How to Improve Effectiveness and Adherence to Antihypertensive Drug Therapy: Central Role of Dihydropyridinic Calcium Channel Blockers in Hypertension.

Essential hypertension is a complex clinical condition, characterized by multiple and concomitant abnormal activation of different regulatory and contra-regulatory pathophysiological mechanisms, leading to sustained increase of blood pressure (BP) levels. Asymptomatic rise of BP may, indeed, promote development and progression of hypertension-related organ damage, which in turn, increases the risk of major cardiovascular and cerebrovascular events. A progressive and independent relationship has been demonstrated between high BP levels and increased cardiovascular risk, even in the high-to-normal range. Conversely, evidence from randomized controlled clinical trials have independently shown that lowering BP to the recommended targets reduces individual cardiovascular risk, thus improving event-free survival and reducing the incidence of hypertension-related cardiovascular events. Despite these benefits, overall rates of BP control remain poor, worldwide. Currently available guidelines support a substantial equivalence amongst various antihypertensive drug classes. However, several studies have also reported clinically relevant differences among antihypertensive drugs, in terms of both BP lowering efficacy and tolerability/safety profile. These differences should be taken into account not only when adopting first-line antihypertensive therapy, but also when titrating or modulating combination therapies, with the aim of achieving effective and sustained BP control. This review will briefly describe evidence supporting the use of dihydropyridinic calcium channel blockers for the clinical management of hypertension, with a particular focus on barnidipine. Indeed, this drug has been demonstrated to be effective, safe and well tolerated in lowering BP levels and in reducing hypertension-related organ damage, thus showing a potential key role for improving the clinical management of hypertension.

Impact of cuff positioning on blood pressure measurement accuracy: may a specially designed cuff make a difference?

During blood pressure (BP) measurement, the recommended positioning of the cuff bladder center is directly above the brachial artery. We investigated the relevance of incorrect cuff positioning during (1) auscultatory measurement with an appropriate or improperly small cuff and (2) oscillometric measurement with a wide-range cuff designed to guarantee accurate measurements regardless of position. In subjects with wide BP and arm circumference ranges, (1) auscultatory BP was repeatedly measured with a properly positioned cuff (reference) and, simultaneously, with an identical cuff placed on the other arm in either a correct or an incorrect position (test). The measurements were performed with a properly sized (N=57) or an improperly small cuff (N=33). (2) Auscultatory measurements obtained with a properly positioned and sized cuff were compared with oscillometric measurements obtained with a specially designed wide-range cuff (Omron IntelliWrap) placed on the contralateral arm either in a correct or an incorrect position. Auscultatory BP measures were unaffected by incorrect positioning of a properly sized cuff, whereas with undercuffing, BP was overestimated with the cuff displaced by 90° laterally (systolic/diastolic BP differences: 4.9±4.6/4.0±4.6 mm Hg, P<0.01) or by 180° (3.9±5.4/4.2±5.1 mm Hg, P<0.01) in relation to the correct position. Incorrect placement of the oscillometric cuff had no significant effect on the accuracy of the measurements (difference with correct position <1.5 mm Hg). Incorrect cuff positioning introduces a systematic overestimation of auscultatory BP when the cuff is too small in relation to arm circumference but not when it is correctly sized. No systematic error was observed with oscillometric measurements obtained with a specially designed wide-range cuff.

Sympathetic nerve traffic and baroreflex function in optimal, normal, and high-normal blood pressure states.

