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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.

Objective: It is well established that adequate blood pressure (BP) control characterizes only a fraction of treated hypertensive patients. Few reports are available on BP control in relation to the cardiovascular risk profile in patients followed by specialist physicians., Methods: We evaluated the cardiovascular risk profile (according to recent ESH/ESC Guidelines), antihypertensive drug treatment and systolic and diastolic blood pressure values (SBP/DBP) by semi-automatic BP monitoring in 2775 hypertensive patients, aged 60.6 +/- 16.1 years (mean +/- SD), followed by 131 specialist centres in northern (34.5%), central (28.1%) and southern (37.4%) Italy. Of these patients, 94.6% received antihypertensive treatment with one (36.9%) or more (57.7%) drugs., Results: Optimal SBP and DBP control (< 140/90 mmHg) was shown by 37.5% of the patients, the rate of controlled values being much greater for DBP (64.4%) than for SBP (40.2%). About one-third of patients displayed BP values in the higher range (>/= 160/95 mmHg). No difference in BP control was found in relation to different geographic areas, patient's gender, occupational activity and attitude to the use of home blood pressure monitoring. BP control was inversely related to patient's age and directly related to educational level. It was more manifest in low- or medium-risk categories than in higher-risk patients (43.2 versus 34.9%). Follow-up visits performed after 6 and 12 months after patient enrollment have shown an improvement in blood pressure control (from 40.7 to 51.8%), related to therapeutic modifications and better compliance., Conclusions: These data provide evidence that BP control in different Italian geographic areas remains largely inadequate, particularly for SBP and high-risk patients. They also suggest that an improvement in treatment compliance may produce favourable therapeutic effects.

Manidipine is a third-generation dihydropyridine calcium antagonist, which causes systemic vasodilation by inhibiting the voltage-dependent calcium inward currents in smooth muscle cells. In clinical studies, manidipine has been shown to significantly lower office and 24-h blood pressure compared with placebo in patients with essential hypertension. The resulting reduction in blood pressure is maintained over 24 h, with preservation of the circadian blood pressure pattern; its blood pressure-lowering capacity appears to be similar to that of other calcium antagonists. In elderly patients with mild-to-moderate essential hypertension, manidipine is able to significantly decrease blood pressure compared with placebo for up to 3 years of treatment. The drug also significantly lowers blood pressure in patients with hypertension and concomitant Type 2 diabetes mellitus or renal impairment, and is devoid of adverse metabolic effects. It is well-tolerated with few untoward adverse effects related to vasodilation. In particular, manidipine appears to have less potential for pedal edema than other calcium channel blockers.

Orthostatic hypotension is associated with significant morbidity and mortality in elderly patients. In orthostatic hypotension caused by central and peripheral nervous system disorders (neurogenic orthostatic hypotension), the release of catecholamine in the standing posture is insufficient to compensate adequately for decreased venous return to the heart. Primary autonomic failure exhibits, often, supine hypertension, that can be worsened by pressor agents, such as midodrine, used to prevent syncope episodes. Salt-retaining steroid fludrocortisone, also, used to treat orthostatic hypotension, increases blood pressure both in supine and in standing position. We describe 3 patients with neurogenic orthostatic hypotension caused by pure autonomic failure. They complained of several syncope episodes. On examination, orthostatic hypotension and supine hypertension were detected in the absence of pharmacological therapy. All the patients presented hypertensive organ disease. Fludrocortisone acetate was started in one patient, and short-acting vasopressor agents during the day and dihydropyridine-calcium antagonist during the night in the other two. During the follow-up a transient ischemic attack occurred in the patient treated with fludrocortisone. When fludrocortisone was titrated down and short-acting antihypertensive drugs were started, the patient did not complain of any symptoms. Supine hypertension is part of pure autonomic failure, and short-acting antihypertensive agents should be associated with vasopressor agents to prevent hypertensive target organ disease.

Objective: Angiotensin II (Ang II)-mediated activation of Rho kinase (ROK) is involved in the pathophysiology of hypertension and cardiovascular remodeling. ROK also controls plasminogen activator inhibitor-1 (PAI-1) which promotes vascular fibrosis contributing to atherogenesis. Bartter's and Gitelman's syndromes (BS/GS) are useful models to investigate abnormalities of vascular tone regulation, due to their reduced short- and long-term signaling pathways of Ang II. This study evaluated, using BS/GS as a model, ROK and PAI-1 gene and protein expression and the effect of Ang II co-incubation on ROK and PAI-1 gene and protein expression., Design, Methods and Results: We measured ROK and PAI-1 gene and protein expression [reverse transcription-polymerase chain reaction (RT-PCR) and Western blot] in mononuclear cells (PBM) from one BS and eight GS patients. The effect of Ang II on ROK and PAI-1 gene and protein expression was also evaluated and compared with 10 controls. ROK gene and protein expression was reduced in BS/GS [0.47 +/- 0.11 densitometric units (d.u.) versus 0.70 +/- 0.04 d.u., P = 0.0038 and 0.39 +/- 0.07 d.u. versus 0.55 +/- 0.07 d.u., P = 0.0026, respectively]. The basal level of PAI-1 gene and protein expression did not differ (0.40 +/- 0.03 d.u. versus 0.39 +/- 0.02 d.u. and 0.81 +/- 0.02 d.u. versus 0.83 +/- 0.02 d.u., respectively). Ang II increased ROK and PAI-1 gene and protein expression only in controls: from 0.70 +/- 0.04 to 0.90 +/- 0.06 d.u., P = 0.007 (ROK mRNA); from 0.55 +/- 0.07 to 0.86 +/- 0.07 d.u., P = 0.0005 (ROK protein); from 0.40 +/- 0.02 to 0.63 +/- 0.03 d.u., P = 0.001 (PAI-1 mRNA); and from 0.83 +/- 0.02 to 1.34 +/- 0.16 d.u., P = 0.0023 (PAI-1 protein)., Conclusions: This study confirms BS/GS as a human model to investigate interrelated systems involved in the pathophysiology of hypertension and throws more light on the cellular mechanisms of BS/GS reduced Ang II short- and long-term signaling pathways.

Significant structural and functional changes in smooth muscle cells (SMCs) of microvessels (diameter 30 to 300 microm) occur in hypertension. However, in microvessels of hypertensive patients, the differentiation pattern of SMCs underlying such changes remains undefined. To analyze the differentiation pattern of SMCs (adult, postnatal, or fetal), 49 muscle biopsies (rectus abdominis) were analyzed: 16 from children (aged 11 months to 11 years), 15 from normotensive adults (aged 55 to 74 years), 18 from hypertensive adults (aged 55 to 74 years). Transverse cryosections of specimens were studied by immunocytochemistry using monoclonal antibodies SM-E7 and NM-F6, which recognize smooth muscle myosin heavy chain (MyHC) and A(pla1)-like nonmuscle MyHC, respectively. The total number of microvessels was assessed via SM-E7 staining. The number of NM-F6 positive (fetal-type SMC) or negative (adult-type SMC) microvessels was assessed. The number of microvessels per area unit was considerably lower (P<0.0005) in normotensive adults (0.22+/-0.17) than in children (0.98+/-0.61). Even more significant reduction was found in hypertensive adults compared with control adults (P=0.013) and children (P<0.0005). The qualitative immunocytochemistry analysis by NM-F6 revealed 2 differentiation patterns of the media layer of microvessels: positive or negative. In hypertensive subjects, the percentage of microvessels positive to NM-F6 was 49.8+/-35.6%, close to that found in children (50.6+/-12.6%), whereas in normotensive subjects it was significantly lower (24.4+/-21.1%). The following conclusions were drawn. (1) The medial layer of microvessels is heterogeneous in terms of SMC differentiation. (2) In hypertension, a prevalence of fetal-type SMCs takes place in microvessels, resembling that of children. Compared with children, a rarefaction of microvessels is present in normotensive adults that is even more remarkable in hypertensive adults.

Hypertension and hypercholesterolemia are frequently associated, and their treatment is proven to reduce cardiovascular risk. Current guidelines on cardiovascular prevention strongly recommend treating both disorders. Unfortunately, the low treatment and control rates, combined with the high prevalence of both conditions, still contribute to the high burden of cardiovascular disease in Western countries. In the past 5 years, many studies evaluating the benefit of combined antihypertensive and lipid-lowering treatment on endothelial dysfunction, coronary atherosclerosis, hypertension control, and on primary and secondary prevention of cardiovascular events have been published. In this article, we discuss and critically evaluate the available evidence on the potential benefits of combined antihypertensive and lipid-lowering treatment.

