Gluten-Free Diet and Lipid Profile in Children With Celiac Disease: Comparison With General Population Standards.

OBJECTIVES: A gluten-free diet (GFD) may carry high energy and fat load. We verified lipid profile and dietary indicators cross-sectionally and prospectively in patients with celiac disease (CD). METHODS: In any consecutive child receiving a GFD (group 1) or newly diagnosed as having CD (group 2), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) cholesterol, blood pressure (BP), anthropometric data, physical activity, and a 24-hour food diary were collected during follow-up visits (yearly in group 1 and during the first year of GFD in group 2). RESULTS: In group 1 (132 girls, 73 boys, 10.7 ±â€Š4.2 years), TC (P = 0.006), TG (P = 0.014), and HDL (P = 0.019) were significantly higher in girls than in boys. Compared with the general pediatric population, group 1 girls had higher TC, TG, HDL, and low-density lipoprotein; group 1 boys had lower TC, TG, and low-density lipoprotein and higher HDL. TC was significantly and positively affected by age, sex, and time receiving GFD, whereas HDL was significantly and positively affected by body mass index, diastolic BP, and sex; TG was negatively affected by diastolic BP. Compared with recommendations, group 1 children introduced less calories, iron, and calcium; one-third more sodium; similar amounts of fiber; and twice as many proteins. In group 2 (20 girls, 10 boys, 8.6 ±â€Š3.55 years), TC did not change over time and TG diminished, whereas HDL, blood glucose, and body mass index increased; saturated fats and caloric intake were below recommendations, whereas proteins were excessively introduced. Fibers were optimal. HDL was inversely correlated to calories and saturated fat (R²â€Š= 80, P = 0.011). CONCLUSIONS: Lipid profiles of children with CD differ across sexes and from reference population. GFD, being unexpectedly appropriate in fibers and fat proportion, may be a contributor.

Systolic and diastolic short-term blood pressure variability and its determinants in patients with controlled and uncontrolled hypertension: a retrospective cohort study.

Absolute blood pressure (BP) values are not the only causes of adverse cardiovascular consequences. BP variability (BPV) has also been demonstrated to be a predictor of mortality for cardiovascular events; however, its determinants are still unknown. This study considers 426 subjects with ambulatory BP monitoring (ABPM) measuring 24-h, diurnal and nocturnal absolute BP values and their standard deviations of the mean, along with nocturnal fall, age, sex and current treatment. Patients were divided in two subgroups, controlled and uncontrolled BP, and BPV of patients with "true" and "false" resistant hypertension was also analyzed. Nocturnal and 24-h BPV were higher in the group with uncontrolled hypertension. Multiple regression analysis showed that absolute BP, age, nocturnal fall, but not sex predicted BPV. Patients with "true" resistant hypertension had greater BPV than "false" resistant hypertension patients. Absolute BP resulted as the main determinant of 24-h and nocturnal BPV but not daytime BPV. Also nocturnal BP fall and age resulted as predictors of BPV in treated and untreated patients. Patients with "true" resistant hypertension have a higher BPV, suggesting a higher sympathetic activation. Evidence is still limited regarding the importance of short-term BPV as a prognostic factor and assessment of BPV cannot yet represent a parameter for routine use in clinical practice. Future prospective trials are necessary to define which targets of BPV can be achieved with antihypertensive drugs and whether treatment-induced reduction in BPV is accompanied by a corresponding reduction in cardiovascular events.

PLCß1-SHP-2 complex, PLCß1 tyrosine dephosphorylation and SHP-2 phosphatase activity: a new part of Angiotensin II signaling?