OBJECTIVE: Adrenergic activation and baroreflex dysfunction are common in established essential hypertension, elderly hypertension, masked and white-coat hypertension, resistant hypertension, and obesity-related hypertension. Whether this autonomic behavior is peculiar to established hypertension or is also detectable in the earlier clinical phases of the disease, that is, the high-normal blood pressure (BP) state, is still largely undefined, however. METHODS: In 24 individuals with optimal BP (age: 37.1  ±  2.1 years, mean  ±  SEM) and in 27 with normal BP and 38 with high-normal BP, age matched with optimal BP, we measured clinic, 24-h and beat-to-beat BP, heart rate (HR), and muscle sympathetic nerve activity (MSNA) at rest and during baroreceptor stimulation and deactivation. Measurements also included anthropometric as well as echocardiographic and homeostasis model assessment (HOMA) index. RESULTS: For similar anthropometric values, clinic, 24-h ambulatory, and beat-to-beat BPs were significantly greater in normal BP than in optimal BP. This was the case when the high-normal BP group was compared to the normal and optimal BP groups. MSNA (but not HR) was also significantly greater in high-normal BP than in normal BP and optimal BP (51.3  ±â€Š 2.0 vs. 40.3  ±  2.3 and 41.1 ±â€Š2.6  bursts per 100  heartbeats, respectively, P < 0.01). The sympathetic activation seen in high-normal BP was coupled with an impairment of baroreflex HR control (but not MSNA) and with a significant increase in HOMA Index, which showed a significant direct relationship with MSNA. CONCLUSION: Thus, independently of which BP the diagnosis is based, high-normal BP is a condition characterized by a sympathetic activation. This neurogenic alteration, which is likely to be triggered by metabolic rather than reflex alterations, might be involved, together with other factors, in the progression of the condition to established hypertension.

Diastolic dysfunction in controlled hypertensive patients with mild-moderate obstructive sleep apnea.

BACKGROUND: Hypertension and severe obstructive sleep apnea (OSA) may independently contribute to left ventricular diastolic dysfunction. However, scanty data is available on this issue in hypertensives with mild-moderate OSA. METHODS AND RESULTS: We performed polysomnography, echocardiography and 24h ambulatory blood pressure monitoring in 115 treated essential hypertensives with suspicion of OSA. After exclusion of severe/treated OSA and/or cardiovascular disease patients, mild-moderate OSA (5 ≤ apnoea/hypopnoea index<30 events·h(-1)) was diagnosed in 47.3% of the remaining 91 patients, while 52.7% were free of OSA. Transmitral early (E) and late (A) peak flow velocities were assessed in 69 patients, and mitral annular velocity (E') in 53. Compared to non-OSA, mild-moderate OSA heart rate was higher (p=0.031) while E/A was lower (p<0.001) without differences in 24h mean systolic and diastolic blood pressures (125.36 ± 12.46/76.46 ± 6.97 vs 128.63 ± 11.50/77.70 ± 7.72 mmHg, respectively, NS). Patients with E'< 10 cm/s and E/A<0.8 showed a lower mean SpO2 than subjects with normal diastolic function (p=0.004; p<0.001). In a logistic regression model age, mean SpO2, daytime heart rate and nocturnal diastolic blood pressure fall were associated with altered relaxation pattern, independently from BMI and gender. CONCLUSIONS: In controlled hypertensives mild-moderate OSA may be associated with early diastolic dysfunction, independently from age, gender and mean blood pressure and in the absence of concentric left ventricular hypertrophy. Moreover nocturnal hypoxia may be a key factor in determining early diastolic dysfunction, under the synergic effects of hypertension and mild-moderate OSA.

Blood pressure control and treatment adherence in hypertensive patients with metabolic syndrome: protocol of a randomized controlled study based on home blood pressure telemonitoring vs. conventional management and assessment of psychological determinants of adherence (TELEBPMET Study).

BACKGROUND: Inadequate blood pressure control and poor adherence to treatment remain among the major limitations in the management of hypertensive patients, particularly of those at high risk of cardiovascular events. Preliminary evidence suggests that home blood pressure telemonitoring (HBPT) might help increasing the chance of achieving blood pressure targets and improve patient's therapeutic adherence. However, all these potential advantages of HBPT have not yet been fully investigated. METHODS/DESIGN: The purpose of this open label, parallel group, randomized, controlled study is to assess whether, in patients with high cardiovascular risk (treated or untreated essential arterial hypertension--both in the office and in ambulatory conditions over 24 h--and metabolic syndrome), long-term (48 weeks) blood pressure control is more effective when based on HBPT and on the feedback to patients by their doctor between visits, or when based exclusively on blood pressure determination during quarterly office visits (conventional management (CM)). A total of 252 patients will be enrolled and randomized to usual care (n = 84) or HBPT (n = 168). The primary study endpoint will be the rate of subjects achieving normal daytime ambulatory blood pressure targets (< 135/85 mmHg) 24 weeks and 48 weeks after randomization. In addition, the study will assess the psychological determinants of adherence and persistence to drug therapy, through specific psychological tests administered during the course of the study. Other secondary study endpoints will be related to the impact of HBPT on additional clinical and economic outcomes (number of additional medical visits, direct costs of patient management, number of antihypertensive drugs prescribed, level of cardiovascular risk, degree of target organ damage and rate of cardiovascular events, regression of the metabolic syndrome). DISCUSSION: The TELEBPMET Study will show whether HBPT is effective in improving blood pressure control and related medical and economic outcomes in hypertensive patients with metabolic syndrome. It will also provide a comprehensive understanding of the psychological determinants of medication adherence and blood pressure control of these patients. TRIAL REGISTRATION: Clinical Trials.gov: NCT01541566.

