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This double-blind, randomised, controlled study compared the efficacy of candesartan cilexetil 8 mg (n = 87) and losartan 50 mg (n = 89), once daily for 6 weeks, relative to placebo (n = 80) in patients with mild-to-moderate essential hypertension (diastolic blood pressure (DBP): 95-115 mmHg). Ambulatory BP measurements were done every 15 min over 36 h. At the end of the 6-week treatment, the mean change in DBP between the baseline and the 0-24-h period after the last dose of study medication was greater in patients receiving candesartan cilexetil 8 mg (-7.3 mmHg +/- 6.9 mmHg) compared with losartan 50 mg (-5.1 mmHg +/- 4.9 mmHg) (p < 0.05) or placebo (0.3 mmHg +/- 6.5 mmHg) (p < 0.001). The mean change in systolic BP (SBP) during this time was greater in patients receiving candesartan cilexetil 8 mg (-10.8 mmHg +/- 11.3 mmHg), or losartan 50 mg (-8.8 mmHg +/- 8.9 mmHg) than placebo (1.2 mmHg +/- 9.9 mmHg) (p < 0.001). Candesartan cilexetil 8 mg was associated with a greater reduction in DBP and SBP, relative to placebo, when compared with losartan 50 mg, during both daytime and night-time, and between 12 and 24 h after dosing (p < 0.001). Both active treatments were well tolerated. In patients with mild-to-moderate essential hypertension, candesartan cilexetil 8 mg therefore had greater, more consistent antihypertensive efficacy throughout the day and the night, and long-lasting efficacy after the last dose, compared with losartan 50 mg. This greater efficacy is maintained with an excellent tolerability associated with members of the angiotensin Il type 1-receptor blocker class.

Decreased baroreflex sensitivity (BRS) is a prognostic marker in essential hypertension. Animal experiments suggest that decreased BRS is related to increased oxidative stress. Our study was aimed at testing whether oxidative stress, estimated by isoprostane 15-F(2t)-IsoP urinary levels, is correlated to BRS variation in healthy subjects as well as in patients suffering from essential hypertension. Urinary 15-F(2t)-IsoP levels and BRS were evaluated in two groups of subjects: healthy volunteers (n=64) and patients with untreated mild-to-moderate hypertension (n=33). Data were analysed in 61 and 31 subjects, respectively, BRS analysis being impossible in three and two subjects, respectively. 15-F(2t)-IsoP levels were measured using gas chromatography/mass spectrometry. BRS was measured using the sequence method [PS+/RR+ and PS-/RR-] and crossspectral analysis (CSP) (MF gain) at rest, lying down. No significant correlation was found between basal urinary 15-F(2t)-IsoP levels and BRS (sequence method and CSP) in either healthy controls or hypertensive patients. Our study shows that oxidative stress is not involved in interindividual variations of BRS in healthy subjects and patients suffering from mild-to-moderate hypertensionJournal of Human Hypertension (2004) 18, 517-521. doi:10.1038/sj.jhh.1001684 Published online 12 February 2004

The 1996 World Health Organization (WHO) recommendations for mild hypertension stressed the need to evaluate target-organ lesions as treatment criteria. The effects of both vascular and heart remodelling on hypertension must to be taken into account, as they adversely influence the prognosis of patients with hypertension. It was previously demonstrated that at least three classes of antihypertensive agents were able to decrease morbidity and mortality in patients with hypertension. Meta-analyses have shown that angiotensin-converting enzyme inhibitors seem to have a marked effect on regression of left ventricular hypertrophy (LVH). However, the relationship between drug-induced LVH regression and reduced morbidity and mortality remains to be confirmed. The effect of antihypertensive agents on vascular hypertrophy, as assessed by intima-media thickness, and their involvement in reducing morbid events, also have to be determined at the vascular level. As experimental data have highlighted the involvement of angiotensin II in animal models of LVH and vascular hypertrophy development, the role of angiotensin II AT1 receptor blockers should also be assessed in this indication.

Hypertensive patients with altered circadian blood pressure (BP) profile experience greater repercussion of hypertension on target organs and a higher risk of cardiovascular events, compared with those with physiological variations in BP. It has been demonstrated in animal models, that circadian variations in BP depend on several regulatory systems, in particular the nitric oxide-cGMP pathway. eNOS298 Glu/Asp polymorphism is a functional variant and may alter the amount of NO generated or eNOS activity. The objective of the present study was to find out whether eNOS298 gene polymorphism affects circadian BP regulation in 110 healthy subjects and 155 never-treated hypertensive patients recruited at Hypertension Units in Grenoble, Toulouse and Lille (France).

