摘要:

Endothelium-dependent flow-mediated dilation is a homeostatic response to short-term increases in local shear stress. Flow-mediated dilation of the brachial artery in response to postischemic reactive hyperemia is impaired in patients with cardiovascular disease risk factors and may reflect local endothelial dysfunction in the brachial artery. However, previous studies have largely neglected the effect of risk factors on evoked shear stress, which is the stimulus for dilation. We evaluated brachial artery percent dilation and evoked diastolic shear stress during reactive hyperemia using high-resolution ultrasound and Doppler in 2045 participants (1107 women, mean age 61 years) in the Framingham Offspring Study. In age- and sex-adjusted models, baseline and hyperemic shear stress were related to brachial artery percent dilation. In stepwise multivariable analyses examining clinical correlates of percent dilation (without shear stress in the model), age, sex, mean arterial pressure, pulse pressure, heart rate, body mass index, lipid medication use, and hormone replacement therapy were related to percent dilation (R2=0.189;P<0.001). When hyperemic shear stress was incorporated, the overallR2improved (R2=0.335;P<0.001), but relationships between risk factors and percent dilation were attenuated (age and mean arterial pressure) or no longer significant (all others). In contrast, risk factors were related to baseline and hyperemic shear stress in multivariable analyses. Evoked hyperemic shear stress is a major correlate of brachial artery flow–mediated dilation. The associations between many risk factors and brachial artery flow–mediated dilation may be attributable to reduced stimulus for dilation rather than impaired local conduit artery response during hyperemia.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

There is controversy whether cyclooxygenase-2 (COX-2) specific inhibitors are associated with elevations in blood pressure requiring treatment in typical clinical practice. We examined the risk of new onset hypertension in a retrospective case-control study involving 17 844 subjects aged ≥65 years from 2 US states. Multivariable logistic models were examined to assess the relative risk of new onset hypertension requiring treatment in patients who used celecoxib or rofecoxib compared with patients taking either the other COX-2 specific inhibitor, a nonspecific NSAID, or no NSAID. During the 1999 to 2000 study period, 3915 patients were diagnosed and began treatment for hypertension; 4 controls were selected for every case. In no model was celecoxib significantly associated with the development of hypertension. Rofecoxib users were at a significantly increased relative risk of new onset hypertension compared with patients taking celecoxib (odds ratio [OR] 1.6; 95% confidence interval [CI], 1.2 to 2.1), taking a nonspecific NSAID (OR 1.4; 95% CI, 1.1 to 1.9), or taking no NSAID (OR 1.6; 95% CI, 1.3 to 2.0). There were no clear dosage or duration effects. In patients with a history of chronic renal disease, liver disease, or congestive heart failure, the relative risk of new onset hypertension was twice as high in those taking rofecoxib compared with celecoxib (OR 2.1; 95% CI, 1.0 to 4.3). In this retrospective case–control study of patients aged ≥65 years, rofecoxib use was associated with an increased relative risk of new onset hypertension; this was not seen in patients taking celecoxib.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

The TRial Of Preventing HYpertension (TROPHY) study is an investigator-initiated trial to examine whether early pharmacological treatment in subjects with “high-normal” blood pressure (BP) might prevent or delay the development of clinical hypertension. This is a 4-year, multicenter, randomized, double-blind study in untreated subjects aged 30 to 65 years with entry BPs of 130 to 139/≤89 or ≤139/85 to 89. The participants were randomized either to placebo or to a fixed (16 mg once daily) dose of candesartan cilexetil (candesartan). After 2 years, the candesartan group was switched to placebo, and the placebo group continued taking placebo. The main outcome measure was the development of clinical (treatment-requiring) hypertension assessed by an automated (blinded) BP measurement device. We randomized 809 subjects (59% males, average age 49.0±SD 8.1 years) in 71 study centers in the United States. The entry BP was 134±4.3/84.8±3.9 mm Hg. During the first 2 years, 187 subjects (23%) developed clinical hypertension. All have been given antihypertensive treatment, and 170 continue to be followed in study centers. The study dropout rate is 14.8% (120 subjects). The hypertension rates are higher than anticipated, whereas the rates of dropout are within the sample size projections; thus, the study will have sufficient power to evaluate its hypotheses. In this article, we describe baseline characteristics of TROPHY subjects and discuss novel analytical issues and statistical approaches to evaluate the findings in this trial of primary prevention of hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