Structural alterations of the retinal microcirculation in the "prehypertensive" high- normal blood pressure state.

The high-normal blood pressure (also known as prehypertension) is a clinical condition characterized by an increased cardiovascular risk as well as by the presence of target organ damage. This include an increased left ventricular mass, an endothelial dysfunction and an early renal functional and structural damage. Whether this is the case also for alterations of retinal vessels network, which are frequently detectable in established hypertension, is still largey undefined. The present paper, after discussing the main characteristics of the high-normal blood pressure state, will review the different approaches used throughout the years for assessing retinal microcirculatory network. Data collected by our group in subjects with high normal blood pressure will be also discussed, showing that arterial venular ratio values are reduced in this individuals with high-normal blood pressure and more so in established hypertension. These data indicate that retinal microvascular alterations 1) are of early appearance in the clinical course of hypertension and 2) are of frequent detection in the high-normal blood pressure state. The possible hemodynamic and non-hemodynamic mechanisms resposible for these structural alteations of the retinal microcirculation will be also discussed.

Metabolic syndrome, left ventricular hypertrophy and carotid atherosclerosis in hypertension: a gender-based study.

BACKGROUND: The influence of gender on the association between metabolic syndrome (MS) and subclinical organ damage (OD) has been poorly investigated. The aim of this study was to investigate whether the risk of developing left ventricular hypertrophy (LVH) and carotid atherosclerosis is different in men and women with MS. METHODS: A total of 3752 untreated and treated hypertensive patients (mean age 53.3 ± 12.6, 52.7% men) were considered for this analysis. All patients underwent standard ultrasonographic investigations searching for LVH and carotid atherosclerosis. The MS was defined according to ATP III criteria. RESULTS: LVH was more prevalent in women and men with the MS compared with their counterparts (58% vs 34% and 48% vs 33%, respectively, p < 0.001). This was also the case for carotid plaque prevalence (61% vs 42% and 57% vs 44%, p < 0.001). The prevalence of OD was not different between men and women with MS, after adjusting for confounders. In multivariate analysis, abdominal obesity was the most important MS component independently related to LVH in both genders, followed by blood pressure. As for carotid plaques, blood pressure, hyperglycemia and hypertriglyceridemia turned out to be independent correlates regardless of gender. CONCLUSIONS: Our data indicate that MS is associated with a higher risk of LVH and carotid atherosclerosis irrespective of gender; these findings do not support a gender influence in the association between MS and subclinical OD.

Association of central and peripheral pulse pressure with intermediate cardiovascular phenotypes.

OBJECTIVE: We assessed the relationship between pulse pressure and intermediate cardiovascular phenotypes in a middle-aged cohort with high prevalence of hypertension. BACKGROUND: It has been suggested that central pulse pressure (cPP) is a better predictor of cardiovascular outcome than peripheral pulse pressure (pPP), particularly in the elderly. Yet, it is unclear if cPP provides additional prognostic information to pPP in younger individuals. METHODS: In 535 individuals we assessed cPP and pPP as well as the intermediate cardiovascular phenotypes pulse wave velocity (PWV; SphygmoCor, Complior, PulsePen), carotid intima-media thickness (C-IMT; carotid ultrasound), left-ventricular mass index (LVMI; echocardiography) and urinary albumin : creatinine ratio (ACR). cPP was derived noninvasively from brachial blood pressure by pulse wave analysis (PWA; SphygmoCor) based on radial pulse wave tonometry and a validated transfer function. RESULTS: The cohort contained 331 hypertensive participants of whom 84% were treated. The average age was 46 ±â€Š16 years. When compared to pPP, cPP had stronger associations with PWV (r = 0.471 vs. r = 0.372; P < 0.01), C-IMT (r = 0.426 vs. r = 0.235; P < 0.01) and LVMI (r = 0.385 vs. r = 0.189; P < 0.01), but equal association with ACR (r = 0.236 vs. r = 0.226; P = n.s.). In contrast, after adjustment for age, mean arterial pressure, heart rate and hypertension status there was no significant difference between cPP and pPP for prediction of PWV (adjusted R, 0.399 vs. 0.413; P = 0.066), C-IMT (adjusted R, 0.399 vs. 0.413; P = 0.487) and LVMI (adjusted R, 0.181 vs. 0.170; P = 0.094) in multivariate analysis. CONCLUSION: In our middle-aged cohort with high prevalence of hypertension cPP is more closely correlated with cardiovascular phenotypes than pPP. When adjusted for relevant cofactors, however, cPP does not provide additional information beyond pPP.