BACKGROUND: Angiotensin II (Ang II) signaling occurs via two major receptors which activate non-receptor tyrosin kinases that then interact with protein tyrosin-phosphatases (PTPs) to regulate cell function. SHP-2 is one such important PTP that also functions as an adaptor to promote downstream signaling pathway. Its role in Ang II signaling remains to be clarified. RESULTS: Using cultured normal human fibroblasts, immunoprecipitation and western blots, we show for the first time that SHP-2 and PLCß1 are present as a preformed complex. Complex PLCß1 is tyr-phosphorylated basally and Ang II increased SHP-2-PLCß1 complexes and caused complex associated PLCß1 tyr-phosphorylation to decline while complex associated SHP-2's tyr-phosphorylation increased and did so via the Ang II type 1 receptors as shown by Ang II type 1 receptor blocker losartan's effects. Moreover, Ang II induced both increased complex phosphatase activity and decreased complex associated PLCß1 tyr-phosphorylation, the latter response required regulator of G protein signaling (RGS)-2. CONCLUSIONS: Ang II signals are shown for the first time to involve a preformed SHP-2-PLCß1 complex. Changes in the complex's PLCß1 tyr-phosphorylation and SHP-2's tyr-phosphorylation as well as SHP-2-PLCß1 complex formation are the result of Ang II type 1 receptor activation with changes in complex associated PLCß1 tyr-phosphorylation requiring RGS-2. These findings might significantly expand the number and complexity of Ang II signaling pathways. Further studies are needed to delineate the role/s of this complex in the Ang II signaling system.

Effect of olmesartan on oxidative stress in hypertensive patients: mechanistic support to clinical trials derived evidence.

The role of oxidative stress in the pathophysiology of hypertension and target organ damage is widely recognized. Using a molecular biology approach, we report, in essential hypertensive patients, the effect of the angiotensin II type 1 receptor blocker olmesartan on the mononuclear cell (PBMC) protein expression of major elements in the oxidative stress and vascular remodeling-related pathways, p22(phox) and HO-1, along with the phosphorylation state of ERK1/2 and plasma oxidized low-density lipoproteins (oxLDL). Twenty untreated essential hypertensive patients (range blood pressure: 142?156/94?98 mmHg) were treated with olmesartan medoxomil (20 mg/day for 6 months) and blood samples collected at baseline, 3 and 6 months for PBMC p22(phox) and HO-1 protein expression, phosphorylation state of ERK1/2 (western blot) and oxLDL level (ELISA) evaluations. Olmesartan normalized blood pressure since the third month (149 ? 4.7/94.88 ? 1.9 mmHg vs 137.89 ? 2.08/88.44 ? 2.0 at 3 months and vs 135.44 ? 2.18/85.78 ? 1.2 at 6 months, analysis of variance: p < 0.001). p22(phox) protein level declined at 3 months (7.10 ? 2.61 vs 9.32 ? 2.43 densitometric units (d.u.; p < 0.001), further declining at 6 months (4.55 ? 1.26 d.u., p < 0.001). HO-1 levels increased at 3 months (10.87 ? 1.92 vs 7.70 ? 0.71 d.u., p = 0.001) and remained elevated (11.11 ? 1.89 d.u., p = 0.001), without further increase at 6 months. Phosphorylated ERK1/2 declined at 3 months (3.94 ? 1.44 vs 5.62 ? 1.11 d.u., p = 0.001), further declining at 6 months (1.94 ? 0.87, p < 0.001). oxLDL significantly declined at 3 and 6 months. These results demonstrate that olmesartan inhibits oxidative stress. Given the involvement of oxidative stress and its signaling in atherogenesis, and the available evidence of olmesartan's vasoprotective, anti-inflammatory and antiatherosclerotic effects derived from clinical trials in humans, the results of our study provide a mechanistic rationale for the omelsartan's antioxidant and anti-inflammatory potential translation, in the long term, toward the antiatherosclerotic and antiremodeling effects reported on the clinical ground.

ACE2 and angiotensin 1-7 are increased in a human model of cardiovascular hyporeactivity: pathophysiological implications.

