Body fat distribution predicts the degree of endothelial dysfunction in uncomplicated obesity.

OBJECTIVE: To ascertain in obesity the role of body fat distribution (the strongest predictor of morbility and mortality in obese subjects) in determining the degree of endothelial dysfunction, an early marker of atherosclerotic disease. SUBJECTS: 18 premenopausal women with uncomplicated obesity excluding other cardiovascular risk factors and 12 age-matched slim healthy women. MEASUREMENTS: Endothelium-dependent vasodilation, studied as diameter variation in response to an increase in shear-stress, was evaluated in the right common femoral artery of obese and slim subjects by a non invasive approach and compared to glyceril-trinitrate vasodilation. To characterize better the vascular functional and/or structural properties, we studied the arterial wall distensibility by an echo-tracking system. Adipose tissue regional distribution was determined by computerised axial tomography. RESULTS: The endothelium-dependent vasodilation was significantly impaired in obese subjects (P<0.005 versus non-obese subjects) while glyceril-trinitrate vasodilation and arterial distensibility were similar in the two groups. In our obese subjects endothelial-dependent vasodilation was inversely correlated to body fat distribution (visceral/subcutaneous adipose tissue ratio: r=- 0. 624, P=0.0058). In contrast, metabolic parameters (except C-peptide response during oral glucose tolerance test (OGTT): r=-0.587, P=0. 01), blood pressure values and body weight did not correlate with the endothelial function. CONCLUSION: Uncomplicated obesity per se is characterised by an alteration of the endothelial function; the degree of this vascular damage is predicted by body fat distribution independently of body weight and metabolic and other haemodynamic parameters, and correlates with an index of insulin secretion.

Effect of losartan on heart rate and blood pressure variability during tilt test and trinitroglycerine vasodilation.

OBJECTIVE: To define the changes in variability of heart rate and of blood pressure during vasodilation in a group of hypertensive patients treated with an angiotensin II type I (AT1) receptor inhibitor. DESIGN: Losartan (50 mg/day at 0800 h) or placebo were administered for 3 weeks according to a single blind, crossover, randomized protocol, to 18 hypertensive patients (16 men and two women, mean age 42 + 3.6 years). Continuous ECG recording and beat-to-beat blood pressure monitoring were carried out with subjects in the supine position and during a head-up tilt test, as well as after sublingual administration of trinitroglycerine. The elaboration of ECG traces in the frequency domain, was carried out using an autoregressive method and measured using the autoregressive moving average technique. RESULTS: Orthostatic stimulus, both during treatment with losartan and with placebo, caused a significant decrease in the heart rate high frequency power; on the other hand, the low frequency power appeared unchanged after placebo and was significantly reduced with losartan. Five minutes after the administration of trinitroglycerine, the low frequency power with placebo showed a significant increase (817 -+ 221 versus 465 + 101 ms2, P < 0.03). No change was recorded in total power nor in low frequency or high frequency power during losartan therapy. The ratio of low frequency to high frequency powers showed a sympathetic prevalence during vasodilation only during placebo treatment, whereas a mainly unchanged balance was maintained during losartan treatment Blood pressure variability showed a sympathetic prevalence after upright and trinitroglycerine stimulation only in placebo-treated subjects. CONCLUSIONS: Our study demonstrated that vasodilation is not able to evoke an unbalancing of the autonomic modulation in hypertensive patients treated with an AT1 receptor inhibitor, but permits the maintenance of a significant vagal component, thus highlighting the favorable profile of this drug in the autonomic control of circulation.

The effects of thromboxane A2 inhibition (picotamide) and angiotensin II receptor blockade (losartan) in primary Raynaud's phenomenon.

