[Angiotensin II receptor antagonists in arterial hypertension: new clinical evidence with candesartan].
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Biomedical subjects
Publications and source records attributed to G Mancia.
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Several trials have shown that antihypertensive drug treatment decreases cardiovascular morbidity and mortality rates. They have also shown, however, that the risk is not decreased to the level of nonhypertensive patients. Trials are therefore underway to determine whether the benefits achieved by older drugs, such as diuretics and beta blockers, can be enhanced by using newer classes of antihypertensive agents, such as calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor antagonists. Among these trials, the International Nifedipine GITS Study of Intervention as a Goal in Hypertension Treatment (INSIGHT) is of special interest because it is the first study to address, in a prospective fashion, the prognostic influence of antihypertensive treatment (nifedipine GITS vs a combined thiazide and potassium-sparing diuretic) in hypertensive patients with concomitant risk factors such as hypercholesterolemia, cigarette smoking, diabetes, and left ventricular hypertrophy. This article briefly describes the rationale and design of the INSIGHT trial and cites the substudies and the preliminary data available.
BACKGROUND: Previous studies have shown that sympathetic cardiovascular outflow is increased in obese normotensive subjects and that this increase is associated with a baroreflex impairment. The purpose of this study was to determine whether these abnormalities are irreversible or can be favorably affected by body weight reduction. METHODS AND RESULTS: In 20 obese normotensive subjects (age, 31.3+/-1.7 years; body mass index, 37.6+/-0.9 kg/m2, mean+/-SEM), we measured beat-to-beat arterial blood pressure (Finapres technique), heart rate (ECG), postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve), and venous plasma norepinephrine (high-performance liquid chromatography) at rest and during baroreceptor stimulation and deactivation induced by increases and reductions of blood pressure via stepwise intravenous infusions of phenylephrine and nitroprusside. Measurements were repeated in 10 subjects after a 16-week hypocaloric diet with normal sodium content (4600 to 5000 J and 210 mmol NaCl/d) and in the remaining 10 subjects after a 16-week observation period without any reduction in the caloric intake. The hypocaloric diet significantly reduced body mass index, slightly reduced blood pressure, and caused a significant and marked decrease in both muscle sympathetic nerve activity (from 50.0+/-5.1 to 32.9+/-4.6 bursts per 100 heart beats, P<.01) and plasma norepinephrine (from 356.2+/-43 to 258.4+/-29 pg/mL, P<.05). This was associated with a significant improvement in the sensitivity of the baroreceptor heart rate (+71.5 +/- 11%, P<.01) and muscle sympathetic nerve activity (+124.5 +/- 22%, P<.001) reflex. Total body glucose uptake also increased significantly (+60.8 +/- 12.0%, P<.05), indicating an increase in insulin sensitivity. All variables remained unchanged in subjects not undergoing caloric restriction. CONCLUSIONS: In obese normotensive subjects, a reduction in body weight induced by a hypocaloric diet with normal sodium content exerts a marked reduction in sympathetic activity owing to central sympathoinhibition. This can be due to the consequences of an increased insulin sensitivity but also to a restoration of the baroreflex control of the cardiovascular system with weight loss.
Mild to moderate hepatic iron overload is frequent in patients with chronic viral hepatitis (CH). We evaluated the role of hemochromatosis (HFE) gene mutations and other acquired factors in the development of iron overload in these patients. We studied 110 patients with chronic B or C viral hepatitis (31 women, 79 men), including 20 with cirrhosis, and 139 controls. Hepatic iron was evaluated by semiquantitative analysis in all the patients, and hepatic iron concentration (HIC) was determined in 97 of them (26 women, 71 men). C282Y and H63D mutations were sought in all the subjects by a polymerase chain reaction-restriction assay. The frequency of HFE genotypes and alleles did not differ in patients and controls. No relation was detected between hepatic iron stores and HFE gene mutations in women. In men, all C282Y heterozygotes had iron overload, and the H63D mutation was significantly more frequent in patients with more marked hepatic siderosis than in those with mild or no siderosis (P = .0039) and in controls (P = .0008). Heavy alcohol intake and hepatic cirrhosis were also associated with increased hepatic iron stores in the men. In the 71 men in whom HIC was measured, multiple regression analysis showed that this variable was related independently only to alcohol intake and HFE gene mutations. We suggest that in patients with CH, iron accumulates in the liver as the result of an interplay between genetic and acquired factors, and that increased liver iron stores may influence progression toward liver fibrosis.