BACKGROUND: ACE and ACE2 produce angiotensin II (Ang II), a vasopressor that induces cardiovascular remodeling, and Ang 1-7, a vasodilator with an antiremodeling effect. While Ang 1-7 has antiarrhythmic properties, at higher concentration it may induce ventricular tachycardia and sudden death. ACE2, therefore, may play an essential role in blood pressure homeostasis, in the long-term complications of hypertension (cardiovascular remodeling), and in the induction of cardiac electric abnormalities. This study evaluated the levels of ACE2 and Ang 1-7 in Bartter's/Gitelman's patients (BS/GS) who have elevated Ang II and endogenous blockade of Ang II type 1 receptor signaling compared with healthy subjects (C) and essential hypertensives (EH). BS/ GS patients were also considered because of their predisposition to cardiac arrhythmias, which has yet to be completely clarified. METHODS: Mononuclear cell ACE2 and Ang 1-7 were evaluated using western blot. RESULTS: One-way ANOVA showed that ACE2 and Ang 1-7 levels were significantly different between the three groups (p=0.0074 and p=0.0001, respectively). Post-hoc analysis (Tukey's HSD) showed that both ACE2 (1.59+/-0.63) and Ang1-7 (2.26+/-1.18) were significantly elevated in BS/GS compared with either C (0.98+/-0.45; p=0.008; 1.12+/-0.48, p=0.002, respectively) or EH (1.06+/-0.24; p=0.043; 0.72+/-0.28; p=0.0001, respectively). ACE2 and Ang 1-7 directly correlated only in BS/GS (r=0.91, p<0.0003). CONCLUSIONS: The elevated ACE2 and Ang 1-7 in BS/ GS patients mirror those in hypertensives and are in line with the clinical, hemodynamic and pathophysiological characteristics of BS/GS, likely contributing to them. In consideration of the clinical picture of these syndromes, the opposite of hypertension, the results of this study further strengthen the importance of the ACE2/Ang 1-7 system in the regulation of vascular tone and cardiovascular biology.

Clinical Outcomes of 1625 Patients With Primary Aldosteronism Subtyped With Adrenal Vein Sampling.

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men (P<0.001). When AVS-guided, surgery provided a higher rate of cure of hypertension than when non-AVS-guided (40.0% versus 30.5%; P=0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications (P<0.001) and exhibited a higher rate of persistent hypokalemia requiring potassium supplementation (4.9% versus 2.3%; P<0.01). The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01234220.

Plasma adiponectin for prediction of cardiovascular events and mortality in high-risk patients.

CONTEXT: The prognostic value of plasma levels of adiponectin, an adipocytokine with antiatherogenic, antiinflammatory, and insulin-sensitizing effects, is contentious. OBJECTIVE: The objective of the study was to investigate whether plasma adiponectin levels predict cardiovascular (CV) events and mortality in high-risk coronary artery disease (CAD) patients. DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME MEASURE: We measured plasma adiponectin and examined its impact on the incidence of CV deaths and events at follow-up in the context of all potentially relevant background covariates in 712 high-risk patients of the Genetic and ENvironmental factors in Coronary Atherosclerosis study who underwent coronary angiography for suspected CAD. Based on the population plasma adiponectin median (6.38 microg/ml, interquartile range 4.2-10.2), we split the patients in a high- and a low-plasma adiponectin subgroup. After a median follow-up of 3.8 years (interquartile range 3.3-4.3 yr), outcome data were obtained in 100% of the patients and 45 CV deaths (6.4%) were recorded. Kaplan-Meier analysis unexpectedly showed a higher CV death rate in high-plasma adiponectin than low-plasma adiponectin patients. By contrast, multivariate Cox regression analysis, in which potential confounders, including ongoing medical treatment, were considered, showed no impact of plasma adiponectin on CV death. Similar negative results were obtained using the propensity score that considered all relevant covariables and medical treatment rate, which differed between the high- and low-plasma adiponectin group. CONCLUSIONS: In high-risk CAD patients, plasma adiponectin above the median (6.38 microg/ml) implies a paradoxical higher risk of CV death. However, when relevant covariates that differ between high- and low-plasma adiponectin groups are considered, this association wanes, indicating that the clustering of plasma adiponectin with other covariates can abolish its impact on CV prognosis.

Body mass index predicts plasma aldosterone concentrations in overweight-obese primary hypertensive patients.

CONTEXT: Body mass index (BMI) shows a direct correlation with plasma aldosterone concentration (PAC) and urinary aldosterone excretion in normotensive individuals; whether the same applies to hypertensive patients is unknown. OBJECTIVE: Our objective was to determine if BMI predicts PAC and the PAC/plasma renin activity ratio [aldosterone renin ratio (ARR)] in hypertensive patients, and if this affects the identification of primary aldosteronism (PA). DESIGN: This was a prospective evaluation of consecutive hypertensive patients referred nationwide to specialized hypertension centers. MAIN OUTCOME MEASURES: Sitting PAC, plasma renin activity, and the ARR, baseline and after 50 mg captopril orally with concomitant assessment of parameters, including BMI and daily sodium intake, were calculated. RESULTS: Complete biochemical data and a definite diagnosis were obtained in 1125 consecutive patients. Of them 999 had primary (essential) hypertension (PH) and 126 (11.2%) PA caused by an aldosterone-producing adenoma in 54 (4.8%). BMI independently predicted PAC (beta = 0.153; P < 0.0001) in PH, particularly in the overweight-obese, but not in the PA group. Covariance analysis and formal comparison of the raw, and the BMI-, sex-, and sodium intake-adjusted ARR with receiver operator characteristic curves, showed no significant improvement for the discrimination of aldosterone-producing adenoma from PH patients with covariate-adjusted ARR. CONCLUSIONS: BMI correlated with PAC independent of age, sex, and sodium intake in PH, but not in PA patients. This association of BMI is particularly evident in overweight-obese PH patients, and suggests a pathophysiological link between visceral adiposity and aldosterone secretion. However, it does not impact on the diagnostic accuracy of the ARR for discriminating PA from PH patients.