OBJECTIVES: To assess the role of thromboxane A2 and of angiotensin II in patients with primary Raynaud's phenomenon. DESIGN: After an eight-day run-in period, the patients were enrolled in a single-blind, cross-over, study. SETTING: Patients were examined at the Ambulatory for Microcirculatory Diseases of the Clinic of Internal Medicine, University Hospital, Verona. SUBJECTS: Fifteen subjects affected by primary Raynaud's phenomenon were included. MAIN OUTCOME MEASURES: A piezoelectric plethysmography to evaluate the distensibility of the digital arteries as the ratio between peak time (PT) and total time (TT), and an oscillometric blood pressure recorder were used after the run-in period, and after a two-week course of picotamide (300 mg b.i.d., i.e. two times daily) or losartan (12.5 mg once daily) with an interval of a week of placebo between the active treatments. The tests were performed after every treatment in basal condition and during mental stress. The patients reported in a diary the number and the severity (from 0 to 4 +) of the vasospastic crises. RESULTS: The change in TP/TT ratio appeared statistically significant only after losartan treatment, both in basal condition and during mathematical stress. Both pharmacological treatments, with respect to placebo, showed an improvement of the scores, derived from the number and severity of vasospastic attacks, but only the therapy with losartan determined a statistically significant improvement. CONCLUSIONS: The inhibition of the type 1 receptor for angiotensin II seems highly effective in the reduction of the vasospastic crises in the subjects with primary Raynaud's phenomenon. According to our experience, losartan could be used more extensively in the treatment of these patients besides arterial hypertension.

Left ventricular diastolic function during adrenergic stress in essential hypertension: acute and chronic effects of ACE inhibition.

We studied the changes in left ventricular (LV) diastolic function induced by angiotensin-converting enzyme (ACE) inhibition at rest and during adrenergic stimulation and their relation to blood pressure (BP) variations to determine whether reductions in the renin-angiotensin system may improve diastolic function irrespective of BP reduction. Echocardiographic indices of systolic and diastolic function, plasma catecholamines as estimated by high-pressure liquid chromatography, and BP variations (Dynamap) were determined at rest and during the cold pressor test (CPT) before and 6 hours and 20 days after ACE inhibition (lisinopril), 20 mg/day by mouth in 10 subjects with uncomplicated essential hypertension. Blood Pressure was significantly reduced after both 6 hours and 20 days of therapy. The cold pressor test induced similar increases in BP in both basal conditions and after acute and chronic treatment. Catecholamine levels were unchanged by the therapy. Systolic function, evaluated by fractional shortening, ejection fraction, and systolic dV/dt, was normal and unchanged during CPT and after treatment. Diastolic function, assessed by volume curve analysis, showed a reduced percentage contribution of rapid filling to total diastolic filling, an increase in the contribution of the atrial systole, and an increase in the isovolumetric relaxation time. During CPT these parameters deteriorated further in response to increased afterload. Lisinopril therapy induced significant increases in end-diastolic volume (p < 0.005) with a progressive increase in the rapid filling dV/dt (p < 0.005 at rest; p < 0.001 during CPT) and a reduction in isovolumetric relaxation (p < 0.0001 at rest and p < 0.01 during CPT). The correlation between systolic BP (afterload) and the rapid filling dV/dt, both at rest and during CPT, was modified by treatment with the ACE inhibitor, with significantly higher rapid filling dV/dt values, and with the pressure loads equal (reduction of the slope and rightward shift of the correlation line). The improvement in diastolic function achieved by ACE inhibition at rest and during CPT appears unrelated to plasma catecholamines and only partly ascribable to the reduced pressure load. The tissue angiotensin II reduction might by itself improve the myocardial response to the pressure load and adrenergic stimulation.

Non-invasive detection of early endothelial dysfunction in hypercholesterolaemic subjects.

Hypercholesterolaemia is associated with accelerated atherogenesis. Before the evidence of morphological lesions or plaques, endothelial dysfunctions, such as impairment in endothelium-dependent vascular tone regulation, may occur. We studied 32 subjects, 16 with primary hypercholesterolaemia and 16 normocholesterolaemic controls. Flow-dependent vasodilation, an endothelium-dependent phenomenon, was evaluated by measuring femoral artery diameter and flow velocity in basal conditions and during distal post-ischemic hyperaemia, using a high resolution echo-Doppler. Arterial distensibility and compliance were evaluated for the common carotid and femoral arteries, using a pulsed echo-tracking system and measuring the absolute and relative stroke change in arterial diameter. In the hypercholesterolaemic group there was no flow-dependent arterial relaxation, indicated by the area under the curve of percentage diameter variation as a function of time. This parameter was inversely correlated with both total and LDL-cholesterol values in all population subjects. No difference was observed between the two groups in endothelium-independent vasodilation induced by glyceryl trinitrate administration or arterial wall distensibility and compliance, confirming the hypothesis of a functional defect.