Clinical relevance of cardiac structure and function abnormalities in patients with Cushing's syndrome before and after cure.

OBJECTIVES: Sustained hypercortisolism impacts cardiac function, and, indeed, cardiac disease is one of the major determinants of mortality in patients with Cushing's syndrome. The aim of this study was to assess the clinical relevance of cardiac structure and function alterations by echocardiography in patients with active Cushing's syndrome and after disease remission. STUDY DESIGN: Seventy-one patients (61 women, 10 men) with Cushing's syndrome and 70 age-, sex- and blood pressure-matched controls were enrolled. Echocardiography was performed in 49 patients with active disease and at several time points after remission in 44 patients (median follow-up 46.4 months), and prevalence of abnormal left ventricular mass measurements and systolic and diastolic functions indices was compared between patients with active disease, after remission and controls. Twenty-two patients were evaluated both before and after remission. RESULTS: Up to 70% of patients with active Cushing's syndrome presented abnormal left ventricular mass parameters; 42% presented concentric hypertrophy and 23% concentric remodelling. Major indices of systolic and diastolic functions, i.e. ejection fraction and E/A ratio, respectively, were normal. Upon remission of hypercortisolism, left ventricular mass parameters ameliorated considerably, although abnormal values were still more frequent than in controls. Both cortisol excess and hypertension contribute to cardiac mass alterations and increase the prevalence of target organ damage. CONCLUSIONS: Cushing's syndrome is associated with an increased risk for abnormalities of cardiac mass, which ameliorates, but does not fully disappear after remission. Systolic and diastolic functions are largely within the normal range in these patients.

Prevalence and correlates of echocardiographic left atrial enlargement in hypertensive outpatients in clinical practice.

Prevalence of left atrial enlargement (LAE) in hypertension has been mostly assessed in population-based samples and selected hypertensive groups. A few data are available in clinical practice. We examined LAE prevalence and severity in a cohort of hypertensive patients referred by general practitioners to a routine echocardiographic examination. A total of 2170 hypertensive individuals (mean age 62 years, 53% men) referred by practitioners to 17 outpatient echocardiographic laboratories across Italy for detection of hypertensive cardiac disease were included in the study. LAE was defined as: A) absolute LA diameter >4.0 cm in men and >3.8 cm in women; B) LA diameter normalized to body surface area (BSA) >2.3 cm/m(2) in both sexes. Left atrial enlargement was graded as mild, moderate, and severe according to Lang's report. Patients with LAE were 38% by criterion A, and 20% by criterion B. A moderate/severe increase in LA size was present in 34% (A) and 32% (B) of patients with LAE. Severe LAE was 3.3-fold (A) and 2.6-fold (B) more frequent in women than in men. Left ventricular mass was the strongest correlate of absolute LA diameter as well as of normalized LA diameter, after age. Left atrial enlargement defined either by absolute or normalized LA diameter is a frequent cardiac phenotype in hypertensive patients referred to echo-labs in clinical practice. This cardiac parameter is closely related to LV mass and its severity is highly prevalent in women.

Indexing cardiac parameters in echocardiographic practice: do estimates depend on how weight and height have been assessed? A study on left atrial dilatation.

