Endotelial activation and flow-mediated vasodilation in young patients with breast cancer.

Endothelial activation and dysfunction may play a significant role in the progression of breast cancer. In our study we examined markers of endothelial activation (soluble ICAM-1, P-selectin, E-selectin) in 98 young patients with breast cancer (< 40 years). In 50 of them (and 20 age-matched controls) we also measured flow mediated vasodilation. Patients with breast cancer had significantly higher serum levels of soluble E-selectin, P-selectin and ICAM-1, P-selectin was higher in patients with larger tumors, node involvement and seemed to be apredictor of poor outcome. We were unable to find significant difference in the parameters of flow mediated vasodilation between patients with breast cancer and healthy subjects, although both peak blood flow (PBF) and flow mediated vasodilation (FMD) seemed to be skewed compared to healthy subjects toward mean and lower levels. Cluster analysis enabled us to distinguish several larger groups of patients with different degree of endothelial activation and function and different outcome. Group of patients with high E-selectin, high ICAM-1 (higher endothelial activation) and low VEGF (putative endothelial damage) had more frequently negative estrogen receptors and had worse outcome compared to the group of patients with lower E-selectin, lower ICAM-1 and mostly positive estrogen receptors. Further studies of larger groups of patients should help to identify the panel of endothelial markers which could help in predicting the outcome of young patients with breast cancer.

Effect of short-term maximal exercise on BNP plasma levels in healthy individuals.

Many studies documented the relationship between elevated plasma concentrations of natriuretic peptides and cardiovascular diseases, especially heart failure. However, it is still uncertain whether physical exercise leads to a significant release of natriuretic peptide in healthy subjects. The aim of this study was to determine the effect of maximal physical activity on plasma BNP concentrations in healthy individuals within 3 hours after the short-term exercise. BNP plasma concentrations were measured in 15 healthy volunteers before, immediately after as well as 1 hour and 3 hours after bicycle spiroergometry. Maximal workload and exercise capacity were assessed in watts, watt-seconds, metabolic equivalents and VO(2max). Mean BNP plasma levels before, immediately after, 1 hour and 3 hours post-exercise were 19.4+/-2.5; 30.6+/-4.7; 17.9+/-2.5 and 18.7+/-3.1 pg/ml, respectively. The increase of BNP concentrations immediately after exercise was statistically significant (p=0.0017) compared to baseline values. We did not find any correlation between the post-exercise increase of BNP levels and age, body mass index, maximal workload or exercise capacity. In conclusion, short-term maximal physical exercise in healthy individuals led to a fast and transient rise of plasma BNP concentrations, which remained well within normal range and far below the cut-off value for heart failure (100 pg/ml).

Natriuretic peptides - physiology, pathophysiology and clinical use in heart failure.

The natriuretic peptides - atrial, brain and C-type - were discovered during the last twenty years. Their effects on cardiovascular, renal, cerebral and other tissues through guanylyl cyclase were uncovered. Over the past decade natriuretic peptides (NPs) became a very useful tool in the management of heart failure patients. Results of many clinical trials have shown that BNP and NT-proBNP are helpful for diagnosis of heart failure. They are also independent markers of prognosis not only in heart failure patients but also in patients with other cardiovascular diseases. Recently published data document the utility of NPs in guiding treatment of heart failure patients. In this article, we focus on basic biochemical and physiological characteristics of NPs as well as on their significance in management of heart failure patients. Some limitations and pitfalls of NPs levels interpretation in diagnosing heart failure are also discussed.

The effect of rosiglitazone on the expression of thrombogenic markers on leukocytes in type 2 diabetes mellitus.