[Updating of relative data on tocopherols in clinical biochemistry]. / Actualisation des données relatives aux tocophérols en biochimie clinique.

The working group on lipophilic vitamins of the FSBC has reviewed current knowledge in the field of tocopherols and tried to summarize the most important and recent aspects that may be useful to clinical practitioners. The molecular structure of tocopherols and tocotrienols, their biogenesis, their analysis in foods, their metabolism in humans, their measurement in biological fluids, and the organism's needs and dietary requirements are reviewed. Their main functions as antioxidants and free radical scavengers are described at the molecular, ultra-structural, cellular and organ levels. The interest of these vitamins in three pathologies in which oxidative-stress has been implicated (atherosclerosis, cancer, kidney failure) is discussed.

[Stability of alpha-tocopherol: pre-analytical conditions in its determination in blood samples]. / Stabilité de l'alpha-tocophérol: conditions préanalytiques à son dosage dans les prélèvements sanguins.

Incomplete and controversial data exist concerning vitamin E or alpha-tocopherol stability in biological samples. Recent clinical interest in the protective function of alpha-tocopherol provided another reason for the setting-up of a multicenter study by the Sociéte Française de Biologie Clinique. Our purpose was to examine the effects on alpha-tocopherol stability, firstly, of collection and transportation of blood samples, and, secondly, of the temperature (-20 degrees C and -80 degrees C) and period of storage of serum or plasma. alpha-tocopherol was determined in serum or plasma by isocratic liquid chromatography with UV detection at 292 nm. Our results established that alpha-tocopherol was extremely stable in blood, serum or plasma over 8 hours without special handling conditions (light, temperature). Pools of serum or plasma were stable for at least 3 months at -20 degrees C and -80 degrees C. They are suitable for use in the quality control of alpha-tocopherol. On the other hand, in some samples, we observed great variability in the rate of alpha-tocopherol degradation. However, there was lesser degradation when these plasma samples were stored at -80 degrees C instead of -20 degrees C. We therefore do not advise storing serum or plasma for more than 1 month at -20 degrees C for more than 3 months at -80 degrees C. This latter temperature is recommended in epidemiological studies.

[Passive smoking in children. Its detection by the assay of urinary cotinine]. / Le tabagisme passif de l'enfant. Son dépistage par le dosage de la cotinine urinaire.

BACKGROUND: Passive tobacco smoking is responsible for increased respiratory morbidity in young children. This point is not always understood by parents and the use of a sensitive marker for nicotine exposure may help them to smoke less. POPULATION AND METHODS: Urinary cotinine concentration was measured in 72 children, aged from 1 to 5 years, that had been admitted to our unit during October and November 1991 for various causes. The results were correlated with the smoking habits of their parents. Urine samples were obtained during the first hours after admission and the cotinine concentration was measured by HPLC. Concentrations > 5 micrograms per liter were considered to be positive. RESULTS: A total of 67 urine samples were analysed: 43 (64.2%) were positive with cotinine concentrations of 5 to 77 micrograms/l (mean: 19.7). Both parents of 21 children were smokers; the fathers of 18 children and the mothers of 11 children, alone, smoked. There was therefore at least one smoker in the environment of 50 children. There was a highly positive correlation between parental smoking and urinary cotinine (p < 0.0001). For the infants with only one parent who was a smoker, their urinary cotinine was higher when the smoker was the mother rather than the father. CONCLUSIONS: An urinary cotinine of > 6 micrograms per liter is a precise, sensitive, test for passive smoking in young children. This test is well accepted by families and its result may persuade parents to stop or moderate their use of tobacco. This test also could be used, as part of a pulmonary check-up, as a public health indicator.

Left ventricular diastolic function and responses to adrenergic stimuli in borderline arterial hypertension.