We examined the difference between self-reported and measured height and weight in detecting echocardiographic left atrial dilatation (LAD), as defined by LA diameter indexed to body size parameters in an outpatient population referred to echocardiographic laboratories for routine examination. LAD was defined by 2 criteria: (1) LA diameter indexed to height greater than 24 mm/m; (2) LA diameter indexed to body surface area greater than 23 mm/m(2). Prevalence of LAD was calculated by indexing LA diameter to both self-reported and measured anthropometric values. In the whole population, LAD tended to be underestimated when LA diameter was indexed to self-reported compared with measured values, by 3.6% according to criterion 1 (26.4% versus 30.0%, P < .001) and by 0.6% according to criterion 2 (21.1% versus 21.6%, P = not significant). The difference between LAD estimates was more pronounced in older than in younger patients, either by criterion 1 (6.4% versus 1.6 %, P < .001) or by criterion 2 (2.1% versus 0.1%, P < .001). The error is related to demographic characteristics of patients and is more pronounced when LA diameter is normalized to height.

Aortic root dilatation in hypertensive patients: a multicenter survey in echocardiographic practice.

BACKGROUND AND AIM: Aortic root dilatation (ARD) is a cardiovascular phenotype of adverse prognostic value; its prevalence has been mostly investigated in population-based samples and selected hypertensive cohorts. Data from clinical practice are rather scant. Thus, we examined the prevalence and correlates of ARD in a large sample of hypertensive patients referred by general practitioners for a routine echocardiographic examination. METHODS: A total of 2229 untreated and treated hypertensive subjects (mean age 62 years) referred to 17 outpatient echocardiographic laboratories across Italy for detection of hypertensive subclinical cardiac damage were included in the study. ARD was defined by aortic diameter exceeding 3.7 cm in women and 3.9 cm in men. RESULTS: ARD was found in 263 patients, with an overall prevalence of 11.8% (16.9% in men and 6.2% in women, p < 0.05). In multivariate regression analyses, body surface area (BSA), left ventricular (LV) mass and age were in ranking order the most important correlates of aortic root size in the whole population study as well as in men. In women, LV mass and its derivative indexes were the most important independent variables associated to aortic root size. CONCLUSIONS: This multicenter nationwide survey indicates that ARD is a frequent cardiovascular phenotype in hypertensives referred to echo-labs for detection of hypertensive organ damage. BSA, LV mass and age are the most important correlates of this phenotype. The hierarchical order of these factors differs between genders, LV mass being the strongest independent variable in women.

Self-reported weight and height: implications for left ventricular hypertrophy detection. An Italian multi-center study.

We examined the difference between self-reported and measured body size values and their impact on detection of left ventricular hypertrophy (LVH) by echocardiographic LV mass indexation. A total of 1963 subjects referred by their practitioners for routine echocardiographic examination to nine outpatient echocardiographic laboratories across Italy were included in the study. Left ventricular hypertrophy was defined according to two gender- specific criteria as: A) Left ventricular mass (LVM) index ≥49 g/h(2.7) in men and ≥45 g/h(2.7) in women; B) LVM index ≥125 g/m(2) in men and ≥110 g/m(2) in women. Prevalence of LVH was calculated by indexing LVM to both self-reported and measured anthropometric values. In the whole population, LVH tended to be underestimated by self-reported values by 5.4% according to criterion A (48.5% vs. 53.9%, p < 0.001) and by 1.2% according to criterion B (29.6% vs. 30.8%, p < 0.01); similar findings were observed in the hypertensive subgroup encompassing one-half of the sample. Underestimation of LVH was more pronounced in older patients than in younger patients: 8.6% vs. 3.2% (p < 0.001) by criterion A, 3.1% vs. 0.1% (p < 0.001) by criterion B, in women than in men (8.6% vs. 3.3% (p < 0.001) by criterion A and 1.8% vs. 0.5% (p < 0.01) by criterion B. In a sample of outpatients attending echocardiographic laboratories, LVH is misclassified when left ventricular mass is normalized to self-reported weight and height. The error is related to the clinical characteristics of patients and is more pronounced when LVM is normalized to height(2.7).

Prevalence and severity of echocardiographic left ventricular hypertrophy in hypertensive patients in clinical practice.

