Jg Wang

Menopause and the characteristics of the large arteries in a population study.

In previous cross-sectional and longitudinal population studies, we found that the slope of systolic pressure on age was steeper in postmenopausal than in premenopausal women. We hypothesised that this observation could be due to a specific effect of menopause on the elasticity of the large arteries. We investigated 315 randomly selected women, aged 30 to 70 years. Based on 5.2 years of follow-up, 166 women were premenopausal and 149 menopausal (44 reaching menopause and 105 postmenopausal). These women were matched on age and body mass index with 315 men. We used a wall-tracking ultrasound system to measure the diameter, compliance and distensibility of the brachial and the common carotid and femoral arteries as well as carotid-femoral pulse wave velocity. Pulse pressure was determined from 24-h blood pressure recordings. Both in menopausal women (r = 0.37; P < 0.001) and in matching male controls (r = 0.16; P = 0.04), pulse pressure widened with increasing age. The slope of the 24-h pulse pressure on age was steeper in menopausal women than in their premenopausal counterparts (0.428 vs −0.066 mm Hg per year; P = 0.003) and than in the male controls (0.428 vs 0.188 mm Hg per year; P = 0.06). After adjustment for age, 24-h mean pressure, body mass index, antihypertensive drug treatment, smoking and the use of oral contraceptives or hormonal replacement therapy, postmenopausal women showed a higher carotid-femoral pulse wave velocity (7.77 vs 6.71 m/s; P = 0.02) and had a slightly greater diameter of the common carotid artery (7.09 vs 6.79 mm; P = 0.07) than their premenopausal counterparts. After similar adjustments, menopausal class was not significantly associated with other vascular measurements in women or with any vascular measurement in control men. In conclusion, menopause per se may increase aortic stiffness. We hypothesise that this phenomenon may contribute to the rise in systolic pressure and pulse pressure in women beyond age 50 and, in turn, may lead to a slight dilatation of the common carotid artery.

Antihypertensive treatment modulates the association between the D/I ACE gene polymorphism and left ventricular hypertrophy: a meta-analysis

This meta-analysis attempted to derive pooled estimates for the putative association between echocardiographic or electrocardiographic left ventricular hypertrophy and the deletion/insertion (D/I) polymorphism of the angiotensin-I converting enzyme. Case-control studies were combined, using the Mantel and Haenszel approach. Joint P-values for continuous variables were calculated by Stouffer’s method. Continuous measurements of left ventricular mass, which were reported in different units, were expressed on a percentage scale using the within-study mean of the II genotype as the denominator. The computerised database used for this analysis, included 28 reports with an overall sample size of 6638 subjects. The prevalence of the D allele was significantly lower in Japanese (37.2%) than in Caucasians (56.2%). A funnel plot including 12 case-control studies (4094 subjects) suggested that no publication bias was present. Overall, left ventricular hypertrophy was not associated with the D allele. Compared with the II genotype, the excess risks of left ventricular hypertrophy associated with DD and DI genotypes were only 14% (95% CI: 0.92–1.42; P = 0.23) and 5% (95% CI: 0.87–1.28; P = 0.61), respectively. However, the sensitivity analysis showed that in untreated hypertensive patients the DD genotype, compared with II homozygozity, was associated with a 192% (P = 0.002) higher risk of left ventricular hypertrophy. If left ventricular mass was analysed as a continuous trait across 23 studies (5438 subjects), overall no association with the D/I polymorphism was present. However, if untreated hypertensive patients were analysed separately, echocardiographic left ventricular mass was on average 10.1% (95% CI: 4.8–15.5%; P = 0.001) higher in DDhomozygotes than in the II reference group. Thus, in untreated hypertensive patients, in case-control studies as well as association studies, the D allele behaved as a marker for left ventricular hypertrophy. These findings support the hypothesis that the enhanced ACE activity associated with the D allele may promote left ventricular hypertrophy if a pathophysiologic process causing this disorder, remains unopposed by treatment.