Regulator of G protein signaling-2 (RGS-2) plays a key role in the G protein-coupled receptor (GPCR) angiotensin II (Ang II) signaling. NO and cGMP exert a vasodilating action also through activation and binding to RGS-2 of cGMP dependent protein kinase 1-alpha, which phosphorylates RGS-2 and dephosphorylates myosin light chain. In Bartter's/Gitelman's patients (BS/GS) Ang II related signaling and vasomotor tone are blunted. Experiments were planned to explore whether RGS-2 may play a role in BS/GS vascular hyporeactivity. NO metabolites and cGMP urinary excretion were also measured. Mononuclear cells (PBM) from six BS/GS patients and six healthy controls were used. PBM RGS-2 mRNA and RGS-2 protein were increased in BS/GS: 0.47 +/- 0.06 d.u. vs 0.32 +/- 0.04, (p < 0.006) (RGS-2 mRNA), and 0.692 +/- 0.02 vs 0.363 +/- 0.06 (p < 0.0001) (RGS2 protein). Incubation of PBM with Ang II increased RGS-2 protein in controls (from 0.363 +/- 0.06 d.u. to 0.602 +/- 0.05; p < 0.0001) but not in BS/GS (from 0.692 +/- 0.02 to 0.711 +/- 0.02). NO(2)(-)/NO(3)(-) and cGMP urinary excretion were increased in BS/GS (0.46 +/- 0.13 vs 0.26 +/- 0.05 micromol/micromol of urinary creatinine, p < 0.005, and 0.060 +/- 0.030 vs 0.020 +/- 0.01 p < 0.009, respectively). These results demonstrate that RGS-2 is increased and maximally stimulated in BS/GS and human RGS-2 system reacts as predicted by knockout mice experiments. This is the first report of RGS-2 level in a human clinical condition characterized by altered vascular tone, underlines the importance of RGS-2 as a key regulator element for Ang II signaling and provides insight into the links between BS/GS genetic abnormalities and abnormal vascular tone regulation.

Little is known about the clinical significance of isolated ambulatory hypertension, a condition characterized by low office but elevated ambulatory blood pressure. This study aimed to investigate the prevalence and the predictive value of isolated ambulatory hypertension diagnosed after 3 months of observation for the development of sustained hypertension within a cohort of 871 never-treated stage-1 hypertensive subjects. The study end point was progression to more severe hypertension and need of antihypertensive medication. In 244 subjects (28%), clinic blood pressure declined to <140/90 mm Hg after 3 months. Of these, 124 (14.2% of total) had low clinic and ambulatory blood pressures after 3 months (nonhypertensive subjects), whereas 120 subjects (13.8% of total) showed low clinic but elevated ambulatory blood pressure (isolated ambulatory hypertension). During the 6 years of observation, the number of end points based on multiple clinic blood pressure readings progressively increased from the nonhypertensive subjects (19%) to the subjects with isolated ambulatory hypertension (35%) and to the subjects with high clinic and high ambulatory blood pressures (65%, P<0.0001). In an adjusted proportional hazard model, isolated ambulatory hypertension status was associated with a 2.2 (P=0.02) increase in the risk of reaching the end point in comparison with the nonhypertensive subjects. Final ambulatory systolic blood pressure was also higher in the former than the latter (P=0.03). Our results indicate that among subjects screened for stage 1 hypertension, individuals with isolated ambulatory hypertension after 3 months of observation have increased risk of developing sustained hypertension in later life compared with subjects in whom both clinic and ambulatory blood pressures are normal.

Background: Studies in experimental animals and human cells have demonstrated increased intracellular calcium (Ca(i2) signalling and Galphai signal transduction associated with hypertension. We have recently shown that angiotensin II-induced mobilization of Ca(i2) is enhanced in fibroblasts from hypertensive individuals in comparison with that in normotensive individuals and that it is blunted by insulin and pertussis toxin in insulin-sensitive, but not in insulin-resistant, patients. This suggests that G(i)-mediated signal transduction is reduced in insulin-resistant hypertension., Objective: To investigate the expression and regulation of Galpha(i2) subunit in insulin-sensitive and insulin-resistant hypertensive individuals., Methods: G protein alpha(i2) subunit mRNA was measured in cultured skin fibroblasts from patients with insulin-sensitive and insulin-resistant hypertension, by real-time reverse transcriptase polymerase chain reaction. We also investigated the effects of short-term exposure to fetal calf serum, angiotensin II and insulin, alone and in combination, on the expression of Galpha(i2) in vitro. Spectrofluorophotometric measurement of free Cai was performed in monolayers of 24 h serum-deprived cells in basal conditions and after exposure to angiotensin II, with and without pre-incubation with insulin., Results: Expression of Galpha(i2) was significantly greater in fibroblasts from hypertensive individuals than in normotensive individuals and the increase was unrelated to age and body mass. The difference was largely accounted for by greater values in insulin-sensitive than in insulin-resistant hypertensive individuals. In fibroblasts from those with insulin-sensitive hypertension, angiotensin II and insulin were additive to fetal calf serum in increasing the expression of Galpha(i2). In these patients, insulin blunted the angiotensin-II induced Cai transient. In contrast, in those with insulin-resistant hypertension, Galpha(i2) was lower and unresponsive to angiotensin II and insulin. Finally, in fibroblasts from insulin-resistant patients, insulin was unable to reduce the angiotensin II-induced Cai peak., Conclusions: A subnormal Galpha(i2)-mediated signal transduction may be involved in the pathogenesis of cellular insulin resistance in hypertension. This novel Galpha(i2)-mediated signal transduction associated with insulin sensitivity in fibroblasts may help to control excessive angiotensin II signalling.

Objective: Whether blood pressure (BP) measured at the wrist differs from blood pressure measured at the arm is not well known. The aim of this study was to compare the BP readings obtained at the arm with those obtained at the forearm and to assess whether the wrist-arm discrepancies were related to subjects' clinical characteristics., Methods: We measured blood pressure at the forearm and at the upper arm in 85 subjects using conventional sphygmomanometry. Wrist-arm blood pressure discrepancies were assessed in relation to gender, age, body mass index, skin-fold thickness, arm size, blood pressure level, and arterial compliance measured with the HDI/Pulsewave CR-2000., Results: Blood pressure measured at the wrist consistently overestimated blood pressure taken at the arm with a mean (+/-SD) discrepancy of 8.2 +/- 9.7/9.2 +/- 6.4 mmHg. The systolic blood pressure differences were greater in men than in women (p=0.006) and, among the men, varied according to arm adiposity (positive association, p=0.01). In men, diastolic blood pressure differences correlated with diastolic blood pressure level (negative association, p=0.01). Among the women, only age (p=0.04) was a significant positive independent predictor of the wrist-arm diastolic BP differences., Conclusions: These results indicate that forearm blood pressure measurement markedly overestimates upper arm blood pressure and that the between-site difference may vary from subject to subject. Wrist blood pressure measurement is not a valid alternative to traditional measurement at the arm and its use should be discouraged.

Oxidative stress (OxSt) is a major damaging factor in arterial hypertension and its long-term complications. This is why considerable attention is paid to the possible effects of antihypertensive drugs on OxSt. Manidipine is a dihydropiridine calcium channel blocker with reported nephroprotective activities, but no information is available on its effect on OxSt and related mechanisms. This study assessed the effect of manidipine on normal subjects' monocyte gene and protein expression of OxSt-related proteins such as p22(phox), a NAD(P)H oxidase system subunit, critical in generating O2-, and heme oxygenase-1 (HO-1), induced by and protective from OxSt, and compared manidipine with the ACE inhibitor captopril and the calcium channel blocker nifedipine, in the presence and absence of sodium arsenite (NaAsO2) as an inducer of OxSt.Co-incubation of manidipine with NaAsO2 dose-dependently decreased p22(phox) mRNA production from basal: 0.87 +/- 0.1 d.u., 0.69 +/- 0.06 and 0.66 +/- 0.09 at 100, 300 and 500 nM respectively versus 0.99 +/- 0.2, P < 0.04, while HO-1 mRNA production was increased by the same concentrations of the drug: 0.87 +/- 0.1 d.u., 0.92 +/- 0.1, 0.98 +/- 0.1 respectively versus 0.63 +/- 0.07; P < 0.03. Monocyte p22(phox) mRNA production was reduced both by manidipine and captopril: 0.48 +/- 0.04 d.u. and 0.43 +/- 0.08, respectively versus 0.58 +/- 0.07, P < 0.006, while no changes were induced by nifedipine (0.61 +/- 0.07, P = ns). Manidipine increased monocyte HO-1 mRNA production (1.6 +/- 0.4 versus 1.2 +/- 0.4, P < 0.008), while nifedipine and captopril showed no effect (1.2 +/- 0.3 and 1.1 +/- 0.3, respectively). The effects of M on p22(phox) and HO-1 gene expression in the presence of OxSt were also paralleled by the same effects at protein level. In conclusion, manidipine decreases p22(phox) and increases HO-1 mRNA production and protein level. The manidipine-induced increase of HO-1 gene and protein expression seems to be a peculiar effect of this drug since it is not observed with captopril and nifedipine. This effect, together with the reduction of p22(phox) mRNA production, could play a role in its protective mechanism against OxSt.

It has been suggested that the insertion(I) allele of the I/deletion(D) polymorphism of the angiotensin converting enzyme (ACE) gene is associated with endurance exercise and increased physical conditioning in response to this type of exercise. To investigate the association between the ACE I/D polymorphism and physical activity status in 355 never treated, stage I hypertensives (265 men, 90 women, mean age: 33 +/- 9 years), in whom power exercise is contraindicated, participants of the HARVEST study. Physical activity was assessed using a standardized questionnaire. BMI and age did not vary among genotypes. None of active subjects performed power oriented exercises. ACE I/D frequencies (II-18%, ID-55%, DD-27%) were in Hardy-Weinberg equilibrium. Sedentary lifestyle was more common among DD than II hypertensives (76% in DD, and 48% in II, Chi(2) = 13.9, P = 0.001). In stepwise MANOVA using age, marital status, profession, sex, and ACE genotype as predictors of physical activity, marital status (F = 24.4, P < 0.0001) and ACE genotype (F = 16.03, P < 0.0001) contributed to more than 50% of the variance in physical activity status of the population. Our results suggest that the ACE I/D polymorphism may be a specific genetic factor associated with physical activity levels in free-living borderline and mild hypertensive subjects., (Copyright 2003 Wiley-Liss, Inc.)

