A meta-analysis of outcome trials in elderly hypertensives.
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Biomedical subjects
R Fagard
Publications and source records attributed to R Fagard.
Erythrocyte membrane lipids and cationic transport systems in men.
OBJECTIVE: The relationship between erythrocyte membrane and plasma lipids and various transmembrane erythrocyte cationic fluxes was examined in 53 normal men. DESIGN: Different measurements of erythrocyte transport systems were obtained: Na(+)-Li+ countertransport activity; Na+, K+ cotransport activity; Na+, K(+)-ATPase pump activity and the ground membrane permeability for Na+ and K+ as well as the intra-erythrocyte Na+, K+ and Mg2+ concentrations. Plasma cholesterol, triglycerides, phospholipids, free fatty acids, low- and high-density lipoprotein cholesterol levels and the erythrocyte membrane contents of cholesterol, phospholipids and free fatty acids were obtained from fasting subjects. RESULTS: In single regression analysis the erythrocyte Na(+)-Li+ countertransport and Na+, K+ cotransport activities were negatively related to the erythrocyte membrane cholesterol, phospholipids and free fatty acids contents. The Na+, K(+)-ATPase pump activity as assessed by the ouabain-sensitive Na+ efflux was also inversely related to the membrane cholesterol and phospholipids contents. In multiple regression analysis the red blood cell Na(+)-Li+ countertransport activity was independently and negatively related to the membrane cholesterol and free fatty acids contents. CONCLUSION: Our data show that an elevated level of erythrocyte membrane lipids in normal men is accompanied by lower Na(+)-Li+ countertransport, Na+, K+ cotransport and Na+, K(+)-ATPase pump activities.
Adult↗
Syst-Eur--a multicenter trial on the treatment of isolated systolic hypertension in the elderly: first interim report.
Syst-Eur is a multicenter placebo-controlled outcome trial designed by the European Working Party on High Blood Pressure in the Elderly to investigate the effect of antihypertensive treatment on the incidence of stroke in elderly patients with isolated systolic hypertension (ISH). Eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160-219 mm Hg with a diastolic blood pressure less than 95 mm Hg. The present paper is an interim report on the first 316 patients randomized into this trial. The placebo (n = 170) and active treatment (n = 146) groups were similar at randomization with respect to age (73 +/- 8 years; mean +/- SD), sitting blood pressure (178 +/- 12 mm Hg systolic; 85 +/- 7 mm Hg diastolic), percentage of men (34%), and percentage of patients with cardiovascular complications (29%). After randomization blood pressure fell more (p less than 0.001) in patients on active treatment than in those in the placebo group (19 +/- 20 mm Hg systolic; 6 +/- 10 mm Hg diastolic vs. 7 +/- 19 and 1 +/- 10 mm Hg for sitting blood pressure). This first interim report on the Syst-Eur trial demonstrates that a multinational trial in elderly patients with ISH is feasible and that a significant blood pressure difference between the two treatment groups can be achieved and maintained. New centers are being recruited in order to randomize a total of 3,000 patients.
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Comparison of the effect of celiprolol and nifedipine on blood pressure and plasma lipids.
During a double-blind, randomized study in hypertensive patients, changes in blood pressure (BP) and in plasma lipid and lipoprotein levels during treatment with celiprolol were compared with those occurring during nifedipine treatment. Fifty-three patients (28 men and 25 women) with mild-to-moderate hypertension, aged 20-64 years, were studied. After a 1-month placebo run-in period, patients were randomly assigned to receive either nifedipine (40 mg daily) or celiprolol (200 mg daily) each time using a double dummy technique. After 6 weeks, dosages of each drug could be doubled. Both drugs caused similar reductions in blood pressure but after 12 weeks treatment, the percentage of decrease in diastolic BP (DBP) was more pronounced (p less than 0.01) in the nifedipine group (-18%) than in the celiprolol group (-12%). After 6 weeks, there were no differences in plasma lipids between the two treatment groups. However, the changes after 12 weeks treatment were different (p less than 0.05) between the groups, leading to lower levels of plasma esterified cholesterol, low-density lipoprotein (LDL) cholesterol and apoprotein AI, AII, and B in the celiprolol group. Plasma lecithin cholesterol acyltransferase activity (LCAT) was not modified, suggesting that reverse cholesterol transport was not affected by the drugs. In both treatment groups, a significant positive relationship was observed between changes in LDL cholesterol and apoprotein B. As compared with nifedipine, celiprolol after 12-week therapy had a rather favorable plasma lipid profile. The clinical relevance of such findings, in terms of prevention of cardiovascular complications, has yet to be established.