Diabetes mellitus is associated with a number of prothrombotic abnormalities, and correction of these abnormalities might translate into the reduction of cardiovascular risk. Glitazones improve endothelial function and reduce inflammation, but much less is known about their effect on thrombogenic factors. We have therefore studied the effect of rosiglitazone on leukocyte and soluble thrombogenic markers in patients with type 2 diabetes mellitus. Thirty-three subjects with type 2 diabetes and 32 normal controls were included; patients were examined at baseline and after 5 months of rosiglitazone treatment (4 mg/day). We measured leukocyte-platelet aggregates and leukocyte expression of either P-selectin glycoprotein ligand 1 (PSGL-1) or receptor for urokinase-type plasminogen activator (uPAR) using flow cytometry, as well as several circulating soluble thrombogenic markers by ELISA method. Leukocyte expression of uPAR and PSGL-1 was significantly higher in patients than in controls. Leukocyte-platelet aggregates and leukocyte expression of uPAR and PSGL-1 significantly decreased after rosiglitazone. There was also significant decrease in CRP and fibrinogen levels, but there was no effect of diabetes and/or rosiglitazone on other circulating molecules. In conclusions, we observed a substantial improvement in the expression of thrombogenic markers on leukocytes after rosiglitazone treatment, suggesting the novel antithrombotic effects of rosiglitazone.

Lower wall shear rate of the common carotid artery in treated type 2 diabetes mellitus with metabolic syndrome.

Arterial sites with low wall shear stress (WSS) are more prone to the development of atherosclerotic plaques, as was observed in carotid arteries in subjects with atherosclerosis risk factors. Type 2 diabetes mellitus (DM), hypertension, hyperlipidemia and other components of the metabolic syndrome, are associated with high risk for symptomatic cerebrovascular disease. It was shown by others that untreated type 2 DM is associated with lower WSS in common carotid arteries. However, the cardiovascular risk of type 2 DM could be modified by therapy. The aim of our study was to test the hypothesis that treated type 2 DM subjects with metabolic syndrome still have lower WSS in common carotid arteries than healthy controls. We enrolled 26 compensated DM subjects with metabolic syndrome, treated by metformin, statins and ACEI for more than 6 months, and 22 aged-comparable healthy controls. Wall shear rate (WSR) was used as a measure of WSS. A linear 3-11 MHz probe was used to measure blood velocity and internal diameter in the common carotid arteries. We compared observed values of WSR adjusted for age by ANCOVA. Wall shear rate was significantly lower in DM group than in control subjects: peak (systolic) values of wall shear rate were 410+/-130 s(-1) vs. 487+/-111 s(-1) (p<0.005). DM subjects had significantly lower WSR, because of both thinner lumen and slower blood flow velocities. Lower WSR was accompanied by higher IMT (0.73+/-0.12 mm vs. 0.64+/-0.11 mm, p<0.001). Treated subjects with compensated type 2 DM with metabolic syndrome still have atherogenic hemodynamic profile. These findings might help to understand faster progression of atherosclerosis in diabetic subjects with metabolic syndrome despite up-to-date medication.

Microvascular Reactivity and Endothelial Function in Type 2 Diabetic Patients with Hyperlipidemia Treated with Simvastatin: 3-year Follow-up.

Aim of this study was to evaluate microvascular reactivity (MVR) by laser Doppler flowmetry in Type 2 diabetes mellitus (T2DM) with hyperlipidemia during three years of simvastatin treatment. Additionally, markers of endothelium and fibrinolysis were evaluated. Twenty patients with T2DM and hyperlipidemia were treated with 20 mg of simvastatin daily for 3 months, treatment was then interrupted for 3 months (wash-out) and again started and maintained continually up to total of 36 months of follow-up. Maximal perfusion (max), velocity of perfusion increase (max/t) and percent increase of perfusion compared to baseline (%) was measured during post-occlusive reactive hyperemia (PORH) and thermal hyperemia (TH). VCAM-1, ICAM-1, E-selectin and P-selectin were used as markers of endothelium, tissue plasminogen activator (tPA) and its inhibitor (PAI-1) as markers of fibrinolysis. Baseline MVR in diabetic patients was comparable to controls. MVR decreased at months 3, 12, and 36 compared to baseline (PORHmax 26+/-12, 35+/-17, 26+/-11 vs. 56+/-30 PU, p<0.05, THmax 67+/-19, 81+/-37, 58+/-24 vs. 134+/-70 PU, p<0.01, PORHmax/t 2.0+/-1.4, 2.8+/-1.7, 1.9+/-1.3 vs. 7.7+/-7.4 PU/s, p<0.05, THmax/t 1.1+/-0.6, 1.0+/-0.4, 0.7+/-0.4 vs. 1.5+/-0.7 PU/s, p<0.05.