Objectives: To assess the proportion of high-risk coronary artery disease (CAD) patients who received lipid lowering drug treatment (LLDT) and met the LDL-Cholesterol (LDL-C) goal of 100 mg/dl defined by the third report of the U.S. National Cholesterol Education Program (NCEP)., Methods: In 86% (n = 1095) of the 1268 consecutive Italian patients, who were enrolled in the GENICA study after undergoing quantitative coronary angiography for suspected coronary artery disease between 1999 and 2001, the levels of total serum cholesterol, HDL-cholesterol, triglycerides, and LDL-C were measured and accurate information on current LLDT were available. All patients were classified according to the NCEP., Results: Seventy-four percent of the patients (n = 805) had established CAD and cardiovascular events and therefore were candidates for secondary prevention with LLDT; 69% of them had concomitant hyperlipidemia. Only 57% of the patients with CAD and hyperlipidemia were on LLDT. Of the 1052 patients who were at the highest risk class according to NCEP, only 34.2% and 16.7% were on LLDT and reached the LDL-C goal, respectively., Conclusions: Only 1 patient of 6 in the highest-risk class according to the NCEP accomplished the LDL-C goal. Accordingly, in the field of secondary prevention of coronary artery disease, the implementation of guidelines that emerged from scientific evidence into clinical practice with LLDT still requires major efforts.

Objective: To evaluate, at a population level, whether total cholesterol (TC) is a risk factor of mortality. To verify whether or not this is true for both genders., Design: Population-based, long-lasting, prospective study., Setting: Institutional epidemiology in primary care., Subjects: A total of 3257 subjects aged 65-95 years, recruited from Italian general population., Intervention: None., Main Outcome Measures: Total cholesterol was measured, analysed as a continuous variable and then divided into quintiles and re-analysed. For each quintile, the multivariate relative risk (RR) of mortality adjusted for confounders was calculated in both genders. Stratification of mortality risk by TC quintiles, body mass index and cigarette smoking was also performed in both genders., Results: Total cholesterol levels directly predicted coronary mortality in men [RR being in the fifth rather than in the first quintile: 2.40 (1.40-4.14)] and any other mortality in women. It also inversely predicted miscellaneous mortality in both genders. This trend was more evident when low cholesterol was associated with malnutrition or smoking., Conclusions: High TC remains a strong risk factor for coronary mortality in elderly men. On the other hand, having a very low cholesterol level does not prolong survival in the elderly; on the contrary, low cholesterol predicts neoplastic mortality in women and any other noncardiovascular mortality in both genders.

Objectives: We investigated the association of polymorphisms in the promoter region and exon 7 endothelial nitric oxide synthase (eNOS) gene with coronary artery disease (CAD)., Background: Endothelial dysfunction foretells cardiovascular events and can be genetically determined., Methods: We genotyped for the promoter (T(-786)C) and exon 7 (Glu298Asp, G(894)T) polymorphisms in 1,225 subjects; 1,106 were consecutive patients undergoing coronary angiography and 119 control subjects without any cardiovascular risk factors. Genotyping was performed with melting curve analysis of polymerase chain reaction products from allele-specific acceptor and donor probes that were 5'- and 3'-end labeled with LCRed640 and fluorescein, respectively; CAD was assessed by quantitative coronary angiography. We performed multiple logistic regression analysis for the effect of the T(-786)C, the missense Glu298Asp variant, and other coronary risk factors on two- and three-vessel CAD., Results: The overall genotype distribution of T(-786)C (CC = 17.7%, CT = 40.4%, and TT = 41.9%) and Glu298Asp (GG = 43.3%, GT = 37.0%, and TT = 19.7%) was consistent with the Hardy-Weinberg equilibrium. The regression analysis showed that the T(-786)C, but not the missense Glu298Asp variant, significantly predicted CAD, independent of other risk factors. Compared with TT homozygous, subjects carrying the C allele had a significant (p = 0.002) increase in the odds ratio of harboring two- or three-vessel CAD of 1.672 (95% confidence interval, 1.062 to 2.527). A subgroup analysis confirmed this effect of the T(-786)C polymorphism in men (p = 0.007), cigarette smokers (p = 0.001), subjects older than 60 years of age (p = 0.007), with hypercholesterolemia (p = 0.011), low high-density lipoprotein cholesterol (p = 0.006), and overweight or with obesity (p = 0.041)., Conclusions: The C allele at the T(-786)C endothelial nitric oxide synthase polymorphism is associated with a higher risk of multivessel CAD in Caucasians.

Objectives: We sought to investigate whether two polymorphisms located in the promoter (T(-786)C) and exon 7 (Glu298Asp) of the endothelial nitric oxide (NO) synthase (eNOS) gene affected agonists-mediated NO release., Background: Endothelial dysfunction can be genetically determined. Therefore, we investigated whether two polymorphisms located in the eNOS gene affected agonists-mediated NO release., Methods: We compared endothelial-dependent and -independent vasodilation of the different eNOS genotypes in a cross-sectional study on 187 subjects, of whom 137 were uncomplicated essential hypertensive patients (PH) (49 +/- 9 years, 151 +/- 11/99 +/- 5 mm Hg) and 50 healthy normotensive subjects (NT) (43 +/- 16 years, 123 +/- 10/78 +/- 7 mm Hg). Endothelial-dependent and -independent vasodilation was assessed as the forearm blood flow response to incrementally increasing doses of acetylcholine (0.15, 0.45, 1.5, 4.5, 15 microg/100 ml/min) and sodium nitroprusside (1, 2, 4 microg/100 ml/min), respectively. Genotyping was performed with melting curve analysis (Lightcycler) of polymerase chain reaction products from acceptor (5' end-labeled with LCRed 640) and donor probes (3' end-labeled with fluorescein) specific for each polymorphism. The genotype distribution of T(-786)C (CC = 21.9%, CT = 48.7%, TT = 29.4%) and Glu298Asp (GG = 39.0%, GT =51.9%, TT = 9.1%) was similar in PH and NT. A repeated measure analysis of variance showed a blunting of endothelium-dependent vasodilation in PH compared with NT (p < 0.001). A significant effect of the T(-786)C (p = 0.002) but not of the Glu298Asp (p = NS) eNOS polymorphism on endothelial-dependent vasodilation was found. However, we also detected a significant interaction between the T(-786)C and Glu298Asp polymorphism (p < 0.001). No effect on either polymorphism on endothelial-independent vasodilation was seen., Conclusions: The T(-786)C promoter polymorphism and its interaction with exon 7 Glu298Asp affect endothelium-dependent vasodilation in mild-to-moderate PH patients and NT Caucasian subjects.

Objectives: We investigated if endothelin (ET)-1 and the renin-angiotensin-aldosterone system play a role in cardiac fibrosis., Background: Angiotensin II (Ang II) can induce cardiac fibrosis, but the underlying mechanisms are incompletely understood., Methods: Four-week-old transgenic (mRen2)27 rat (TGRen2) received for four weeks a placebo, the mixed ET(A)/ET(B) endothelin receptor antagonist bosentan, the angiotensin II type I receptor (AT-1) antagonist irbesartan, the ET(A) endothelin receptor antagonist BMS-182874, and a combined treatment with irbesartan plus BMS-182874. We measured collagen density on Sirius red-stained serial sections of the left ventricle (LV) with a photomicroscope equipped with specific software and assessed the gene expression of procollagen alpha1(I), atrial natriuretic peptide (ANP), transforming growth factor-beta 1 (TGFbeta1), endothelin converting enzyme, and ET(B) receptor., Results: In the placebo group, hypertension was associated with LV hypertrophy and cardiac fibrosis (LV weight: 4.0 +/- 0.3 mg/g body weight; collagen density: 2.21 +/- 0.16%), which were all prevented with irbesartan (2.3 +/- 0.1, 1.30 +/- 0.13, p < 0.001), but not with BMS-182874 (4.0 +/- 0.2, 2.41 +/- 0.22). Bosentan also prevented fibrosis (1.39 +/- 0.18) but not hypertension and LV hypertrophy (3.38 +/- 0.27). Combined irbesartan and BMS-182874 treatment prevented LV hypertrophy (2.9 +/- 0.1) but not fibrosis (2.52 +/- 0.16). Collagen density correlated (r = 0.414, p < 0.05) with plasma aldosterone levels. In TGRen2 with LV hypertrophy, the gene expression of ANP and ET(B) but not that of TGFbeta1 and procollagen alpha1(I) was increased., Conclusions: In Ang II-dependent hypertension, cardiac fibrosis was associated with LV hypertrophy and was hindered by both mixed ET(A)/ET(B) blockade and AT-1 blockade. Only the latter treatment prevented both hypertension and LV hypertrophy. Thus, there is a dissociation between the mechanisms of cardiac fibrosis and hypertension, which do and do not entail ET-1, respectively.