Ambulatory blood pressure monitoring (ABPM) is a particularly useful method for evaluating the effects of antihypertensive drugs. ABPM allows the therapeutic effect of an agent to be assessed continually by a large number of measurements, and the greater number of readings contributes to the higher degree of reproducibility associated with ABPM compared to other methods for measuring blood pressure. ABPM also enable measurements to be taken in "real-life" situations and removes the problem of observer bias. The number of patients required for clinical studies can be significantly reduced by using ABPM. It is still essential, however, to identify "white coat" subjects, placebo responders, and patients who do not respond to the treatment. ABPM studies have demonstrated that the novel dihydropyridine calcium antagonist, lacidipine, significantly reduces both systolic and diastolic blood pressures over a 24-h period, both during the day and at night. Furthermore, although the trough-to-peak ratios of many calcium antagonists have been shown to fall below the recommended level of 50%, lacidipine has a ratio above 60%. Other ABPM studies have also shown that lacidipine can correct the 'early morning increase' in blood pressure without effecting the 24-h nycthemeral profile.

A 62-year-old man had an acute episode of hypertension 72 h after fine needle aspiration biopsy of an intra- hepatic nodule. The patient had been operated 3 years previously for a right adrenal phaeochromocytoma with no evidence of metastases at that time. Thus, a relapse of the tumour was postulated and confirmed by raised levels of urinary metanephrines. The extent of the metastases precluded surgical intervention and thus localised embolisation was proposed and permitted a clinical stabilisation over 8 months. This case indicates the necessity of long-term post-operative follow-up of phaeochromocytoma as well as the dangers of fine needle aspiration biopsy of metastases from this kind of tumour. Treatment of malignant phaeochromocytoma is difficult and embolisation was a useful therapeutic alternative in this case where the metastases were well defined.

Compliance with antihypertensive therapy is usually monitored by questionnaire, tablet counts, or estimation of drug levels in blood or in urine. The aim of this study was to examine patient compliance by means of an "electronic monitor." After 2 weeks of run-in on placebo, 34 moderately hypertensive patients were included in an open, randomized, crossover trial examining the efficacy and tolerance of nitrendipine, 20 mg as a single daily dose (morning or evening) for 1 month. We analyzed the results in 26 patients. Patients were supplied with tablet boxes equipped with a microprocessor (MENS) that registered the timing and duration of opening of the box over both the placebo and nitrendipine periods. Compliance (%) was calculated as the ratio of the number of days that the pill box was opened to the number of days between visits. The compliance was analyzed for each treatment group, namely placebo and nitrendipine morning and evening, over 1 month. Compliance (mean + SD) was 96.5 +/- 7.4% on placebo and 94.4 +/- 10.7% in the morning and 90.6 +/- 15.4% in the evening. Nitrendipine was taken in the morning at 0700 h +/- 2 h and in the evening at 1859 h +/- 2 h 12 min. The frequency of 24 h +/- 1 h intervals between medication was 83.5% on placebo. This frequency was 72.6% for morning dosage and 71.8% for evening dosage on nitrendipine. There were no differences in compliance between the morning and evening groups when analyzed according to age and sex. There was a negative correlation with time (r = -0.57, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

A 74-year-old man had a resistant hypertension with an increase in plasma aldosterone and active plasma renin levels, and an irregular appearance of the left kidney outline by ultrasound. The CT scan showed a stenosis of the left renal artery, which was pushed against the aorta by the left crus of the diaphragm. An angioplasty with placement of an autoexpansible stent was carried out with a good result on the arterial pressure level. After 3 years, the patient was re-hospitalised with severe hypertension. The CT scan demonstrated a compression of the stent by the left crus of the diaphragm, with good permeability of the artery downstream from the stent, and radiographic examination showed a fracture of the left renal artery stent. Thus, a reimplantation of the left renal artery in the aorta was carried out. Stenosis of the renal artery by fibres from a crus of the diaphragm is a rare cause of renovascular hypertension. Helicoidal angioscanner imaging is particularly useful to do the diagnosis. In the present case, renal angioplasty with stenting was complicated by a fracture of the stent that led to the surgery. Thus, when renal artery stenosis by a crus of the diaphragm is diagnosed, surgical treatment needs to be considered on a case-by-case basis in relation to the anatomy and the biological and functional data.