OBJECTIVE: To detect the existence of a possible relationship between arterial hypertension and adrenergic reactivity to pressure stimuli, and changes in left ventricular diastolic function (LVDF). PATIENTS: Fifty-nine young subjects with borderline arterial hypertension and ten sex- and age-matched controls were investigated. After three medical examinations, the subjects were divided into hypertensive and borderline groups on the basis of the blood pressure reading at visit 3. A complete echocardiographic study was performed in 25 of the 59 subjects. DESIGN: Blood pressure was measured in baseline conditions and during pressure stimuli (mental stress, handgrip and cold pressor tests). LVDF was evaluated primarily by means of filling velocities during diastolic phases taken from the left ventricular volume curve (obtained from a complete echocardiographic study). RESULTS: No significant changes in blood pressure responses were observed for the borderline or hypertensive groups during the adrenergic test. The echocardiographic indices of diastolic function were statistically different for the two groups when compared with the control group. The LVDF parameters correlated significantly with systolic blood pressure and diastolic blood pressure measured at the time of the echocardiogram, but not with blood pressure measured occasionally. CONCLUSIONS: Blood pressure increases similarly during adrenergic stimuli in both the hypertensive and borderline groups. The correlation between systolic blood pressure, diastolic blood pressure and LVDF parameters may indicate a very early onset of reduced compliance of the left ventricle, even in a preclinical phase of hypertension.

Early regression of left ventricular diastolic abnormalities in hypertensive patients treated with nifedipine.

The effects of nifedipine on blood pressure (BP), left ventricular hypertrophy, and diastolic function were evaluated in 14 patients with essential hypertension (EH). All males with a mean age of 44 +/- 6 years (range 35-58 years), and in ten normotensive subjects (control group) aged 32-42 years (mean age 36 +/- 4). A complete echocardiogram (ECHO) was performed in basal conditions after 1 and 6 months of therapy with nifedipine (20-40 mg/day). Left ventricular echocardiograms (LV ECHO, M-mode, two-dimensional guided) were plotted with a simultaneous ECG tracing by means of a computerized system that allows evaluation of the following parameters: LV end-diastolic and systolic diameters (EDD, ESD); variations in LV diameter and volume during the entire cardiac cycle, and the velocities of such variations; end-diastolic thicknesses of the interventricular septum and posterior wall (ST, PWT); LV mass, mass/volume (M/V) index, end-diastolic diameter/thickness (D/Th) index, and LV ejection fraction (EF). Left ventricular volume curves were obtained and the contributions of rapid filling (RF) and atrial systole (AS) to EDV were evaluated. Filling velocities during RF (vRF) and AS (vAS) were estimated, as well as the isovolumic relaxation period (IR). No significant changes were observed in the heart rate. After 1 month of therapy, systolic and diastolic BP were significantly decreased (p less than 0.05). ST and PWT were reduced, with a simultaneous increase in EDD and EDV (p less than 0.01). LV mass was slightly reduced, as was the M/V index. The D/Th index was increased (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

High plasma levels of a ouabain-like factor in normal pregnancy and in pre-eclampsia.

Recent reports have described high levels of one or more substances which cross-react with digoxin antibodies in the serum of women with pre-eclampsia. We measured plasma ouabain-like activity and intraerythrocyte sodium and potassium concentrations, in addition to performing routine hypertensive laboratory tests, in 13 normotensive non-pregnant subjects, 15 normotensive pregnant women and 16 pre-eclamptic women (gestational age: 33-36 weeks). Plasma ouabain-like activity, measured as plasma-induced variations in ouabain binding to human erythrocytes, proved significantly higher in both groups of pregnant subjects as compared to normotensive non-pregnant women, and a significant difference was also found between pre-eclamptic and normotensive pregnant women, the former exhibiting higher plasma ouabain-like activity. No differences in intracellular sodium and potassium levels were detected among the three groups studied. Though there is reason to believe that the high plasma levels found both in normal and hypertensive pregnancy may depend on placental production, we are not in a position to define with any degree of certainty what the mechanism or mechanisms are that regulate ouabain-like factor production.

Altered excretion of prostaglandin and thromboxane metabolites in pregnancy-induced hypertension.