Silencing regulator of G protein signaling-2 (RGS-2) increases angiotensin II signaling: insights into hypertension from findings in Bartter's/Gitelman's syndromes.

OBJECTIVE: Regulator of G-protein signaling (RGS)-2 is a regulator of angiotensin II (Ang II) signaling. In Bartter's syndrome/Gitelman's syndrome (BS/GS), we have demonstrated increased RGS-2 levels and blunted Ang II signaling which contribute to their reduced vasomotor tone and remodeling. The present study investigates the effect of silencing RGS-2 in fibroblasts from six BS/GS patients on intracellular Ca2+ (CaI2+) mobilization and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, established Ang II-mediated responses. METHODS: Fibroblasts were RGS-2 silenced by transfecting chemically synthesized small interfering RNA. Silencing efficiency and Ang II-induced ERK 1/2 phosphorylation were evaluated by western blot and Ang II-induced Cai2+ using Fura-2 AM. RESULTS: RGS-2 expression in not silenced BS/GS fibroblasts from patients is increased compared with healthy controls [0.34 +/- 0.02 vs. 0.19 +/- 0.01 densitometric units (d.u.), P = 0.0005]. Silencing RGS-2 in BS/GS patients was achieved to the level of controls. Ang II-induced Cai2+ release and ERK 1/2 phosphorylation were reduced in not silenced cells from BG/GS patients compared with controls (112.16 +/- 13.2 vs. 130.33 +/- 13.64 mmol/l, P = 0.011 and 0.64 +/- 0.08 vs. 0.91 +/- 0.03 mmol/l, P < 0.006, respectively). Silencing RGS-2 in BS/GS patients increased Ang II-induced Cai2+ release and ERK 1/2 phosphorylation in silenced cells compared with not silenced cells [59.3 +/- 10.8 (peak-basal) vs. 40.5 +/- 14.1 nmol/l, P = 0.017 and 0.84 +/- 0.06 vs. 0.64 +/- 0.08 nmol/l, P < 0.03, respectively], whereas they were not different compared with controls (60.1 +/- 4.3 and 0.91 +/- 0.03 nmol/l). Integrating the Cai2+ response over time showed increased Cai2+ area under the curve (AUC) of BS/GS silenced cells compared with that of not silenced cells (P = 0.013). CONCLUSION: This is the first report of silencing RGS-2 effect on Ang II signaling in a human clinical condition of altered vascular tone regulation and remodeling and establishes RGS-2 as a key regulatory element of Ang II signaling in humans.

Role of angiotensin II, endothelin-1 and L-type calcium channel in the development of glomerular, tubulointerstitial and perivascular fibrosis.

OBJECTIVE: Fibrosis is a hallmark of renal damage in several diseases, including arterial hypertension. We, therefore, investigated the role of angiotensin II, endothelin-1 and of L-type calcium channels in the development of the glomerular, vascular, and tubulointerstitial fibrosis in a model of severe angiotensin II-dependent hypertension. METHODS: Five-week-old Ren-2 transgenic rats (TGRen2) received for 4 weeks a placebo, bosentan (100 mg/kg body weight), irbesartan (50 mg/kg body weight), the ETA-selective endothelin receptor antagonist BMS-182874 (BMS; 52 mg/kg body weight), the combination of irbesartan (50 mg/kg body weight) plus BMS (52 mg/kg body weight), and nifedipine (30 mg/kg body weight). RESULTS: Glomerular volume, tubulointerstitial fibrosis, glomerular, and perivascular fibrosis were accurately quantified by histomorphometry in four-to-six sections per kidney. Glomerular fibrosis was lowered by BMS (P < 0.001), whereas tubulointerstitial fibrosis was blunted by bosentan (P < 0.001) and irbesartan (P < 0.005). Perivascular fibrosis was reduced by nifedipine and BMS. As only irbesartan and irbesartan plus BMS decreased blood pressure (P < 0.001 vs. placebo), these effects on fibrosis were independent of blood pressure. CONCLUSION: Angiotensin II and L-type calcium channels modulate fibrosis selectively in the tubulointerstitial and in the perivascular compartments, respectively. The prevention of fibrosis with ET-1 receptor antagonism in all three compartments supports a major role of ET-1 in the development of renal fibrosis.