Elderly patients with isolated systolic hypertension (ISH)--systolic blood pressure (SBP) > or =140 mmHg and diastolic blood pressure (DBP)

To study the influence of position changes on 24-h ambulatory blood pressure (ABP) in normotensive or mildly hypertensive normoalbuminuric patients with type 1 diabetes.A cross-sectional evaluation of patients was staged according to the duration of diabetes (DD) and the presence of microangiopathy. We recruited 37 patients (30 men and 7 women), aged 38 +/- 12 years, who were normotensive or mildly hypertensive (diastolic blood pressure [DBP]105 mmHg) and free of antihypertensive treatment and microalbuminuria. They were included according to DD (group 1,5 years; group 2,or =10 years). An additional group of seven diabetic patients with microalbuminuria and mild untreated hypertension was also investigated. We recorded 24-h ambulatory blood pressure every 15 min with a position sensor, which allowed for the discrimination between standing or supine/sitting position in the patient.Mean daytime (10:00 A.M. to 8:00 P.M.) ABP in supine/sitting position did not significantly differ between groups 1 and 2. However, standing ambulatory systolic blood pressure (ASBP) and ambulatory DBP (ADBP) were significantly higher than supine/sitting ASBP and ADBP in group 1 (DeltaSBP 4 +/- 5, DeltaDPB 4 +/- 6 mmHg, P0.01) but not in group 2 (DeltaSBP 2 +/- 8, DeltaDBP 2 +/- 4 mmHg, P = NS). Patients free of microangiopathy presented with significantly higher ABP in standing position than in sitting/lying position, whereas patients with retinopathy and/or nephropathy exhibited no significant increase of ABP during standing.The monitoring of position during ambulatory measurement of blood pressure in type 1 diabetic patients shows different patterns in relation to disease duration and the presence of microangiopathy.

This study was designed to analyse the relationship between the different blood pressure (BP) variabilities obtained in a non-invasive way and to determine the potential contribution of aging, severity of hypertension and increased ventricular mass to these different BP variabilities. Two hundred and six hypertensive patients underwent a 24-h ambulatory BP measurement (ABPM) as well as a photoplethysmographic BP recording and a standard echocardiography. Nocturnal BP fall and standard deviations of hourly mean BP levels as well as post-prandial fall in BP were calculated from the 24-h ABPM and were considered as indexes of long-term variability. Baroreflex sensitivity (BRS) and spectral powers of systolic BP, diastolic BP and heart rate (HR) over the low frequency band (LF: 0.05--0.14 Hz) were obtained from photoplethysmographic recording and were used as indexes of short-term variability. Short-term variability indexes were shown to be significantly related to those of long-term variability. A decrease in LF spectral powers was associated with a particular profile characterised by an attenuation of nocturnal BP fall, an increase of daytime BP standard deviations, an increase in post-prandial BP fall, a decrease in BRS and to a lesser extent, a diminution in night-time HR standard deviation. Moreover, a negative significant relationship was found between standard deviation of daytime systolic BP and both night systolic BP fall and BRS. Age and nocturnal BP level were associated with all BP variability disorders, whereas left ventricular hypertrophy was associated only with a decrease in LF spectral powers and in night BP fall, and an increase in standard deviation of daytime BP. Finally, LF spectral power of SBP was identified as independently predicted by age and night SBP fall. Journal of Human Hypertension (2001) 15, 41-48

Objectives: The SHEAF study (Self measurement of blood pressure at Home in the Elderly: Assessment and Follow-up) is a 3-year prospective cohort study of French elderly (⩾60 years) hypertensive patients designed to assess whether home blood pressure (HBP) measurement provides additional prognostic information over office blood pressure (OBP) in terms of cardiovascular mortality and morbidity. The objective of the present work is to describe the baseline data of the population enrolled in the SHEAF study with special emphasis on blood pressure control in treated hypertensives. Methods:During the 2-week initial inclusion phase, baseline demographics, cardiovascular risk factors, antihypertensive treatments as well as office and home blood pressure were recorded. Baseline OBP was assessed using a mercury sphygmomanometer (three consecutive measurements during two visits performed 2 weeks apart). HBP was performed over a 4-day period (three consecutive measurements in the morning and in the evening). Results:A total of 4939 (95%) of the 5211 patients included in the SHEAF study were treated with at least one antihypertensive drug. Their ages ranged from 60 to 99 years (mean age 70 ± 7 years); 49% were men, 12% had a previous history of coronary artery disease, 14% diabetes and 43% a treated dyslipidaemia. A total of 45% of the treated patients received a single antihypertensive drug, 34% two drugs, 21% three drugs or more. Overall 23% of treated hypertensives were normalised at the doctor’s office (systolic BP

Candesartan is one of the first angiotensin II receptor antagonists (AIIRAs) to be developed. It binds tightly to and dissociates slowly from the angiotensin subtype 1 (AT1) receptor in vitro. These binding characteristics differ from those of losartan, which demonstrates lower affinity and faster dissociation from the AT1 receptor. Candesartan causes long-lasting antagonism of the vascular contractile response to angiotensin II compared with irbesartan, losartan or the active metabolite of losartan - EXP-3174. While there are relatively few distinctions that can be made between the AIIRAs in terms of their pharmacokinetic profiles, the antagonistic potency of candesartan cilexetil at the AT1 receptor over 24 h clearly differentiates it from other members of its class. These differences are reflected in the antihypertensive efficacy and duration of action of candesartan in clinical trials.