Acyltransferases↗
Effects of cadmium exposure on the cardiovascular system and on calcium metabolism: results of a cross-sectional population study.
This paper summarizes the findings of the Cadmibel Study, a cross-sectional population study of the health effects of cadmium, but only with respect to the cardiovascular system and calcium metabolism. The study disproved the hypothesis that exposure to cadmium would lead to an increase in blood pressure and in the prevalence of hypertension and other cardiovascular diseases. On the other hand, there was a positive relationship between urinary cadmium (Cd-U) and both serum alkaline phosphatase activity and urinary excretion of calcium. The regression coefficients obtained after adjustment for significant co-variates indicated that, when Cd-U increased two-fold, serum alkaline phosphatase and urinary calcium rose by 4% and 0.25 mmol/24 h, respectively. These findings suggest that calcium metabolism is gradually affected as cadmium accumulates in the body. The morbidity associated with the latter phenomenon is still unknown, and requires further investigation, preferably in a longitudinal prospective population study, in which the incidence of morbid events would be monitored in relation to the cadmium body burden.
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Ambulatory blood pressure monitoring in elderly patients with isolated systolic hypertension.
OBJECTIVES: This study compared clinic and ambulatory blood pressure measurement and the reproducibility of these measurements in older patients with isolated systolic hypertension (ISH). PATIENTS: Eighty-seven patients aged greater than or equal to 60 years with ISH on clinic measurement were followed in the placebo run-in phase of the Syst-Eur trial. METHODS: Clinic blood pressure was defined as the mean of two blood pressure readings on each of three clinic visits (six readings in total). Ambulatory blood pressure was measured over 24 h using non-invasive ambulatory blood pressure monitors. RESULTS: Daytime ambulatory systolic pressure was, on average, 21 mmHg lower than the clinic blood pressure, whereas diastolic pressure was, on average, similar with both techniques of measurement. In the 42 patients who had repeat measurements, clinic blood pressure levels nad the amplitude of the diurnal blood pressure profile (fitted by Fourier analysis) were equally reproducible. However, both were less reproducible than ambulatory blood pressure levels. The repeatability coefficients, expressed as per cent of near maximum variation (four times the standard deviation of a given measurement), were 52% and 45% for the clinic systolic and diastolic pressures, 56% and 42% for the amplitude of the diurnal profile, and 29% and 26% for mean 24-h pressures. CONCLUSIONS: In older patients with ISH, clinic and ambulatory systolic blood pressure measurements may differ largely: the prognostic significance of this difference remains to be elucidated. Furthermore, in these patients the level of pressure is more reproducible by daytime ambulatory blood pressure measurement than by clinic measurement.
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Hypertensive heart disease: pathophysiology and clinical and prognostic consequences.
The determinants of cardiac output were investigated in 161 patients with essential hypertension World Health Organization (WHO) stages I and II. In multiple regression analysis, cardiac output was inversely and independently related to blood pressure and to age. In patients with more severe hypertension, the lower cardiac output was associated with a lower stroke volume and a higher peripheral oxygen extraction. When age and blood pressure were taken into account, cardiac output was not a significant predictor of total mortality and of future cardiovascular events. Clinic and casual blood pressure explain only up to about 30% of the variability of echocardiographic left ventricular mass. The relationship of electrocardiographic voltages with blood pressure at various levels of bicycle exercise was highly significant in 169 patients with essential hypertension (r = 0.29-0.38; p less than 0.001) but the relationship was not better than with pressure at rest (r = 0.39). Ambulatory blood pressure, however, may be better related to left ventricular mass than clinic pressure. Several studies indicate that left ventricular hypertrophy is a significant risk factor for future cardiovascular events, independent of age and blood pressure. Left ventricular systolic function is usually normal in established hypertension, but diastolic function is frequently impaired, which could explain the reduced peak oxygen uptake in patients with more severe hypertension.
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[SYST-EUR: a multicenter trial of treatment of systolic hypertension in aged subjects. An initial report].
