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BACKGROUND: The impact of high blood pressure (BP) on target organs (TO) in premenopausal women is not well known. The purpose of this study was to describe gender differences in TO involvement in a cohort of young-to-middle-aged subjects screened for stage 1 hypertension and followed for 8.2 years. METHODS: Participants were 175 women and 451 men with similar age (range 18-45 years). Ambulatory BP at entry was 127.5±12.5/83.7±7.2 mm Hg in women and 131.9±10.3/81.0±7.9 mm Hg in men. Ambulatory BP, albumin excretion rate (AER), and echocardiographic data (n=489) were obtained at entry, every 5 years, and before starting antihypertensive treatment. RESULTS: Female gender was an independent predictor of final AER (p=0.01) and left ventricular mass index (LVMI) (p<0.001). At follow-up end, both microalbuminuria (13.7% vs. 6.2%, p=0.002) and left ventricular hypertrophy (LVH) (26.4% vs. 8.8%, p<0.0001) were more common among women than men. In a multivariable Cox analysis, after adjusting for age, lifestyle factors, body mass, ambulatory BP, heart rate, and parental hypertension, female gender was a significant predictor of time to development of microalbuminuria (p=0.002), with a hazard ratio (HR) of 3.06, (95% confidence interval [CI] 1.48-6.34) and of LVH (p=0.004), with an HR of 2.50 (1.33-4.70). Inclusion of systolic and diastolic BP changes over time in the models only marginally affected these associations, with HRs of 3.13 (1.50-6.55) and 3.43 (1.75-6.70), respectively. CONCLUSIONS: These data indicate that premenopausal women have an increased risk of hypertensive TO damage (TOD) and raise the question about whether early antihypertensive treatment should be considered in these patients.

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We did a prospective study to investigate whether clinic heart rate (HR) and 24-h ambulatory HR were independent predictors of subsequent increase in body weight (BW) in young subjects screened for stage 1 hypertension. The study was conducted in 1,008 subjects from the Hypertension and Ambulatory Recording Venetia Study (HARVEST) followed for an average of 7 years. Ambulatory HR was obtained in 701 subjects. Data were adjusted for lifestyle factors and several confounders. During the follow-up BW increased by 2.1 ± 7.2 kg in the whole cohort. Both baseline clinic HR (P = 0.007) and 24-h HR (P = 0.013) were independent predictors of BMI at study end. In addition, changes in HR during the follow-up either measured in the clinic (P = 0.036) or with 24-h recording (P = 0.009) were independent associates of final BMI. In a multivariable Cox regression, baseline BMI (P < 0.001), male gender (P < 0.001), systolic blood pressure (BP) (P = 0.01), baseline clinic HR (P = 0.02), and follow-up changes in clinic HR (P < 0.001) were independent predictors of overweight (Ov) or obesity (Ob) at the end of the follow-up. Follow-up changes in ambulatory HR (P = 0.01) were also independent predictors of Ov or Ob. However, when both clinic and ambulatory HRs were included in the same Cox model, only baseline clinic HR and its change during the follow-up were independent predictors of outcome. In conclusion, baseline clinic HR and HR changes during the follow-up are independent predictors of BW gain in young persons screened for stage 1 hypertension suggesting that sympathetic nervous system activity may play a role in the development of Ob in hypertension.

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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.