The renal and systemic metabolites (the latter as 2,3-dinor derivatives) of prostacyclin and thromboxane A2 were measured, along with renal prostaglandin E2 and kallikrein, in the urine of 15 patients with pregnancy-induced hypertension, 15 normotensive pregnant women matched for both age and gestational age, and 15 normotensive nonpregnant control women. Urinary excretion of all prostaglandin and thromboxane metabolites studied proved significantly higher in normotensive pregnant women than in controls. Prostaglandin E2, 6-keto-prostaglandin F1 alpha, and 2,3-dinor-6-keto-prostaglandin F1 alpha were significantly lower in pregnancy-induced hypertensive women than in normotensive pregnant women, whereas thromboxane B2 and 2,3-dinor-thromboxane B2 showed no significant differences in the two groups. A significant negative correlation (r = -0.636, p less than 0.01) was found between urinary 2,3-dinor-6-keto-prostaglandin F1 alpha and mean blood pressure in the two groups of pregnant women taken as a whole. These data indicate that, in pregnancy-induced hypertension, there is an imbalance between vasodilator and vasoconstrictor factors, not only in the kidneys, but also at the systemic vascular level. This imbalance, which may in itself produce vasoconstriction, may also potentiate the hypertensive effect of catecholamines and angiotensin II.

Intracellular free Ca2+ in platelets of essential hypertensive patients. Lack of correlation with clinical and laboratory data.

Platelet intracellular free Ca2+, [Ca2+]i, was found to be higher in 64 hypertensive patients than in 65 age- and sex-matched normotensive controls (142.7 +/- 3.8 nmol/l vs 126.6 +/- 2.4 nmol/l, M +/- SEM, respectively; P less than 0.001). No differences were observed in hypertensive patients in relation to age, duration of hypertension or severity of retinopathy, but a slight correlation was observed (r = 0.275, P less than 0.05) between platelet [Ca2+]i and systolic blood pressure. No correlations were found between platelet [Ca2+]i and plasma cholesterol, triglycerides, aldosterone or renin activity. These data appear to support the hypothesis that increased platelet [Ca2+]i in hypertensive patients is more likely to be related to a primary cellular abnormality than to activation by extrinsic humoral or vascular factors.

Increased basal and thrombin-induced free calcium in platelets of essential hypertensive patients.

Intracellular free calcium, [Ca2+]i, was studied in platelets of essential hypertensive subjects and normotensive controls under basal conditions and after stimulation with epinephrine, norepinephrine, angiotensin II, ouabain, and thrombin, using the fluorescent calcium indicator quin 2. Basal [Ca2+]i was significantly higher in hypertensive subjects (n = 32) than in normotensive controls (n = 30; 167.4 +/- 5.0 vs 143.2 +/- 3.1 nmol/L; p less than 0.001). Epinephrine, norepinephrine, angiotensin II, and ouabain had no effect on platelet calcium, whereas thrombin induced a dose-dependent increase in [Ca2+]i in both the presence and absence of extracellular calcium. This [Ca2+]i increase in the presence of extracellular calcium, which depends mainly on calcium influx, was significantly higher (p less than 0.05) in platelets of hypertensive subjects at all thrombin concentrations (ranging from 0.025-0.1 U/ml), while the [Ca2+]i increase in the absence of extracellular calcium, which depends only on release from intracellular stores, was similar in hypertensive subjects and controls. These results suggest that, in essential hypertension, there is not only increased platelet resting [Ca2+]i but also an increase in agonist-mediated calcium influx, which appears to indicate a cell membrane abnormality in the platelets of subjects with essential hypertension.

Regression of cardiac hypertrophy after antihypertensive therapy with nifedipine and captopril.

The effects of two antihypertensive agents, nifedipine (N) and captopril (C), on left ventricular (LV) mass and volume were studied in 16 patients with essential hypertension (8 treated with N and 8 with C for 6 months) by means of a complete M-mode echocardiogram monitored by two-dimensional echocardiography. Both N and C induced a significant reduction in end-diastolic, but not systolic, posterior wall and septum thickness and an increase in end-diastolic volume, but not in end-systolic volume. A significant increase in the contribution of rapid filling together with a simultaneous reduction in the contribution of atrial systole to end diastolic volume were also observed. The reduction in LV wall thickness and mass after both C and N might be attributed to an improvement in diastolic function and to a reduction in wall tension, rather than to an effective regression of LV hypertrophy.