The role of pulse pressure (PP) in cardiovascular remodelling was studied in 61 never treated hypertensive subjects who were selected on the criteria of ambulatory blood pressure (BP) monitoring (mean BP over 24 h: 147 +/- 14/96 +/- 10 mm Hg). Echocardiography and carotid ultrasonography were performed and the vascular images analysed using a specific automatic measuring program. Thirty percent of subjects had left ventricular hypertrophy (LVH). Left ventricular mass index (LVMI) was related to the clinic (r = 0.35) and ambulatory (r = 0.41 over 24 h, r = 0.38 daytime and r = 0.42 night-time) PP and to the systolic BP. PP was higher when there was LVH. Vascular thickening was found in 6.6% of subjects (carotid intima-media thickness (IMT) >/=1.0 mm). Among the BP parameters, IMT and cross-sectional area (CSA) were related only to the clinic PP (r = 0.27, r = 0.29 respectively) and to the ambulatory PP (over 24 h: r= 0.29, r = 0.28; daytime: r = 0.22, r = 0.23; night-time: r = 0.32, r = 0.30). In men, the relationship between CSA and PP (clinic and over 24 h) was independent of age. A total of 16.7% of subjects with LVH had intima-media thickening in contrast to 2.3% in the group without LVH. LVMI was related to the CSA (r = 0.37) and to the IMT (r = 0.31). However, after multivariate analysis taking into account the PP, relationships between IMT or CSA and LVMI disappeared. Our data showed that the PP was the most important BP parameter in the development of cardiac and arterial remodelling in hypertension. Journal of Human Hypertension (2000) 14, 23-30.

First-line treatment of hypertension: from monotherapy to fixed low-dose combination therapy

Aims Cardiac failure patients were studied systematically using polysomnography 1 month after recovering from acute pulmonary oedema, and again after 2 months of optimal medical treatment for cardiac failure. Methods and Results This prospective study of consecutive patients was conducted in a cardiac care unit of a university hospital. V o2measurements and left ventricular ejection fraction were recorded. Thirty-four patients, initially recruited with pulmonary oedema, improved after 1 month of medical treatment to NYHA II or III. They were aged less than 75 years and had a left ventricular ejection fraction less than 45% at the time of inclusion. Age was 62 (9) years, body mass index=27 (5)kg.m−2and an ejection fraction=30 (10)%. Eighteen of the 34 patients (53%) had coronary artery disease. Twenty-eight of the 34 had sleep apnoea syndrome with an apnoea+hypopnoea index >15.h−1of sleep. Thus, the prevalence of sleep apnoea in this population was 82%. Twenty-one of 28 (75%) patients had central sleep apnoea and seven of 28 (25%) had obstructive sleep apnoea. Patients with central sleep apnoea had a lower Pa co2than those with obstructive sleep apnoea (33 (5) vs 37 (5) mmHg, P

The aim of this study was to evaluate the antihypertensive effect of drugs according to the initial ambulatory blood pressure (BP) level. After a 15-day placebo run-in period, 105 patients with moderate essential hypertension (mean age, 52 years) underwent 24-h BP monitoring (spacelabs: 1 measure/15 min). Patients were subdivided into two groups: the "High" group, with 24-h mean values of systolic BP (SBP) > 137 or diastolic BP (DBP) > 87 mm Hg, and the "Low" group, with SBP < or = 137 and DBP < or = 87 mm Hg. All patients received, in a random and double-blind design, either bisoprolol (10 mg q.d.) or lisinopril (20 mg q.d.) for 8 weeks. At the end of this active treatment period, office and ambulatory BP measurements were performed. Casual measurements revealed similar BP decreases in all subgroups receiving bisoprolol and lisinopril; BP monitoring showed that the antihypertensive effect depended on the baseline mean 24-h value; -15/-12 mm Hg for bisoprolol and -18/-13 mm Hg for lisinopril in the High group; -7/-6 mm Hg for bisoprolol and -6/-6 mm Hg for lisinopril in the Low group. This study shows that the antihypertensive effect depended on initial ambulatory BP values, with a lower BP decrease in the Low group. Assessment of the antihypertensive effect on ambulatory BP is useful in clinical trials.