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OBJECTIVE: Angiotensin II (Ang II) signaling via type 1 receptor (AT1R) has been extensively characterized, whereas Ang II signaling via type 2 receptors (AT2R), although counteracts actions mediated by AT1R, is still not completely understood. Bartter's/Gitelman's patients (BS/GS) have intrinsically blunted AT1R signaling, making them a good model to examine Ang II signaling via AT2R with particular emphasis on mitogen-activated protein kinase phosphatase 1 (MKP-1) that interacts with the Ang II-stimulated ERK pathway of cell signaling. METHODS: BS/GS and healthy controls fibroblasts AT1R and AT2R level and the time course of Ang II's effect on MKP-1 levels and ERK1/2 phosphorylation over 1-h time course were assessed by western blot. The time course of Ang II's effect on MKP-1 levels and ERK1/2 phosphorylation alone or in the presence of either PD123319, an AT2R blocker, or Losartan, an AT1R blocker, or in combination was characterized. RESULTS: AT1R and AT2R levels did not differ between BS/GS and healthy controls. Ang II induced ERK1/2 phosphorylation in BS/GS fibroblasts, but peak ERK1/2 phosphorylation declined more rapidly than that in control and BS/GS fibroblasts also exhibited increased MKP-1 levels at 30-min incubation. PD123319, an AT2R blocker in BS/GS fibroblasts, abolished the increased MKP-1 and ERK1/2 phosphorylation time course became same as that for control. Losartan, an AT1R blocker, alone altered the time course of control fibroblast MKP-1 to mimic the increase seen in BS/GS fibroblasts, whereas ERK1/2 declined concomitantly. Treatment with Losartan and PD123319 in controls reduced MKP-1 and elevated ERK1/2 phosphorylation to the level observed in BS/GS patients treated with PD123319. CONCLUSION: ERK1/2 phosphorylation time course found in BS/GS fibroblasts tracked changes in MKP-1 levels and incubation with an AT2R blocker, PD123319, abrogated those responses. Losartan, an AT1R blocker, reproduced these changes in healthy controls, whereas the presence of both AT1R and AT2R inhibitors in controls abolished these changes. These data strongly suggest that MKP-1 is a major effector in altering ERK1/2 phosphorylation status. Moreover, the results provide insight into the blunted responses in BS/GS reported for Ang II short-term and long-term effects, the mechanisms responsible, and thereby yield additional support for the role of AT2R signaling in the proposed effects of Ang II AT1R blockers beyond AT1R blockade.

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This is a short synopsis of the importance of nutrition and disease, which is especially centered on the achievements concerning renal diseases. With regard to renal nutrition, the paper analyzes the contributions of Beale, Peters and van Slyke, Addis, and Borst, and discusses the advent of the Giordano-Giovannetti diet and its modifications.

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BACKGROUND: The evolution of hypertension (HT) subtypes in young-to-middle-age subjects is unclear. METHODS: We did a prospective study in 1,141 participants aged 18-45 years from the HARVEST study screened for stage 1 HT, and 101 nonhypertensive subjects of control during a median follow-up of 72.9 months. RESULTS: At baseline, 13.8% of the subjects were classified as having isolated systolic HT (ISH), 24.8% as having isolated diastolic HT (IDH), and 61.4% as having systolic-diastolic HT (SDH). All hypertensive groups developed sustained HT (clinic blood pressure > or =140/90 mm Hg from two consecutive visits occurring at least after > or =6 months of observation) more frequently than nonhypertensive subjects (P < 0.001 for all) with adjusted odds ratio of 5.2 (95%CI 2.9-9.2) among the SDH subjects, 2.6 (95%CI 1.5-4.5) among the IDH subjects, and 2.2 (95%CI 1.2-4.5) among the ISH subjects. When the definition of HT was based on ambulatory blood pressure (mean daytime blood pressure > or =135/85 mm Hg, n = 798), odds ratios were 5.1 (95%CI 3.1-8.2), 5.6 (95%CI 3.2-9.8), and 3.3 (95%CI 1.7-6.3), respectively. In the fully adjusted logistic model, the risk of ambulatory HT was smaller for the ISH than the IDH (P = 0.049) or SDH (P = 0.053) individuals. CONCLUSIONS: The present results indicate that young-to-middle-age subjects with ISH have a smaller risk of developing ambulatory HT than either subjects with SDH or IDH. Whether antihypertensive treatment can be postponed for long periods of time in young subjects with mild elevations of clinic systolic BP and low global cardiovascular risk should be examined in further studies.

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OBJECTIVE: Whether heart rate predicts the development of sustained hypertension in individuals with hypertension is not well known. We carried out a prospective study to investigate whether clinic and ambulatory heart rates assessed at baseline and changes in clinic heart rate during 6 months of follow-up were independent predictors of subsequent blood pressure (BP). METHODS: The study was conducted in a cohort of 1103 white, stage 1 hypertensive individuals from the HARVEST study, never treated for hypertension and followed-up for an average of 6.4 years. Data were adjusted for baseline BP, age, sex, body fatness, physical activity habits, parental hypertension, duration of hypertension, cigarette smoking, alcohol consumption, and change of body weight from baseline. RESULTS: Clinic heart rate and heart rate changes during the first 6 months of follow-up were independent predictors of subsequent systolic blood pressure (SBP) and diastolic blood pressure (DBP) regardless of initial BP and other confounders (all P < 0.01). A significant interaction was found between sex (male) and baseline resting heart rate on final SBP (P = 0.017) and DBP (P < 0.001). The ambulatory heart rate and the heart rate white-coat effect did not add prognostic information to that provided by the clinic heart rate. Patients whose heart rate was persistently elevated during the study had a doubled fully adjusted risk (95% confidence interval 1.4-2.9) of developing sustained hypertension in comparison with subjects with a normal heart rate. CONCLUSIONS: Baseline clinic heart rate and heart rate changes during the first few months of follow-up are independent predictors of the development of sustained hypertension in young persons screened for stage 1 hypertension.