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BACKGROUND/AIMS: Hepatitis C virus (HCV) easily undergoes genomic changes, thus accounting for the presence of different genotypes, with different geographic distributions and different outcomes of chronic hepatitis. Type 1b is frequently found in advanced diseases; however, since this genotype is the most prevalent in older patients, the association with advanced age and severity of the disease is confounding. The aim of this study was to assess changes in the prevalence of HCV genotypes by surveying a large population of chronic hepatitis C patients in Northern Italy, and to assess if the high prevalence of genotype 1b in older patients with advanced diseases simply reflects the duration of HCV infection, rather than intrinsic biological properties of HCV. METHODS: We studied 1368 HCV-RNA positive patients, with histologically proven chronic hepatitis. Drug addiction, blood transfusions and sporadically acquired infections represented the risk factors. RESULTS: Genotype 1b, the most prevalent isolate, and genotype 2a were associated with older age, cirrhosis, sporadically-acquired infections and blood transfusion, while types 1a, 3a, and 4 were associated with younger age, chronic persistent hepatitis and drug addiction. Patients with a history of transfusions were divided into four groups depending on the period of transfusion. The prevalence of genotype 1b decreased with time. Type 3a appeared only after 1979. CONCLUSION: The severity of chronic hepatitis C could be related more to the duration of the infection rather than to the intrinsic pathogenicity of HCV genotypes.
OBJECTIVES: The present study was designed to assess whether a diuretic- or an angiotensin-converting enzyme inhibitor-based treatment can reduce arterial wall hypertrophy of a distal muscular medium-sized artery--the radial artery--and the stiffness of a proximal large elastic artery--the common carotid artery. BACKGROUND: Large-artery wall thickness and stiffness are increased during sustained essential hypertension and contribute to the increased risk of complications. Whether antihypertensive treatment can normalize the wall hypertrophy of conducting arteries has not yet been determined. METHODS: Seventy-seven elderly hypertensive patients were randomized to receive 9 months of double-blind treatment with perindopril (2 to 8 mg/day) or the diuretic combination of hydrochlorothiazide (12.5 to 50 mg/day) plus amiloride (1.25 to 5 mg/day) after a 1-month placebo washout period. If systolic blood pressure remained at >160 mm Hg after 5 months, chlorthalidone or atenolol was added, respectively. Arterial variables, including radial artery mass and common carotid artery compliance, were calculated from noninvasive measurements of internal diameter and wall thickness with the use of high resolution echo-tracking systems at baseline and after 5 and 9 months. RESULTS: During treatment, blood pressure and arterial variables changed to the same extent in both groups. After a 9-month treatment, systolic, diastolic and pulse pressures and radial artery wall thickness, mass and thickness/radius ratio decreased significantly (p < 0.01), whereas carotid compliance increased (p < 0.001). The decrease in radial artery thickness/radius ratio after a 9-month treatment was significantly related to the reduction in pulse pressure (p < 0.01), whereas the improvement in carotid compliance was related to the reduction in mean arterial pressure (p < 0.01). In healthy subjects and untreated hypertensive patients, radial artery diameter, wall thickness and thickness/radius ratio and carotid artery compliance did not change significantly during a 9-month observation period. CONCLUSIONS: These results indicate that in elderly hypertensive patients, both angiotensin-converting enzyme inhibitor- and diuretic combination-based treatments can reduce radial artery wall hypertrophy and improve carotid artery compliance.
Conflicting reports exist as to whether air traffic controllers (ATC) have an increase in blood pressure (BP) and prevalence of hypertension because of the stressful nature of their job. We have addressed the issue in male ATC working at the Linate airport of Milan. A total of 80 ATC participated, and the 24 h blood pressure monitoring was obtained during two working shifts separated by one night of rest. Blood pressure was measured conventionally and by 24 h ambulatory monitoring; data were compared with those of an age matched male sample three times as large, selected from the data of the Studio delle Pressioni Ambulatoriali delle Loro Associazioni (PAMELA), ie, a large sample representative of the population of the nearby town of Monza. Treated hypertensive subjects were excluded from both groups. Conventional diastolic BP and heart rate were similar in ATC and controls, whereas conventional systolic BP was significantly greater in the former than in the latter group. No difference, however, was seen between ATC and controls as far as ambulatory BP and heart rate were concerned; namely, 24 h, day, and night average systolic BP, and diastolic BP and heart rate were similar in the two groups. Thus daily life BP is not increased in ATC. This may result from the fact that, being a highly selected group with suitable training, these subjects adequately cope with the stress inherent to the job.