Effects of the C825T polymorphism of the GNB3 gene on body adiposity and blood pressure in fertile and menopausal women: a population-based study.

OBJECTIVES: The 825T allele of the GNB3 gene is implicated in adipose distribution, predisposing to obesity and hypertension. Menopause is also considered a condition leading to excess adiposity and hypertension. The aim of the present study was to clarify whether the effects of menopause on body weight and blood pressure are influenced by the C825T polymorphism of the GNB3 gene. METHODS: The study involved 1339 subjects (43% men) aged 18-95 years, genotyped at the GNB3 825 locus, undergoing, in an epidemiological population-based frame, questionnaire, anthropometrics and blood examinations. RESULTS: Mean skinfold thickness (MST), truncal obesity and excess subcutaneous adiposity (MST greater than median) were higher in women than in men. A significant interaction was detected between menopausal status and the C825T polymorphism (Pint > 0.0001). MST, truncal obesity and excess subcutaneous adiposity were lower in CC fertile than menopausal women, but were comparable in TT fertile and menopausal women. In a multivariate logistic model for excess subcutaneous adiposity, the relative risk of menopause was 4.12 (95% confidence interval 2.35-7.22) in CC women but was insignificant in the other two genotypes. In fertile women only, higher systolic blood pressure (SBP) was detected in TT than in CC genotypes. CONCLUSION: An interaction exists between the C825T polymorphism and menopause in controlling body adiposity and blood pressure in women. Adiposity and SBP are higher in menopausal than in fertile women, provided they have the CC genotype. TT fertile women show the same adiposity as those in menopause. Men have the same excess adiposity as menopausal women, independent of the GNB3 genotype.

Menopause does not affect blood pressure and risk profile, and menopausal women do not become similar to men.

OBJECTIVE: Menopause is considered to be a cardiovascular risk factor, but this belief is based on opinions rather than on evidence. Confounding effects of age are often neglected. DESIGN: Population-based study with further subanalysis of case-to-case age-matched cohorts of men and fertile and menopausal women. SETTING: Epidemiology in primary, public, institutional frame. PARTICIPANTS: Nine thousand three hundred and sixty-four men and women aged 18-70 years representative of Italian general population followed-up for 18.8 +/- 7.7 years. MAIN OUTCOME MEASURES: Blood pressure (BP), prevalence and incidence of hypertension, serum total, high-density lipoprotein and low-density lipoprotein cholesterol, glucose tolerance, body adiposity, vascular reactivity, target organ damage, overall and cardiovascular mortality and morbidity, by gender and by menopausal status. RESULTS: Cross-sectional: crude BP, pressor response to cold, orthostatic BP decrease, BMI, skinfold thickness, fasting and postload blood glucose and insulin, serum lipids, left ventricular mass, serum creatinine, microalbuminuria and augmetantion index were higher in menopausal than in fertile women, and comparable in menopausal women and men, a difference that was no longer present when adjusting for age or considering age-matched cohorts. Longitudinal: BP increase during follow-up, cardiovascular mortality and morbidity were greater in menopausal than in fertile women, and comparable in menopausal women and men, a difference no longer present in age-matched cohorts. Menopausal status was rejected from multivariate Cox analysis also including age. CONCLUSION: The cardiovascular effects usually attributed to menopause seem to be a mere consequence of the older age of menopausal women.

RhoA/Rho-kinase pathway: much more than just a modulation of vascular tone. Evidence from studies in humans.

