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R Fagard

Publications and source records attributed to R Fagard.

At least 37 records · Page 2Linked to original sources
PubMed2001

Renal function in relation to three candidate genes.

We recently found that femoral intima media thickness, as well as the incidence of hypertension, is influenced by genes encoding the angiotensin-converting enzyme (ACE; insertion/deletion [I/D]) polymorphism, alpha-adducin (Gly460Trp), and aldosterone synthase (-344C/T). By interfering with blood pressure or sodium homeostasis, these genetic polymorphisms also may change renal function. We therefore investigated serum creatinine level, calculated and measured creatinine clearances, and 24-hour urinary protein excretion in subjects previously genotyped for these three polymorphisms. The 1,454 participants drawn at random from the population (64.3% of those invited) were aged 43.4 years and included 744 women (51.2%). Blood pressure, measured by study nurses at subjects' homes, averaged 123/76 mm Hg. Mean values were 90 micromol/L for serum creatinine; 84 and 88 mL/min/1.73 m(2) for calculated and measured (n = 855) creatinine clearances, respectively; and 90 mg/d of protein for proteinuria (n = 556). The prevalence of mild renal dysfunction (creatinine clearance </= 60 mL/min/1.73 m(2)) was nearly 11%. In single-gene analyses with adjustment for significant covariables, the risk for mild renal dysfunction was positively associated with the ACE D allele. However, multiple-gene analyses showed that these associations were restricted to carriers of the mutated alpha-adducin Trp allele (40.1% of all subjects). Findings remained similar after hypertensive patients and women on hormonal therapy were excluded. In this phenotypically more homogeneous subgroup, serum creatinine level was 3.6 micromol/L (P = 0.02) and relative risks for mild renal dysfunction and proteinuria were 1.7-fold (P < 0.001) and 26% (P = 0.02) greater in ACE D subjects than ACE II homozygotes, respectively. The aldosterone synthase T allele did not strengthen genetic associations with the ACE D allele considered alone or in combination with the alpha-adducin Trp allele. Thus, in the present cross-sectional analysis, renal function was slightly but consistently impaired when both the ACE D and alpha-adducin Trp alleles were present. These findings, together with experimental studies and our previous reports on femoral intima media thickness and the incidence of hypertension, constitute a growing body of evidence delineating a clinical entity genetically determined by the risk-carrying ACE D and alpha-adducin Trp alleles.

Adolescent↗
PubMed2001

Risks of smoking in treated and untreated older Chinese patients with isolated systolic hypertension.

OBJECTIVES: To examine the health risks associated with smoking and blood pressure in Chinese hypertensive patients and to compare the benefit of antihypertensive drug treatment with the risk attributable to smoking. METHODS: We used multiple Cox regression to correlate outcome with blood pressure and smoking status in 2284 older (aged > or = 60 years) patients enrolled in the Systolic Hypertension in China (Syst-China) Trial (systolic/diastolic blood pressure > or = 160/< 95 mmHg). RESULTS: Median follow-up was 3.0 years. After adjustment for sex, age, active antihypertensive treatment and various entry characteristics, the relative hazard rates associated with smoking more than 20 cigarettes per day were 2.04 (P = 0.04), 4.66 (P < 0.001) and 4.74 (P = 0.002) for all-cause, noncardiovascular and cancer mortality, respectively. With similar adjustments applied, the relative hazard rates for total (fatal and non-fatal) stroke associated with smoking 10-20 and more than 20 cigarettes per day were 1.78 (P = 0.04) and 2.23 (P = 0.03), respectively. Furthermore, both smoking and systolic blood pressure were associated with higher risk of stroke. Compared with the overall risk in the whole group, treating 1,000 patients for 5 years prevented 40 [95% confidence interval (CI), 5-75] strokes in smokers as well as never smokers. Prognosis in never smokers and past smokers was similar. Quitting smoking had the potential to prevent 51 (95% CI, -21 to 122) strokes in untreated hypertensive patients and to prevent 45 (95% CI, - 14 to 104) additional strokes in treated patients, over and above the effects of antihypertensive treatment. If, in addition to stroke, non-cardiovascular mortality was also accounted for, the estimated absolute benefit of quitting smoking increased to 69 (95% CI, -18 to 155) and 97 (95% CI, 23-171) events in the untreated and the treated group, respectively. CONCLUSIONS: In elderly Chinese patients, smoking was a risk factor for all-cause, non-cardiovascular and cancer mortality, as well as fatal and non-fatal stroke. The potential benefits of antihypertensive treatment and quitting smoking were approximately similar. In our view, these findings are important in terms of public health policies and health economics.