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BACKGROUND: Systolic hypertension of the elderly is characterized by a reduction in arterial compliance. Whether and to what extent this involves arteries of various structure and size is not well known. OBJECTIVE: To study carotid and radial artery compliance in systolic hypertension of the elderly, compared to essential hypertension and normotension. METHODS: We investigated 28 elderly patients with systolic hypertension (age 68.6 +/- 1.4 years, mean +/- SE; systolic blood pressure > 160 mmHg and diastolic blood pressure < 90 mmHg) plus 17 age-matched patients with essential hypertension and 15 age-matched healthy normotensive subjects. Radial and carotid artery compliance were evaluated using echotracking techniques. In both arteries compliance was assessed statistically and dynamically, i.e. as compliance values throughout the diasto-systolic pressure range. Measurements included intima-media wall thickness of the radial artery. RESULTS: Compared to normotensive subjects, carotid artery compliance was reduced in essential hypertension and more so in systolic hypertension. However, although in both groups radial artery wall thickness was markedly greater than in the normotensive group, radial artery compliance was markedly reduced in systolic hypertension, but unchanged in essential hypertension. CONCLUSIONS: In systolic hypertension of the elderly the reduction of arterial compliance is marked in both muscular and large elastic arteries, while in elderly essential hypertensives changes in arterial compliance are more heterogeneous, i.e. only carotid artery compliance is reduced. The different effects of these two types of hypertension on arterial mechanics are visible throughout the physiological range of blood pressure and probably accounted for by different alterations in vessel wall structure.
BACKGROUND: The difference between clinic and ambulatory average daytime blood pressures is frequently taken as a surrogate measure of the 'white-coat effect' (i.e. the pressor reaction triggered in the patient by the physician's visit). OBJECTIVE: To assess the reproducibility of this difference and its relationship with clinic and average ambulatory daytime blood pressure levels. DESIGN AND METHODS: These issues were addressed with two large groups of subjects in whom both clinic and ambulatory blood pressures were measured, namely 783 outpatients with systolic and diastolic essential hypertension [Group 1, aged 50.8+/-9.4 years (mean +/- SD)], participating in standardized Italian trials of antihypertensive drugs, and 506 elderly patients (group 2, age 71+/-7 years) with isolated systolic hypertension, participating in the European Syst-Eur trial. RESULTS: The clinic-daytime blood pressure difference for the essential systolic and diastolic hypertensive patients (group 1) was 13.6+/-14.3 mmHg for systolic and 9.1+/-8.6 mmHg for diastolic blood pressure (P always < 0.01). This difference for the elderly patients with isolated systolic hypertension (group 2) was 21.2+/-16.0 mmHg for systolic and only 1.3+/-10.2 mmHg for diastolic blood pressure (P < 0.01 and P < 0.05, respectively). In both studies little or no systematic clinic-daytime difference could be observed for heart rate. The reproducibility of the clinic-daytime blood pressure difference, tested for 108 essential systolic and diastolic hypertensive patients from group 1 and 128 isolated systolic hypertensives from group 2, was invariably lower than that both of daytime and of clinic blood pressure values. Finally, the clinic-daytime blood pressure difference was progressively higher for increasing levels of clinic blood pressure and progressively lower for higher levels of ambulatory daytime blood pressure. CONCLUSIONS: Thus, the clinic-daytime blood pressure difference has a limited reproducibility; depends not only on clinic but also on daytime average blood pressure, which means that its size is a function of the blood pressure criteria employed for selection of the patients in a trial; and is never associated with a systematic clinic-daytime difference in heart rate, which further questions its use as a reliable surrogate measure of the true pressor response induced in the patient by the doctor's visit.
OBJECTIVE: To clarify the controversial issue of whether autonomic influences modulate vascular nitric oxide-mediated vasodilatation or even directly contribute to production of nitric oxide (NO) via nitroxidergic fibers. METHODS: Chronic venous and arterial catheters were implanted in Wistar-Kyoto rats (n = 65) for continuous blood pressure measurement, drug administration and blood sampling. Tonic NO-dependent vasodilatation in the conscious free-moving animal was evaluated as the pressor response to inhibition of NO synthesis by intravenous L-monomethylarginine (a 100 mg/kg intravenous bolus plus 0.5 mg/kg per min infusion for 30 min). Experiments were performed under control conditions, chemical sympathectomy by 6-hydroxy-dopamine, ganglionic blockade by hexamethonium, and surgical denervation of sino-aortic baroreceptors. RESULTS: Baseline mean arterial pressure was 100+/-4 mmHg (mean +/- SEM) in control rats and 73+/-3, 62+/-5, and 105+/-10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. The peak increase in mean arterial pressure after administration of L-monomethylarginine was 38+/-3 mmHg in control rats and 51+/-3, 50+/-6, and 63+/-10 mmHg in sympathectomized, ganglion-blocked, and denervated rats, respectively. Epinephrine and norepinephrine levels in rats of separate groups of unanesthetized control, sympathectomized and ganglion-blocked animals were measured by high-performance liquid chromatography from an arterial blood sample, the results indicating drastic reductions in levels of both catecholamines in the ganglion-blocked (but not in the sympathectomized) rats compared with those in the control rats. CONCLUSIONS: Tonic NO-dependent vasodilatation can normally be maintained in the unanesthetized unrestrained rat irrespective of autonomic or humoral adrenergic influences.
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OBJECTIVE: To assess whether modifications in the nighttime blood pressure fall caused by antihypertensive treatment predict the regression of end-organ damage of hypertension. METHODS: The analysis was performed in patients with essential hypertension and echocardiographically detected left ventricular hypertrophy involved in the SAMPLE study. For each patient, ambulatory blood pressure monitoring and echocardiographic determination of left ventricular mass index were performed at the end of a 4-week wash-out pretreatment period, after 3 and 12 months of treatment with lisinopril or with lisinopril plus hydrochlorothiazide and after a final 4-week placebo period. For each ambulatory blood pressure monitoring the 24 h average, daytime average (0600-2400 h), night-time average (2400-0600 h) and day-night difference was computed. The percentages of dipper and non-dipper patients (i.e. the patients with night blood pressure falls greater and less than 10% of the daytime average, respectively) were also computed. RESULTS: The reproducibility of the day-night difference was low, both for comparison of the pretreatment and final placebo periods (n = 170) and for comparison of the third and the 12th month of treatment (n = 180). The reproducibility of the dipper-non-dipper dichotomy was also low, 35-40% of patients becoming non-dippers if they were dippers and vice versa, both with and without treatment The changes in left ventricular mass index after 12 months of treatment were significantly (P<0.01) related to the changes in 24 h, daytime and night-time blood pressure (r always > 0.33), but this was not the case for the treatment-induced modification of the day-night difference (r= -0.03 and -0.008 for systolic and diastolic blood pressures, respectively). CONCLUSIONS: Our results show that day-night blood pressure changes and the classification of patients into dippers and non-dippers are poorly reproducible over time. It also provides the first prospective evidence that treatment-induced changes in day-night blood pressure difference are not related to treatment-induced regression of left ventricular mass index, thus having a limited clinical significance.
BACKGROUND: The possibility that calcium antagonists exert an anti-atherosclerotic action at least partly independently of the blood-pressure-lowering effect is supported by results of a large number of experimental studies and can now be investigated by quantitative B-mode ultrasound imagining of the carotid artery walls. DESIGN: The European Lacidipine Study on Atherosclerosis (ELSA) is a prospective, randomized, double-blind, multinational trial comparing effects of 4-year treatment based on the long-acting, highly lipophilic calcium antagonist lacidipine with those of treatment based on the beta-blocker atenolol on the development of carotid artery wall alterations in patients (aged 45-75 years) with mild-to-moderate hypertension (systolic blood pressure 150-210 mmHg and diastolic blood pressure 95-115 mmHg). While the intervention study is progressing, this article summarizes baseline data obtained from the whole cohort of 2259 patients randomly allocated to treatment. METHODS: Baseline ultrasound data were obtained from two replicate examinations performed shortly before random allocation to treatment by certified sonographers at 23 referral centres and read at the ultrasound coordinating centre at the Wake Forest University School of Medicine. Intima-media thickness was measured at up to 12 different sites in the carotid artery tree and expressed as the mean of the maxima at these sites (Mmax), the mean of the maxima at four sites in the distal common carotid artery and bifurcation (CBMmax) and the maximum intima-media thickness (Tmax). Baseline demographic and clinical measurements were performed by investigators in 410 peripheral clinical units and 24 h ambulatory blood pressure monitorings read and validated by members of a centralized unit at the University of Milan. The statistical analysis centre at the Technische Universität München received and analysed all baseline data, by calculating means +/- SD, medians and ranges and performing correlation (Spearman correlation coefficients) and multiple regression analyses. RESULTS: Prevalence of carotid artery wall alterations among the hypertensive patients randomly allocated to treatment in the ELSA was very high: 82% had Tmax > or = 1.3 mm ('plaques' according to protocol) and 17% had Tmax > or = 1.0 and < 1.3 mm ('thickening'), with a median of two plaques per patient. We found significant correlations between ultrasound measurements and the following demographic and clinical variables: age, sex, systolic blood pressure and pulse pressure (both clinic and ambulatory), concentrations of total, high-density lipoprotein and low-density lipoprotein cholesterol and triglycerides, smoking habit and duration of hypertension. We found no significant correlation to diastolic blood pressure and glucose concentration. A multiple regression analysis indicated significant variables in the following rank order: age, 24 h ambulatory pulse pressure, sex, low-density lipoprotein cholesterol concentration, triglyceride concentration, smoking and clinic systolic blood pressure. CONCLUSIONS: Analysis of baseline data from the ELSA has shown that there is an extremely marked prevalence of carotid artery wall alterations among mild-to-moderate, middle-aged hypertensive patients. In addition to age, systolic blood pressure and pulse pressure, particularly if they are accurately measured by ambulatory monitoring, play a major role, somewhat greater than those of sex, low-density lipoprotein cholesterol concentration and smoking, in influencing intima-media thickness.
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OBJECTIVE: Clinic blood pressure values are known to change according to seasonal influences. We therefore examined home and 24 h ambulatory blood pressure values to determine whether these measurements are also affected by the seasons. DESIGN AND METHODS: In 2051 subjects of the Pressione Arteriose Monitorate E Loro Associazioni (PAMELA) study, we measured clinic (sphygmomanometric measurements), home (semi-automatic device) and ambulatory (Spacelabs 90207) systolic blood pressure, diastolic blood pressure and heart rate. Because the overall sample was evenly distributed over each month (except August), we were able to make a cross-sectional determination of whether the values differed between seasons. The corresponding heart rates were also evaluated. RESULTS: As expected, summer was associated with the lowest clinic blood pressure and winter with the highest, and this was the case also for home and 24 h average blood pressure, although seasonal differences in the latter were less pronounced. Seasonal clinic, home and ambulatory blood pressure patterns were similar for normotensive subjects (n = 1152), untreated hypertensives (n = 540) and treated hypertensives (n = 359). Heart rate values did not differ by season. CONCLUSIONS: Seasonal influences on blood pressure are not limited to conventional measurements but characterize daily values as well. These effects are visible in both normal and elevated blood pressure values, regardless of the effect of antihypertensive drugs. This has implications both for the clinician and for studies aimed at evaluating the effects of antihypertensive treatment.
OBJECTIVE: To determine the value of the supine heart rate as a marker of sympathetic tone by assessing, in a large group of subjects, the relationships between this parameter and two other indices of sympathetic activity, plasma norepinephrine and sympathetic nerve traffic. PATIENTS AND METHODS: We studied 243 subjects aged 50.0+/-12.1 years (mean +/- SD). Of these, 38 were normotensive healthy controls, 113 subjects had untreated essential hypertension, 27 were obese normotensives and 65 had congestive heart failure. In each subject, over a 10 min supine period, we measured mean arterial pressure (Finapres), heart rate (electrocardiogram), venous plasma norepinephrine (high-performance liquid chromatography) and efferent postganglionic muscle sympathetic nerve activity (microneurography at a peroneal nerve). RESULTS: In the whole study group, supine heart rate was correlated with both plasma norepinephrine (r = 0.32, P < 0.0001) and muscle sympathetic nerve activity (r = 0.38, P < 0.0001). This was also the case in the normotensive obese subjects and the heart failure subjects considered separately. Heart rate values were greater in the obese and the heart failure patients than in controls (75.1+/-13.0 and 78.2+/-13.0 versus 69.2+/-11.6 beats/min; P < 0.05 and P < 0.001, respectively), as were plasma norepinephrine (362.7+/-202 and 400.3+/-217 versus 230.4+/-126 pg/ml; P < 0.01 and P < 0.001, respectively) and muscle sympathetic nerve activity (44.1+/-14.7 and 55.3+/-14.3 versus 27.8+/-11.0 bursts/min; P < 0.001 for both). In contrast, in the essential hypertensive subjects, no significant relationship was found between these three indices of sympathetic activity. Furthermore, in the hypertensives, the heart rate was not increased, at variance with the sympathetic nerve traffic, which was greater than in controls (36.2+/-10.0 versus 27.8+/-11.0 bursts/min, P < 0.001). CONCLUSIONS: These data suggest that the supine heart rate can be regarded as a marker of intersubject differences in sympathetic tone, and that this is the case both in the general population and in those with cardiovascular diseases. Its value for this purpose is limited, however, and the limitations may be more evident in essential hypertension than in conditions such as obesity and heart failure.