RhoA/Rho-kinase signaling and its relationship/balance with the nitric oxide level, angiotensin II and vasopressors for cardiovascular pathophysiology is of increasing importance, and its involvement goes far beyond blood pressure regulation. The deep involvement of this pathway in cardiovascular biology is now known to include a wide spectrum of conditions relating to the long-term complications of hypertension, and in general of cardiovascular pathophysiology, such as changes in cardiovascular structure (remodeling) and the induction of atherosclerosis, involvement in the pathophysiological relationships between inflammation and hypertension, and in those between hypertension, glucose metabolism and insulin resistance. Studies from our laboratory have made an important contribution to the understanding of the cellular and molecular mechanisms mediated by the RhoA/Rho-kinase pathway, which include all the aspects of cardiovascular pathophysiology in which this pathway plays a role. In addition, if it is considered that our contribution to the clarification of these mechanisms only comes from studies in humans, their impact on the scenario of the RhoA/Rho-kinase pathway's biology, essentially supported by studies 'in vitro' or in animal models, is immediate. This review examines all the aspects of RhoA/Rho-kinase signaling in the light of the available data, and gives an updated and useful overall picture of its involvement in cardiovascular pathophysiology.

Skinfold thickness and blood pressure across C-344T polymorphism of CYP11B2 gene.

OBJECTIVE: To ascertain whether body adiposity is associated with the C-344T polymorphism of the CYP11B2 gene codifying for aldosterone synthase. DESIGN: A cross-sectional epidemiological evaluation of a highly homogeneous unselected general population of Caucasians. METHODS: Lifestyle, medical history, anthropometrics, subscapular, triceps and suprailiac skinfold thickness, lying blood pressure and biochemical measures were recorded in a population-based study among 1386 unselected subjects (56.5% women) living in a secluded valley. All were genotyped for C-344T allele status. Continuous variables were compared across genotypes with analysis of covariance and correlations evaluated using the Pearson method. Odds ratios (OR) were calculated for the TT and CT genotype versus the CC homozygotes and compared with the T-carriers with a logistic model. RESULTS: The C-344T genotypic frequency did not deviate from Hardy-Weinberg equilibrium. In women, higher values of triceps and subscapular skinfold thickness were found in the CC homozygotes than in the T-carriers. In this sex, skinfold thickness also directly correlated with both systolic and diastolic blood pressure in the T-carriers only. The logistic regression for the dependent variable arterial hypertension showed an influence of triceps [OR 1.07, 95% confidence interval (CI) 1.02-1.12, P=0.006], subscapular (OR 1.13, 95% CI 1.06-1.20, P<0.0001) and suprailiac (OR 1.08, 95% CI 1.01-1.15, P=0.03) skinfold in T-carrier women only. These relationships were not detectable in men. The aldosterone-to-renin ratios were comparable across genotypes and sexes. CONCLUSION: The C-344T polymorphism of the CYP11B2 gene seems to exert a sex-specific influence on body adiposity, independent of adrenal aldosterone.

Left ventricular diastolic dysfunction in elderly hypertensives: results of the APROS-diadys study.

BACKGROUND: A number of patients with chronic heart failure (CHF) have diastolic but not systolic dysfunction. This occurs particularly in the elderly and in hypertension, but the prevalence of diastolic dysfunction in elderly hypertensives without CHF has never been investigated systematically. METHODS AND RESULTS: The Assessment of PRevalence Observational Study of Diastolic Dysfunction (APROS-diadys) project was a cross-sectional observational study on elderly (age >/= 65 years) hypertensives without systolic dysfunction [left ventricular ejection fraction (LVEF) >/= 45%] consecutively attending hospital outpatient clinics in Italy, in order to establish the prevalence of echocardiographic signs of diastolic dysfunction according to various criteria, and to correlate them with a number of demographic and clinical characteristics. Primary criteria for diastolic dysfunction was an E/A ratio (ratio between transmitral peak velocities of E and A waves) < 0.7 or > 1.5 on echocardiographic Doppler examination. Secondary criteria were: E/A < 0.5 and deceleration time (DT) > 280 ms, or isovolumic relaxation time (IVRT) > 105 ms or pulmonary vein (PV) peak systolic/peak diastolic flow (S/D) ratio > 2.5 or PV atrial retrograde flow (PV A) > 35 cm/s. Throughout Italy, 27 447 patients were screened in 107 clinics, with 24 141 excluded according to protocol. Among the remaining 3336 patients, 754 (22.6%) had signs of CHF. After exclusion of 37 protocol violators, 2545 patients (49.0% men, mean age 70.3 years, 95.4% under antihypertensive treatment) were studied ultrasonographically. Diastolic dysfunction (primary criteria) was found in 649 (25.8%) patients. Multiple logistic regression analysis found age, gender, left ventricular mass, systolic and pulse pressures and midwall shortening fraction as significant covariates. Using secondary criteria, the prevalence of diastolic dysfunction was higher (45.6%), mostly because of IVRT > 105 ms or PVA flow > 35 cm/s. CONCLUSION: CHF and diastolic dysfunction are highly prevalent in elderly hypertensives attending hospital clinics.