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The database of echocardiographic examinations performed during the military screening of 20,946 young men in northeastern Italy was systematically reviewed to assess the frequency, hemodynamic characteristics, and aortic sizes of subjects with bicuspid aortic valves (BAVs). One hundred sixty-seven patients with BAVs were identified (0.8%), of whom 80 (48%) were diagnosed de novo during military screening. Aortic insufficiency was the predominant hemodynamic lesion in 110 subjects (66%), mild in 90, and moderate to severe in 20. Patients with BAVs displayed larger aortic sizes than controls at each aortic level, and the degree of dilation was related to the presence but not the severity of aortic insufficiency.

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OBJECTIVE: Microalbuminuria (MA) is a marker of adverse outcome in hypertension. The aim of this study was to investigate the association of MA with cardiovascular risk factors and glomerular hyperfiltration in the early stage of hypertension and to assess its predictive value for the development of sustained hypertension requiring antihypertensive treatment. DESIGN AND PARTICIPANTS: We studied 1041 young stage 1 hypertensive subjects. Study variables were 24-h ambulatory blood pressure and heart rate, anthropometric measures, metabolic variables, creatinine clearance and lifestyle factors analyzed as a function of ascending urinary albumin measured from 24-h collections. Subjects were followed until they developed sustained hypertension and were eligible for antihypertensive medication according to current guidelines. SETTING: Seventeen outpatient clinics in Italy. RESULTS: Eighty-five percent of the subjects were normoalbuminuric, 9% had borderline MA, and 6% had overt MA. No between-group differences were found for age, body mass index, heart rate, lifestyle factors and biochemistry in both genders. Creatinine clearance was greater in the subjects with overt MA and borderline MA than in the normoalbuminuric subjects (P = 0.003 and 0.011, respectively). In a two-way ANCOVA, microalbuminuric subjects both with hyperfiltration (P < 0.001) and with normal filtration (P = 0.04) had higher 24-h systolic blood pressure than subjects with normoalbuminuria and normal filtration. In a Cox analysis, neither MA nor hyperfiltration were significant predictors of development of sustained hypertension. CONCLUSION: MA is not associated with an adverse metabolic risk profile in the early stage of hypertension. MA is associated with greater hemodynamic load and with glomerular hyperfiltration in this clinical setting, but does not help in predicting those subjects destined to develop sustained hypertension requiring antihypertensive therapy.

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The 825T allele of the GNB3 gene has been associated with essential hypertension and obesity in cross-sectional studies. We have therefore planned a longitudinal cohort study to assess whether the GNB3 825T allele is predictive of blood pressure increase in young subjects with grade I hypertension. We genotyped at the GNB3 825 locus 461 participants of the Hypertension and Ambulatory Recording Venetia Study (HARVEST) study (age, 18 to 45 years) at low cardiovascular risk, according to 1999 ISH/WHO criteria. The study end point was eligibility for antihypertensive medication, that is, progression to grade II hypertension during the first year of observation or office systolic blood pressure > or =150 mm Hg and/or office diastolic blood pressure > or =95 mm Hg in two later consecutive visits during follow-up. At baseline, there was no statistically significant difference among genotypes with respect to body mass index, blood pressure, and heart rate. During follow-up (mean, 4.7 years), 113 (51.1%) patients with CC genotype and 145 (60.4%) patients with TT/TC genotype reached the end point. According to survival analysis, the patients carrying the 825T allele had an increased risk of reaching the blood pressure end point (CI, 1.108 to 1.843; P=0.006). In young patients with grade I hypertension, the 825T allele is associated with increased risk of progression to more severe hypertension requiring antihypertensive therapy. The GNB3 825T allele may be considered a genetic marker of predisposition for hypertension.