The objective of this study was to assess heritability and identify chromosomal regions showing evidence of linkage to pulse pressure (PP), a simple indicator of proximal conduit vessel stiffness. Blood pressure data were analyzed for 8478 members of the National Heart, Lung and Blood Institute’s (NHLBI) Framingham Heart Study. Long-term PP was defined using 2-stage analysis. First, the difference between systolic and diastolic blood pressure was averaged over all qualifying clinic examinations. In the second stage, mean PP was adjusted for mean age, time period of examination, and body mass index by regression analysis. PP values were available for 6421 individuals in 1593 families for heritability estimation and for 2492 individuals in 330 families for linkage analysis. Microsatellite markers covering the genome at 10 cM intervals were typed by the NHLBI Mammalian Genotyping Service; genome scan data were available on 1585 individuals with PP data. Heritability estimates of long-term PP accounting for hypertension treatment and for ignoring treatment were 0.52 and 0.51, respectively. Variance component linkage analysis identified several locations with suggestive evidence of linkage: chromosome 15 at 122 cM (logarithm of odds [LOD]= 2.94), chromosome 7 at 71 cM (LOD= 2.42), chromosome 5 at 53 cM (LOD= 2.03), and chromosome 10 at 81 cM (LOD= 1.83) for PP accounting for treatment. LOD scores were slightly lower when ignoring treatment, with the exception of a peak on chromosome 10 at 81 cM (LOD= 2.58). In conclusion, we have demonstrated a substantial genetic component to PP and have identified 4 chromosomal regions that may harbor genes influencing vascular stiffness.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Sympathetic tone increases with stimulation of the renin-angiotensin system and is under the influence of salt intake. In the European Project On Genes in Hypertension (EPOGH), we investigated whether polymorphisms in the genes encoding aldosterone synthase (CYP11B2C–344T) and the type-1 angiotensin II receptor (AT1RA1166C) affect the autonomic modulation of heart rate at varying levels of salt intake. We measured the low frequency (LF) and high frequency (HF) components of heart rate variability and their ratio (LF:HF) in the supine and standing positions in 1797 participants (401 families and 320 unrelated subjects) randomly selected from 6 European populations, whose average urinary sodium excretion ranged from 163 to 245 mmol/d. In multivariate analyses with sodium excretion analyzed as a continuous variable, we explored the phenotype–genotype associations using generalized estimating equations and quantitative transmission disequilibrium tests. Across populations, there was no heterogeneity in the phenotype–genotype relations. The genotypic effects differed according to sodium excretion. In subjects with sodium excretion <190 mmol/d (median), supine heart rate, LF, and LF:HF increased and HF decreased with the number ofCYP11B2–344T alleles, and the orthostatic changes in LF, HF, and LF:HF were blunted in carriers of theAT1R1166C allele. In subjects with sodium excretion >190 mmol/d, these associations with theCYP11B2andAT1Rpolymorphisms were nonsignificant or in the opposite direction, respectively. Thus,CYP11B2C–344T andAT1RA1166C polymorphisms affect the autonomic modulation of heart rate, but these genetic effects depend on sodium excretion.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Oxidative stress induced by superoxide is implicated in hypertension. NADPH oxidase is the main source of superoxide in phagocytic and vascular cells, and the p22phoxsubunit is involved in NADPH oxidase activation. Recently we reported an association of −930A/Gpolymorphism in the humanp22phoxgene promoter with hypertension. This study was designed to investigate the functional role of this polymorphism in hypertension. We thus investigated the relationships between the −930A/Gpolymorphism and p22phoxexpression and NADPH oxidase–mediated superoxide production in phagocytic cells from 70 patients with essential hypertension and 70 normotensive controls. Genotyping of the polymorphism was performed by restriction fragment length polymorphism. NADPH oxidase activity was determined by chemiluminescence assays, and p22phoxmRNA and protein expression was measured by Northern and Western blotting, respectively. Compared with hypertensive subjects with the AA/AG genotype, hypertensive subjects with the GG genotype exhibited increased (P<0.05) phagocytic p22phoxmRNA (1.26±0.06 arbitrary unit [AU] versus 0.99±0.03 AU) and protein levels (0.58±0.05 AU versus 0.34±0.04 AU) and enhanced NADPH oxidase activity (1998±181 counts/s versus 1322±112 counts/s). No differences in these parameters were observed among genotypes in normotensive cells. Transfection experiments on vascular smooth muscle cells showed that theA-to-Gsubstitution of this polymorphism produced an increased reporter gene expression in hypertensive cells. Nitric oxide production, as assessed by measurement of serum nitric oxide metabolites, was lower in GG hypertensive subjects than in AA/AG hypertensive subjects. In conclusion, these results suggest that hypertensive subjects carrying the GG genotype of thep22phox−930A/Gpolymorphism are highly exposed to NADPH oxidase-mediated oxidative stress.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

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.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