Aged↗
PubMed2001

Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

BACKGROUND: In the outcome trials that provided information on renal function in older hypertensive patients, diuretics and beta-blockers were mostly used as first-line drugs. The long-term renal effects of calcium-channel blockers remain unclear. OBJECTIVE: To compare the changes in renal function in 2,258 treated and 2,148 untreated patients with isolated systolic hypertension, of whom 455 had diabetes mellitus and 390 had proteinuria. METHODS: We performed a post-hoc analysis of the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Active treatment was initiated with nitrendipine (10-40 mg/day) with the possible addition of enalapril (5-20 mg/day), hydrochlorothiazide (12.5-25 mg/day), or both, titrated or combined to reduce the sitting systolic blood pressure by at least 20 mmHg, to less than 150 mmHg. The main outcome measures were serum creatinine concentration and creatinine clearance calculated by the formula of Cockroft and Gault. RESULTS: Serum creatinine concentration at the time when participants were randomly allocated to study groups was less than 176.8 micromol/l (2.0 mg/dl), averaging 88 micromol/l. At the time of the last serum creatinine measurement, the blood pressure difference (P< 0.001) between the two groups was 11.6/4.1 mmHg. In the intention-to-treat analysis (11,427 patient-years), serum creatinine and the calculated creatinine clearance were not influenced by active treatment. However, in the patients assigned randomly to receive active treatment, the incidence of mild renal dysfunction (serum creatinine at least 176.8 mmol/l) decreased by 64% (P= 0.04) and that of proteinuria by 33% (P= 0.03). Active treatment reduced the risk of proteinuria more in diabetic than in non-diabetic patients: by 71%, compared with 20% (P= 0.04). In non-proteinuric patients, active treatment did not influence serum creatinine, whereas in patients with proteinuria at entry to the study, serum creatinine decreased on active treatment (P< 0.001). Furthermore, in on-randomized treatment comparison stratified for risk at baseline, serum creatinine concentration did not change (P= 0.98) in patients continuing to receive monotherapy with nitrendipine, whereas it increased by 6.73 mmol/l (P < 0.001) in patients who received hydrochlorothiazide alone or in combination with other study medication (P < 0.001 for difference in trends). CONCLUSIONS: In older patients with isolated systolic hypertension, antihypertensive treatment starting with the dihydropyridine calcium-channel blocker, nitrendipine, did not decrease blood pressure at the expense of renal function and prevented the development of proteinuria, especially in diabetic patients.

Aged↗
PubMed2001

Effects of three candidate genes on prevalence and incidence of hypertension in a Caucasian population.

BACKGROUND: The genes encoding angiotensin converting enzyme (ACE, I/D), alpha-adducin (ADD, Gly460Trp) and aldosterone synthase (AS, -344C/T) share the potential of influencing blood pressure (BP) via sodium homeostasis. However, most studies in humans focused on single-gene effects and disregarded epistasis, the suppression or potentiation of a gene by other non-allelic genes. METHODS: We studied the singular and combined effects of the aforementioned candidate genes: (1) in relation to BP, plasma renin activity (PRA) and urinary aldosterone in 1461 subjects randomly selected from a Caucasian population; and (2) in relation to the incidence of hypertension in a subgroup of 678 initially normotensive subjects followed up for 9.1 years (median). RESULTS: In cross-sectional analyses, AS/CC homozygosity was associated with slightly lower systolic BP (-1.32 mmHg; P = 0.08). AS/TT homozygotes showed both lower PRA and higher urinary aldosterone excretion (P < or = 0.05). In multiple-gene analyses, compared with the whole study population, ADD/Trp subjects had a higher relative risk of hypertension in the presence of the AS/T allele (1.29; P = 0.05), whereas in combination with AS/CC homozygosity ADD/Trp subjects had the smallest relative risk (0.48; P = 0.003). Hypertension developed in 229 subjects (36.6 cases per 1000 person-years). ACE/DD homozygosity, in comparison with the other ACE genotypes, was associated with increases in the incidence of hypertension, which amounted to 31% (P = 0.005) in single-gene analyses, to 59% (P = 0.004) in carriers of the ADD/Trp allele and to 122% (P = 0.0007) in AS/CC subjects. Among subjects who had both the ADD/Trp allele and the AS/CC genotype, ACE/DD homozygotes manifested a 252% (P = 0.001) higher incidence of hypertension. CONCLUSIONS: Epistatic interactions between the ACE, ADD and AS genes contribute to the prevalence and incidence of hypertension in Caucasians. The clinical relevance of the risk-conferring haplotypes identified in our prospective study was underscored by their positive predictive values, which under the assumption of a 20% life-time risk of hypertension, ranged from 29.8-40.1%.