Ambulatory blood pressure monitoring (ABPM) is a particularly useful method for evaluating the effects of antihypertensive drugs. ABPM allows the therapeutic effect of an agent to be assessed continually by a large number of measurements, and the greater number of readings contributes to the higher degree of reproducibility associated with ABPM compared to other methods for measuring blood pressure. ABPM also enable measurements to be taken in "real-life" situations and removes the problem of observer bias. The number of patients required for clinical studies can be significantly reduced by using ABPM. It is still essential, however, to identify "white coat" subjects, placebo responders, and patients who do not respond to the treatment. ABPM studies have demonstrated that the novel dihydropyridine calcium antagonist, lacidipine, significantly reduces both systolic and diastolic blood pressures over a 24-h period, both during the day and at night. Furthermore, although the trough-to-peak ratios of many calcium antagonists have been shown to fall below the recommended level of 50%, lacidipine has a ratio above 60%. Other ABPM studies have also shown that lacidipine can correct the 'early morning increase' in blood pressure without effecting the 24-h nycthemeral profile.

Blood pressure and heart rate of 15 male shift workers were measured every 15 minutes for 24 hours during three work shifts: morning, 4:00 AM to noon; afternoon, noon to 8:00 PM; and night, 8:00 PM to 4:00 AM. For each shift, 24-hour systolic and diastolic blood pressure showed a large "trough" (the low pressure span) and a continuous range of elevated pressure (the high pressure span). Fourier series were used to model the 24-hour blood pressure profiles. A careful examination of the residuals (measured minus predicted pressures) showed that four harmonics were necessary to describe the data accurately. The model enabled localization in each blood pressure profile of the high and low pressure spans that did not coincide with the subject's work and rest periods. The time and slope of blood pressure entering and leaving these spans could also be individually determined. Mean blood pressure during the high pressure span was the same for the three shifts, but mean blood pressure during the low pressure span was lower when the subject worked in the afternoon. During that shift, the systolic blood pressure slopes entering and leaving the low pressure span were steeper than during the two other shifts. The high pressure span was longest during the night shift and shortest during the afternoon shift. Therefore, a change in the working time profoundly perturbed the 24-hour blood pressure profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Variations in blood pressure were investigated by an automatic, non-invasive ambulatory method in 9 subjects with essential hypertension. Recordings were made after 6 week periods during which captopril was taken either once or twice daily, in a double-blind cross-over study. Although the effects of captopril administration either once or twice daily were broadly similar, there was a significant decrease in diastolic blood pressure values on the once-daily regimen. These results suggests that treatment once a day can advantageously replace twice-daily treatment.

The authors studied the reproductibility of the measures of the haemodynamic (HR-SAP-DAP) and hormonal (PRA-plasma catecholamine) parameters at rest and during stress. 11 normotensive male subjects, age 20-26 years, have release 2 stress tests on ergometric bicycle spaced from 8 to 180 days (mean 54.2 days). The measure of haemodynamic parameters is reproducible during stress. The PRA measures is reproducible at stress instead of individual variations of natriuresis between 3-10 g. The measure of plasma norepinephrine levels is reproducible for strict rest and during stress. This express an identical participation of the sympathetic system for the same physical work load. This results express the interest of stress tests for the definition of a normal blood pressure and hormonal profile.

In a randomized, double-blind, parallel-group study of middle-aged and elderly patients, we examined the effects of treatment with the angiotensin receptor blocker valsartan (Val) in combination with hydrochlorothiazide (HCTZ) on pulse pressure (PP). After a 2-week washout period, patients entered a 4-week single-blind Val 160 mg once daily run-in period before randomization to one of three treatment groups: Val 160 mg ( n = 666), Val 160 mg/HCTZ 12.5 mg ( n = 670) or Val 160 mg/HCTZ 25 mg ( n = 666), once daily for eight weeks. Sitting PP at baseline was similar in all groups. From baseline to randomization, Val monotherapy reduced PP by 4.7 ± 10.2 mmHg (mean ± SD). At the end of the study, overall reductions in PP were 6.7 mmHg for Val 160/HCTZ 12.5 and 7.5 mmHg for Val 160/HCTZ 25. Val monotherapy reduced PP in mild-to-moderate hypertensive patients. Val combined with HCTZ provides an additional dose-related reduction in PP.