Autonomic nervous system function in chronic hypotension associated with Bartter and Gitelman syndromes.

Autonomic nervous system dysfunction has a major role in the blood pressure (BP) decrease associated with orthostatic hypotension and syncope. The clinical picture of Bartter and Gitelman syndromes includes reduced extracellular fluid volume and normotension or hypotension, but no study has explored autonomic nervous system status in patients with hypotensive episodes associated with these diseases. We tested sympathetic and parasympathetic nervous system function in 4 patients with Bartter and Gitelman syndromes with chronic hypotension. Each patient underwent a battery of autonomic reflex tests, including BP and heart rate response to orthostatism, Valsalva maneuver, cold-pressor test, hand-grip test, and deep breathing. Plasma catecholamines also were measured. BP was monitored during tests by means of continuous noninvasive finger BP recording. Orthostatic hypotension was observed in 1 patient who experienced syncope episodes. Valsalva ratio ranged from 1.21 to 1.61. During the cold-pressor test, the range of systolic and diastolic BP increases were 8 to 31 and 6 to 24 mm Hg, respectively. During the hand-grip test, systolic and diastolic BP increases ranged from 10 to 39 and 8 to 32 mm Hg, respectively. During hyperventilation, the difference between the highest and lowest heart rates was 12 or more beats/min in all patients. Patients' plasma norepinephrine concentrations increased during standing. Our preliminary results suggest that chronic hypotension in patients with Bartter and Gitelman syndromes is not associated with sympathetic and parasympathetic nervous system dysfunction, even when orthostatic hypotension is present. This normal autonomic function suggests that other pathophysiological mechanisms, such as the characteristic vasoconstrictor abnormal cell signaling, may account for hypotension in patients with Bartter and Gitelman syndromes.

Insulin generates free radicals in human fibroblasts ex vivo by a protein kinase C-dependent mechanism, which is inhibited by pravastatin.

Insulin can generate oxygen free radicals. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, exert a powerful antioxidant effect. The present study aimed to clarify the mechanisms through which insulin generates free radicals and to assess whether pravastatin modulates such effects. In cultured skin fibroblasts from human volunteers exposed to high insulin concentration, either in the presence or in the absence of pravastatin, insulin induced translocation of the p47(phox) subunit of NAD(P)H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC delta-dependent mechanism. The insulin-induced translocation of p47(phox) was PKC delta dependent and attenuated by pravastatin, but independent of the activation of Akt and Rac1. Insulin-induced Akt phosphorylation was increased by pravastatin and ERK1/2 phosphorylation attenuated. The present study demonstrates a novel mechanism by which insulin stimulates the generation of free radicals in human fibroblasts, ex vivo. It involves phosphatidylinositol 3-kinase, PKC delta, and p47(phox) translocation and promotes ERK1/2 phosphorylation. Pravastatin inhibited radical oxygen species production by inhibiting PKC delta. These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome.

Evolution of blood pressure and cholesterol in stage 1 hypertension: role of autonomic nervous system activity.

OBJECTIVE: Controversy remains concerning the pathogenetic mechanisms for the relationship between sympathetic activity, hypertension and lipid abnormalities. We tested the hypothesis that a condition characterized by sympathetic predominance may affect the evolution of blood pressure and lipids in the early stage of hypertension. METHODS: We prospectively studied 163 young stage 1 hypertensive individuals and 28 normotensive control individuals. The hypertensive subjects were divided by cluster analysis into two groups according to low frequency and high frequency components of heart rate variability. Large artery and small artery compliance was assessed at the end of the follow-up. RESULTS: Fifty-nine subjects showed reduced total power and signs of sympathetic predominance in the resting condition, on standing and during mental stress (group 1). At baseline, they had similar blood pressure and metabolic data to the rest of the group (n = 104, group 2) and a greater white-coat effect (P = 0.03). During a 6-year follow-up, 23.7% of group 1 subjects versus 9.6% of group 2 subjects developed sustained hypertension requiring antihypertensive treatment (P = 0.02). In group 1 subjects, there was also a greater increase in total cholesterol (P = 0.01) than in group 2. In addition, at the end of follow-up group 1 subjects had impaired large artery compliance (P < 0.001 versus group 2). CONCLUSIONS: These data indicate that a condition characterized by sympathetic predominance may favour the development of sustained hypertension and hypercholesterolemia early in life, and lead to increased susceptibility to vascular complications. They further indicate that the increased white-coat effect is not an innocent phenomenon.

The renal antifibrotic effects of angiotensin-converting enzyme inhibition involve bradykinin B2 receptor activation in angiotensin II-dependent hypertension.

OBJECTIVE: The renoprotective action of angiotensin I-converting enzyme inhibitors (ACE-Is) is well established, but the role played by bradykinin (BK) remains unclear. We therefore investigated whether an enhanced BK effect on B2 receptor subtype mediated the antifibrotic effect of ACE-Is and whether neutral endopeptidase (NEP) inhibition, which can blunt BK degradation more effectively than ACE inhibition, provided further renoprotection in a rat model of angiotensin (Ang) II-dependent renal damage. METHODS: Five-week-old Ren-2 transgenic rats (TGRen2) received, for 8 weeks, a placebo, ramipril (5 mg/kg body weight) or the dual ACE + NEP inhibitor MDL 100,240 (MDL) (40 mg/kg body weight). After 4 weeks, the B2 receptor antagonist icatibant (0.5 mg/kg body weight) was administered on top of active treatment for 4 weeks to 50% of the TGRen2 rats. Blood pressure was measured weekly by a tail-cuff method and, after sacrifice, kidney weight, glomerular volume, density of glomerular profiles were measured; tubulo-interstitial fibrosis, glomerular and perivascular fibrosis were quantified by histomorphometry. RESULTS: The development of hypertension and tubulo-interstitial fibrosis was prevented by both ramipril and MDL (P = 0.0001 versus placebo); icatibant annulled the latter effect. Glomerular and perivascular fibrosis were unaffected by either ramipril or MDL alone; however, combined treatment with icatibant enhanced glomerular fibrosis (P = 0.0001 versus placebo). CONCLUSION: Enhanced BK effect on B2 subtype receptors is essential for the prevention of tubulo-interstitial fibrosis with ACE or dual ACE + NEP inhibition in TGRen2 rats.

Lifestyle, family history and progression of hypertension.

BACKGROUND: Unhealthy lifestyle practices are risk factors for future hypertension. OBJECTIVES: The aim of this study was to investigate the association between lifestyle changes over a 6-year period and the risk of developing sustained hypertension in a cohort of young hypertensive individuals, and to identify the predictors of lifestyle impairment over time. METHODS: Seven-hundred and eighty never-treated hypertensive HARVEST participants, 18-45 years old, were studied. RESULTS: Only modest mean behavioral changes were observed during follow-up. This, however, was the net result of many participants improving and others worsening their lifestyle. Participants with a family history of hypertension (FH+, n = 459) had more undesirable lifestyles (P = 0.004) and higher clinic and ambulatory blood pressures (P = 0.03) at baseline than participants without a family history of hypertension (FH-). During the 6-year follow-up, FH- individuals strikingly worsened their lifestyle while FH+ participants exhibited impressive improvements (P < 0.00001). Other predictors of lifestyle impairment were male gender (P = 0.003) and age (P = 0.02). Adoption of an unfavorable lifestyle was accompanied by an increased risk of developing sustained hypertension (P = 0.04). Initiation of drug therapy for hypertension was significantly higher among FH- than FH+ individuals (53 versus 45%, respectively; P = 0.045). CONCLUSIONS: 'Lower risk' FH- stage 1 hypertensive individuals may initially be at higher risk of developing more severe hypertension in comparison with their FH+ counterparts. This increased risk may be attributed to worsening of their lifestyle profiles over time. Healthy lifestyles should be emphasized to all hypertensive individuals including patients with favorable lifestyle profiles.