Leukocyte and endothelial adhesion molecules in patients with hypercholesterolemia: the effect of atorvastatin treatment.

Atherogenesis involves the migration of leukocytes into vascular subendothelial space, a process mediated by endothelial and leukocyte cell adhesion molecules. Endothelial molecules are assessed indirectly via serum levels, but leukocyte molecules can be assessed directly. We have therefore hypothesized that leukocyte adhesion molecules are altered to a greater degree in hypercholesterolemia than serum endothelial adhesion molecules. We examined 29 subjects with hypercholesterolemia and 27 controls at baseline and after 12 weeks of atorvastatin treatment (20 mg/day). Expression of leukocyte integrins CD11a, CD11b, CD18, and CD49d and of L-selectin was measured by flow cytometry. Serum ICAM-1, E-selectin and von Willebrand factor were measured by ELISA. Expression of leukocyte adhesion molecules was significantly higher in patients at baseline than in the controls, except for CD11a. Expression significantly decreased after atorvastatin in most adhesion molecules except for CD11b. In contrast, there was no effect of hypercholesterolemia and/or atorvastatin on the serum endothelial molecules. Leukocyte but not endothelial adhesion molecules were influenced by hypercholesterolemia and by lipid lowering treatment. Leukocyte molecules may therefore be a more sensitive marker of atherogenesis than endothelial molecules. Our results support the role of increased leukocyte adhesiveness in atherogenesis.

Understanding the dialysis access steal syndrome. A review of the etiologies, diagnosis, prevention and treatment strategies.

Distal hypoperfusion ischemic syndrome (DHIS), commonly referred to as hand ischemia or 'steal' after dialysis access placement, occurs in 5-10% of cases when the brachial artery is used, or 10 times that of wrist arteriovenous fistulas (AVFs) using the radial artery. It is typically seen in elderly women with diabetes, and may carry severe morbidity including tissue or limb loss if not recognized and treated. Three distinct etiologies include (1) blood flow restriction to the hand from arterial occlusive disease either proximal or distal to the AV access anastomosis, (2) excess blood flow through the AV fistula conduit (true steal), and (3) lack of vascular (arterial) adaptation or collateral flow reserve (ie atherosclerosis) to the increased flow demand from the AV conduit. These three causes of steal may occur alone or in concert. The diagnosis of steal is based on an accurate history and physical examination and confirmed with tests including an arteriogram, duplex Doppler ultrasound (DDU) evaluation with finger pressures and waveform analysis. Treatment of steal includes observation of developing symptoms in mild cases. Balloon angioplasty is the appropriate intervention for an arterial stenosis. At least three distinct surgical corrective procedures exist to counteract the pathophysiology of steal. The ultimate treatment strategy depends on severity of symptoms, the extent of patient co-morbidity, and the local dialysis access technical team support and skills available.

Effect of PPAR-gamma agonist treatment on markers of endothelial dysfunction in patients with type 2 diabetes mellitus.