Adult↗
PubMed2001

In vitro assay of collagen gel contraction by cardiac fibroblasts in serum-free conditions.

The aim of the present study was to investigate whether collagen gel contraction can be induced by cardiac fibroblasts in serum-free conditions. Cardiac fibroblasts (from normal male adult rats) from passage 2 were cultured to confluency and added to a hydrated collagen gel in Dulbecco's Modified Eagle's Medium with or without fetal bovine serum for 1, 2, 3 or 7 days. Control gels containing adult rat cardiac fibroblasts showed a significant amount of contraction after 2 days of incubation in a serum-free medium, causing a contraction to 47% of the area at the start of the incubation. Increasing the percent of fetal bovine serum induced further stimulation of the collagen gel contraction by cardiac fibroblasts. Optimal conditions for collagen gel contraction by adult fibroblasts were obtained with 100,000 cells incubated for 1 (up to 3) days. The presence of insulin-transferrin-selenium in the medium caused a more pronounced stimulation of the collagen gel contraction by cardiac fibroblasts, while sodium azide inhibited this contraction.

Animals↗
PubMed2001

The influence of zygosity and chorion type on fat distribution in young adult twins consequences for twin studies.

An adverse intra-uterine environment has been associated with abdominal fat distribution in singletons. Twins often have a low birth weight and a short gestation. Therefore, they may have an increased risk to develop abdominal obesity. Furthermore, monozygotic monochorionic twins (MZ MC) have a larger intra-pair birth weight difference compared to monozygotic dichorionic twins (MZ DC). If adult anthropometry is programmed in utero, this may affect the intra-pair correlations in adulthood and, consequently, also the results from the classic twin method to estimate genetic and environmental influences. In the present study, we compared the absolute values, the intra-pair differences, and the intra-pair correlations of body mass, height, BMI, and abdominal fat distribution of 424 MZ MC, MZ DC and dizygotic (DZ) twin pairs (aged 18-34 yrs). DZ, MZ DC and MZ MC twins did not differ for most anthropometric characteristics. Only MZ women tended (p = 0.03) to accumulate more abdominal fat compared to DZ twins. Overall, the contribution of zygosity and chorion type to adult anthropometry was rather low (< or = 1.7%). Although the intra-pair birth weight difference of MZ MC pairs (10.5% in men, 12.3% in women) was significantly larger compared to that of MZ DC pairs (6.9% and 9.2% resp.), the intra-pair differences in adult anthropometry were similar for both MZ twin types. Also the intra-pair correlations of MZ MC and MZ DC pairs were strikingly alike, suggesting no significant influence of the prenatal environment on adult concordance. In conclusion, the substantial difference in the prenatal environment of MZ MC and MZ DC twins did not result in a difference in intra-pair concordance of adult anthropometry and fat distribution. Therefore, we suggest that the chorion type of MZ twins does not bias the twin design and the estimation of the genetic contribution to adult anthropometry.

Adipose Tissue↗
PubMed2000

Exposure to cadmium and conventional and ambulatory blood pressures in a prospective population study. Public Health and Environmental Exposure to Cadmium Study Group.