Background: In acute ischemic stroke, a transient blood pressure (BP) elevation is common, but the best management is still unknown. Therefore, we investigated retrospectively the relationship between BP after ischemic stroke and neurological outcome (evaluated by means of the National Institutes of Health Stroke Scale score at day 7)., Methods: The medical records of 92 consecutive patients with acute ischemic stroke, aged 47 to 96 years, were examined. Blood pressure was measured on admission, 4 times during the first 24 hours, 3 times daily for the first 4 days, and twice daily on day 7 (or at discharge). Antihypertensive treatment was given according to American Heart Association guidelines., Results: The region damaged by the stroke was total anterior in 16 patients (17%), partial anterior in 30 (33%), lacunar in 34 (37%), and posterior circulation in 12 (13%). Stroke pathogenesis was cardioembolic in 28 (30%), atherothrombotic in 29 (32%), and lacunar in 34 (37%). The systolic BP range was 140 to 220 mm Hg; diastolic BP, 70 to 110 mm Hg. Initial BP was higher in the group with lacunar infarction than in the other groups (P<.05). The patients with the best outcome had the highest BP during the first 24 hours. The neurological outcome was strongly influenced by baseline stroke severity (NIH Scale score) and admission BP. Better initial neurological conditions and higher initial BP resulted in better neurological outcomes., Conclusions: The outcome of stroke is influenced by the type of stroke and initial BP. Lacunar stroke and the highest BP on admission carry the best prognosis, whereas the reverse is true for posterior circulation infarction and low BP. We found no evidence that, within the present BP range, hypertension is harmful and that its lowering is beneficial.

Background: Endothelin (ET)-1 contributes to raising blood pressure (BP) and inducing cardiovascular disease by vasoconstriction and potent stimulation of aldosterone secretion. In the rat this latter effect occurs via ET(B) receptors; in humans in vitro studies implicated both ET(A) and ET(B) receptors, but there is no conclusive evidence in vivo., Methods: We recruited 13 consenting hypertensive patients: six with primary aldosteronism (PA) and seven with high-to-normal renin hypertension (HNRH). They were infused with a low dose (200 nmol/min for 5 min followed by 100 nmol/min for 10 min) of the ET(A)-selective antagonist BQ-123 either alone or, on a different day, together with an identical dose of the ET(B)-selective antagonist BQ-788. Plasma aldosterone, cortisol and ACTH concentration and plasma renin activity (PRA) were measured with radioimmunoassay at -15, 0, 30, 60, 120, 240, 360 min, while BP was recorded non-invasively., Results: BQ-123 alone and combined with BQ-788 significantly lowered mean BP in both PA and HNRH patients (by 6-10 mmHg at nadir; P<0.01). In PA patients, a short-lived decrease of aldosterone was elicited by combined BQ-123 and BQ-788 (-14%; P<0.05), but not by BQ-123 alone; cortisol, ACTH, and PRA were unaffected by either treatment. In HNRH patients, BQ-123 both alone and combined with BQ-788 lowered aldosterone (-39 and -28%, respectively) and PRA (-43 and -16%, respectively), while cortisol and ACTH were unaffected., Conclusions: Endogenous ET-1 contributes to maintaining the high BP values and the aldosterone secretion in both PA and HNRH patients. In the former patients, the aldosterone secretagogue effect of ET-1 is mediated via ET(B) receptors, while in the latter it occurs mainly via ET(A)-mediated stimulation of renin production.

Background: The aim of this study was to evaluate at a population level whether hypertension is a risk factor for cardiovascular mortality and to verify whether or not this is true for both genders at any age., Methods: This population-based, long-lasting, prospective study includes a 14-year mortality (institutional epidemiology in primary care). Unselected, unbiased subjects (5185) aged 22 to 95 years were recruited from the Italian general population, and divided into normotensive (<140 mm Hg systolic blood pressure [BP] and <90 mm Hg diastolic BP and untreated) and hypertensive groups. The main aim was to identify the significant predictors of mortality due to stroke, coronary artery disease, heart failure, and pulmonary embolism, and to quantify the age-adjusted relative risk of hypertension in men and women, at different age classes (<70, 70 to 79, >or =80 years) for each mortality cause. The analysis was repeated among 1091 normotensive and 1091 hypertensive age-matched subjects to clean statistics from the effects of age., Results: There were 846 cardiovascular deaths, 178 due to stroke, 273 to coronary disease, 351 to heart failure, and 44 to pulmonary embolism. Hypertension predicted stroke mortality, but not that due to other causes. This prediction was only significant in women, not in men. No prediction was possible after the age of 80 years. Age-matching increased the significance level of stroke mortality prediction in women aged <80 years; in these women, systolic BP predicted stroke mortality directly and diastolic inversely. CONCLUSIONS; In this population, hypertension predicted only stroke mortality in women aged <80 years. High systolic and low diastolic BP were predictive of stroke mortality, confirming a prognostic role for high pulse pressure.

Background: Irrespective of their clinical relevance, side effects cannot be considered a negligible problem in antihypertensive therapy. The aim of this trial was to evaluate the tolerability profile of lercanidipine with that of two other calcium antagonists (amlodipine and lacidipine) in elderly hypertensives., Methods: In a multicenter, double-blind, parallel study 828 elderly (aged > or =60 years) hypertensives were randomized to lercanidipine 10 mg/day (n = 420), amlodipine 5 mg/day (n = 200), or lacidipine 2 mg/day (n = 208) (ratio 2:1:1). If blood pressure (BP) control was unsatisfactory (systolic BP/diastolic BP > or =140/90 mm Hg), the dose of the double-blind medication was doubled and, as a further step, enalapril or atenolol (plus diuretic, if needed) was added. Patients were treated for an average of 12 months., Results: Amlodipine patients had significantly (P <.001) higher rates of edema (19%) and of early study discontinuations due to edema (8.5%) compared with lercanidipine (9% and 2.1%) and lacidipine patients (4% and 1.4%). Similarly, edema-related symptoms (lower limb swelling and heaviness) occurred significantly (P <.01) more often with amlodipine (50% and 45%, respectively) than with lercanidipine (35% and 33%) and lacidipine (34% and 31%). Most edema cases occurred in the first 6 months, a between-treatment difference being evident since beginning of treatment. Other drug-related adverse events did not differ between treatments. Blood pressure was equally and effectively reduced in the three groups., Conclusions: The two lipophilic dihydropyridine calcium antagonists, lercanidipine and lacidipine, have an antihypertensive effect comparable to that of amlodipine, but a better tolerability profile.

Objective: We investigated the potential association between -514 C-->T polymorphism in the promoter of the hepatic lipase gene (LIPC) and the prevalence of inflammatory cells in the plaque of patients with severe carotid artery stenosis., Background: This common LIPC polymorphism has been related to the presence of an atherogenic lipoprotein pattern., Methods: We studied 68 consecutive patients undergoing carotid endarterectomy. The LIPC genotype was determined by polymerase chain reaction. Endarterectomy specimens were examined by immunocytochemistry using monoclonal antibodies for smooth muscle cells, macrophages, or lymphocytes., Results: In 50 of 68 patients who had evidence of previous ipsilateral ischemic events, 36 (72%) were carriers of the CC genotype, whereas only 14 (28%) were carriers of the CT/TT genotype (p = 0.002). Among the 18 patients without evidence of events, the two genotypes were equally distributed (9 vs. 9). The low-density lipoprotein (LDL) particles were denser in CC than in CT/TT genotype carriers (flotation rate: 0.315 +/- 0.025 vs. 0.356 +/- 0.019, p < 0.0005). The CC genotype was associated with an abundance of macrophages (6.7 +/- 3.5 vs. 2.1 +/- 2.1 cells/area unit in the CT/TT group, p < 0.0005) and a reduced number of smooth muscle cells (6.9 +/- 6.2 vs. 14.5 +/- 6.4 in the CT/TT group, p < 0.0005) in the plaque. An inverse relationship was found between LDL buoyancy and the number of macrophages in the plaque (r = -0.639, p < 0.0005)., Conclusion: We provide evidence, for the first time, that LIPC promoter -514 C-->T polymorphism, by modulating LDL density, significantly affects the number of macrophages in the plaque and possibly affects the occurrence of cerebrovascular events in patients with carotid artery stenosis.

The aim of this work was to evaluate whether pulse pressure (PP) in elderly people is a better predictor of coronary mortality than systolic and diastolic blood pressure taken alone. For this aim, 3282 elderly subjects aged >or=65 years were studied in a population-based frame. Blood pressure was repeatedly measured and averaged; historical data, anthropometrics, blood tests and 14-year coronary mortality were recorded. Statistics included analysis of covariance, Cox analysis and bivariate vectorial analysis. Coronary mortality in women was predicted by PP (1.01 excess risk/mm Hg PP) and was significantly higher in the 3rd than in the 1st tertile of PP (relative risk 2.90); neither systolic nor diastolic pressure taken alone influenced mortality. When systolic and diastolic pressures were both entered into a Cox model, the former had a positive and the latter a negative effect on survival, confirming a prognostic role of PP. For any given level of systolic pressure, mortality was inversely associated with diastolic pressure. Finally, the mean vector representing both systolic and diastolic pressures of non-surviving women was characterised by higher systolic and lower diastolic components than in non-surviving. No significant trend of mortality in relation to either systolic blood pressure or PP was observed in men. In conclusion, the combination of systolic and diastolic pressure called PP is an independent predictor of coronary mortality in elderly females, and a better predictor than systolic or diastolic pressure alone.

Background: We investigated the effect of nifedipine, AT-1 and ET-1 receptor blockade on arterial smooth muscle cell phenotypes and collagen deposition in TGRen2 transgenic rat (TGR)., Methods: Four-week-old TGR were blood pressure (BP)-matched and allocated to receive a placebo (n=8), the calcium antagonist nifedipine (n=6), the AT-1 specific receptor antagonist irbesartan (n=6), the ET(A)/ET(B) antagonist bosentan (n=6) or the ET(A)-selective antagonist BMS-182874 (n=5). Sprague-Dawley normotensive rats served as controls (n=6). After 4 weeks of treatment animals were euthanized and the left ventricle (LV) and the structural changes in intracardiac arterioles and aorta were assessed histomorphometrically. Smooth muscle cell phenotypes and fibrillar collagen content of the aortic wall were evaluated by immunostaining, using differentiation markers-specific antibodies and Syrius red staining, respectively. The changes in ET(A) and ET(B) receptor density were also assessed with quantitative autoradiography., Results: Compared to placebo, only irbesartan lowered BP (P<0.001) and prevented LV and small resistance artery hypertrophy. The aorta of placebo-treated TGR showed an increase in foetal-type smooth muscle cell content and fibrillar collagen staining, compared to controls. These changes were blunted by irbesartan, which increased ET(A) receptors in the arterial wall, enhanced by BMS-182874 and unaffected by bosentan. Nifedipine also blunted both the VSMC and collagen changes despite having no effect on BP and ET(A) receptors., Conclusions: In TGRen2, vascular hypertrophy entails both smooth muscle cell phenotypic modulation and collagen deposition. These alterations do not follow closely the BP changes and seem to imply the dihydropyridine-sensitive calcium channels.

In a population-based study, three groups of individuals were examined: 334 hypertensive subjects (group 1) received 7 years of intervention therapy by a Hypertension Team (HyT); 418 subjects (group 2) were simply observed with blood pressure (BP) measurement on demand and given lifestyle advice; and 437 subjects (group 3) had no contact with HyT. Hypertension intervention therapy was then withdrawn, leaving patients to their general practitioners. After phase A, BP was significantly lower than baseline in group 1 (-14.2%, P < .01) and group 2 (-12.4%, P < .01), whereas it was unchanged in group 3. Cerebrovascular (but not coronary) events were observed less in group 1 (fatal 2.7%, nonfatal 3.7%) than in group 2 (7.2% and 5.2%, respectively, both P < .001 v group 1) or group 3 (8.3% and 6.9%, respectively, both P < .001 v group 1). During a further 7 years of observation (phase B), no between-group differences in mortality were observed. We conclude that simple observation improves BP control, but that intervention is needed to reduce the incidence of stroke.

Objective: To investigate the effects of the dual angiotensin-converting enzyme (ACE) + neutral endopeptidase (NEP) inhibitor, MDL-100,240 (MDL), on hypertension and cardiovascular damage in male heterozygous transgenic Ren2 rats., Methods: Blood-pressure-matched 5-week-old transgenic rats were allocated to receive a placebo, MDL (40 mg/kg body weight) or ramipril (5 mg/kg body weight) for 8 weeks. During the last 4 weeks, the bradykinin B2 receptor antagonist, icatibant (0.5 mg/kg body weight), was also administered subcutaneously via osmotic minipumps to 50% of the transgenic rats receiving MDL or ramipril. We measured blood pressure, heart weight, structural changes in the aorta and small resistance mesenteric arteries, and the plasma concentrations of adrenomedullin, aldosterone, atrial natriuretic peptide and cGMP. To verify if MDL could regress long-standing hypertension and full-blown cardiovascular damage, 3-month-old transgenic rats received MDL subcutaneously (3 and 10 mg/kg body weight, osmotic minipumps) for 4 weeks., Results: Compared with placebo, MDL decreased blood pressure (P < 0.001) and prevented left ventricular hypertrophy (P < 0.001), being as effective as ramipril. Hypertrophy and dilatation of the aorta and hypertrophy of the resistance arterioles were all prevented by MDL. Plasma aldosterone was decreased by MDL (P < 0.001), but not by ramipril. Icatibant blunted the decrease in blood pressure (P < 0.001), decreased cGMP concentrations and blunted the decrease in cross-sectional area of the resistance arteries in MDL-treated, but not in ramipril-treated, transgenic rats. In 3-month-old transgenic rats, MDL normalized blood pressure, regressed left ventricular hypertrophy and decreased adrenomedullin concentrations., Conclusions: The dual ACE+NEP inhibitor MDL prevented and regressed severe hypertension and cardiovascular damage, even in this model of severe angiotensin II-dependent hypertension with pronounced cardiovascular damage. Enhancement of the effects of bradykinin has a role in such favourable outcomes.

Hyperaldosteronism has been causally linked to myocardial interstitial fibrosis experimentally, but it remains unclear if this link also applies to humans. Thus, we investigated the effects of excess aldosterone due to primary aldosteronism (PA) on collagen deposition in the heart. We used echocardiography to estimate left ventricular (LV) wall thickness and dimensions and for videodensitometric analysis of myocardial texture in 17 consecutive patients with PA and 10 patients with primary (essential) hypertension who were matched for demographics, casual blood pressure, and known duration of hypertension. The groups differed in serum K+, ECG PQ interval duration, plasma renin activity, and aldosterone levels (all P< or =0.002) but not for casual blood pressure values, demographics, and duration of hypertension. Compared with hypertensive patients, PA patients showed a higher LV mass index (53.7+/-1.8 versus 45.5+/-2.0 g/m(2.7); P=0.008) and lower values of the cyclic variation index of the myocardial mean gray level of septum (CVI(s); -12.02+/-5.84% versus 6.06+/-3.08%; P=0.012) and posterior wall (-11.13+/-6.42% versus 8.63+/-9.62%; P=0.012). A regression analysis showed that CVI(s) was predicted by the PQ duration, supine plasma renin activity, plasma aldosterone, and age, which collectively accounted for approximately 36% of CVI(s) variance. PA is associated with alterations of myocardial textures that suggest increased collagen deposition and that can explain both the dependence of LV diastolic filling from presystole and the prolongation of the PQ interval.

Several peptides of the RAS other than angiotensin (1-8) have been identified. They are generally referred as 'angiotensin fragments': Ang (2-8), Ang (3-8) and Ang (1-7) and have been detected in human tissues. There is evidence that they may play a functional role in humans by acting in concert with angiotensin (1-8) and aldosterone. Available knowledge on the pathways leading to synthesis and degradation of angiotensin fragments, as well as on their interactions with receptors and on their possible role in cardiovascular homeostasis and disease are reviewed.

Objective: To assess the usefulness of indexes derived from renal vein renin measurements., Design: A 12-year prospective study., Setting: A tertiary institutional referral centre., Patients and Methods: Between 1988 and 2000, we studied 152 consecutive hypertensive patients with a high pre-test probability of renovascular hypertension (RVH). RVH was diagnosed retrospectively on the basis of reduction in blood pressure after correction of ischaemia at follow-up. Renal vein renin measurements were used to calculate the ratios: Visch/Vctl (renal vein renin ratio; RVRR); Vctl/Viivc; (Visch - Viivc)/Viivc; (Vctl - Viivc)/Viivc, where Visch and Vctl indicate plasma renin activity (PRA) in the ischaemic and contralateral renal veins, respectively, and Viivc denotes PRA in the infrarenal inferior vena cava. A receiver operator characteristics (ROC) curve analysis was used to determine the cut-off value of renal vein renin measurement indexes that provided the best discrimination between patients with and without RVH and to identify patients with RVH caused by total occlusion of the renal artery., Results: Sixty-seven patients were diagnosed as having RVH: 51 had significant renal artery stenoses (RVH non-occluded) and 16 had total renal artery occlusion (RVH occluded). Of the remaining 85 patients in whom RVH was excluded (non-RVH group), 27 had reno-parenchymal hypertension and 58 had essential hypertension. Of the renal vein renin measurement indexes, only RVRR and (Visch - Viivc)/Viivc in RVH-occluded patients differed significantly (P < 0.005) from those in the non-RVH group and showed the best performance by ROC curve analysis. This analysis also showed that, at any cut-off value, RVRR was far more accurate for identification of RVH-occluded patients than for identification of RVH non-occluded patients, both in the subgroup with unilateral and, even more so, in those with bilateral renal artery lesions. The best trade-off between sensitivity and false-positive rate was provided by cut-off values of 1.55 and 1.70 of the RVRR for identification of non-occluded and occluded RVH, respectively., Conclusions: RVRR is more useful for establishing an indication for nephrectomy in patients with renal artery occlusion than for identifying those patients with renal artery stenosis who will benefit from revascularization. In patients with RVH with bilateral renal artery lesions, lateralization of renin secretion occurs only in the presence of total renal artery occlusion. Different cut-off values are necessary for identification of non-occluded and occluded RVH.