Thiazolidinediones are insulin-sensitizing drugs acting through peroxisome proliferator-activated receptor (PPAR)-gamma. The aim of our study was to evaluate the effect of 5-month treatment with PPAR-gamma agonist--rosiglitazone (4 mg/day), on the circulating markers of endothelial dysfunction and to evaluate the role of changes in endocrine function of adipose tissue in this process. Biochemical and metabolic parameters, circulating adiponectin, resistin, ICAM-1, VCAM-1, E-selectin, P-selectin, PAI-1, myeloperoxidase (MPO), and matrix metalloproteinase-9 (MMP-9) concentrations were assessed in 10 women with type 2 DM before and after rosiglitazone treatment and in a control group of healthy women. At baseline, diabetic group had significantly higher serum concentrations of glucose, glycated hemoglobin, V-CAM and PAI-1 compared to control group. Adiponectin levels tended to be lower in diabetic group, while resistin concentrations did not differ from control group. Rosiglitazone treatment improved diabetes compensation, significantly reduced VCAM-1, PAI-1 and E-selectin concentrations and increased adiponectin levels, while it did not affect serum resistin concentrations. Adiponectin concentrations at baseline were inversely related to E-selectin and MPO levels, this correlation disappeared after rosiglitazone treatment. We conclude that 5-month rosiglitazone treatment significantly reduced several markers of endothelial dysfunction. This effect could be at least in part attributable to marked increase of circulating adiponectin levels.

Relationship between peripheral diabetic neuropathy and microvascular reactivity in patients with type 1 and type 2 diabetes mellitus -- neuropathy and microcirculation in diabetes.

The aim of the study was to evaluate differences in the relationship between peripheral diabetic neuropathy and microvascular reactivity in type 1 and type 2 diabetic patients. Twenty-eight type 1 and 37 type 2 diabetic patients were included in the study. Control groups consisted of 18 and 25, age and body mass index matched healthy persons. The presence of peripheral neuropathy was estimated by vibration perception threshold higher than 20 V evaluated by biothesiometry. Microvascular reactivity was examined by laser doppler fluxmetry using postocclusive reactive hyperemia and thermal hyperemia. The following variables of vascular reactivity were examined: peak flow after occlusion as a difference between maximal and basal perfusion (PORH (max)), mean velocity increase during postocclusive hyperemia (PORH (max)/t (1)), peak flow during thermal hyperemia (TH (max)) and the mean velocity increase in the perfusion during thermal hyperemia (TH (max)/t (2)). These parameters are expressed in perfusion units (PU) or in perfusion units per second (PU . s (-1)). The microvascular reactivity in type 1 diabetic patients without evidence of peripheral neuropathy was comparable with that in healthy persons and it was significantly higher than in type 1 diabetic patients with peripheral neuropathy in all tested parameters (PORH (max): 64 [40; 81] PU vs. 24 [17; 40] PU, p < 0.001, PORH (max)/t (1): 5.41 [2.69; 8.18] PU/s vs. 1.21 [0.69; 2.5] PU/s, p < 0.001, TH (max): 105 [77; 156] PU vs. 56 [46; 85] PU, p < 0.001 and TH (max)/t (2): 2.48 [1.67; 3.33] PU/s vs. 0.87 [0.73; 1.06] PU/s, p < 0.001). On the contrary, no difference in the microvascular reactivity parameters was found between type 2 diabetic patients with and without neuropathy (PORH (max): 48 [30; 60] PU vs. 49 [36; 57] PU, NS, PORH (max)/t (1): 3.46 [2.15; 5.19] PU/s vs. 3.29 [2.45; 4.8] PU/s, NS, TH (max): 95 [78; 156] PU vs. 97 [73; 127] PU, NS and TH (max)/t (2): 1.45 [0.95; 2.84] PU/s vs. 1.37 [1.12; 1.95] PU/s, NS). In both these groups microvascular reactivity was comparable with that estimated in the age and BMI matched healthy persons. An inverse relationship was observed between microvascular reactivity and vibratory perception threshold in type 1 diabetic patients, but it was not true in type 2 diabetic patients. We suppose that the pathogenesis of neuropathy and impaired microvascular reactivity may be differently influenced by metabolic factors in type 1 and type 2 diabetic patients.

Microvascular reactivity in patients with hypercholesterolemia: effect of lipid lowering treatment.

Impaired NO-dependent vasodilation of resistance vessels is an early marker of an increased risk of atherosclerosis; utility of the examination of microcirculation, however, is far less established. We have therefore tested the hypothesis that hypercholesterolemia is associated with an impaired microvascular reactivity and that this defect is at least partially reversible by lipid-lowering treatment. Twenty-seven otherwise healthy patients with severe hypercholesterolemia (HLP) were examined at rest and then after 10 weeks of atorvastatin treatment (20 mg/day). Skin microvascular reactivity (MVR) was examined by laser-Doppler flowmetry. Baseline MVR values of the studied group were compared to healthy control subjects, HLP patients with coronary artery disease (CAD) and diabetic patients with and without diabetic retinopathy. MVR was normal in HLP subjects without CAD. On the contrary, MVR was impaired in HLP patients with CAD. There was no effect of atorvastatin on MVR, despite the profound reduction of serum lipids. MVR values did not correlate with cholesterol levels. In diabetic subjects, the MVR was substantially impaired only in patients with retinopathy. In the subjects without retinopathy, MVR was either normal (type I diabetes) or moderately impaired (type II diabetes). MVR was thus normal in HLP patients without manifest vascular disease and was not influenced by lipid lowering therapy. Impairment in the MVR was only evident in subjects with HLP and severe CAD. These results suggest that microcirculation is not involved in the early vascular dysfunction induced by HLP and that MVR rather reflects changes which appear later in the course of the atherosclerotic disease.

[Biothesiometry in the diagnosis of peripheral neuropathies]. / Vysetrení biotesiometrem v diagnostice periferních neuropatií.

The aim of review is to give basic information on the method of peripheral neuropathy examination using biothesiometry technique. Impaired vibratory threshold can be identified in all patients with peripheral neuropathies, the diabetic, uremic, alcoholic or paraneoplastic ones. It is a simple, sensitive and comfortable method for daily screening. On the other hand it is sufficiently sensitive for detection and evaluation of peripheral neuropathy. Principle is a vibrating probe, vibration amplitude can be changed by voltage adjustment. Biothesiometry is used in diagnostics of peripheral neuropathies with impaired vibratory perception threshold, mainly in diabetology and neurology.

[Effect of insulin in hypertension with high and low levels of renin]. / Pusobení inzulinu u vysokoreninových a nízkoreninových hypertenzí.