BACKGROUND AND AIM: The prevalence of left ventricular hypertrophy (LVH) in human hypertension has been mostly documented in population-based samples and selected hypertensive cohorts. Rather scant data are available from clinical practice. Thus, we examined the prevalence of LVH in a large group of hypertensive patients referred by general practitioners to a routine echocardiographic examination. METHODS: A total of 2249 hypertensive subjects (mean age 62 years, 52.3% men, 84.5% treated) referred by their practitioners to 17 outpatient echocardiographic laboratories across Italy for detection of hypertensive early cardiac damage were included in the study. LVH was defined as left ventricular mass (A) ≥ 225/163 g, (B) ≥ 116/96 g/m(2), (C) ≥ 49/45 g/m(2.7) in men/women, respectively; LVH was graded as mild, moderate and severe according to Lang's report. RESULTS: Overall, patients with LVH were 58%, 58% and 65% by criteria A, B and C, respectively. LVH was mild in 33% (A), 36% (B) and 29% (C), moderate in 31% (A), 28% (B) and 27% (C), and severe in 36% (A), 36% (B) and 44% (C). CONCLUSIONS: Data provided by this multicentre nationwide survey support the view that, despite therapeutic interventions, LVH remains a highly frequent phenotype in human hypertension and that severe LVH is present in a large fraction of hypertensives.

Efficacy and tolerability of olmesartan/amlodipine combination therapy in patients with mild-to-severe hypertension: focus on 24-h blood pressure control.

European guidelines recommend that treating patients with hypertension to blood pressure (BP) goal is an important target for cardiovascular (CV) risk reduction. However, office BP may be a suboptimal target, given its limitations. Indeed, there is evidence that 24-h ambulatory BP monitoring (ABPM) parameters may score better in this regard, representing more accurate predictors of CV risk. In particular, mean 24-h BP and BP variability both correlate closely with hypertension end-organ damage and rate of CV events, which suggests that antihypertensive therapy should provide smooth BP control over the full 24-h dosing interval. The use of ABPM has demonstrated that fixed-dose combination therapy, comprising agents with complementary mechanisms of action, may overcome the challenge of suboptimal BP control by providing improvements in antihypertensive efficacy and tolerability throughout the 24-h period. Olmesartan/amlodipine is one of the latest combination therapies to be approved, and a number of large clinical trials have demonstrated the efficacy and tolerability of this combination in patients with mild-to-severe hypertension. Furthermore, recent ABPM studies of olmesartan/amlodipine-based treatment algorithms have shown the satisfactory 24-h antihypertensive efficacy of this fixed-dose combination. This review provides an overview of recent clinical data on the efficacy and tolerability of fixed-dose olmesartan/amlodipine combination therapy for the treatment of mild-to-severe hypertension, with a focus on sustained 24-h BP control.

Effectiveness of barnidipine 10 or 20 mg plus losartan 50-mg combination versus losartan 100-mg monotherapy in patients with essential hypertension not controlled by losartan 50-mg monotherapy: A 12-week, multicenter, randomized, open-label, parallel-group study.

