Showing papers by "Robert Fagard published in 1995"

Prognostic value of training-induced change in peak exercise capacity in patients with myocardial infarcts and patients with coronary bypass surgery

Abstract: An inverse association between mortality and exercise capacity has been demonstrated previously in patients with coronary artery disease. Physical training generally increases exercise capacity. Only 1 study investigated the prognostic value of exercise capacity after training, but only in a limited number of patients. No data are available on the relation between mortality and the change in exercise performance with training. Peak oxygen uptake (VO2) was measured before and after a 3-month, predominantly dynamic training period in 417 patients with coronary artery disease. Apart from peak VO2, several patient characteristics, risk factors for cardiovascular disease, and exercise data were considered in a Cox proportional-hazards model. Peak VO2 had increased by 33% after the training period. During the total follow-up of 2,583 patient-years, 37 patients died. The cause of death was cardiovascular in 21. The prognostic value of peak VO2 was higher after training than before training, even after adjustment for age and other significant covariates. Cardiovascular mortality decreased more with greater increases in peak VO2 after training. The relative hazard rate of 0.98 indicates that a 1% greater increase in peak VO2 after training would be associated with a decrease in cardiovascular mortality of 2%. No differences in prognostic value and in training effects were observed between patients with myocardial infarcts and patients after coronary bypass grafting. Peak VO2, evaluated after a physical training program, and its change in response to training are independent predictors for cardiovascular mortality in patients with coronary artery disease.

A Consensus View on the Technique of Ambulatory Blood Pressure Monitoring

Abstract: This review, based on the Fourth International Consensus Conference on Ambulatory Blood Pressure Monitoring (Leuven, Belgium, 1994), deals with the technical aspects of ambulatory blood pressure monitoring. Ambulatory blood pressure monitoring by noninvasive intermittent techniques is widely used despite artifacts due to cuff size, movement, body position, short-term blood pressure variability, and interference with sleep. The performance of the currently available monitors under truly ambulatory conditions and during exercise remains a matter of debate, as are the procedures required to validate portable monitors under these circumstances. There is general agreement that whenever a monitor is to be used in special populations, such as older subjects or pregnant women, or in special conditions, such as exercise, a specific demonstration of its accuracy in these defined subgroups or conditions is warranted. Whether the auscultatory or oscillometric method is preferred remains controversial because each technique has specific advantages and disadvantages and because both can provide accurate results. Most experts in the field strongly believe that manufacturers should disclose the algorithms of their devices and that they should specify all changes made to the hardware and software of a previously validated monitor. Finally, the development of the volume-clamp method, which makes continuous noninvasive registration of blood pressure at the finger possible in both stationary and ambulatory conditions, opens new perspectives in research, in particular in relation to short-term blood pressure variability.

The relationships between left ventricular mass and daytime and night-time blood pressures : a meta-analysis of comparative studies

Abstract: Objective : To review the literature to examine critically the assertion that night-time blood pressure is a better predictor of echocardiographic left ventricular mass than daytime blood pressure, and that left ventricular mass is inversely related to the day-night blood pressure difference. Study selection : Published studies in which left ventricular mass (index) of normotensive or hypertensive individuals, or both, was related to automated blood pressure measurement during the day and night, or their difference, or both. Results of data analysis : The meta-analysis of 19 comparative studies, involving 1223 participants, indicates that the weighted correlation coefficient for the relationship between left ventricular mass (index) and systolic night-time blood pressure (0.44 ; 95% confidence limit 0.39-0.48) is not significantly different from the correlation with systolic daytime blood pressure (0.48 ; 95% confidence limit 0.44-0.52 ; P>0.2). The corresponding correlation coefficients for diastolic blood pressure both average 0.37. In half of the eight studies in which the association between left ventricular mass (index) and the day-night difference in blood pressure was analysed, investigators found no significant relationship between those variables ; in the others, the variance of the mass (index) that can be explained by the blood pressure difference is 15% at the most. Conclusion : The overall analysis suggests that night-time blood pressure is not a significantly better predictor of left ventricular mass than daytime blood pressure is, and that the relationship to the day-night blood pressure difference is not a unanimous finding and is only ever weakly significant.