BACKGROUND: Setback in insulin resistance has been described in patients with essential hypertension. The aim of our study was to verify at the receptor and postreceptor levels the presence of insulin resistance in patients with high or low renin activity. METHODS AND RESULTS: Six patients with the renal artery stenosis (20 to 65 years, average age was 51 +/- 12 years, BMI: 27 +/- 2.0 kg.m2) and six patients with primary hyperaldosteronism (28 to 61 years, average age was 50 +/- 13 years, BMI: 26.9 +/- 3.2 kg.m2) were investigated. Their diagnose was confirmed by laboratory examination, computer tomography, and duplex sonography. Blood pressure was monitored for 24 hours with Spacelab tonometer (SBP: 161 +/- 29 mmHg, DBP: 98 +/- 12 mmHg versus SBP: 168 +/- 21 mmHg, DBP: 103 +/- 9 mmHg; plasma renin activity was 8.1 +/- 5.6 versus 0.3 +/- 0.4 ng.ml-1.h-1, p < 0.001; recumbent plasma aldosterone level was 98 +/- 31 versus 358 +/- 103 pg.ml-1, p < 0.001, normal value till 150 pg/ml, serum potassium was 3.9 +/- 0.4 and 3.5 +/- 0.6 mmol/l). All patients had normal course of the oral glucose tolerance test. Six volunteers of corresponding age and BMI formed the control group. Patients had normal values of the basal morning glycemia (4.9 +/- 0.5 and 5.0 +/- 0.6 versus 4.9 +/- 0.6 mmol/l), basal insulinemia level was 28.8 +/- 12.4 and 21.0 +/- 10.2 versus 15.9 +/- 8.8 mU.l-1 in healthy controls. Insulin effect was tested using isoglycemic hyperinsulinemic clamp method on Biostator with insulin infusion of 1 mU.kg.min-1. Plasma potassium concentration was kept at constant physiological levels using linear infusion pump (in patients with primary hyperaldosteronism after the prior supplementation). In patients with high-renin or low-renin hypertension, the glucose consumption during clamping was lower than that of healthy controls (M, glucose disposal rate: 23.7 +/- 4.8 and 19.5 +/- 3.4 versus 33.0 +/- 5.7 mumol.kg.-1.min-1, p < 0.001), increase of the metabolic glucose clearance (MCRG: 5.1 +/- 1.5 and 3.9 +/- 0.7 versus 7.9 +/- 1.4 ml.kg-1.min-1, p < 0.001) and tissue insulin sensitivity index (M/I: 24.3 +/- 10.1 and 26.4 +/- 8.3 versus 38.4 +/- 10.1 mumol.kg-1.min-1 to mU.l-1 x 100, p < 0.001). CONCLUSIONS: Patients with high-renin and low-renin hypertension have the insulin effectiveness significantly impaired. Such insulin resistance probably does not depend on the renin activity, plasma aldosterone concentration or on serum potassium level. The ethiopathogenesis of the described changes will be the aim of our next study.

[Can hormonal contraceptives affect plasma levels of IGF-1 and IGFBP-1 in slim women with polycystic ovary syndrome?]. / Muze hormonální antikoncepce ovlivnit plazmatickou koncentraci IGF-1 a IGFBP-1 u stíhlých zen se syndromem polycystických ovarií?

BACKGROUND: Polycystic ovary syndrome (PCOS) represents a frequent endocrinopathy among fertile women. Ethiopathogenesis of the syndrome is multifactorial and it is a subject of scientific discussions. Considered is the possibility of intraovarial IGF system disorder affecting maturation of ovarial folicles. The aim of our work was to determine effects of peroral contraceptives with low-androgen progestin on IGF system in PCOS patients and healthy woman controls. METHODS AND RESULTS: 14 patients fulfilling diagnostic criteria of PCOS and 7 healthy controls were included into the study. All persons were examined before and after six months lasting administration of monophasic estrogen-progesteron contraceptive therapy with 35 micrograms of ethinylestradiol per day and 250 micrograms of low-androgen progestin norgestimate per day. In PCOS patients low increase of basal insulinemia levels occurred (16.3 +/- 4.8 vs. 20.8 +/- 4.8 mU.l-1, p < 0.05). IGF-1 serum levels were not influenced (230 +/- 70 vs. 235 +/- 112 pg.ml-1, n.s.), IGFBP-1 serum concentration significantly increased (46.3 +/- 24.1 vs. 75.6 +/- 24.0 pg.ml-1, p < 0.001). Insulinemia in healthy women also slightly increased (15.9 +/- 4.0 vs. 18.4 +/- 4.0 pg.ml-1, p < 0.05). IGF-1 serum concentration significantly increased (140 +/- 65 vs. 241 +/- 89 pg.ml-1, p < 0.001). IGFBP-1 was also higher (45.0 +/- 19.19 vs. 80.0 +/- 15.6 pg.ml-1, p < 0.001). Influence of the hormonal contraception on the followed parameters was estimated using Wilcoxon's test. While BP-1 increase was significant in both groups, the increase of IGF-1 was significant only in healthy controls. CONCLUSIONS: Increased levels of IGFBP-1 were found in both studied groups of women. Women with PCOS had higher serum levels of IGF-1 before the therapy and the treatment did not influence it. Contrary to it, in healthy women the increased value was observed. Explanation of that finding will become the aim of our next study.