We investigated the effects of MDL-100,240 in a transgenic rat model (TGRen2) of hypertension with severe cardiovascular damage (CVD) due to enhanced tissue synthesis of angiotensin II (Ang II). Male heterozygous TGRen2 rats (5 weeks old) were allocated to receive MDL-100,240, ramipril (RAM) or placebo (PLAC) for 4 weeks, during which blood pressure (BP) was measured. We then evaluated: 1) left ventricle (LV) and right ventricle (RV), brain, kidney and adrenals weight; 2) structural changes in the aorta and the mesenteric arterioles wall; 3) tension responses of segments of the aorta to phenylephrine, KCl, and endothelin-1; and 4) creatinine, aldosterone, atrial natriuretic peptide (ANP), and cyclic GMP (cGMP) plasma levels. Compared to PLAC, both MDL-100,240 and RAM significantly (P < .001) lowered BP (after 4 weeks: 255 +/- 15 mm Hg PLAC, v 174 +/- 6 MDL-100,240, v 166 +/- 5 RAM). They hindered LV hypertrophy (3.73 +/- 0.25 mg/g body weight (PLAC) v 2.71 +/- 0.22 (MDL-100,240) P < .001; v 2.36 +/- 0.2 (RAM), P < .001). MDL-100,240 also prevented aortic dilatation and hypertrophy of the mesenteric arterioles (media thickness, 25.3 +/- 0.5 microm PLAC, v 21.1 +/- 0.9 MDL-100,240, P < .007; v 20.2 +/- 1.5 RAM, P = .033) and lowered the tension responses to phenylephrine (P < .01), KCl (P < .01), and endothelin-1 (P < .001). Plasma aldosterone (710 +/- 153 pmol/L PLAC, v 237 +/- 61 MDL-100,240, v 180 +/- 22 RAM) and creatinine levels (0.69 +/- 0.33 mg/dL PLAC, v 0.41 +/- 0.02 MDL-100,240, v 0.41 +/- 0.04 RAM) were also decreased (P < or = .001). Compared to PLAC, plasma ANP levels were 11% and 2.4% higher in MDL-100,240 and RAM, respectively (both P = not significant); cGMP levels were unaffected. Thus, severe hypertension and related CVD were regressed by MDL-100,240, which resulted to be as effective as a full dosage of ramipril in TGRen2.

The aim of the CASTEL, a population-based (n=3282) prospective study which began 14 years ago, was to identify those items which had a prognostic impact in the elderly, and to evaluate whether the typical cardiovascular risk factors, particularly arterial hypertension, play a role after the age of 65 years. Initial screening, final follow-up and annual detection of mortality were performed. Mantel-Hanszel approach and multivariate Cox model were used for statistics. Cardiovascular mortality was 23.3% in normotensive, 23.3% in borderline, and 25% in the sustained hypertensive subjects (insignificant difference). In women, the incidence of stroke and coronary artery disease weakly depended on pulse pressure. Historical stroke and myocardial infarction predicted cardiovascular mortality in women; diabetes, uricaemia and high heart rate in men. In the very old, the predictors were less numerous, and blood pressure was not a predictor whatsoever; pulse blood pressure and murmurs at the neck were especially predictive in women, historical heart failure, proteinuria and tachycardia in men, historical stroke and myocardial infarction, pulmonary disease, left ventricular hypertrophy, diabetes and uricaemia in both genders. The elderly have a different cardiovascular risk pattern compared to younger people. Hypertension is not a predictor of coronary and stroke mortality. Prognosis depends on pulse pressure rather than on the label 'hypertension'. Hypercholesterolaemia is not a risk factor. This could simply indicate that elderly persons are the survivors in a population where significant mortality has already made its mark, eliminating those with the worst risk pattern. The two genders have a different risk profile due to sex-specific susceptibility to risk factors.

The antihypertensive efficacy of nebivolol and amlodipine and their tolerability were compared in a multicentre, randomized, active-controlled, double-blind parallel-group trial in elderly patients with mild to moderate essential arterial hypertension. One hundred and eighty-four subjects aged > or = 65 years were screened. After a run-in phase of 4 weeks, only 168 of these were randomized with either nebivolol 2.5-5 mg daily (n = 81) or amlodipine 5-10 mg daily (n = 87) over a period of 12 weeks. The response rate to treatment and the changes of sitting diastolic blood pressure (BP) at week 12 were similar between the two groups. A lower sitting systolic BP (SBP) was detected with amlodipine at week 4 (p < 0.05) and at week 8 (p < 0.05). Standing BP showed no changes between the two groups; only SBP was lower with amlodipine at week 8 (p < 0.05). Heart rate was lower at all treatment visits with nebivolol (p < 0.001). The incidence of adverse events was no different between the two groups; however the incidence of headache and ankle oedema was significantly higher with amlodipine (p < 0.05). In elderly subjects with essential hypertension, the antihypertensive efficacy of nebivolol and amlodipine was similar. Both drugs were well tolerated, although amlodipine was accompanied by higher incidence of drug-related adverse events.

Background: Whether abnormalities of diastolic function are the earliest cardiac change in hypertension is still a matter for dispute. The aim of this study was to assess whether left ventricular diastolic dysfunction is an early sign of cardiac involvement in hypertension., Methods: In 578 young patients with stage I hypertension from the Hypertension and Ambulatory Recording Venetia Study (HARVEST) and 101 normotensive control patients echocardiographic Doppler examination and ambulatory blood pressure monitoring were performed., Results: Left ventricular mass, wall thickness, and relative wall thickness, adjusted for confounders, were greater in the hypertensive than in the normotensive patients (all P <.0001). After adjustment for confounders, the A-wave peak velocity was higher in the hypertensive patients (51.5 +/- 11.5 vs 43.4 +/- 8 cm/s, P <.001) as were A-wave velocity time integral (5.6 +/- 1.7 vs 4.6 +/- 1.3 cm, P =.01), total area (16.9 +/- 4.4 vs 15.6 +/- 3.1 cm, P =.04), and E-wave peak velocity (69.9 +/- 15.2 vs 67.5 +/- 13.3 cm/s, P =.03). All indexes of diastolic function were similar in the hypertensive subjects subdivided according to whether they had "white-coat" or sustained hypertension. Among the hypertensive subjects, age and heart rate were the strongest predictors of diastolic indexes, whereas ambulatory blood pressure explained only a marginal part of the E/A ratio, A-wave peak velocity, and the first one third total area ratio (P =.04, P =.02, and P =.05, respectively). Left ventricular mass and wall thickness were not associated with any Doppler index. When a clustering of diastolic indexes (E/A wave ratio, deceleration time, first one third of diastole, and peak E-wave-velocity) was used to identify subjects with diastolic dysfunction, no significant differences in either clinic or ambulatory blood pressure were observed between the group with diastolic dysfunction and the group with normal function., Conclusions: We conclude that the earliest signs of cardiac involvement in hypertension are left ventricular structural abnormalities. Left ventricular diastolic function is only marginally affected, even when multiple parameters of left ventricular filling are taken into account.

Nebivolol, compared with classical beta-blockers, exerts a high selectivity for beta-adrenergic receptors and also reduces peripheral vascular resistance by modulating nitric oxide (NO) release. This dual mechanism of action leads to effective control of blood pressure at a low degree of beta-blockade and explains the lack of any interference with lipid metabolism. For the same reason, the tolerability profile of nebivolol is highly favorable compared with the classical beta-blockers, with less fatigue and dyspnea in hypertensive subjects, and with an improvement of functional capacity and exercise tolerance in patients with left ventricular dysfunction. Furthermore, contrary to atenolol and propranolol, nebivolol does not diminish specific airway conductance. Compared with other first-line antihypertensive agents, nebivolol was shown to be better tolerated than nifedipine and enalapril, and to have a positive effect on general wellbeing. Among the currently available antihypertensive drugs, nebivolol therefore appears to have a most alteractive safety and tolerability profile, which can be attributed to its NO-mediated effects allowing effective control of hypertension at a lower degree of beta-blockade than with first-generation beta-blockers.

Background: We investigated the relationships between plasma lipids and lipoprotein fractions and carotid artery lesions (CAL) in 177 cerebro-vascularly asymptomatic subjects, of whom 107 were primary hypertensive patients and 70 normotensive controls., Methods: The prevalence and severity of CAL, as assessed by calculating a score of severity (score of CAL) and the maximal stenosis of both sides, as well as the intimal-medial thickness (IMT) were evaluated with a high-resolution echo-Doppler technique. We measured total serum cholesterol, triglycerides, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, lipoprotein (a) [Lp(a)], Apo (apolipoprotein)AI, ApoAII, ApoB, and fibrinogen., Results: Both the prevalence (59.4% vs 26.2%) and severity of sex- and age-adjusted and unadjusted CAL and IMT were significantly higher in hypertensive patients than in controls. Regression analysis showed different predictors of IMT and maximal stenosis. The variables that remained in the model were age, mean blood pressure (BP), and smoking for IMT; pulse pressure, known duration of hypertension (HT), fibrinogen, and ApoB for the score of CAL; and the last four variables along with age and mean BP for maximal stenosis. Furthermore, we identified a link between the atherogenic lipoprotein fractions Lp(a) and ApoB, fibrinogen and early carotid artery atherosclerotic changes., Conclusions: The different correlates of IMT, CAL, and maximal degree of stenosis suggest that they reflect different events occurring in the arterial wall in response to aging, HT, and other risk factors, rather than simply different stages of the same atherosclerotic process.