BACKGROUND: Increasing the dose or adding a second antihypertensive agent are 2 possible therapeutic choices when blood pressure (BP) is poorly controlled with monotherapy. OBJECTIVE: This study investigated the effectiveness and tolerability of barnidipine 10 or 20 mg added to losartan 50 mg versus losartan 100 mg alone in patients with mild to moderate essential hypertension whose BP was uncontrolled by losartan 50-mg monotherapy. METHODS: This was a 12-week, multicenter, randomized, open-label, parallel-group study. Eligible patients (aged 30-74 years) had uncontrolled hypertension, defined as office sitting diastolic BP (DBP) > or =90 mm Hg and/or systolic BP (SBP) > or =140 mm Hg, and mean daytime DBP > or =85 mm Hg and/or SBP > or =135 mm Hg. All were being treated with losartan 50 mg at enrollment. After a 1-week run-in period while taking losartan 50 mg, patients were randomly assigned to 6 weeks of treatment with open-label barnidipine 10 mg plus losartan 50 mg or losartan 100-mg monotherapy. At the end of this period, patients with uncontrolled BP had barnidipine doubled to 20 mg and continued for an additional 6 weeks, whereas patients not achieving control on treatment with losartan 100 mg were discontinued. Office BP was measured at each visit, whereas 24-hour ambulatory BP monitoring (ABPM) was performed at randomization and at the final visit (ie, after 12 weeks of treatment, or at 6 weeks for patients not controlled on losartan 100 mg). The intent-to-treat population included all randomized patients who received at least one dose of study treatment and had valid ABPM recordings at baseline and the final visit. The primary end point was the change in daytime DBP between baseline and 12 weeks of treatment, compared between the combination treatment and monotherapy. Adverse events (AEs) were evaluated during each study visit. RESULTS: A total of 93 patients were enrolled (age range, 30-75 years; 60% [56/93] men). After the 1-week run-in period, 68 patients were randomly assigned to 6 weeks of treatment with open-label barnidipine 10 mg plus losartan 50 mg (n = 34) or losartan 100-mg monotherapy (n = 34). A total of 53 patients were evaluable (barnidipine plus losartan, n = 28; losartan, n = 25). After 6 weeks of treatment, 18 patients in the combination treatment group (64.3%) had their dose of barnidipine doubled from 10 to 20 mg because BP was not normalized by treatment, whereas 8 patients in the losartan group (32.0%) were discontinued for the same reason. The between-treatment difference (losartan alone - combination treatment) for changes from baseline in daytime DBP was -1.7 mm Hg (95% CI, -5.8 to 2.4 mm Hg; P = NS). A similar result was observed for daytime SBP (-3.2 mm Hg; 95% CI, -8.1 to 1.7 mm Hg; P = NS). Likewise, no significant differences were found for nighttime values (mean [95% CI] DBP, 0.5 mm Hg [-3.7 to 4.7 mm Hg]; SBP, 1.5 mm Hg [-4.1 to 7.1 mm Hg]) or 24-hour values (DBP, -0.9 mm Hg [-4.8 to 2.9 mm Hg]; SBP, -1.6 mm Hg [-5.9 to 2.7 mm Hg]). Combination treatment was associated with a significantly higher rate of SBP responder patients (ie, <140 mm Hg or a reduction of > or =20 mm Hg) compared with monotherapy (82.1% [23/28] vs 56.0% [14/25]; P = 0.044). Drug-related AEs were reported in 4 patients taking combination treatment (total of 7 AEs, including 2 cases of peripheral edema and 1 each of tachycardia, atrial flutter, tinnitus, confusion, and polyuria) and in 2 patients taking losartan alone (total of 2 AEs, both tachycardia). CONCLUSIONS: This open-label, parallel-group study found that there was no significant difference in the BP-lowering effect of barnidipine 10 or 20 mg in combination with losartan 50 mg compared with losartan 100-mg monotherapy in these patients with essential hypertension previously uncontrolled by losartan 50-mg monotherapy. However, the percentage of responders for SBP was significantly higher with the combination. Both treatments were generally well tolerated. European Union Drug Regulating Authorities Clinical Trials (EudraCT) no. 2006-001469-41.

Left ventricular hypertrophy detection and body mass index in essential hypertension.

BACKGROUND AND AIM: Weight and height are two major determinants of left ventricular mass (LVM); the anthropometric parameter to which LVM should be normalized remains, however, debated. In a population of hypertensives, we compared the prevalence of left ventricular hypertrophy (LVH) defined by two indexation criteria of LVM in different subgroups of body mass index (BMI). METHODS: A total of 4468 essential hypertensives included in the Evaluation of Target Organ Damage in Hypertension (ETODH), were divided in four groups according to BMI thresholds: lean (BMI<20 kg/m(2), 4.5%), normal (20-24.9 kg/m(2), 36.5%), overweight (25-29.9 kg/m(2), 41.9%) and obese (≥ 30 kg/m(2), 17.1%). All patients underwent quantitative echocardiography; LVH was defined by two criteria of LVM indexation: (A) ≥ 116 g/m(2) in men and ≥ 96 g/m(2) in women; (B) ≥ 49 g/m(2.7) in men and ≥ 45 g/m(2.7) in women. RESULTS: Overall, 44.9% of the patients were found to have LVH by criterion A, 48.2% by criterion B and 37.0% by both criteria. Prevalence rates of LVH in the four BMI groups were 34.3%, 40.5%, 47.3%, 53.9% by criterion A, 19.8%, 37.0%, 53.6%, 69.7% by criterion B, and 14.2%, 30.9%, 41.5%, 47.8% by both criteria, respectively (p at least <0.05 for all). CONCLUSIONS: Our findings show that LVH prevalence in both overweight and obese hypertensives is higher when LVM is normalized to height(2.7) compared with body surface area (BSA), whereas the opposite trend occurs in normal weight/lean hypertensives. Thus, the risk related to LVH is underestimated when the LVH/height(2.7) criterion is applied to lean/normal weight individuals and the LVH/BSA criterion in overweight/obese individuals.