Independent prognostic value of the ambulatory arterial stiffness index and aortic pulse wave velocity in a general population

Independent prognostic value of the ambulatory arterial stiffness index and aortic pulse wave velocity in a general population

β-Adducin polymorphisms, blood pressure, and sodium excretion in three European populations

The associations of the beta-adducin C1797T polymorphism with blood pressure (BP) and various indexes of sodium homeostasis were investigated in 388 men and 456 women, aged 18 to 60 years, recruited from three European populations (Cracow, Poland, n = 300; Novosibirsk, Russian Federation, n = 274; Mirano, Italy; n = 270). Phenotypes included 24-h ambulatory BP and urinary excretion of electrolytes and aldosterone. Subjects were genotyped for the beta-adducin polymorphism. Both a population-based association study and a family-based analysis were performed. Urinary sodium excretion was higher in Cracow than in Mirano (241 v 185 mmol/24 h, P <.05) and intermediate in Novosibirsk (206 mmol/24 h). The beta-adducin T allele (15.2% v 9.1%, P <.0001) was more prevalent in Mirano than in the two Slavic centers. In both population-based and family-based association analyses, there was significant heterogeneity between Slavic and Italian subjects in the phenotype-genotype relationships with beta-adducin. In the Slavic centers, 24-h systolic BP was higher in T allele carriers than in CC homozygotes (122.3 v 119.7 mm Hg, P =.03), whereas this was not the case in Mirano (121.8 v 122.9 mm Hg, P =.42). In Slavic (212.6 v 233.1 mmol/24 h) as well as in Italian (166.1 v 191.5 mmol/24 h) participants, 24-h sodium excretion was lower (P =.01) in T allele carriers than in CC homozygotes. These results were confirmed in the family-based analysis of offspring using a quantitative transmission disequilibrium test. In conclusion, the frequency of the beta-adducin T allele and salt intake differ across European populations. Thus, both variation in genetic background and salt intake may explain the observed heterogeneity in the phenotype-genotype relationships. Genetic determinants of complex quantitative traits such as BP can only be investigated within their epidemiologic context.

Blood pressure in relation to three candidate genes in a Chinese population.

Objective In a prospective analysis of a Caucasian population, we recently found that the genes encoding angiotensin-converting enzyme (ACE, I/D polymorphism), α-adducin (Gly460Trp) and aldosterone synthase (–344C/T) jointly influence the incidence of hypertension. We therefore investigated the association between blood pressure and these three genes in a Chinese population. Methods We genotyped 479 Han Chinese from 125 nuclear families recruited in northern China via random sampling (∼75%) and at specialized hypertension clinics (∼25%). We performed population-based and family-based association analyses using generalized estimating equations (GEE) and the quantitative transmission disequilibrium test (QTDT), respectively, while controlling for covariables. Results The participants included 239 (49.9%) women and 132 (27.6%) hypertensive patients, of whom 77 took antihypertensive drugs. The blood pressure, measured at the subjects’ homes, averaged 126/80 mmHg. Mean values of urinary sodium, potassium and Na+/K+ ratio were 226 mmol/day, 37 mmol/day and 6.31, respectively. In adjusted GEE analyses, systolic blood pressure was 9.3 mmHg (95% confidence interval 3.6–15.0 mmHg; P = 0.001) and 14.6 mmHg (95% confidence interval 3.4–25.8 mmHg; P = 0.01) higher in the ACE DD than II subjects among the α-adducin TrpTrp (n = 141) and aldosterone synthase CC (n = 33) homozygotes, respectively (P ⩽ 0.05 for interactions of the ACE genotype with the α-adducin and aldosterone synthase polymorphisms). Among 40 informative offspring homozygous for the α-adducin Trp allele, systolic blood pressure was significantly associated with transmission of the ACE D allele (β = 5.5 mmHg; P = 0.046). Conclusions The ACE I/D, α-adducin Gly460Trp and aldosterone synthase –344C/T polymorphisms interact to influence systolic blood pressure in Chinese, suggesting that these genes might indeed predispose to hypertension, especially in an ecogenetic context characterized by a high salt intake.

Reproducibility of the ambulatory arterial stiffness index in hypertensive patients.

Background We studied the repeatability of the ambulatory arterial stiffness index (AASI), which can be computed from 24-h blood pressure (BP) recordings as unity minus the regression slope of diastolic on systolic BP. Methods One hundred and fifty-two hypertensive outpatients recruited in Nijmegen (mean age = 46.2 years; 76.3% with systolic and diastolic hypertension) and 145 patients enrolled in the Systolic Hypertension in Europe (Syst-Eur) trial (71.0 years) underwent 24-h BP monitoring at a median interval of 8 and 31 days, respectively. We used the repeatability coefficient, which is twice the SD of the within-participant differences between repeat recordings, and expressed it as a percentage of four times the SD of the mean of the paired measurements. Results Mean AASI (crude or derived by time-weighted or robust regression) and 24-h pulse pressure (PP) were similar on repeat recordings in both cohorts. In Nijmegen patients, repeatability coefficients of AASI and PP were ∼50%. In Syst-Eur trial patients, repeatability coefficient was ∼60% for AASI and ∼40% for PP. For comparison, repeatability coefficients for 24-h systolic and diastolic BP were ∼30%. Differences in AASI between paired recordings were correlated with differences in the goodness of fit (r2) of the AASI regression line as well as with differences in the night-to-day BP ratio. However, in sensitivity analyses stratified for type of hypertension, r2, or dipping status, repeatability coefficients for AASI did not widely depart from 50 to 60% range. Conclusion Estimates of mean AASI were not different between repeat recordings, and repeatability coefficients were within the 50–60% range.

Is blood pressure during the night more predictive of cardiovascular outcome than during the day

The objective of this study was to investigate the prognostic significance of the ambulatory blood pressure (BP) during night and day and of the night-to-day BP ratio (NDR). We studied 7458 participants (mean age 56.8 years; 45.8% women) enrolled in the International Database on Ambulatory BP in relation to Cardiovascular Outcome. Using Cox models, we calculated hazard ratios (HR) adjusted for cohort and cardiovascular risk factors. Over 9.6 years (median), 983 deaths and 943 cardiovascular events occurred. Nighttime BP predicted mortality outcomes (HR, 1.18–1.24; P<0.01) independent of daytime BP. Conversely, daytime systolic (HR, 0.84; P<0.01) and diastolic BP (HR, 0.88; P<0.05) predicted only noncardiovascular mortality after adjustment for nighttime BP. Both daytime BP and nighttime BP consistently predicted all cardiovascular events (HR, 1.11–1.33; P<0.05) and stroke (HR, 1.21–1.47; P<0.01). Daytime BP lost its prognostic significance for cardiovascular events in patients on antihypertensive treatment. Adjusted for the 24-h BP, NDR predicted mortality (P<0.05), but not fatal combined with nonfatal events. Participants with systolic NDR of at least 1 compared with participants with normal NDR (≥0.80 to <0.90) were older, at higher risk of death, but died at higher age. The predictive accuracy of the daytime and nighttime BP and the NDR depended on the disease outcome under study. The increased mortality in patients with higher NDR probably indicates reverse causality. Our findings support recording the ambulatory BP during the whole day.

Haematological phenotypes in relation to the C1797T β-adducin polymorphism in a Caucasian population

beta-Adducin plays a role in maintaining the structural integrity of the red blood cell (erythrocyte) membrane. Moreover, beta-adducin-deficient knock-out mice show a phenotype characterized by mild anaemia and compensated haemolysis. We therefore investigated whether, in humans, common haematological phenotypes of red blood cells were associated with a polymorphism in exon 15 of the human beta-adducin gene (C1797T). We studied 802 unrelated individuals and 294 families (459 parents and 609 offspring) randomly selected from a Caucasian population. We employed generalized estimating equations to allow for the non-independence of the observations within families, while controlling for co-variables. In 917 men, with adjustments applied for age, body mass index, serum total cholesterol, smoking and alcohol intake, CC homozygotes had significantly ( P =0.02) lower values for red blood cell count (4.93 x 10(12)/l compared with 4.86 x 10(12)/l), haemoglobin level (9.30 compared with 9.18 mmol/l) and haematocrit (45.0% compared with 44.4%) than T allele carriers. In the 329 men who consumed alcohol, the differences between CC homozygotes and T allele carriers were 0.13 x 10(12)/l ( P =0.02) for red blood cell count, 0.23 mmol/l ( P =0.005) for haemoglobin and 1.08% ( P =0.02) for haematocrit. In 953 women, none of these associations was significant ( P >/=0.06), regardless of alcohol intake [13.3% of women ( n =127) consmued alcohol]. In conclusion, in men consuming alcohol, the beta-adducin CC genotype was associated with lower red blood cell count, haemoglobin level and haematocrit. We hypothesize that, in CC homozygotes, alcohol consumption may unveil the greater fragility of the red blood cell membrane. This genotype may slightly potentiate the structural and functional haematological disturbances associated with alcohol intake.

Cardiovascular risk and blood pressure reduction: an overview of the outcome trials

We performed a quantitative overview of the literature to investigate whether properties of antihypertensive drugs may play a role in cardiovascular protection over and beyond blood pressure (BP) lowering. We extracted summary statistics from published articles and computed pooled odds ratios (ORs) for experimental vs reference treatment from stratified 2 x 2 contingency tables after application of Zelen’s test of heterogeneity. Subsequently, we correlated ORs with BP differences across individual trials, using meta-regression. Among 5 trials in hypertension which compared cardiovascular risk on diuretics or b-blockers with that on calcium-channel blockers (CCBs) or angiotensin-converting enzyme (ACE) inhibitors, all drug classes offered similar cardiovascular protection. However, on CCBs there was more reduction in the risk of stroke (15.1%, CI 2.8–25.9%, p50.02) and less reduction in the risk of myocardial infarction (20.1%, CI 3.90–38.9%, p50.01). Meta-regression across 21 trials showed that for cardiovascular mortality the relationship between the ORs and BP differences was linear, whereas for other outcomes there was no further decrease in risk once the systolic/diastolic differences had reached ~15/5 mm Hg. In recent trials of doxazosin vs chlorthalidone in hypertensive patients and of ramipril vs placebo in high-risk patients, outcome was better on the diuretic and the ACE inhibitor, respectively. However, there were also 2-3/1 mm Hg BP differences between the groups. For systolic BP in the 2 trials, all ORs conformed with the regression lines. For diastolic BP, there was also no separation between predicted (0.99, CI 0.88–1.10) and observed ORs, except for the risk of all cardiovascular events on doxazosin (1.24, CI 1.15–1.33) or ramipril (0.76 CI 0.67–0.85). In conclusion, in the recent trials BP largely accounts for outcome. Older and newer antihypertensive drugs provide similar overall cardiovascular benefit, but CCBs may offer more protection against stroke than myocardial infarction. The hypothesis that ACE inhibitors or a-blockers might influence outcome over and beyond their BP lowering effects remains to be proven.

7B.09: BLOOD PRESSURE LOWERING EFFICACY OF AMLODIPINE AND NIFEDIPINE-GITS IN AMBULATORY HYPERTENSION.

Objective: We investigated whether the long-half time dihydropyridine calcium-channel blocker amlodipine was more efficacious than the gastrointestinal therapeutic system (GITS) formulation of nifedipine in lowering morning blood pressure in ambulatory hypertension. Design and method: The study was designed as a multicentre, randomized, parallel-group comparison trial in patients with stages 1 and 2 clinic (mean of 6 readings on 2 occasions off antihypertensive medication, systolic blood pressure 140–179 mm Hg and/or diastolic blood pressure 90–109 mm Hg) and ambulatory hypertension (24-hour mean blood pressure of at least 130 mm Hg systolic or 80 mm Hg diastolic). Eligible patients were randomly assigned to 8-week treatment with amlodipine 5 mg/day or with nifedipine GITS 30 mg/day, which could be up-titrated, respectively, to 10 mg/day or 60 mg/day at 4 weeks of follow-up. The primary efficacy variable was the change from baseline to the end of 8-week treatment in morning systolic blood pressure (4:00 to 8:00) of the first 24-hour ambulatory monitoring. Results: In the intention-to-treat analysis, blood pressure at 4 and 8 weeks of follow-up was similarly reduced in the amlodipine (n = 257) and nifedipine GITS (n = 248) groups for clinic measurement and 24-hour, daytime, night-time, and morning ambulatory measurements (P> = 0.07). However, amlodipine, compared with nifedipine GITS, was 2–3 mm Hg more efficacious in lowering ambulatory blood pressure within 4 hours of drug ingestion and after a dose of medication was missed (P< = 0.05). The results of the per-protocol analysis were confirmatory. Conclusions: Both amlodipine and nifedipine GITS are efficacious in reducing clinic and ambulatory blood pressure. However, when a dose of medication is delayed or missed, amlodipine, but not nifedipine GITS, remains efficacious in lowering blood pressure.