The results of the Randomized Aldactone Evaluation Study (RALES) and of several experimental studies have indicated that excess aldosterone detrimentally affects cardiovascular morbidity and mortality by acting through both classical and non-classical mineralocorticoid receptors. The effects mediated through classical mineralocorticoid receptors entail enhanced sodium and water reabsorption, potassium loss and hypokalaemia, congestion, increased vascular resistance and hypertension. Those occurring through non-classical mineralocorticoid receptors located on myofibroblasts comprise cardiac hypertrophy and fibrosis, which may be due to a direct effect of aldosterone on collagen synthesis. Data obtained in primary aldosteronism patients demonstrated left ventricular hypertrophy, as well as changes in left ventricular filling that can be accounted for by cardiac fibrosis. Available clinical data indicate that in a considerable proportion of congestive heart failure (CHF) patients treated with angiotensin converting enzyme (ACE) inhibitors, aldosterone secretion can escape from blockade of the renin-angiotensin system, thus suggesting that additional mechanisms, besides angiotensin II, can play an important role in the regulation of aldosterone secretion. Compelling evidence indicates that endothelin (ET)-1 is overtly increased in severe CHF and thus is a likely candidate for the aldosterone 'escape' phenomenon in CHF. Endothelin-1 is expressed in the adrenal cortex, together with its receptor subtypes A (ETA) and B (ETB), and directly stimulates aldosterone secretion in different species, in humans by acting via both ETA and ETB receptor subtypes. Moreover, we have recently found that the novel endothelin peptide ET-1 (1-31), by acting as an ETA agonist, can also be involved in the regulation of growth of the adrenal cortex, as well as in the pathogenesis of Conn's adenoma. In this paper, we review the findings suggesting a relationship between activation of the ET-1 system, enhanced aldosterone secretion and cardiac fibrosis and discuss the implications of endothelin antagonism for cardiovascular disease.

Despite the use of antihypertensive drugs, mortality (but not morbidity) from cerebrovascular diseases has been reduced significantly. As a consequence, an increasing number of patients suffer from recurring strokes and from the debilitating consequences of cerebrovascular diseases and develop progressive cognitive impairment. Its pathological substrates are regional alteration of cerebral perfusion, lacunae, white matter lesions, progressive cortical atrophy, even in the asymptomatic patient and in the absence of extracranial carotid artery stenosis. Lacunar infarction and white matter lesions are particularly frequent in the hypertensive diabetic patient. Lacunae and white matter lesions sometimes coexist and may favour the development of dementia in the hypertensive patient, through focal ischaemia, perivascular oedema, disruption of the blood-brain barrier, cerebral diaschisis and cortical deafferentation. Treatment with calcium channel blockers, angiotensin converting enzyme inhibitors and diuretics smooth the patchy hypoperfusion despite the fall in pressure. However, the time course and the extent of this effect vary according to the drug administered. In particular, only a calcium channel blocker increased perfusion of both cortical and subcortical areas, while diuretic treatment increased perfusion only after prolonged treatment, and this effect was limited to the cortical areas. Such differences may explain the discrepant results on risk reduction for dementia observed in large intervention trials.

The aim of the present study was to assess how cardiac structural changes contribute to increasing left ventricular pump function during exercise in subjects with mild hypertension. In 23 young male subjects with mild hypertension and 12 male normotensive control subjects, left ventricular function was measured echocardiographically using the fractional shortening/ meridional stress relationship at rest and during longlasting exercise at the anaerobic threshold. Mean exercise duration and intensity were 61 (SEM 1.7) min and 71.3 (SEM 2.5)% VO2max (maximal oxygen uptake), respectively, in the hypertensive subjects, and 63 (SEM 1.5) min and 75.7 (SEM 2.2)% VO2max, respectively, in the normotensive subjects (all differences= n.s.). Left ventricular fractional shortening was measured both at the endocardium and at the midwall. In the hypertensive subjects the endocardial fractional shortening, predicted on the basis of the shortening/stress relationship in the normotensive controls, overestimated midwall fractional shortening throughout rest (P=0.04) and exercise (P=0.004). To study how an increase in left ventricular wall thickness contributed to increasing ejection performance during exercise, the hypertensive subjects were divided according to whether their relative wall thickness was less than 0.35 or equal to or greater than 0.35. Subjects with relative wall thicknesses equal to or greater than 0.35 had a depressed myocardial contractility at rest (P=0.0001). During exercise they increased their stroke volume and cardiac output adequately through an increase in ejection performance, while myocardial contractility remained subnormal (P < 0.0001). In conclusion, the present results indicated that in mildly hypertensive subjects an increased left ventricular wall thickness is crucial in preserving left ventricular pump function during exercise.

The objectives of this study were to investigate the usefulness of adrenal vein sampling in identifying the etiology of primary aldosteronism (PA) in patients with equivocal CT and MR findings. Between 1990 and 1999, 104 referred hypertensive patients (45 women and 59 men, aged 49.6 +/- 11.6 yr) were diagnosed to have PA with inconclusive computed tomography scan and magnetic resonance results, based on established criteria. Adrenal vein sampling (AVS) for measurement of plasma aldosterone (A) and cortisol (C) levels was performed in all. Selectivity of AVS was assessed by the ratio between C levels in each adrenal vein and in the infrarenal inferior vena cava plasma (C(side)/C(IVC)). A receiver operator characteristics analysis was carried out to establish 1) the best AVS-derived index, 2) the degree of selectivity that could provide an accurate diagnosis, and 3) whether a correct diagnosis could be made from a unilaterally selective AVS. An aldosterone-producing adenoma (average diameter, 12.2 +/- 0.08 mm) was eventually diagnosed in 41 patients (39.4%) and was excluded in the rest. Adrenal vein rupture leading to partial adrenal loss occurred in 1 patient (0.9% complication rate). By assuming a cut-off value of C(side)/C(IVC) > or = 1.1, AVS was selective in 85.7% and 94.1% of cases on the right and left sides, respectively, and bilaterally in 80.6% of cases. Of all AVS-derived indexes, the A/C of one over the A/C contralateral side [(A/C)(side)/(A/C)(contralateral side)] furnished the best diagnostic accuracy. With a bilaterally selective AVS, a value of (A/C)(side)/(A/C)(contralateral side) > or = 2 provided a conclusive etiological diagnosis of PA in 79.7% of cases. At variance, no accurate diagnosis could be made from unilaterally selective AVS. AVS was feasible and safe in most PA patients with inconclusive computed tomography and magnetic resonance scans. When bilaterally selective (i.e. C(side)/C(IVC) > or = 1.1) a ratio of (A/C)(side)/(A/C)(control) > or = 2 provided the best compromise of sensitivity and false positive rate for lateralization of the etiology of PA.

A deletion/insertion (D/I) polymorphism within the ACE gene may increase the risk of cardiovascular events through still unknown mechanisms. The latter may involve increased angiotensin II-induced NO breakdown and/or reduced agonist-mediated NO release. We therefore investigated whether the D allele of the ACE gene affects endothelium-dependent vasodilatation in mild-to-moderate primary hypertensive patients and healthy normotensive subjects. We compared in a cross-sectional study the forearm blood flow response of the 3 D/I genotypes with 5 incrementally increasing doses of the endothelium-dependent vasodilator acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg. 100 mL(-1). min(-1)) in 142 subjects: 103 mild-to-moderate uncomplicated primary hypertensives (49.3+/-9.1 years old, 152+/-11/99+/-5 mm Hg) and 39 normotensives (44.6+/-15.3 years old, 122+/-12/78+/-6 mm Hg). We also assessed the endothelium-independent vasodilatation in the forearm, as blood flow response to 3 incrementally increasing doses of sodium nitroprusside (1, 2, and 4 microg. 100 mL(-1). min(-1)). The overall genotype distribution was II, n=10; ID, n=70; and DD, n=62. It did not differ significantly between primary hypertensives and normotensives. A significant blunting of endothelium-dependent vasodilatation in primary hypertensive patients compared with normotensive subjects (P:<0.001) was found. No effect of the DI genotype on endothelium-dependent and -independent vasodilatation was detected. Thus, these results obtained in a relatively large population do not support the contention that the D allele is associated with a blunting of either stimulated endothelial NO or donated NO responses in both mild-to-moderate primary hypertensive patients and normotensive subjects.