Reinforcement of the adrenergic overdrive in the metabolic syndrome complicated by obstructive sleep apnea.

BACKGROUND: Metabolic syndrome is characterized by a marked sympathetic overactivity. It is unknown, however, whether the neuroadrenergic activation can be ascribed to obstructive sleep apnoea (OSA), OSA exerts potentiating effects on the metabolic syndrome-related sympathetic activation and reflex/metabolic variables (insulin resistance) participate at the phenomenon. METHODS AND RESULTS: We conducted a cross-sectional study of healthy individuals and metabolic syndrome patients recruited in our outpatient clinic. Fifty-five middle-age men classified according to Adult Treatment Panel III criteria and apnea-hypopnea index (overnight polysomnographic evaluation) as healthy controls without OSA and metabolic syndrome patients without and with OSA were studied. Blood pressure (Finapres), heart rate (ECG) and muscle sympathetic nerve activity (MSNA; microneurography) were measured at rest and during baroreflex manipulation. Compared with controls, patients with metabolic syndrome with and without OSA displayed higher waist-hip ratio, blood pressure, triglycerides and homeostasis model assessment index values but lower high-density lipoprotein cholesterol. MSNA was significantly higher in patients with metabolic syndrome without OSA than in controls (61.9 +/- 3.9 vs. 37.7 +/- 4.1 bursts/100 heartbeats, respectively, P < 0.01), a further marked increase being detected in patients with metabolic syndrome with OSA (77.1 +/- 4.3 bursts/100 heart beats, P < 0.01). Compared with controls, baroreflex control of heart rate and MSNA was markedly impaired in patients with metabolic syndrome with OSA, a further impairment in baroreflex-heart rate modulation being detected in metabolic syndrome with OSA. In the metabolic syndrome group as a whole, at the multivariate analysis, MSNA was significantly related to the apnoea-hypopnoea index but not to other variables. CONCLUSION: Thus the sympathetic activation of metabolic syndrome occurs independently on OSA. OSA, however, markedly potentiates this neuroadrenergic abnormality via a hypoxic-dependent chemoreflex activation.

Patients with antiphospholipid syndrome display endothelial perturbation.

BACKGROUND: There is strong evidence that antiphospholipid antibodies (aPL) perturb endothelium both in vitro and in experimental animal models. by inducing a vasculopathy and an endothelial pro-inflammatory/coagulant phenotype. However, few contrasting studies raised the issue about the possibility to detect a comparable endothelial perturbation in anti-phospholipid syndrome (APS) patients. The aim of this observational case-control study was to evaluate several parameters of endothelial perturbation in patients with APS and without any other atherosclerosis risk factor. PATIENTS AND METHODS: We investigated plasma levels of soluble adhesion molecules (s-ICAM-1, s-VCAM-1, s-E-selectin), soluble thrombomodulin (sTM), von Willebrand factor (vWF) and tissue plasminogen activator (t-PA) by solid-phase assays in 40 selected APS patients and 40 age- and sex-matched healthy subjects. In addition, we evaluated circulating endothelial cells by flow cytometry and brachial artery flow-mediated vasodilation. Patients and controls were free of conditions known to affect both the biological and the functional endothelial parameters. RESULTS: Plasma levels of sTM, s-E-selectin and s-VCAM-1 did not differ from controls, while a significant increase in s-ICAM-1 (P = 0.029), t-PA (P = 0.003) and vWF titres (P = 0.002) was found. Circulating mature endothelial cells were also significantly higher in patients than in controls (P = 0.05) and decreased during both vitamin K antagonists (P = 0.001) and antiplatelet (P = 0.032) treatments. Mean brachial artery flow-mediated vasodilation responses were significantly impaired compared to healthy subjects (P = 0.0001). CONCLUSIONS: As a whole these findings indicate that APS patients display an endothelial perturbation in the absence of other detectable traditional risk factors for atherosclerosis.