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BACKGROUND: Hypertension occurs in some 10% of pregnancies and its effects on the left ventricular (LV) morphology and systolic function have been well elucidated. Little is known, however, about the changes in LV diastolic function in such a condition. The aim of this study was to evaluate the LV diastolic function in women with pregnancy-induced hypertension (PIH) using new Doppler echocardiographic methods. METHODS: Twenty-two women with PIH (mean age 31.0 +/- 4.1 years) were examined during the third trimester of pregnancy. Other 15 normotensive pregnant women (mean age 31.8 +/- 5.7 years, p = NS) were used as controls. Doppler parameters of diastolic function included: mitral inflow variables, pulmonary venous flow (PVF) variables, M-mode color Doppler of LV inflow and pulsed tissue Doppler of the mitral annulus. Furthermore, patients underwent an echocardiographic evaluation immediately after delivery and 1 month later. RESULTS: PIH women showed an increased E/A ratio and an increase in the diastolic forward components of PVF. The ratio of systolic to diastolic time-velocity integral and the systolic fraction of time-velocity integrals subsequently decreased. Women with PIH also presented a significantly increased velocity of reversal PVF at atrial contraction, a decrease in the ratio between mitral and PVF duration at atrial contraction and a slower flow propagation velocity with M-mode color Doppler. LV wall thickness and mass were significantly higher in hypertensive pregnant women. In women with PIH the abnormal PVF parameters became similar to those of controls immediately after delivery, while the E/A ratio, M-mode flow propagation velocity and LV mass did so after 1 month. CONCLUSIONS: Hypertension complicating pregnancy significantly affects ventricular diastolic filling. These alterations chiefly involve PVF, mitral inflow and intraventricular flow propagation velocities. The LV systolic function is preserved, in the presence of a transient LV remodeling.

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The question on whether menopause is an independent cardiovascular risk factor is still under debate. The results of four studies conducted by our staff in North East Italy, including > 11,000 subjects from the general population and covering a range of ages from 18 to 95 years, have been employed. We found apparently higher blood pressure (BP) values in naturally menopausal than in fertile women, but this difference disappeared after age-correction, or after identifying fertile and menopausal age-matched women. Significantly higher levels of serum lipids were also observed in menopausal than in fertile women but, in this case too, any difference disappeared after age-correction/matching. In a 16-year longitudinal analysis we found that BP increase and incidence of hypertension were the same in the women who remained fertile, in those becoming naturally menopausal and in those already menopausal at baseline; going through the menopause period, therefore, has no effect on BP. A mild and transitory BP increase was only observed during the climacterium. The BP increase during a follow-up and the incidence of new cases of hypertension were also similar in the women who remained fertile and in those who underwent bilateral ovariectomy, indicating no direct effect on BP for surgical menopause. In contrast, vectorial analysis demonstrated an excess increment of serum lipids among the women who underwent oophorectomy. In our populations, menopause had no predictive role and was rejected from the multivariate equations of risk, cardiovascular risk being completely explained by age and BP (both higher in menopausal then in fertile women).

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BACKGROUND: Elevated heart rate (HR) has been found to be related to an increased death rate in patients with acute myocardial infarction (AMI), but sex differences and optimal timing for HR measurement have not been sufficiently investigated. OBJECTIVES: To verify the predictive value of HR for one-year mortality in a cohort of subjects hospitalized for AMI, with men and women considered separately. PATIENTS AND METHODS: HR was measured in 424 patients (303 men and 121 women) with constant sinus HR, on the first, third and seventh days after hospital admission for AMI. Clinical and laboratory data were obtained on the same days. All patients were followed up for one year. RESULTS: Among the men, the one-year mortality rate was 5% for the subjects with a seven-day HR of less than 80 beats/min, and the one-year mortality rate was 39% for patients with a seven- day HR of 80 beats/min or more (P<0.0001). Among the women, the differences in mortality related to HR were not significant. In a multivariate Cox regression analysis, the relative risks of mortality in men who had an HR of 80 beats/min or more were 3.1 (CI=1.4 to 7.0, P=0.003) on the first day, 4.1 (CI=1.8 to 9.8, P=0.001) on the third day and 8.6 (CI=2.9 to 27.0, P<0.0001) on the seventh day. In the 203 men in whom echocardiographic left ventricular ejection fraction was measured, an interactive effect of high HR with depressed ejection fraction on mortality was found. Beta-blocking therapy influenced HR during AMI but did not influence the HR-mortality association. CONCLUSIONS: The results of the present prospective study show that HR measured during the first week after admission for AMI is an important predictor of mortality in men. The predictive power of HR increased from the first to the seventh day after AMI.

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