Syst-Eur is a multicentre placebo-controlled outcome trial, designed by the European Working Party on High Blood Pressure in the Elderly (EWPHE), to investigate the effect of antihypertensive treatment on the incidence of stroke in elderly patients with isolated systolic hypertension (ISH). Eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160-219 mmHg with a diastolic blood pressure less than 95 mmHg. The present paper in an interim report on the first 316 patients randomized into this trial. The placebo (N = 170) and active treatment (N = 146) groups were similar at randomization with respect to age (73 +/- 8 years; mean +/- standard deviation), sitting blood pressure (178 +/- 12/85 +/- 7 mmHg), percentage men (34%) and percentage of patients with cardiovascular complications (29%). After randomization blood pressure fell more (p < 0.001) on active treatment than in the placebo group (19 +/- 20/6 +/- 10 mmHg versus 7 +/- 19/1 +/- 10 mmHg for the sitting blood pressure). This first interim report on the Syst-Eur trial demonstrates that a multinational trial in elderly patients with ISH is feasible and that a significant blood pressure difference between the 2 treatment groups can be achieved and maintained. New centres are being recruited in order to randomize a total of 3,000 patients.
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Trials in elderly patients with isolated systolic hypertension.
The hypothesis that antihypertensive drugs should be prescribed to elderly patients with isolated systolic hypertension is being addressed in at least 3 trials: the Systolic Hypertension in the Elderly Program (SHEP) in the United States, a trial in China, and the Syst-Eur study in Europe. The SHEP trial has recently reported its final morbidity and mortality results. This article summarizes the protocol of the European study. To be eligible for the Syst-Eur trial, patients must be at least 60 years old and have a systolic blood pressure averaging 160-219 mmHg with a diastolic pressure less than 95 mmHg. Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry. The patients are randomized into active treatment or placebo. Active treatment consists of nitrendipine (10-40 mg/d), combined with enalapril (5-20 mg/d) and hydrochlorothiazide (12.5-25 mg/d), as necessary. The control group received matching placebos. The drugs (or matching placebos) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg. Morbidity and mortality are monitored to enable an intention-to-treat and per protocol comparison of the outcome in the two treatment groups.
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Mean and range of the ambulatory pressure in normotensive subjects.
To perform a meta-analysis of published reports in an attempt to determine the mean and range of normal ambulatory blood pressure (BP), 23 studies including a total of 3,476 normal subjects were reviewed. Most studies were compatible with a mean 24-h BP in the range of 115-120/70-75 mmHg, a mean day time BP of 120-125/75-80 mmHg, and a mean night time BP of 105 to 110/60 to 65 mmHg. With weighting for the number of subjects included in the individual studies, the 24-h BP averaged 118/72 mmHg, the day time BP 123/76 mmHg, and the night time BP 106/64 mmHg. The night/day pressure ratio averaged 0.87 for systolic and 0.83 for diastolic BP, with ranges across the individual studies from 0.79 to 0.92 and from 0.75 to 0.90, respectively. If the mean +/- 2 standard deviation interval in the various studies was considered normal, the range of normality was on average 97 to 139/57 to 87 mmHg for the 24-h BP, 101 to 146/61 to 91 mmHg for the day time BP, and 86 to 127/48 to 79 mmHg for the night time BP. Until the results of prospective studies on the relation between the ambulatory BP and the incidence of cardiovascular morbidity and mortality become available, the aforementioned intervals, which summarize the experience of 23 investigators, could serve as a temporary reference for clinical practice.
Adolescent↗
Regulation of SRC-family protein tyrosine kinases by interleukins, IL-2, and IL-3.
Unlike many other growth factor receptors, the known subunits of the receptors for the Interleukins IL-2 and IL-3 lack intrinsic tyrosine kinase activity, and yet increases in the phosphorylation of proteins on tyrosines is a rapid event in hematolymphoid cells following stimulation with these lymphokines. Here we show that IL-2 and IL-3 regulate the activity of specific members of the SRC-family of non-receptor protein tyrosine kinases (PTKs). In IL-2-dependent T-cell lines, IL-2 induced rapid and transient increases in the activity of the p56-LCK kinase without influencing the activities of other SRC-like PTKs (p59-FYN, p62-YES) in these T-lymphocytes. In contrast to IL-2's effects on p56-LCK in T-cells, studies of an IL-2-responsive cell line of the B-cell lineage that lacks p56-LCK revealed that IL-2 specifically regulates the activity of the p53/56-LYN kinase. Thus, some flexibility exists in the ability of various SRC-like PTKs to functionally couple to IL-2 signalling pathways. In several IL-3-dependent myeloid-committed leukemic cell lines, IL-3 was found to specifically regulate the activity of the p53/56-LYN kinase without affecting the activities of other SRC-like PTKs (p59/64-HCK, p59-FYN, p62-YES) in these hematopoietic cells. This finding that p53/56-LYN can be regulated by both IL-2 in B-lineage cells and IL-3 in myeloid-committed cells demonstrates that the same SRC-family PTK can participate in signal transduction events mediated via two independent receptor systems. Taken together, our findings imply that the specific combinations of lymphokine receptors and SRC-like PTKs available for coupling with those receptors are coordinately controlled during the differentiation of hematopoietic cells.
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Blood pressure, the prevalence of cardiovascular diseases, and exposure to cadmium: a population study.
In a population study conducted from 1985 to 1989 in Belgium, the authors investigated whether exposure to cadmium is associated with blood pressure elevation and with an increased prevalence of cardiovascular diseases. The participants, aged 20-88 years, constituted a random sample of the households living in two low exposure areas (n = 803) and two high exposure areas (n = 1,283). For each exposure level, a rural and an urban district were selected. The cadmium levels in blood (8.5 vs. 11.0 nmol/liter) and urine (7.2 vs. 8.7 nmol/24 hours) were significantly (p less than 0.001) raised in the two high exposure areas compared with the two low exposure areas (p less than 0.001). Systolic pressure was similar in both rural areas, but in the urban area with high exposure systolic pressure was 5 mmHg (p less than 0.001) higher than in the control town. Diastolic pressure was similar in the four districts and the same was true for the prevalence of hypertension and of other cardiovascular diseases. Adjustment of systolic pressure for blood and urinary cadmium did not remove the difference in systolic pressure between both urban areas, suggesting that it was not related to the cadmium burden on the environment. Further analyses in individual subjects showed that neither blood pressure nor the presence of cardiovascular diseases were significantly and positively correlated with blood and urinary cadmium. Thus, the present population study did not confirm the hypothesis that increased exposure of the population to cadmium is associated with blood pressure elevation and with a higher prevalence of cardiovascular diseases.
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Relation of cardiac output at rest and during exercise to age in essential hypertension.
It has been suggested that the decline of cardiac output with age is due to increased prevalence of disease, particularly occult coronary artery disease. Therefore, the relation of cardiac output (direct oxygen Fick method) to age was analyzed in 110 sixteen- to 64-year-old men with World Health Organization stage I or II essential hypertension at the time of the hemodynamic study, who were alive and free of cardiovascular complications 7 years later. At supine and seated rest, during upright bicycle exercise at 50 W and and at peak work load, cardiac output was inversely (p less than 0.01) related to age. These relations were independent of weight and mean intraarterial pressure. Stroke volume decreased with advancing age at supine rest, but not at rest and during exercise in the seated position. Heart rate was not affected by age in the supine position, but was slower in older patients during upright rest and at peak exercise. In conclusion, in patients with essential hypertension who remained free of cardiovascular complications for 7 years, cardiac output was independently and inversely related to age at various levels of activity. These findings suggest that occult cardiovascular disease does not explain the decline in cardiac output with age in patients with essential hypertension.
Adolescent↗
The tyrosine kinase activity of p56lck is increased in human T cells activated via CD2.
An early biochemical event associated with T cell activation is tyrosine phosphorylation. We have previously shown that p56lck, a lymphocyte-specific protein tyrosine kinase, is hyperphosphorylated on serine and tyrosine residues 15 minutes after activation via CD2 with a concomitant shift to a higher molecular mass. We now demonstrate that the tyrosine kinase activity of p56lck is increased within seconds following CD2 triggering. This activity decreases thereafter correlating with the appearance of changes in phosphorylation previously described. These results suggest that p56lck may play an important role in the CD2 activation pathway.
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Review of the major hypertension trials in the elderly.
The different intervention trials in elderly hypertensives are compatible with the hypothesis that hypotensive drug treatment can decrease cardiovascular mortality mainly by decreasing cerebrovascular mortality. A decrease in the fatal and nonfatal cardiovascular event rate is mainly due to a decrease in cerebrovascular events. It is not established whether hypotensive drug treatment is advisable in symptomless patients with isolated systolic hypertension and in patients with uncomplicated hypertension above age 80. A sudden reduction in blood pressure should be avoided, but whether a progressive reduction of systolic blood pressure below 140 mmHg and of diastolic blood pressure below 85 mmHg is dangerous or advantageous remains to be established.
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Hormonal effects of the diuretic xipamide in healthy men.
The effect of xipamide on plasma alpha-atrial natriuretic peptide and the renin-aldosterone-kallikrein system have been studied in 12 healthy men, using a double-blind cross-over design. After a run-in period on placebo of 1 week, the subjects were treated with either placebo (n = 6) or xipamide 20 mg once daily (n = 6) for 16 weeks and were then switched to the alternative medication for another 16 weeks. The plasma concentration of alpha-atrial natriuretic peptide fell after 1 week of xipamide administration and increased during prolonged xipamide administration but remained reduced. The changes in plasma alpha-ANP observed after 1 week of xipamide were negatively correlated with the changes in hematocrit and hemoglobin. Plasma renin activity (PRA), aldosterone concentration (PAC), and urinary excretion of aldosterone and kallikrein increased after 1 week of xipamide administration, levelled off during the second and fourth weeks, but remained elevated during further prolonged xipamide administration for 16 weeks. The xipamide-induced changes in PRA and PAC were positively correlated with the changes in the hematocrit and hemoglobin. The changes in plasma renin, aldosterone, and alpha-atrial natriuretic peptide during xipamide administration may be related to diuretic-induced volume contraction.
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Syst-Eur. A multicentre trial on the treatment of isolated systolic hypertension in the elderly: objectives, protocol, and organization.
The Syst-Eur Trial is a concerted action of the European Community's Medical and Health Research Programme. The trial is carried out in consultation with the World Health Organization, the International Society of Hypertension, the European Society of Hypertension and the World Hypertension League. This article describes the objectives and the protocol of Syst-Eur, a multicentre trial designed by the European Working Party on High Blood Pressure in the Elderly (EWPHE), to test the hypothesis that antihypertensive treatment of elderly patients with isolated systolic hypertension results in a significant change in stroke morbidity and mortality. Secondary endpoints include cardiovascular events, such as myocardial infarction and congestive heart failure. To be eligible patients must be at least 60 years old and have a systolic blood pressure averaging 160-219 mmHg with a diastolic pressure less than 95 mmHg. Patients must give their informed consent and be free of major cardiovascular and non-cardiovascular diseases at entry. The patients are randomized to active treatment or placebo. Active treatment consists of nitrendipine (10-40 mg/day), combined with enalapril (5-20 mg/day) and hydrochlorothiazide (12.5-25 mg/day), as necessary. The patients of the control group receive matching placebos. The drugs (or matching placebos) are stepwise titrated and combined in order to reduce systolic blood pressure by 20 mmHg at least to a level below 150 mmHg. Morbidity and mortality are monitored to enable an intention-to-treat and per-protocol comparison of the outcome in the 2 treatment groups. A one-year pilot trial (1989) showed that the protocol is practicable. The Ethics Committee therefore decided to start the definite study (1990), in which randomized patients will be followed for 5 years. Recruitment of new centres and of the required 3,000 patients will last 3 years (until 1993).
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The inheritance of left ventricular structure and function assessed by imaging and Doppler echocardiography.
The heritability of left ventricular structure and function was studied in 53 pairs of monozygotic and dizygotic twins, aged 18 to 31 years, by means of M-mode and Doppler echocardiography. A significant fraction of the phenotypic variances of left ventricular wall thickness was explained by genetic variance. For the left ventricular internal dimension, however, no genetic effect was found after correction for body weight. After appropriate adjustment a genetic component of 32% was found for aortic peak flow velocity, 55% for stroke distance, and 47% for minute distance. The early and late diastolic peak flow velocities at the mitral valve showed a genetic component estimated at 43% and 26%, respectively. The inheritance of the late/early diastolic peak flow velocity ratio was estimated at 53%. In conclusion, these data suggest a significant genetic component for left ventricular structural features but not for cavity dimension. A significant influence of heredity was detected for left ventricular inflow and outflow characteristics.
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