Heritability of conventional and ambulatory blood pressures : a study in twins

Abstract: Conventional and 24-hour ambulatory blood pressures were measured in 26 pairs of monozygotic twins and 27 pairs of dizygotic twins, all male, ages 18 to 38 years, to determine the heritability of blood pressure measured under various conditions. Conventional pressure was the average of three well-standardized measurements in the supine position, and ambulatory pressure was recorded during the subjects' normal activities by use of the SpaceLabs 90202 device. Heritability was assessed by classic methods and by model fitting and path analysis. In the latter approach, the percent genetic variance was 70% for mean 24-hour systolic pressure and 73% for diastolic pressure, which was similar to the results for the conventional pressures (64% and 73%, respectively). During the night, these estimates were 72% and 51% for systolic and diastolic pressures, respectively, and also the average pressures of the total awake daytime period were under partial genetic control (63% and 55%, respectively). The remaining variances could be attributed primarily to unique environmental influences. However, shared and nonshared environmental factors were predominant for the pressures during a fixed 6-hour afternoon period. We conclude that the heritability of blood pressure is relatively high in young adult healthy men, for standardized conventional pressure and the average 24-hour pressure. Genetic variance is somewhat higher for the asleep pressure than for the awake systolic pressure.

INDANA: a meta-analysis on individual patient data in hypertension. Protocol and preliminary results.

Abstract: The overall effect of antihypertensive drug treatment has been well documented. The proportion of patients who benefit varies according to their baseline cardiovascular risk, and is small for the majority of people treated. Some investigators propose limiting the treatment target population to patients at high cardiovascular risk, but several assumptions must be made to justify this procedure. The INDANA project is a meta-analysis based on individual patient data, and thus offers the opportunity to check the validity of these assumptions. Its main objective is to identify responders (and non-responders) in the drug treatment of hypertension. The rationale and methods for such an approach are presented here, with the solution for some technical problems. The conclusion of the data collection has shown that the project is feasible. The results of the main analysis should be available in 1996, and should contribute to the selection of responders and to the individualization of the treatment of hypertension.

Prescription and results of physical activity.

Abstract: Les etudes epidemiologiques ont revele l'existence d'une correlation negative entre l'activite physique ou l'aptitude physique et la pression arterielle. Une meta-analyse portant sur 36 essais controles a montre un gain tensionnel moyen de -5.3 mmHg pour la pression systolique et de -4.8 mmHg pour la pression diastolique, obtenu apres un entrainement physique dynamique aerobique. Cette baisse tensionnelle dependait des valeurs initiales de la pression arterielle et du gain en capacite a l'effort. Le gain tensionnel moyen en exercice d'endurance a ete de -3/-3 mmHg chez les normotendus, de -6/-7 mmHg chez les patients ayant une hypertension limite, et de -10/-8 mmHg chez les hypertendus. Les reductions tensionnelles ont aussi ete observees dans des epreuves d'effort et durant les enregistrements ambulatoires. Les programmes d'exercice physique peuvent contribuer a la phase en charge de l'hypertension arterielle. Le choix d'un antihypertenseur chez les patients actifs necessite quelques precautions afin de ne pas alterer leur capacite a l'effort

Reversibility of left ventricular hypertrophy by antihypertensive drugs

Abstract: Although the development of left ventricular hypertrophy in hypertension is mainly explained as a response to an increased pressure load and wall tension, the relation of left ventricular mass with blood pressure is usually weak, even when 24-hour blood pressure monitoring is used. Other factors have therefore been considered, such as anthropometric and demographic characteristics, differences in life-style, genetic influences and neurohumoral factors. Antihypertensive drugs differ in their effects on neurohumoral factors and it has been suggested that these properties may influence their potency to reduce left ventricular mass, mainly on the basis of open single-drug studies. Several prospective randomized comparative studies have however been performed to assess whether some (classes of) drugs are more effective than others in reducing left ventricular mass. A meta-analysis of such studies, comparing diuretics, beta-blockers, calcium antagonists and/or converting enzyme inhibitors, suggests that the reduction of left ventricular mass with each of these classes is similar to the reduction obtained with the other 3 classes statistically combined. Of particular interest is the observation that the 4 studies which compared a converting enzyme inhibitor and a calcium antagonist concluded that the effect on left ventricular mass was not significantly different. There is evidence, however, that drugs such as minoxidil and hydralazine, do not reduce left ventricular mass.

Relation of left ventricular mass and filling to exercise blood pressure and rest blood pressure

Abstract: Ninety-two young men with normal blood pressure (BP) or borderline elevated BP underwent echocardiography and maximal exercise testing to study whether left ventricular (LV) mass and the mitral inflow velocity pattern are more closely related to BP measured during dynamic exercise than to pressure measured at rest. LV mass was significantly related (p < 0.05) to systolic BP measured at rest and at various workloads; however, the variance of LV mass that could be explained by exercise pressures, in addition to preexercise pressure, age, body size, resting heart rate, and peak oxygen uptake, was not significant. The ratio of the late to early mitral inflow velocity was significantly related to systolic BP at rest but not to the pressures during exercise, and there was no independent contribution of exercise BP to its variance. Thus, systolic BP at various levels of dynamic exercise does not contribute independently to the interindividual variance of LV mass and mitral inflow pattern in young men with normal or borderline elevated BP.

The Trough-to-Peak Ratio as an Instrument to Evaluate Antihypertensive Drugs

Abstract: The U.S. Food and Drug Administration designed the trough-to-peak ratio as an instrument for the evaluation of long-acting antihypertensive drugs, but the ratios are usually reported without accounting for interindividual variability. This study investigated how the trough-to-peak ratio would be affected by interindividual and intraindividual variability and by smoothing of the diurnal blood pressure profiles. The ambulatory blood pressure was recorded on placebo in 143 hypertensive patients (diastolic pressure on conventional measurement >95 mm Hg). After 2 months, the recordings were repeated on 10 mg (n=66) or 20 mg (n=77) lisinopril given once daily between 7 and 11 pm. The baseline-adjusted trough-to-peak ratios were determined from diurnal blood pressure profiles with 1-hour precision. Lisinopril reduced (±SD) the 24-hour pressure by 16±17 mm Hg for systolic and 10±10 mm Hg for diastolic ( P .001). According to the usual approach, disregarding interindividual variability, the trough-to-peak ratio was 0.72 for systolic pressure and 0.67 for diastolic pressure. In the 143 patients the ratios were not normally distributed. They were the same on both lisinopril doses. When interindividual variability was accounted for, the median trough-to-peak ratio was 0.34 (P 5 to P 95 interval, −0.46 to 0.87) for systolic pressure and 0.26 (−0.44 to 0.84) for diastolic pressure. In 66 patients examined twice on 10 mg lisinopril at a median interval of 32 days, the trough-to-peak ratios were characterized by large intraindividual variability. The median trough-to-peak ratios increased ( P

The effect of gender on aerobic power and exercise hemodynamics in hypertensive adults.

Abstract: To study the influence of gender on peak oxygen uptake and on the hemodynamic response to dynamic exercise in essential hypertension, 45 male and 45 female patients, matched for age and blood pressure, were studied. Blood pressure was measured intra-arterially and cardiac output by the direct oxygen Fick method. Anthropometric gender differences were accounted for by statistical adjustment for height and weight. The increase of absolute and adjusted stroke volume from sitting at rest to submaximal (50 W) and to peak bicycle exercise was smaller in women than in men (P < 0.05). At 50 W, oxygen uptake (0.96 vs 0.97 l.min-1) and cardiac output (10.9 vs 11.2 l.min-1) were not different between women and men, due to the steeper exercise-induced rises of heart rate (P < 0.001) and arteriovenous oxygen difference (P < 0.05) in the women. Women reached the same peak heart rate as men (168 vs 173 b.min-1), so that the lower (P < 0.001) stroke volume (77 vs 99 ml) and cardiac output (12.9 vs 17.0 l.min-1), together with the lower hemoglobin concentration, contributed to their impaired peak oxygen uptake (P < 0.001), both before (1.35 vs 2.17 l.min-1) and after adjustment for body size (1.44 vs 2.07 l.min-1). In conclusion, at fixed submaximal exercise, women achieve the same oxygen uptake and cardiac output as men despite a lower stroke volume, through adaptations of heart rate and peripheral oxygen extraction; their peak aerobic power and cardiac output are, however, substantially lower than in men.

Diurnal blood pressure profile in older patients with isolated systolic hypertension. The SYST-EUR Investigators.

Abstract: This study describes the diurnal blood pressure (BP) profile and identifies its correlates in older patients with isolated systolic hypertension (ISH). The ambulatory BP readings of 408 patients, aged > or = 60 years, with ISH on clinic measurement, enrolled in the placebo run-in phase of the Syst-Eur Trial were examined. The time-weighted 24 h BP, daytime and night-time BP and the cusum-derived crest and trough BP were computed to express the BP level. The daily alteration between the high and low BP span was estimated from the day-night BP difference, the cusum derived circadian alteration magnitude and plot height, as well as the amplitude of the Fourier curve. The 24 h SBP and DBP tended to be higher in men (150 +/- 15/82 +/- 9 mm Hg) than in women (147 +/- 17/79 +/- 10 mm Hg), but the sex difference was only significant for DBP. In multiple regression analysis, the 24 h SBP increased (P < 0.05) by 3 mm Hg for each 10 year increment in age and was also 10 mm Hg higher (P < 0.001) in smokers than in non-smokers; the 24 h DBP was 2 mm Hg higher (P < 0.05) in men than in women and decreased (P < 0.05) by 1.5 mm Hg for each 10 year increment in age. The day-night difference in SBP increased with 2 mm Hg for each 10 mm Hg increase in the conventional pressure, decreased with 5 mm Hg for each 10 year increment in age and was 6 mm Hg higher in smokers than in non-smokers; the day-night difference in diastolic pressure was 2 mm Hg greater in women than in men. We conclude that the main determinants of the diurnal BP variation in older patients with isolated systolic hypertension were sex, age, smoking habits and the level of pressure on conventional measurement.

Trough-to-peak versus surface ratio in the assessment of antihypertensive agents. APTH Investigators. Ambulatory Blood Pressure and Treatment of Hypertension.

Abstract: This study investigated whether the 'surface ratio', a novel index to characterize long-acting antihypertensive agents, would provide a more reproducible estimate of the duration of the antihypertensive effect than the more commonly used trough-to-peak ratio. In 66 hypertensive patients (diastolic pressure on conventional measurement > 95 mmHg), the ambulatory blood pressure was measured on a placebo at baseline and 2 months later, while the patients took 10 mg lisinopril once a day between 7 p.m. and 11 p.m. Diurnal treatment effect curves were obtained by subtracting the blood pressure at baseline from the corresponding value at 2 months for all time intervals considered in the analysis. In order to calculate the surface ratio, the area under the treatment effect curve was divided by the product of the maximal blood pressure lowering effect and the dosing interval (24 h). Reproducibility of the trough-to-peak and surface ratios was investigated by the Bland and Altman techniques. At 2 months, lisinopril reduced (+/- standard deviation) the 24 h pressure by 13 +/- 16 mmHg systolic and by 8 +/- 8 mmHg diastolic (p < 0.001). According to the usual approach, disregarding inter-individual variability, the trough-to-peak ratio was 0.7 for systolic and diastolic pressure. When in individual patients diurnal treatment effects curves with a 1 h resolution were investigated, the median trough-to-peak ratio was 0.30 for systolic pressure (5th-95th percentile interval [PI]: -0.51, 0.82) and 0.28 for diastolic pressure (PI: -0.37, 0.78); the corresponding values for the surface ratio were 0.33 (PI: 0.03, 0.58) and 0.30 (PI: -0.01, 0.55). In the same manner, the trough-to-peak ratios and surface ratios became larger when the individual blood pressure profiles were progressively smoothed by substituting 1 h averages by 2 h moving averages, 2 h averages, 3 h moving averages or by 3 h averages. The distributions of the trough-to-peak ratios and surface ratios were non-normal in 37 of 40 instances (p < 0.001, Shapiro-Wilk's test). Consistency was higher (p < 0.001) for the surface than for the trough-to-peak ratios. The within-subject reproducibility of the surface ratios tended to be superior to that of the corresponding trough-to-peak ratios. In conclusion, the surface ratio provides an index of the duration of action of antihypertensive agents. Moreover, in the present patients, the surface ratio tended to be characterized by a higher within-subject reproducibility than the trough-to-peak ratio.

The ambulatory blood pressure in normotensive and hypertensive subjects: results from an international database

Abstract: Objective: To delineate more precisely an operational threshold for making clinical decisions based on ambulatory blood pressure (ABP) measurement by studying the ABP in subjects who were diagnosed as either normotensive or hypertensive by conventional blood pressure (CBP) measurement. Subjects: Twenty-four research groups recruited 7069 subjects. Of these, 4577 were normotensive (systolic CBP ≤ 140 mmHg and diastolic CBP ≤ 90 mmHg) and 1773 were hypertensive (systolic CBP ≥ 160 mmHg and/or diastolic CBP ≥ 90 mmHg). Of the latter, 1324 had systolic and 1310 had diastolic hypertension. Results: Ninety-five percent of the normotensive subjects had a 24-h ABP below (systolic and diastolic, respectively) 133 and 82 mmHg. Of the patients with systolic hypertension, 24% had a 24-h systolic ABP of Conclusion: The ABP distributions of the normotensive subjects included in the present international database were not materially different from those in previous reports in the literature. One-fifth to more than one-third of the hypertensive patients had an ABP which was below the 95th centile of the ABP in normotensive subjects, but this proportion decreased if the hypertensive patients had shown a higher CBP upon repeated measurement. The prognostic implications of elevated CBP in the presence of normal ABP remain to be determined.

Signs of functional efferent reinnervation of the heart in patients after cardiac transplantation.

Abstract: Short-term heart rate and blood pressure variability were assessed in 62 patients, studied within 1 month, at 1, at 2 or at 3-5 years after cardiac transplantation and in 13 healthy control subjects. Means and total variances were calculated and the powers of the low frequency (LF, 0.07-0.14 EqHz) and of the high frequency (HF, 0.14-0.35 EqHz) components were derived from power spectral analysis. Mean heart period, its total variance and the powers of the LF and HF components were lower in the transplanted patients than in the controls (P < 0.001). The total variance and the LF and HF powers differed significantly among the groups of transplanted patients (P < 0.01) and intergroup comparison showed significantly higher values in patients 3-5 years after transplantation than in those studied within 1 month. The variance of systolic blood pressure and its power spectrum did not differ between patients and controls. The results suggest that partial functional reinnervation of the sinus node occurs after heart transplantation in man.

Changes in plasma lipids, lipoproteins and apolipoproteins in hypercholesterolaemic patients treated with pravastatin.

Abstract: Plasma lipids, lipoproteins and apolipoproteins were studied before and during 6 months of pravastatin administration in patients with hypercholesterolaemia. After a 1 month placebo run-in period, the patients were treated double-blind either with placebo (n = 25) or with pravastatin (n = 25) for 6 months. Placebo or pravastatin 10 mg during the first month, 20 mg during the second month and 40mg during the additional 4 months was administered once daily in the evening. Compared with the placebo group the plasma concentration of total cholesterol and phospholipids, free cholesterol and cholesterol esters as well as the plasma LDL-cholesterol and LDL-phospholipids were decreased during 6 months of pravastatin therapy. No changes in plasma VLDL-, HDL-, HDL 2 - or HDL 3 -cholesterol, -phospholipids or -triglycerides were observed in the pravastatin-treated patients. A decrease in the plasma level of apolipoprotein B and of LDL-apo B, but not of VLDL-apo B, was observed during pravastatin therapy ; the plasma apolipoprotein Al and All levels as well as HDL 2 - and HDL 3 -apo Al and apo All levels remained, however, unchanged. Plasma lipoprotein Lp(a) did not change during pravastatin therapy whereas the plasma lecithin cholesterol acyltransferase activity (LCAT) increased. In conclusion, treatment of hypercholesterolaemic patients with pravastatin results in a decrease in the plasma concentration of total and free cholesterol, LDL-cholesterol, apolipoprotein B, LDL-apo B, phospholipids and cholesterol esters and in an increase in plasma LCAT activity. Plasma Lp(a), HDL-cholesterol and triglyceride levels remained, however, unchanged.

Once-daily antihypertensive treatment with calcium antagonists: utopia or reality?

Abstract: Although a large number of antihypertensive drugs have been approved for once- or twice-daily dosing, no standardized set of evidence is required to demonstrate that the blood pressure reduction is sustained for 24 h. The recent literature on calcium antagonists was therefore searched for the arguments usually put forward to objectify a long duration of action. Most studies relied on ambulatory blood pressure monitoring. However, several published reports were difficult to interpret for a variety of reasons, such as: (1) a non-blinded non-randomized study design; (2) a statistical analysis, which was discordant with the study design; (3) analyses confined to the 24 h, day-time and night-time pressure means; (4) the absence of a baseline adjustment and/or formal statistical testing; (5) the “post hoc” subdivision of patients into responders and non-responders; and (6) the absence of a well-specified time-frame linking drug intake to the observed antihypertensive effects. According to the authors' interpretation, amlodipine, diltiazem SR (modified release), felodipine SR, isradipine SR, nifedipine SR, nitrendipine and verapamil SR have all been confirmed to reduce both the conventional and the 24 h blood pressure. Some studies went beyond the 24 h blood pressure means and also presented separate results for the day-time (or awake) and night-time (or sleeping) periods, or investigated the blood pressure reduction at the end of the dosing interval, or compared the diurnal blood pressure profiles on different treatments. However, the latter reports gave rise to discordant results, suggesting that, at least under certain experimental conditions, diltiazem SR, felodipine SR, isradipine SR, nifidepine SR and nitrendipine did not cover a full 24 h interval with once-daily dosing. The interpretation of studies on long-acting antihypertensive agents with the use of ambulatory monitoring would be much facilitated if quality standards were applied similar to those commonly required for clinical experiments with conventional blood pressure measurements.

Environmental cadmium pollution and public health : the Belgian experience

Abstract: The CadmiBel Study was a cross-sectional population study, which investigated the health effects of environmental exposure to cadmium and lead. The 2 327 participants constituted a random sample of the population of 4 Belgian districts, chosen in order to provide a wide range of environmental exposure to cadmium. After adjustment for confounding factors, such as smoking and occupational exposure, the urinary cadmium excretion, a measure of lifetime exposure, was nearly 30% higher in the polluted areas. The CadmiBel Study produced evidence inconsistent with the hypothesis that environmental exposure to cadmium would lead to an increase in blood pressure and to a higher prevalence of hypertension and other cardiovascular diseases. On the other hand, the serum alkaline phosphatase activity and the urinary excretion of calcium were significantly and positively correlated with urinary cadmium in both sexes. These findings suggested that the homeostasis of calcium was gradually affected, as cadmium accumulated in the body. Furthermore, several markers of renal tubular dysfunction (urinary excretion of retinol-binding-protein, N-acetyl-β-glucosaminidase, β 2 -microglobulin and amino-acids) were significantly and positively associated with urinary cadmium. Across 10 small areas, of which 6 were polluted with cadmium, there was also an inverse association between the creatinine clearance and several indexes of environmental exposure to cadmium (cadmium concentration in the soil, cadmium content of locally grown vegetables, the inhabitants' 24h urinary cadmium excretion). Thus, environmental exposure to cadmium was associated with alterations in renal function. The significance in terms of morbidity and mortality of the functional disturbances observed in the CadmiBel Study, and the possible strategies to prevent the transfer of cadmium from the environment to man are under investigation in the prospective PheeCad Study, in which half of the CadmiBel participants have been enrolled (participation rate 80%).

Lack of association between HLA class II polymorphisms and essential hypertension in a Belgian population.

Abstract: The aim of the present study was to investigate whether the HLA class II polymorphisms contributes to the susceptibility to essential hypertension in the Belgian population. For this purpose we studied 120 hypertensive patients and 168 normotensive controls by means of a PCR-SSO assay. No significant difference in allele and genotype frequencies of the DRB and DPB1 loci could be found between the two groups. We concluded that essential hypertension as a multi-factorial and heterogeneous disease cannot be associated with one of the HLA class II DRB and DPB1 alleles in Belgian patients.