This prospective population study investigated in a random sample of 692 subjects (age 20-83 years) how changing environmental exposure to cadmium influenced blood pressure (BP) and the incidence of hypertension. At baseline (1985 to 1989; participation rate, 78%) and follow-up (1991 to 1995; re-examination rate, 81%), blood pressure was measured by conventional sphygmomanometry (CBP; 15 readings in total) and, at follow-up, also by 24-h ambulatory blood pressure monitoring (ABP). Systolic/diastolic CBP at baseline averaged 128.4/77.3 mm Hg. At baseline, blood cadmium concentration (B-Cd) and urinary cadmium excretion (U-Cd) averaged (geometric means) 11.1 nmol/L and 10.2 nmol/24 h. Over 5.2 years (median follow-up), B-Cd fell by 29.6% and U-Cd by 15.2%. B-Cd fell less in subjects living closer to three zinc smelters and in premenopausal women. During follow-up, systolic CBP decreased by 2.2 mm Hg in men and remained unchanged in women, and diastolic CBP increased by 1.8 mm Hg in both sexes. No relationship could be demonstrated between the secular trends in CBP and B-Cd or U-Cd or between B-Cd or U-Cd at baseline and the incidence of hypertension. In addition, in cross-sectional analyses involving the average of all available CBP measurements in each participant or 24-h ABP at follow-up (mean, 119.1/71.4 mm Hg), blood pressure was not correlated with B-Cd or U-Cd. In conclusion, environmental exposure to cadmium was not associated with higher CBP or 24-h ABP or with increased risk for hypertension. The lesser fall in B-Cd in the residents living closer to the zinc smelters or in premenopausal women underscores the necessity to sanitize cadmium-polluted areas and to systematically reinforce the preventive measures to be adopted by exposed communities to reduce cadmium uptake.

Adult↗
PubMed2000

Effect of protease inhibitors on angiotensin-converting enzyme activity in human T-lymphocytes.

The purpose of these investigations was to determine whether the aminopeptidase B and leucine aminopeptidase inhibitor bestatin, the chymase inhibitor chymostatin, the calpain inhibitor E-64, and the neutral serine protease inhibitor leupeptin affect the angiotensin converting enzyme (ACE) activity in T-lymphocytes. ACE activity in homogenates of T-lymphocytes or in intact T-lymphocytes in suspension was measured by determining fluorimetrically histidyl-leucine, formed from the conversion of hippuryl-histidyl-leucine, coupled with ophtaldialdehyde. The effect of various concentrations (10(-9) to 10(-3) mol/L) of the angiotensin-converting enzyme inhibitors lisinopril and captopril and of the various protease inhibitors on ACE activity was studied. Lisinopril and captopril reduced the ACE activity in homogenates of T-lymphocytes in a concentration-dependent manner. Lisinopril exhibited a more pronounced inhibition of ACE in T-lymphocytes than did captopril. Chymostatin and E-64 had no effect on the ACE activity in T-lymphocytes, whereas leupeptin inhibited its activity in a dose-dependent fashion. Bestatin, on the contrary, increased the ACE activity in homogenates of T-lymphocytes as well as in intact T-lymphocytes in proportion to the concentration. Our data showed that the ACE activity in T-lymphocytes was stimulated by bestatin and inhibited by leupeptin, whereas chymostatin and E-64 did not affect the ACE activity in T-lymphocytes.

Adult↗
PubMed2000

Twenty-four hour blood pressure after exercise in patients with coronary artery disease.

The objective was to assess the influence of a cardiac rehabilitation training session on blood pressure measured shortly after exercise and during the subsequent 24 h in patients with stable coronary artery disease. Blood pressure was measured conventionally and by use of 24-h ambulatory blood pressure monitoring in seven men, mean age 53+/-8 (s.d.) years, after participation in a cardiac rehabilitation session and, in randomised order, on a non-exercise control day. Conventional blood pressure averaged 112+/-7/77+/-5 mm Hg in the sitting position on the control day and was not different at the same time of the day shortly after the patients had participated in a cardiac rehabilitation training session. Standing systolic pressure was lower by 7.8+/-4.3 mm Hg (P < 0.005) after exercise compared to the control situation, but this was not associated with orthostatic symptoms. However, ambulatory monitoring showed no differences in blood pressure with the non-exercise day during the subsequent 24-h period. In conclusion, standing but not sitting blood pressure was slightly lower shortly after a cardiac rehabilitation session, but the postexercise orthostatic hypotension was not sustained during normal activities of daily living.

Blood Pressure↗
PubMed2000

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.

Alleles↗
PubMed2000

Comparison of cardiac output measured by two automated methods of CO2 rebreathing.

PURPOSE: The aim of the present study was to investigate the reproducibility of the exponential method of CO2 rebreathing with the use of automated curve fitting and to determine whether this method is superior to the equilibrium method in terms of reproducibility and clinical practicability. METHODS: Repeated measurements of cardiac output were performed using the automated equilibrium and exponential methods. These measurements were compared in 12 healthy male subjects at rest and during incremental exercise tests. RESULTS: Estimated cardiac output was not significantly different between duplicate measurements at rest nor at any level of exercise with either method. At rest the exponential method showed a tendency toward larger variability than the equilibrium method. The exponential method produced significantly higher (P < or = 0.001) estimates at rest (averaging up to 9.8 L x min(-1)) compared with the equilibrium method (averaging up to 6.5 L x min(-1)). Reproducibility improved for both methods with increasing workloads, and a second measurement at rest also seemed more reproducible and valid than the first. During exercise, both methods produced comparable values for cardiac output, and highly significant relations between cardiac output and oxygen uptake were observed for both methods (ranging from r2 = 0.79 to r2 = 0.88, P < or = 0.001). The equilibrium method produced unpleasant side effects more frequently (75% vs 21%, P < or = 0.001) compared with the exponential method and lead more subjects to premature interruption of the exercise test because of the rebreathing maneuver (42% vs 17%, P = 0.058). CONCLUSIONS: Automated curve fitting for the exponential method gave reproducible and valid results during submaximal and maximal exercise but not at rest. The equilibrium method on the other hand interfered with exercise. Therefore, the equilibrium method is recommended at rest and at lower levels of exercise and the exponential method at higher intensities.

Adolescent↗
PubMed2000

Breath-hold contrast-enhanced three-dimensional MR angiography of the abdomen: time-resolved imaging versus single-phase imaging.

PURPOSE: To evaluate a technique for time-resolved breath-hold contrast material-enhanced three-dimensional magnetic resonance (MR) angiography of the abdomen. MATERIALS AND METHODS: In a prospective study, 43 patients underwent time-resolved MR angiography (acquisition time per data set, 7 seconds). The patients also underwent single-phase high-spatial-resolution MR angiography (acquisition time, 27 seconds) (n = 6), conventional angiography (n = 7), or both (n = 30). No bolus timing study was performed for time-resolved MR angiography. Image quality (presence of artifacts, ability to prevent venous overlap on arterial phase images, contrast enhancement) and demonstration of anatomic variants (renal arterial and venous variants, vena caval anomaly, visceral arterial variants) and vascular diseases were assessed. RESULTS: Time-resolved MR angiographic images were characterized by fewer and less severe artifacts, less overlap of enhancing veins, and better contrast enhancement than were single-phase MR angiographic images (P < .05). The mean sensitivity and specificity were 90% (nine of 10) and 100% (1 73 of 1 73), respectively, for detection of arterial anatomic variants and 93% (28 of 30) and 100% (324 of 325), respectively, for detection of disease. The technique also proved to be reliable for demonstration of venous disease. CONCLUSION: In comparison with current non-time-resolved MR angiographic techniques, time-resolved MR angiography is more robust and easier to perform and allows simultaneous evaluation of arterial and venous disease.

Abdomen↗
PubMed2000

Efficacy of diuretics and beta-blockers in diabetic hypertensive patients. Results from a meta-analysis. The INDANA Steering Committee.

OBJECTIVE: To review the effectiveness of diuretic or beta-blocker-based treatment of hypertension in diabetic patients. RESEARCH DESIGN AND METHODS: A meta-analysis on individual patient data was performed on four trials of the treatment of hypertension in which diabetic patients were included and treated with first-line diuretics or beta-blockers. The main outcomes were the relative risk of death, fatal or nonfatal stroke, fatal or nonfatal coronary events, and major cardiovascular events. RESULTS: There were 92 diabetic patients who received first-line beta-blockers and 1,008 who received diuretics. In the control groups, diabetic patients had nearly twice the risk of any outcome when compared with nondiabetic patients. The same blood pressure reduction was achieved under treatment in the diabetic and nondiabetic patients, except for systolic pressure, which decreased more in the nondiabetic patients at 1 year. In the 15,843 nondiabetic patients, the risk of all four outcomes was reduced significantly in the treated group. In the 2,254 diabetic patients, the risk reduction was significant only for fatal and nonfatal stroke (36%, P = 0.011) and major cardiovascular events (20%, P = 0.032), but not for death (5%, P = 0.65) and fatal or nonfatal coronary events (15%, P = 0.23). However, no heterogeneity was detected between diabetic patients and nondiabetic patients for any outcome. The numbers of outcomes avoided for 1,000 patients treated for 5 years were higher in diabetic patients (e.g., 38 major cardiovascular events) than with nondiabetic patients (e.g., 28 major cardiovascular events). CONCLUSIONS: These results show that hypertensive diabetic patients benefit from first-line treatment with diuretics. No conclusion can be drawn for beta-blockers, owing to the small sample size.

Adrenergic beta-Antagonists↗
PubMed1999

Identification of risk factors in hypertensive patients: contribution of randomized controlled trials through an individual patient database.

BACKGROUND: Predicting individual risk is needed to target preventive interventions toward people with the highest probability of benefit over a given time period. We assessed which prognostic factors should be used in predicting risk for hypertensive patients and in searching for treatment modifiers. METHODS AND RESULTS: Data from 24 390 hypertensive participants who constituted the control groups from 8 controlled trials (1726 deaths over 5 years) were analyzed in multivariate survival models. Outcomes were coronary heart disease death, stroke death, and cardiovascular death. We explored systematically the heterogeneity of results between trials. Left ventricular hypertrophy was electrocardiographically confirmed to be a powerful risk factor and should be included in risk scoring. Height, glomerular filtration rate, and serum uric acid deserve further exploration. Body mass index and heart rate were not confirmed as independent cardiovascular risk factors in this population. The association between male sex and coronary heart disease death was significantly stronger in British cohorts. The lack of prognostic value of diastolic blood pressure was explained by an interaction with age, with a positive association before 65 years and a negative association thereafter. Previous antihypertensive treatment was a significant risk factor. CONCLUSIONS: Clinical trials provide valuable information for risk prediction. Carefully exploring the heterogeneity among trials is a way to assess the generalizability of findings. This approach, if systematically performed, should increase the ability to identify risk modifiers and to predict individual therapeutic benefit.

Age Factors↗
PubMed1999

Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators.

CONTEXT: The clinical use of ambulatory blood pressure (BP) monitoring requires further validation in prospective outcome studies. OBJECTIVE: To compare the prognostic significance of conventional and ambulatory BP measurement in older patients with isolated systolic hypertension. DESIGN: Substudy to the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial, started in October 1988 with follow up to February 1999. The conventional BP at randomization was the mean of 6 readings (2 measurements in the sitting position at 3 visits 1 month apart). The baseline ambulatory BP was recorded with a noninvasive intermittent technique. SETTING: Family practices and outpatient clinics at primary and secondary referral hospitals. PARTICIPANTS: A total of 808 older (aged > or =60 years) patients whose untreated BP level on conventional measurement at baseline was 160 to 219 mm Hg systolic and less than 95 mm Hg diastolic. INTERVENTIONS: For the overall study, patients were randomized to nitrendipine (n = 415; 10-40 mg/d) with the possible addition of enalapril (5-20 mg/d) and/or hydrochlorothiazide (12.5-25.0 mg/d) or to matching placebos (n = 393). MAIN OUTCOME MEASURES: Total and cardiovascular mortality, all cardiovascular end points, fatal and nonfatal stroke, and fatal and nonfatal cardiac end points. RESULTS: After adjusting for sex, age, previous cardiovascular complications, smoking, and residence in western Europe, a 10-mm Hg higher conventional systolic BP at randomization was not associated with a worse prognosis, whereas in the placebo group, a 10-mm Hg higher 24-hour BP was associated with an increased relative hazard rate (HR) of most outcome measures (eg, HR, 1.23 [95% confidence interval [CI], 1.00-1.50] for total mortality and 1.34 [95% CI, 1.03-1.75] for cardiovascular mortality). In the placebo group, the nighttime systolic BP (12 AM-6 AM) more accurately predicted end points than the daytime level. Cardiovascular risk increased with a higher night-to-day ratio of systolic BP independent of the 24-hour BP (10% increase in night-to-day ratio; HR for all cardiovascular end points, 1.41; 95% CI, 1.03-1.94). At randomization, the cardiovascular risk conferred by a conventional systolic BP of 160 mm Hg was similar to that associated with a 24-hour daytime or nighttime systolic BP of 142 mm Hg (95% CI, 128-156 mm Hg), 145 mm Hg (95% CI, 126-164 mm Hg) or 132 mm Hg (95% CI, 120-145 mm Hg), respectively. In the active treatment group, systolic BP at randomization did not significantly predict cardiovascular risk, regardless of the technique of BP measurement. CONCLUSIONS: In untreated older patients with isolated systolic hypertension, ambulatory systolic BP was a significant predictor of cardiovascular risk over and above conventional BP.

Aged↗
PubMed1999

Mode of regulation of the extracellular signal-regulated kinases in the pancreatic beta-cell line MIN6 and their implication in the regulation of insulin gene transcription.

Physiological concentrations of glucose that lead to Ca2+ entry and insulin secretion activate extracellular signal-regulated protein kinases (ERK1 and ERK2) in the MIN6 pancreatic beta-cell line. Here we show that this activation is inhibited by the down-regulation of protein kinase C (PKC) and by genistein, an inhibitor of protein tyrosine kinases. In contrast with results obtained in other cell types, neither the epidermal growth factor activity nor the Src family protein tyrosine kinases seem to be involved in the Ca2+-dependent activation of ERKs. inhibition of tyrosine phosphatases by vanadate leads to the activation of ERKs. As observed in the response to glucose, this activation is dependent on Ca2+ entry through L-type voltage-dependent Ca2+ channels. Thus the activation of ERKs in response to glucose depends on PKC and possibly on a tyrosine kinase/tyrosine phosphatase couple. To define the role of ERK activation by glucose we studied the regulation of transcription of the insulin gene. We found that this transcription is regulated in the MIN6 cells in the same range of glucose concentration as in primary islets, and that specific inhibition of mitogen-activated protein kinase kinase, the direct activator of ERK, impaired the response of the insulin gene to glucose. This was observed by analysis of the transfected rat insulin I gene promoter activity and a Northern blot of endogenous insulin mRNA.

Animals↗
PubMed1999

Environmental exposure to cadmium, forearm bone density, and risk of fractures: prospective population study. Public Health and Environmental Exposure to Cadmium (PheeCad) Study Group.

BACKGROUND: Chronic low-level exposure to cadmium may promote calcium loss via urinary excretion. We undertook a prospective population study to investigate whether environmental exposure to cadmium lowers bone density and increases risk of fractures. METHODS: We measured urinary cadmium excretion, a biomarker of lifetime exposure, in people from ten districts of Belgium, of which six districts bordered on three zinc smelters. We also measured cadmium in soil and in vegetables from the districts, and collected data on incidence of fractures and height loss. Bone density was measured at the forearm just above the wrist by single photon absorptiometry, and calculated as the mean of six proximal and four distal scans. FINDINGS: Mean cadmium excretion at baseline was 8.7 nmol daily. Across the ten districts, mean cadmium concentration in soil ranged from 0.8 to 14.7 mg/kg, and from 0.1 to 4.0 mg/kg dry weight in vegetables. Median follow-up was 6.6 years. Mean forearm bone density in proximal and distal scans was 0.54 g/cm2 and 0.43 g/cm2 in men, and 0.44 g/cm2 and 0.34 g/cm2 in women. In postmenopausal women, a twofold increase in urinary cadmium correlated with 0.01 g/cm2 decrease in bone density (p<0.02). The relative risks associated with doubled urinary cadmium were 1.73 (95% CI 1.16-2.57; p=0.007) for fractures in women and 1.60 (0.94-2.72, p=0.08) for height loss in men. Cadmium excretion in districts near smelters was 22.8% higher (p=0.001) than in other districts, with fracture rates of 16.0 and 10.3 cases per 1000 person-years, respectively, and a population-attributable risk of 35.0%. INTERPRETATION: Even at a low degree of environmental exposure, cadmium may promote skeletal demineralisation, which may lead to increased bone fragility and raised risk of fractures.

Absorptiometry, Photon↗