The aim of this paper is to evaluate whether pulse pressure is an independent risk factor for coronary and stroke mortality in 3282 subjects (1281 males and 2001 females) aged +/- 65 years, taking part in the CArdiovascular STudy in the Elderly (CASTEL). After dividing subjects into tertiles of pulse pressure, adjusted relative risk (RR) and confidence intervals (CI) for 14-year coronary and stroke mortality was evaluated for each tertile. Among females, coronary mortality rate was 2.7% in the first tertile of pulse pressure, 4.7% in the second (RR 1.38, 95% CI [1.15-2.66]) and 6.2% in the third (RR 2, CI [1.20-3.51]). Stroke mortality was 3.6%, 4.1% (RR 1.23, CI [1.02-2.23]) and 8.3% (RR 2.27, CI [1.37-3.74]), respectively. This trend was recognizable in normotensive, borderline and sustained hypertensive women, where mortality increased with rising pulse pressure. No relationship was found between pulse pressure and mortality in males. In elderly women, pulse pressure was a good predictor of coronary and stroke mortality, even superior to the label of hypertension. No matter how any given pulse pressure level was obtained, it was more predictive of both coronary and cerebrovascular mortality than belonging to a normo- or hypertensive category.

Objective: The main purpose of this study was to compare efficacy, tolerability and influence on quality of life (QOL) of nifedipine gastrointestinal therapeutic system (NI) 30-60 mg once a day vs amlodipine (AM) 5-10 mg once a day in elderly patients with mild-moderate hypertension., Design: This was a randomized, double-blind, parallel-group, multicenter study. After a 2-week single-blind placebo run-in, patients were randomized to either NI 30 mg or AM 5 mg. Responders continued on the same dosage for 16 additional weeks, while non-responders were titrated to 60 mg NI or 10 mg AM., Methods: Blood pressure was measured by mercury sphygmomanometer and efficacy equivalence of NI and AM tested by covariance analysis. Diastolic blood pressure (DBP) was the primary efficacy parameter, its baseline value being taken as covariate while centers effect and treatment interaction were included as fixed effects in the analysis model. The secondary efficacy variables systolic blood pressure (SBP) and scores for QOL were analyzed according to the same model., Results: At the end of the study, overall mean DBPs, calculated as least-square means (LSMEANS), in the "by protocol" population were 87.5 mmHg for NI and 86.7 for AM (difference 0.8 mmHg with 90% CI -1.2 to 2.8 mmHg). In the "by intention to treat" (ITT) population LSMEANS were 87.6 mmHg for NI and 86.4 mmHg for AM (difference 1.2 mmHg with 90% CI -0.6 to 3.1 mmHg). SBP LSMEANS in the "by protocol" population were 147.7 mmHg for NI and 147.3 mmHg for AM (difference 0.3 mmHg, with 90% CI -3.7 to 4.3); corresponding values in the "by ITT" population were 148.0 mmHg for NI and 147.2 for AM (difference 0.8 mmHg, with 90% CI -2.8 to 4.6). Mean values for QOL parameters were not significantly different. A total of 173 episodes of adverse events were documented in 54 patients (26 NI and 28 AM), dropouts were 15 (20% of group) on NI and 21 (28%) on AM., Conclusions: NI 30-60 mg was shown to be as efficacious and safe as AM 5-10 mg in elderly patients with mild-moderate hypertension. QOL improved compared to baseline with no significant difference between the two drugs, thus confirming a positive class effect for calcium antagonists.

Stroke occurs particularly frequently in elderly people and, being more often disabling than fatal, entails a high social burden. The predictors of stroke mortality have been identified in 3282 subjects aged > or = 65 years, taking part in the CArdiovascular STudy in the ELderly (CASTEL), a population-based study performed in Northeast Italy. Historical and clinical data, blood tests and 14-year fatal events were recorded. Continuous items were divided into quintiles and, for each quintile, adjusted relative risk (RR) with 95% confidence intervals [CI] was derived from multivariate Cox analysis. Age, historical stroke (RR: 5.2; 95% CI: 3.18-8.6) and coronary artery disease (RR: 1.38; CI: 1.18-2.1), atrial fibrillation (RR: 2.40; CI: 1.42-4.0), arterial hypertension (RR: 1.33; CI: 1.15-1.76), systolic blood pressure > or = 163 mmHg (RR: 1.84; CI: 1.20-2.59), pulse pressure > or = 74 mmHg (RR: 1.50; CI: 1.13-2.40), cigarette smoking (RR: 1.60; CI: 1.03-2.47), electrocardiographic left ventricular hypertrophy (RR: 1.72; CI: 1.10-2.61), impaired glucose tolerance (IGT, RR: 1.83; CI: 1.10-3.0), uric acid (UA) > 0.38 mmol/l (RR: 1.61; CI: 1.14-2.10), serum potassium > or = 5 mEq/l (RR: 1.70; CI: 1.24-2.50) and serum sodium < or = 139 mEql/l (RR: 1.34; 1.10-2.10) increased the risk of stroke. In the CASTEL, stroke was the first cardiovascular cause of death. Some independent predictors usually unrelated to stroke mortality (namely pulse pressure, pre-diabetic IGT, UA and blood electrolytes disorders) have been identified.

Background: This study was aimed at investigating whether a circadian rhythm of peripheral resistance exists in patients with orthotopic cardiac transplantation (OCT) and whether it parallels that of blood pressure (BP)., Methods: BP and leg flow and resistance (plethysmography) were monitored for 24 hours in 13 denervated OCT recipients and 13 control patients with native heart, matched for casual blood pressure., Results: On the basis of BP trend, control patients showed a BP reduction during sleep, whereas OCT recipients did not. Leg resistance was significantly lower and leg flow significantly higher during sleep than during waking in all patients, and the extent of the nocturnal decrease was similar in the two categories., Conclusions: The decrease in leg resistance in patients confined to bed for 24 hours is caused by peripheral mechanisms and does not depend on the autonomic control of the heart. The nocturnal decline in BP depends, on the contrary, on cardiac control and is lost in patients with denervated heart.

Objective: To collect statistically significant information on patterns of antihypertensive therapy in medical practice, with particular attention to the drugs used in the pharmacological management of hypertensive patients and the reasons for the limited achievement of therapeutic goals during treatment, Design: A survey conducted among general practitioners, specialists, and hypertensive patients., Methods: A total of 28,000 physicians were contacted by letter and 3,394 declared their willingness to participate and received a questionnaire. Subsequently, 1,255 questionnaires suitable for analysis (corresponding to 37.0% of adhering physicians) were received. In addition, 4,612 questionnaires completed by patients were pooled and evaluated. The prevalence of hypertension was calculated from a base of 254,192 patients, seen by general practitioners., Results: The prevalence of hypertension, defined as systolic blood pressure > or = 160 mmHg or diastolic blood pressure > or = 95 mmHg, or current treatment, was 19.7%. The average number of hypertensive patients in each general practitioner's file, covering the previous 12 months, was approximately 230. Physicians reported a 66% rate of discontinuation of treatment or switching to another drug. Physicians and patients both considered inadequate blood pressure control and side effects to be the two main reasons for switching antihypertensive therapy, but in opposite order. Furthermore, physicians indicated a prevalence of drug side effects between 10 and 20%, according to class of drug used, whereas 69% of patients reported to have experienced side effects. In the doctors' opinions, there were many reasons for poor patient adherence: complexity of the drug regimen, appearance of side effects, forgetfulness, reduced patient understanding of the need for long-term continuation of treatment, and refusal to accept a chronic pathological condition., Conclusions: The survey showed awareness of the disease among physicians and provides a representation of the experiences of both general practitioners and specialists, in addition to that of their patients. During antihypertensive therapy, a disconcerting degree of discontinuation and switching of drugs occurred. Insufficient blood pressure control and side effects accounted for most of the observed treatment changes. This survey revealed the existence of a gap between the physicians' perception of tolerability and the real experience of patients, a clear need for greater tolerability of treatments, and a need for an enhancement of patient-physician communication.

Background: The evidence linking activation of the renin-angiotensin system with accelerated cerebro-vascular atherosclerosis remains controversial. We therefore prospectively investigated the relationships of plasma renin activity and aldosterone levels with carotid artery lesions (CAL) in essential hypertension., Methods: We evaluated the prevalence and severity of CAL and the intimal-medial thickness (IMT) with a high-resolution echo-Doppler technique in 107 cerebrovascularly asymptomatic consecutive primary hypertensives (55 male, 52 female) and in 70 (42 male, 28 female) normotensive controls. We also measured supine plasma renin activity (PRA) and aldosterone before and 45 min after captopril administration, while daily urinary excretion of sodium was measured., Results: Both the prevalence (59.4 versus 26.2%) and severity of sex- and age-adjusted and unadjusted CAL and IMT were significantly higher in hypertensives than in controls. Regression analysis showed different predictors of IMT (age and captopril-stimulated-PRA, R2 = 0.27, P < 0.0001), score of CAL (mean blood pressure, R2 = 0.15, F=12.73, P< 0.0001) and maximal stenosis (pulse pressure and known duration of hypertension R2 = 0.29, F = 14.58, P< 0.0001). Sex- and age-adjusted IMT did not differ between quartiles of renin-sodium profile. However, patients in the quartile with the highest PRA had the lowest score of CAL and an inverse relationship between age-adjusted PRA and IMT and CAL was found., Conclusions: These results, besides confirming an association of both IMT and CAL with primary hypertension and ageing, demonstrate that CAL and IMT have different correlates. However, they do not support the contention that a high renin-sodium profile carries an excess risk of CAL in primary hypertensives with no clinical evidence of cerebro-vascular disease.