severity, cardiovascular risk factors and treatment with angiotensin-converting enzyme (ACE)-inhibitors, hypolipidaemic and antiplatelet drugs. The power of GFR in predicting all-cause death was higher than that of ankle-brachial pressure index (P = 0.029) and Framingham risk score (P < 0.0001). CONCLUSION: Chronic kidney disease strongly predicts long-term mortality in patients with symptomatic LEAD irrespective of disease severity, cardiovascular risk factors and concomitant treatments.

Prognostic impact of low-shear whole blood viscosity in hypertensive men.

BACKGROUND: The role of blood viscosity as a marker for discriminating cardiovascular risk in essential hypertension remains uncertain. The aim of this study was to assess whether whole blood viscosity (WBV) could be useful in assessing cardiovascular risk in men with a first diagnosis of hypertension. DESIGN: A total of 331 middle-aged men with newly diagnosed essential hypertension (age at entry 40-64 years, average blood pressure 151/95 mmHg) underwent low-shear-rate (0.94 s(-1)) and high-shear-rate (94.5 s(-1)) WBV determination and were then followed for a mean of 4.8 +/- 3 years (range 0-12 years). RESULTS: Cardiovascular event rates in the bottom, middle and top tertiles of the distribution of low-shear WBV were 1.10, 2.13 and 4.43 per 100 patient-years, respectively (log-rank test, P < 0.001). After taking into account several established cardiovascular risk factors in a Cox survival analysis, a raised low-shear WBV conferred an increased risk for cardiovascular events (top vs. bottom tertile hazard ratio = 3.42, 95% confidence interval = 1.4-8.4, P = 0.006; middle vs. bottom tertile hazard ratio = 2.25, 95% confidence interval = 0.9-5.6, P = 0.09). The independent association between high-shear-rate WBV and cardiovascular events bordered statistical significance (P = 0.07). Inclusion in the survival model of low-shear-rate resulted in a significantly greater chi(2) improvement (P < 0.05) than inclusion of high-shear-rate WBV. CONCLUSIONS: In hypertensive men, an increased WBV at low shear rate is a predictor of cardiovascular events independently from the effect of several traditional risk factors. Low-shear WBV is a better discriminator of cardiovascular risk than high-shear WBV.

A human model of platelet-leucocyte adhesive interactions during controlled ischaemia in patients with peripheral vascular disease.

AIMS: In humans, little is known about the effects of platelet-leucocyte interactions on blood viscosity and microvascular perfusion. This study tested the hypotheses that (1) activation and interactions between platelets and leucocytes may have an impact on microvascular blood viscosity and perfusion in patients with stage II peripheral arterial occlusive disease, and (2) a powerful antiplatelet drug such as Clopidogrel might help to improve microvascular perfusion by reducing platelet-leucocyte activation and blood viscosity. METHODS: Plasma concentrations of certain markers of leucocyte and platelet activation, in addition to low and high shear rate blood viscosity, were measured before and after a repeated exercise treadmill test. Functional parameters including maximum walking time, transcutaneous oxygen pressure, and half recovery time were also measured. RESULTS: Blocking platelet activation only with a single dose of Clopidogrel (300 mg) did not improve microvascular blood viscosity and perfusion after repeated exercise, but a significant improvement in microvascular perfusion during controlled ischaemia and a lack of post exercise increase in low shear rate blood viscosity was achieved when both platelet and leucocyte activation were suppressed by a relatively longer treatment with Clopidogrel (four days). CONCLUSIONS: Clopidogrel, by inhibiting platelet activation and aggregation, might also block the vicious cycle of leucocyte-platelet activation, thus improving the functioning of the microcirculation.

Blood rheology in men with essential hypertension and capillary rarefaction.

The pathophysiological significance of hyperviscosity and capillary rarefaction in untreated essential hypertension is unknown. Fifty untreated hypertensive men with capillary rarefaction (intravital capillaroscopy) and 20 age- and sex-matched normotensive controls underwent full haemorheological profiling (blood viscosity at high and low shear, haematocrit, platelet and leukocyte counts, fibrinogen and total protein concentrations, P-selectin levels, erythrocyte and leukocyte filterability rates and erythrocyte deformability and aggregation indexes). Subjects with skin capillary density below the group median had younger age, higher diastolic pressure, higher blood viscosity at low shear, higher P-selectin levels, higher erythrocyte and leukocyte filterability rates, and higher erythrocyte aggregation indexes (all P < 0.01). In contrast, patients with greater skin capillary density had a greater plasma viscosity (P < 0.05). The conclusions were that in untreated hypertensive men, capillary rarefaction and hyperviscosity are associated to an increased diastolic blood pressure and to an adverse haemorheological profile.

Clopidogrel: hemorheological effects in subjects with subclinical atherosclerosis.

The usefulness of Clopidogrel as inhibitor of platelet aggregation has been demonstrated, but its effect on hemoreological parameters, such as whole blood viscosity at low and high shear rate, red cell aggregation and deformability indexes, filterability rate and and deformability of red blood cells has not been studied. This study revealed that, in subjects with impaired blood rheology and ultrasound evidence of atherosclerosis, 3-weeks treatment with clopidogrel (75 mg daily) improved blood viscosity at high shear rate and other hemorheological parameters, including red cell filterability rates and dynamic red cell deformability index (p<0.01 for all), without any unwanted side effect. Blood viscosity at low shear rate and red cell aggregation index improved after only 1-week treatment, and the reductions were mantained after two and three weeks (p<0.01). These results indicate that, similarly to another thienopyridine such as ticlopidine, Clopidogrel may have a positive influence on several hemorheological parameters, thus exerting its protection not only through inhibition of platelet function, but also through changes in the hemorheological profile.

Flow-mediated vasoactivity and circulating adhesion molecules in hypertriglyceridemia: association with small, dense LDL cholesterol particles.

BACKGROUND: Endothelial dysfunction is considered one of the earliest events in the process of atherosclerosis, and an impaired vasodilatory response has been reported in patients with dyslipidemias. However, the independent association between hypertriglyceridemia and endothelial dysfunction is controversial, and the relation between endothelium-dependent vasodilation and circulating cell adhesion molecules as markers of endothelial dysfunction has not been fully determined. METHODS: Brachial artery flow mediated vasodilation (FMV) and the soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) were determined after overnight fasting in 16 men with hypertriglyceridemia (age 33 +/- 6 years) and in 16 age-matched healthy men with normal triglycerides and cholesterol. Subjects who smoked and those with known cardiovascular disease, diabetes, hypertension, recent or active infections, or any other disease that could affect leukocyte activation were excluded from the study. RESULTS: Compared with normal subjects, subjects with hypertriglyceridemia showed a higher level of sVCAM-1 and sICAM-1 (both P <.001), a reduced FMV (P <.01), and a smaller LDL particle size (P <.05). FMV had a significant inverse correlation with sVCAM-1 (r = -0.61, P <.001) and sICAM-1 (r = -0.38, P <.03). LDL particle size had a strong, direct association with FMV (r = 0.75, P <.001) and an inverse association with adhesion molecules. By multiple regression analysis, triglycerides (P <.001) and small LDL particle size (P <.002) predicted a reduced FMV. CONCLUSIONS: Serum level of cell adhesion molecules is increased and FMV is impaired in young healthy men with hypertriglyceridemia compared with age-matched men with normal lipid levels. Small, dense LDL particles may play a role in determining endothelial dysfunction in these subjects.

Hyperhomocyst(e)inemia is associated with carotid atherosclerosis.

The atherogenicity of homocyst(e)ine--H(e) --emerged from many studies showing an association between moderately elevated levels and vascular occlusive disease. The aim of this study was to evaluate whether high homocyst(e)ine levels were associated with carotid atherosclerosis. Carotid atherosclerosis was defined as an intimal media thickness of internal and carotid bifurcation of at least 2 mm on the near and far walls as determined by B-mode ultrasonography. The study population included 91 patients: group 1 (61% males, mean age 64+/-10 years, 57% with history of hypertension) with ultrasound evidence of carotid atherosclerosis and 100 with normal carotid walls--group 2 (36% males, mean age 52+/-15 years, 27% with history of hypertension). Homocyst(e)ine levels (mol/L) were determined by high-performance liquid chromatography with a fluorescent detector. Body mass index, dyslipidemia, smoking, diabetes, serum creatinine, plasma folic acid and vitamin B12 were not significantly different in the two groups. Homocyst(e)ine levels (micromol/L) were significantly higher in patients with carotid ather osclerosis than in those with normal arteries (11.7+/-6.5 micromol/L, 95% CI 10.4-13.1 vs 8.07+/-4.4 micromol/L, 95% CI 7.2-8.9, p<0.0001). By multiple regression analysis H(e) levels were positively correlated with male gender (p<0.02), age (p<0.001), and negatively with folic acid (p<0.0001). By logistic regression the independent predictors of carotid atherosclerosis were male gender (OR 2.65), hypertension (OR 2.55), age (x10 years, OR 2.15) and H(e) levels (x1 micromol/L, OR 1.11). This study confirmed homocyst(e)ine is associated with carotid atherosclerosis. Consequently the authors recommend H(e) levels be screened in all patients at risk for atherosclerosis.

Circulating leucocyte adhesion molecules in chronic venous insufficiency.

BACKGROUND: Enzyme-linked immunosorbent assay (ELISA) techniques have detected the existence of circulating forms of intercellular adhesion molecule-1 (ICAM-1), vascular endothelial adhesion molecule-1 (VCAM-1) and E-selectin, all of which mediate leucocyte-endothelial adhesion. This study determined whether circulating cell adhesion molecules were increased in patients with chronic venous insufficiency (CVI) which causes venous stasis. PATIENTS AND METHODS: Before and after walking and upon recovery blood samples were drawn from the saphenous vein in 20 CVI patients: 10 with varicose veins (group 1), 10 with deep venous insufficiency (group 2). 10 healthy controls were enrolled. The total leucocyte count and the soluble levels of ICAM-1, VCAM-1 and E-selectin were determined. RESULTS: After walking, the total leucocyte count decreased significantly (p < 0.01) only in group 2 and sICAM-1 and sVCAM-1 increased significantly (p < 0.01). Upon recovery, these significant differences remained in group 2. No significant modification was observed at any stage of the study in group 1 or in the control group. CONCLUSIONS: These results suggest persistently high levels of circulating adhesion molecules may contribute to worsen microvascular perfusion, which leads to the onset of trophic damage in CVI.

Vascular 131I-low-density lipoprotein imaging in patients with hypertension and early atherosclerotic lesions in the carotid artery.

BACKGROUND: The reinjection of autologous 131I-labelled low-density lipoprotein (LDL) followed by vascular scintigraphy has been used to investigate lipid-containing plaques, but no information is available on the early stages of plaques in hypertensives. Vascular scintigraphy after re-injection of autologous 131I-labelled LDL was used to investigate early atherosclerotic lesions visualized by sonography in the carotid arteries of patients with hypertension. PATIENTS AND METHODS: 10 male patients (4 smokers; mean age 56 +/- 8 years;) with early carotid atherosclerosis (mono- or bilateral; intima-media-thickness ranging from 1.5 to 3.5 mm) as shown by sonography were studied. All these normolipemic patients suffered from primary hypertension and were treated with diuretics. As controls 6 healthy male subjects (3 smokers; mean age 54 +/- 9 years;), with normal blood pressure and lipid pattern were recruited. RESULTS: Hot spots appeared in the areas with early atherosclerosis in 7 patients, while none were seen in controls. Positive kinetic curves were observed in 4 patients. No significant differences emerged in the target/non-target ratios. CONCLUSIONS: Vascular lipoprotein uptake in hypertensive patients is apparently late and rather limited; the uptake pattern may depend on plaque composition.

Leucocyte-endothelial interactions in chronic critical limb ischaemia.

Forearm blood samples were drawn from 18 patients with critical limb ischaemia (stage IIIb peripheral arterial obliterative disease) and 18 age- and sex-matched controls at 8.00 a.m., 2.00 p.m. and 8.00 p.m. We monitored the total and differential leucocyte counts and leucocyte expression of CD11/CD18 integrins (on whole blood samples by indirect immunofluorescence on a FACScan flow cytometer). Our results show no significant difference in any parameter at any stage of the day. At all study times, the total and differential leucocyte counts and granulocyte expression of CD11/CD18 were significantly (p < 0.001) greater in patients compared with controls. Associated with a high leucocyte count, constant up-regulation appears to be a feature of chronic tissue ischaemia. Activated neutrophils seem to aggravate peripheral arterial obliterative disease locally and may contribute to disseminated organ damage.

Effect of low-dose oral triphasic contraceptives on blood viscosity, coagulation and lipid metabolism.

The purpose of the study was to determine the relationship between hemorheological profile, i.e. blood viscosity, and other risk factors for cardiovascular and thrombotic diseases in women taking oral contraceptives and if blood viscosity may be considered a marker of cardiovascular risk in OC users. Plasma levels of coagulation parameters, serum lipids, blood viscosity and RBC deformability were determined in a group of 10 women taking OC vs. 10 controls. The blood parameters were evaluated before OC use and thereafter at 3 and 6 months. A significant change in the partial thromboplastin time, fibrinogen, HDL and apolipoprotein A-I was observed, while the other parameters remained unchanged. Plasma viscosity was significantly increased during OC treatment; whole blood viscosity and RBC deformability remained unchanged. However, although some parameters were significantly modified during OC treatment, all alterations remained within the normal range of laboratory values. The data confirm that low-dose triphasic OC therapy does not affect significantly the coagulation system, serum lipid metabolism and blood viscosity. Plasma viscosity measurement may be considered as a marker for monitoring women using OC because it is apparently the most sensitive parameter.

PIP: Previous studies have documented an association between blood viscosity and risk factors for cardiovascular and thromboembolic disease. The present study assessed the impact of use of a low-dose, triphasic oral contraceptive (OC) containing ethinyl estradiol in combination with gestodene on the coagulation system, serum lipid metabolism, and blood viscosity. Enrolled were 10 OC users with no history of OC use before the study and 10 non-users. At 3 and 6 months after initiation of OC use, significant changes were recorded in partial thromboplastin time, fibrinogen, high density lipoprotein, and apolipoprotein A-1. Plasma viscosity was significantly increased during OC use, while whole blood viscosity and erythrocyte deformability remained unchanged. All alterations associated with OC treatment remained within the normal range of laboratory values, however. Thus, these findings suggest an absence of any significant OC effects on the hemostatic balance or lipid metabolism that might represent a risk factor for cardiovascular disease. Moreover, the measurement of blood viscosity may be a promising marker for monitoring thrombotic risk in women taking OCs given its apparent high sensitivity.

Neutrophil-derived adhesion molecules in human digital ischaemia and reperfusion.

In order to see whether leucocyte-derived adhesion molecules are involved in ischaemia and reperfusion, the total and differential leucocyte counts and expression of the LFA complex i.e. CD11a/CD18 (LFA-1), CD11b/CD18 (Mac-1) and CD11c/CD18 (p 150,95) were monitored before and after standard cold and heat tests in 8 females with Raynaud's Disease and 8 matched controls. All patients suffered from vasoconstriction during the cold test which, compared with controls, was associated with fewer granulocytes expressing significantly more CD11b/CD18 (Mac-1) integrin and a significant degree of neutropenia persisting during reperfusion. Leucocyte-endothelial adhesive interactions may therefore occur during ischaemia and reperfusion.

Leucocyte activity in chronic venous insufficiency.

Before and after venous stasis and upon recovery blood samples were drawn from the saphenous vein in 10 patients with varicose veins (Group 1), in 10 with venous hypertension (Group 2) and in 10 healthy controls. The total leucocyte count, the leucocyte filterability rate (LFR), superoxide dismutase blood concentrations (SOD) and the production of superoxide anions from granulocytes were determined. After stasis, the total leucocyte count increased significantly (p < 0.01) in both groups of patients and the LFR was significantly (p < 0.01) impaired. SOD blood concentrations fell significantly (p < 0.01) and oxygen free radical production dropped significantly (p < 0.01) in both groups. Upon recovery, all parameters returned to normal in Group 1 but significant differences remained in Group 2. No significant modification was observed at any stage of the study in the control group. These results suggest that impairments in leucocyte rheology and granulocyte production of oxygen free radicals cause capillary plugging and possibly damage to microcirculatory vessel walls in venous disease.

Treating peripheral arterial occlusive disease: pentoxifylline vs exercise.

The effects of three months therapy with Pentoxifylline (800 mg three times daily) and physical training were compared in two age- and sex-matched groups of Stage II PAOD patients. Before therapy and after 12 and 13 weeks each patient underwent a standard treadmill test. The maximum walking time, TcPO2 half recovery time to basal values after the induced ischaemia, granulocyte production of free radicals (by the superoxide dismutase-inhibitable reduction of ferricytochrome) and surface expression of the CD11/CD18 complex of adhesion molecules (by using specific monoclonal antibodies) were determined. Pentoxifylline inhibited free radical production and reduced the percentage of granulocytes expressing adhesion receptors while exercise had no significant effect on these parameters. These changes, which reflect improved microcirculatory functioning, were associated with a greater walking capacity and shorter half recovery time (+14% vs exercise group, p < 0.01; -39% vs exercise group, p < 0.01 respectively).

Lipoprotein (a) in peripheral arterial occlusive disease.

Recent studies have shown high levels of lipoprotein (a),--Lp(a)-, an atherogenic and thrombogenic lipoprotein, are considered a risk factor for coronary heart disease. This study evaluated Lp(a) levels, as well as other lipid factors, in a group of 45 patients affected by stage II peripheral arterial occlusive disease (PAOD). An age-, sex- and Body Mass Index-matched group of healthy controls was also recruited. Exclusion criteria were diseases or drugs which could alter Lp(a) levels. Alterations in lipid profiles, which are often associated with PAOD, were observed in the patients. Lp(a) levels did not differ significantly in the two groups (median 16.4 mg/dl, range 10-104, in PAOD and 9.9 mg/dl, range 7.4-66.7, in controls and means 21.7 +/- 17.5 mg/dl and 21.2 +/- 16.8 mg/dl respectively) but in 51% of the controls Lp(a) levels were < 10 mg/dl compared with 20% of the PAOD patients (p < 0.05).

Severe osteomalacia due to gluten-sensitive enteropathy.

This report discusses a severe case of osteomalacia due to gluten-sensitive enteropathy: it stresses the clinical features and describes an atypical form of gluten-sensitive enteropathy, in which gastroenterological symptoms were absent. Wasting and osteomalacia causing skeletal deformation with spontaneous fractures were observed in a 31-year-old woman who had marked hypophosphoremia, a tendency to low serum calcium levels and slight multi-deficiency anaemia. The patient was in a state of depression. The causes of osteomalacia and then a general malabsorption syndrome were investigated. Anti-gliadin antibodies were positive. Histological tests on duodenal mucous revealed a pattern indicative of gluten-sensitive enteropathy. A gluten-free diet was prescribed and at a check-up one month later the patient had improved markedly. Skeletal symptoms are predominant in 30% of atypical forms of gluten-sensitive enteropathy. The severity of this case was due to a late diagnosis.