ECG criteria for left ventricular hypertrophy (LVH) were mostly validated using left ventricular mass (LVM) as measured by M-mode echocardiography. LVM as measured by cardiac MRI has been demonstrated to be much more accurate and reproducible. We reevaluated the sensitivity and specificity of 4 ECG criteria of LVH against LVM as measured by cardiac MRI. Patients with systemic hypertension (n= 288) and 60 normal volunteers had their LVM measured using a 1.5-Tesla MRI system. A 12-lead ECG was recorded, and 4 ECG criteria were evaluated: Sokolow-Lyon voltage, Cornell voltage, Cornell product, and Sokolow-Lyon product. Based on a cardiac MRI normal range, 39.9% of the hypertensive males and 36.7% of the hypertensive females had elevated LVM index. At a specificity of 95%, the Sokolow-Lyon product criterion had the highest sensitivity in females (26.2%), the Cornell criterion had the highest sensitivity in males (26.2%), and the Cornell product criteria had a relatively high sensitivity in both males and females (25.0% and 23.8%). Receiver operating characteristic curves showed the Cornell and Cornell product criteria to be superior for males whereas the Sokolow-Lyon product criterion was superior for females. Comparing the mean LVM index values of the subjects who were ECG LVH positive to the normal volunteers indicated that the ECG LVH criteria detect individuals with an LVM index substantially above the normal range. We have redefined the partition values for 4 different ECG LVH criteria, according to gender, and found that they detect subjects with markedly elevated LVM index.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Thus, we studied vascular responses to combination therapy in hypercholesterolemic patients. A randomized, double-blind, placebo-controlled, crossover trial was conducted with 50 hypercholesterolemic patients with simvastatin and either placebo or ramipril (study I) and in 45 hypercholesterolemic diabetic patients with simvastatin or ramipril with placebo or simvastatin combined with ramipril (study II) for 2 months with 2 months washout. In study I simvastatin combined with ramipril significantly reduced blood pressure after 2 months. Simvastatin alone or combined with ramipril significantly changed lipoproteins, improved percent flow-mediated dilator response to hyperemia by 30±5% and 53±6%, respectively (P<0.001), and reduced plasma levels of malondialdehyde by 4±7% (P=0.026) and 25±4% (P<0.001), respectively. Monocyte chemoattractant protein-1 levels decreased by 3±3% and 12±2%, respectively (P=0.049 andP<0.001, respectively), C-reactive protein levels changed by 0% and 18%, respectively (P=0.036 andP<0.001, respectively), and plasminogen activator inhibitor-1 antigen levels changed by −7±7% and 17±5%, respectively (P=0.828 andP<0.001, respectively). In study II ramipril alone did not significantly change lipoproteins and C-reactive protein levels, however, simvastatin combined with ramipril significantly changed lipoproteins and C-reactive protein levels more than ramipril alone (P<0.001 andP=0.048 by ANOVA, respectively). Ramipril alone or simvastatin combined with ramipril significantly improved the percent flow-mediated dilator response to hyperemia (bothP<0.001), however, simvastatin combined with ramipril showed significantly more improvement than ramipril alone (P<0.001 by ANOVA). Simvastatin combined with ramipril significantly improved endothelium-dependent vasodilation and fibrinolysis potential and reduced plasma levels of oxidant stress and inflammation markers in hypercholesterolemic patients.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Statins, inhibitors of cholesterol biosynthesis, are endowed with pleiotropic effects that may contribute to their favorable clinical results. Hypertensive Dahl salt-sensitive (DS) rats have endothelial dysfunction and cardiorenal injury associated with decreased NO bioavailability and increased superoxide (O2−) production linked to a functional upregulation of angiotensin II. We investigated whether atorvastatin (30 mg/kg per day; by gavage) would prevent endothelial nitric oxide (eNOS) downregulation and the increase in O2−in DS rats, thereby reducing end-organ injury. DS rats given a high-salt diet (4% NaCl) for 10 weeks developed hypertension (systolic blood pressure [SBP] 200±8 versus 150±2 mm Hg in DS rats fed 0.5% NaCl diet [NS];P<0.05), impaired endothelium-dependent relaxation, functional upregulation of endothelin-1, left ventricular hypertrophy (LVH; 30%), and proteinuria (167%), accompanied by downregulation of aortic eNOS activity (0.7±0.2 versus 1.8±0.3 nmol/min per gram protein in NS;P<0.05) and increased aortic O2−(2632±316 versus 1176±112 counts/min per milligram in NS;P<0.05) and plasma 8-F2&agr; isoprostanes. Atorvastatin prevented the decrease in eNOS activity (1.5±0.3 nmol/min per gram protein) as well as the increase in O2−(1192±243 counts/min per milligram) and plasma 8-F2&agr; isoprostanes, reduced LVH and proteinuria, and normalized endothelial function and vascular response to endothelin-1, although reduction in SBP was modest (174±8 mm Hg). Atorvastatin combined with removal of high salt normalized aortic eNOS activity, SBP, LVH, and proteinuria. These findings strongly suggest that concomitant prevention of vascular eNOS downregulation and inhibition of oxidative stress may contribute to the protection against end-organ injury afforded by this statin in salt-sensitive hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID