Showing papers by "Robert Fagard published in 2002"

The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study.

Abstract: Background After the double-blind, placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial ended in February 1997, randomized patients were offered active study medication for a further period of observation. Objective To refine the estimates of the long-term effects of antihypertensive therapy on the incidence of dementia. Methods Eligible patients had no dementia and were at least 60 years old. Their systolic blood pressure at entry was 160 to 219 mm Hg, with diastolic blood pressure below 95 mm Hg. Antihypertensive therapy was started immediately after randomization in the active treatment group, but only after termination of the double-blind trial in the control patients. Treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d), hydrochlorothiazide (12.5-25 mg/d), or both add-on drugs. Results Median follow-up increased from 2.0 years in the double-blind trial to 3.9 years overall. The incidence of dementia doubled from 32 to 64 cases, 41 of whom had Alzheimer disease. Throughout follow-up, systolic/diastolic blood pressure was 7.0/3.2 mm Hg higher in the 1417 control patients than in the 1485 subjects randomized to active treatment. At the last examination, the blood pressure difference was still 4.2/2.9 mm Hg; 48.1%, 26.4%, and 11.4% of the control patients were taking nitrendipine, enalapril, and/or hydrochlorothiazide, whereas in the active treatment group these proportions were 70.2%, 35.4%, and 18.4%, respectively. Compared with the controls, long-term antihypertensive therapy reduced the risk of dementia by 55%, from 7.4 to 3.3 cases per 1000 patient-years (43 vs 21 cases, P P Conclusion The extended follow-up of Syst-Eur patients reinforces the evidence that blood pressure–lowering therapy initiated with a long-acting dihydropyridine protects against dementia in older patients with systolic hypertension.

Stimulation of Collagen Production by Transforming Growth Factor-β1 During Differentiation of Cardiac Fibroblasts to Myofibroblasts

Abstract: The aim of the present study was to elucidate how transforming growth factor-beta(1) (TGF-beta(1)) can stimulate collagen deposition in cardiac tissue by interstitial cells via stimulation of fibroblasts, via myofibroblasts, or via differentiation of fibroblasts to myofibroblasts. The dose- and time-dependent stimulation of collagen production and of expression of alpha-smooth muscle actin (alpha-SMA), a marker of myofibroblasts, was studied in cultures of second-passage adult rat cardiac fibroblasts. The TGF-beta(1)-stimulated collagen production is positively correlated (r=0.68, P<0.001) with the appearance of alpha-SMA. Only at high concentrations (40 to 600 pmol/L) and after a long time (24 to 48 hours) of incubation, TGF-beta(1) increases the collagen production and stimulates the differentiation of fibroblasts to myofibroblasts. The maximal stimulation of the collagen production (2-fold, P<0.001) observed after incubation of cultures of fibroblasts with 600 pmol/L TGF-beta(1) for 48 hours is accompanied by a maximal stimulation of alpha-SMA expression (3.5-fold, P<0.001), when cultures consist mainly of myofibroblasts. The stimulation of collagen production cannot be reversed either after additional incubation of TGF-beta(1)-stimulated second-passage cultures for 2 days or in their offspring in the next third passage after incubation for 7 days without TGF-beta(1). The increased collagen production in these third-passage cultures cannot be further stimulated by TGF-beta(1). Our data suggest that TGF-beta(1)-stimulated collagen production in cultures of adult rat cardiac ventricular fibroblasts cannot be explained by a direct stimulation of the collagen production either in fibroblasts or in myofibroblasts. Instead, TGF-beta(1) induces the differentiation of fibroblasts to myofibroblasts, which have a higher activity for collagen production than fibroblasts.

Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension

Abstract: Objective: To examine the association of clinic and ambulatory heart rate with total, cardiovascular, and noncardiovascular death in a cohort of elderly subjects with isolated systolic hypertension from the Systolic Hypertension in Europe Trial. Methods: A total of 4682 patients participated, whose untreated blood pressure on conventional measurement at baseline was 160 to 219 mm Hg systolic and lower than 95 mm Hg diastolic. Clinic heart rate was the mean of 6 readings during 3 visits. Ambulatory heart rate was recorded with a portable intermittent technique in 807 subjects. Results: Raised baseline clinic heart rate was positively associated with a worse prognosis for total, cardiovascular, and noncardiovascular mortality among the 2293 men and women taking placebo. Subjects with heart rates higher than 79 beats/min (bpm) (top quintile) had a 1.89 times greater risk of mortality than subjects with heart rate lower than or equal to 79 bpm (95% confidence interval, 1.33-2.68 bpm). In a Cox regression analysis, predictors of time to death were heart rate (P.001), age (P.001), serum creatinine level (P=.001), presence of diabetes (P = .002), previous cardiovascular disease (P=.01), triglyceride readings (P=.02), smoking (P=.04), and elevated systolic blood pressure (P=.05), while total cholesterol level was found to be nonsignificant in the model. In the ambulatory monitoring subgroup, clinic and ambulatory heart rates predicted noncardiovascular but not cardiovascular mortality. However, in a Cox regression analysis in which clinic and ambulatory heart rates were included, a significant association with noncardiovascular mortality was found only for clinic heart rate (P=.004). In the active treatment group, the weak predictive power of clinic heart rate for mortality disappeared after adjustment for confounders. Conclusions: In untreated older patients with isolated systolic hypertension, a clinic heart rate greater than 79 bpm was a significant predictor of all-cause, cardiovascular, and noncardiovascular mortality. Ambulatory heart rate did not add prognostic information to that provided by clinic heart rate. Arch Intern Med. 2002;162:2313-2321

J-Shaped Relationship between Blood Pressure and Mortality in Hypertensive Patients: New Insights from a Meta-Analysis of Individual-Patient Data

Abstract: BACKGROUND: Population-based longitudinal studies of hypertension have usually shown a continuous and positive relationship between blood pressure and mortality. However, several studies in hypertensive patients receiving treatment have described this relationship as J-shaped, with an increased risk for events in patients with low blood pressure. OBJECTIVE: To assess the evidence for a J-shaped relationship between blood pressure and mortality and its relation to treatment. DESIGN: Meta-analysis of individual-patient data. SETTING: Seven randomized clinical trials from the INDANA (INdividual Data ANalysis of Antihypertensive intervention) database. PATIENTS: 40 233 persons with hypertension (mean follow-up, 3.9 years). INTERVENTION: Primarily beta-blockers or thiazide diuretics versus placebo or no treatment. MEASUREMENTS: Diastolic and systolic blood pressure and number of cardiovascular, noncardiovascular, and all-cause deaths in yearly periods of follow-up. RESULTS: The analysis included data on 1655 deaths (56% cardiovascular). A J-shaped relationship between diastolic blood pressure and risk for death was observed for total and cardiovascular mortality in treated patients (nadir, 84 and 80 mm Hg, respectively) and untreated patients (nadir, 90 and 85 mm Hg, respectively). For noncardiovascular deaths, the relationship was J-shaped in the treated group (nadir, 84 mm Hg) and negative in the control group. Similar results were observed for systolic blood pressure. The presence of patients with wide pulse pressure did not explain these findings. CONCLUSIONS: The increased risk for events observed in patients with low blood pressure was not related to antihypertensive treatment and was not specific to blood pressure-related events. Poor health conditions leading to low blood pressure and an increased risk for death probably explain the J-shaped curve.

Prognostic Significance of Renal Function in Elderly Patients with Isolated Systolic Hypertension: Results from the Syst-Eur Trial

Abstract: Several reports suggest that markers of renal function such as serum creatinine, serum uric acid, and urinary excretion of protein may be related to cardiovascular complications and mortality. This study analyzed the data from the Syst-Eur trial, which was a randomized, placebo-controlled, double-blind intervention trial in elderly patients with isolated systolic hypertension. The purpose was to evaluate whether serum levels of creatinine and uric acid and urinary protein excretion at entry are related to subsequent morbidity and mortality. Incidence rates of total mortality, cardiovascular mortality, stroke (fatal as well as nonfatal), coronary events, and all cardiovascular endpoints were calculated for each quintile of serum creatinine or serum uric acid or for each category of protein excretion (none, trace, and overt). Crude and adjusted relative hazard rates were also determined for each 20 micro M increase in serum creatinine, each 50 micro M increase in serum uric acid, and for each protein excretion category. Even when adjusted for age, gender, and various other covariates, serum creatinine was significantly associated with a worse prognosis. There was an U-shaped relationship between serum uric acid and total mortality, but otherwise no obvious relationships were detected between serum uric acid levels and complications when appropriate adjustments were made for confounding variables. Proteinuria at entry was a significant predictor of total mortality and all cardiovascular endpoints. It is concluded that higher levels of serum creatinine and trace or overt proteinuria are associated with an increased number of cardiovascular events and with a higher mortality in patients with isolated systolic hypertension.

Pulsatile blood pressure component as predictor of mortality in hypertension: a meta-analysis of clinical trial control groups.

Abstract: ObjectiveAlthough current guidelines rest exclusively on the measurement of systolic and diastolic blood pressures, the arterial pressure wave is more precisely described as consisting of a pulsatile (pulse pressure) and a steady (mean pressure) component. This study explored the independent roles o

Survey on treatment of hypertension and implementation of World Health Organization/International Society of Hypertension risk stratification in primary care in Belgium.

Abstract: Objective To gain insight into the prevalence, treatment and control of hypertension and into the implementation of the 1999 World Health Organization/International Society of Hypertension guidelines for the management of hypertension in general practice in Belgium.Design A prospective cross-section

Epidemiology of hypertension in the elderly.

Abstract: In Western populations, mean systolic and diastolic blood pressures rise with advancing age up to the sixth decade of life, whereupon systolic blood pressure continues to increase and diastolic pressure starts to decline. The ensuing widening of pulse pressure is mainly ascribed to stiffening of the arterial vasculature. When hypertension is defined as systolic blood pressure of at least 140 mm Hg and/or diastolic pressure of at least 90 mm Hg, its prevalence amounts to 60%-70% of the population above 60 years of age. About 60% of these hypertensives have isolated systolic hypertension--that is, elevated systolic pressure and normal diastolic pressure. It should be realized, however, that approximately 25% of those labeled hypertensive on the basis of conventional blood pressure measurements have normal blood pressure on ambulatory blood pressure monitoring, or so-called white-coat, isolated clinic, or nonsustained hypertension. There is little doubt that elevated blood pressure leads to a number of cardiovascular complications. Whereas diastolic blood pressure has been emphasized for many years, the paradigm has shifted toward systolic blood pressure. In addition, pulse pressure has been shown to be an important predictor of cardiovascular events and death, above and beyond the predictive power of mean blood pressure.

Cardiovascular risk in white-coat and sustained hypertensive patients.

Abstract: We compared cardiovascular outcome between patients with white-coat and sustained hypertension who had previously participated in the Ambulatory Blood Pressure Monitoring and Treatment of Hypertension (APTH) trial. Baseline characteristics, including office and ambulatory blood pressure (BP), were measured during the 2-month run-in period of the APTH trial. During follow-up, information on the occurrence of major cardiovascular events (death, myocardial infarction, stroke and heart failure), achieved office BP and treatment status was obtained. At entry, 326 patients had sustained hypertension (daytime ambulatory BP S 140 mmHg systolic and/or S 90 mmHg diastolic) and 93 had daytime ambulatory BP below these limits and were classified as white-coat hypertensives. During 2088 patientyears of follow-up (median follow-up 5.3 years), all major cardiovascular events ( n = 22) occurred in the patients with sustained hypertension (rate 12.7 per 1000 patient-years, p = 0.02 for between-group difference). Fur...

Carotid and femoral intima-media thickness in relation to three candidate genes in a Caucasian population

Abstract: Background In a Caucasian population, the prevalenceand incidence of hypertension, renal function and largeartery stiffness were significantly correlated withpolymorphisms in the genes encoding the angiotensin-converting enzyme (ACE I/D), aldosterone synthase(2C344T) and the cytoskeleton protein AE-adducin(Gly460Trp).Objective This study investigated intima–mediathickening, a precursor of atherosclerosis, in relation tothese genetic polymorphisms.Methods Carotid and femoral intima–media thicknesswere assessed with a wall-track system in 380 subjectsenrolled in a population study. Subjects were genotypedfor the presence of the ACE D, aldosterone synthase2344T and AE-adducin 460Trp alleles. The statisticalanalysis allowed for confounders, interactions amonggenes, and the non-independence of the phenotypeswithin families.Results The sample included 188 men (49.5%). Mean agewas 39.8 years. Intima–media thickness of the carotid andfemoral arteries averaged 575 and 719 m, respectively.Intima–media thickness of the femoral–but not carotid–artery increased with the number of ACE D alleles. Theeffect of ACE genotype on femoral intima–mediathickness was confined to carriers of the 460Trp allele andthe 2344T allele. Expressed as a percentage of thepopulation mean, the mean differences between II and DDhomozygotes averaged 13.4% (95% CI 5.6–21.2%) in allsubjects, 21.2% (8.0–34.5%) in carriers of the 460Trpallele, 15.4% (4.1–26.8%) in carriers of the 2344T allele,and 25.2% (10.7–39.7%) if the 460Trp and 2344T alleleswere both present.Conclusion This study shows that a relationship existsbetween the intima–media thickness of the large muscularfemoral artery and the ACE gene. This relationship is onlyapparent in the presence of either the AE-adducin 460Trp orthe aldosterone synthase 2344T allele. These findingsmay have clinical implications for the assessment ofgenetic cardiovascular risk. J Hypertens 20:1551–1561 &2002 Lippincott Williams & Wilkins.

Terminal digit preference and single-number preference in the Syst-Eur trial: influence of quality control.

Abstract: BACKGROUND: Terminal digit and single-number preference may produce inaccuracy and biased results when measuring blood pressure We describe these preferences in the Syst-Eur randomized placebo-controlled trial of the treatment of isolated systolic hypertension and describe how we sought to eliminate these problems METHODS: The Data Monitoring Committee of the trial conducted yearly quality control meetings in Belgium and visited the participating centres to check their adherence to the protocol These meetings involved identifying terminal digit preference, improving blood pressure control and boosting recruitment RESULTS: The prevalence of use of terminal digit zero when measuring sitting systolic blood pressure (first readings) reduced from an average of 424% in the year prior to the date when a centre first randomized a patient to 315, 25, 223, 263, 232 and 22% in the subsequent 6 years This trend was independent of the calendar year during which a centre entered the trial and supports the hypothesis that data-quality monitoring, including the feedback of digit preference to centres, led to a reduction in terminal digit zero preference In addition, a higher than expected prevalence of the systolic blood pressure value of 148 mmHg was found in the active treatment groups in the double-blind phase Selection for 148 mmHg persisted over time and constituted a single-number preference bias This arose from the instruction to investigators to reduce systolic blood pressure to below 150 mmHg CONCLUSION: Monitoring and feedback of data quality should be undertaken to minimize digit and number preference Automatic devices should ideally be employed to help to avoid these problems as long as the devices are fully validated and regularly serviced, and providing that readings are not rejected and repeated

Host and environmental determinants of polychlorinated aromatic hydrocarbons in serum of adolescents.

Abstract: This study investigated host factors and environmental factors as potential determinants of polychlorinated aromatic hydrocarbons (PCAHs) in serum of adolescents. We recruited 200 participants (80 boys and 120 girls), with a mean age of 17.4 years (SD, 0.8), in Belgium from a rural control area (Peer) and from two polluted suburbs of Antwerp where a nonferrous smelter (Hoboken) and waste incinerators (Wilrijk) are located. We quantified polychlorinated biphenyls (PCBs; congeners 138, 153, and 180) in serum by gas chromatography and obtained the toxic equivalents (TEQs) of PCAHs in serum with the chemically activated luciferase gene expression bioassay (CALUX). Serum PCB concentration was higher in boys than in girls (1.67 vs. 1.02 nmol/L or 377 vs. 210 pmol/g serum lipids; p< 0.001). In the whole adolescent group, multiple regression showed that serum PCB concentration decreased 0.06 nmol/L per 1% increase in body fat content (p< 0.001) and increased 0.39 nmol/L and 0.14 nmol/L per 1 mmol/L increase in serum concentrations of triglycerides (p < 0.001) and cholesterol (p = 0.002), respectively. Host factors explained 44% of the serum PCB variance. In the same model, serum PCB concentration increased 0.14 nmol/L with 10 weeks of breast-feeding (p< 0.001) and 0.06 nmol/L with intake of 10 g animal fat per day (p < 0.001), and was associated with residence in the waste incinerator area (9% higher; p = 0.04); 11% of the variance could be explained by these environmental factors. The geometric mean of the serum TEQ value was similar in boys and girls (0.15 TEQ ng/L or 33.0 pg/g serum lipids). In multiple regression, TEQ in serum decreased 0.03 ng/L per centimeter increase in triceps skinfold (p = 0.006) and was 29% higher in subjects living close to the nonferrous smelter (p < 0.001). This study showed that in 16- to 18-year-old teenagers host factors are important determinants of serum concentrations of PCAHs, whereas environmentally related determinants may to some extent contribute independently to human exposure to these persistent chemicals in the environment.

Depression and the heart: a systematic overview of definition, measurement, consequences and treatment of depression in cardiovascular disease.

Abstract: Depression is an independent risk factor in the pathogenesis of cardiovascular disease and it is a prevalent disorder after cardiovascular disease associated with negative outcome in terms of mortality and morbidity. It is a dangerous condition requiring adequate screening and treatment, however, it often remains undiagnosed and thus untreated. Non-psychiatric healthcare workers, like nurses, general practitioners, physiotherapists and cardiologists are the health providers most closely involved in the management of patients with cardiovascular disease. They can play an important role in screening cardiovascular patients for depressive symptoms and in referring them for treatment. The purpose of this article therefore is to provide an evidence-based framework, aiming to educate non-psychiatric healthcare providers on depressive disorder in the context of chronic cardiovascular disease. In this paper, an overview of the definition, prevalence and consequences of depression will be discussed. Moreover, an overview of measurement methods and treatment modalities for depression will be provided. In addition, a step-by-step guide is provided in order to help non-psychiatric healthcare providers in dealing with depressed patients.

Comparison of conventional and automated blood pressure measurements: interim analysis of the THOP trial. Treatment of Hypertension According to Home or Office Blood Pressure.

Abstract: Background Automated techniques of blood pressure (BP) measurement are increasingly being used to diagnose white-coat hypertension [1,2]. Compared to conventional blood pressure (CBP) measurement by the Korotkoff method, they are more reproducible and not subject to digit preference or observer bias. Self-measurement of the blood pressure at home (HBP) is less expensive than ambulatory blood pressure monitoring (ABP), but needs further clinical validation.

Heritability of plasma renin activity and plasma concentration of angiotensinogen and angiotensin-converting enzyme.

Abstract: The purpose of the present investigation was to describe the relative impact of genes and environment on the variance of the plasma constituents of the renin angiotensin system. We ascertained 56 male and 80 female adult same-sex twin pairs from the Flemish population. Plasma renin activity (PRA), the concentration of angiotensinogen (AGT) and angiotensin-converting enzyme (ACE) were measured, and path analysis was applied, after transformation toward normality. For PRA and AGT significant heritability was only detected in the male subgroup, with heritability estimates of 66% and 90%, respectively. Angiotensin-converting enzyme concentration was determined by additive genes for 43% of its variance, by shared environmental influences for 42%, and by specific environmental influences for 15%. The high heritability found for AGT is compatible with the results of earlier studies linking the M235T polymorphism of the angiotensinogen gene to plasma AGT levels. For PRA, we are the first to show significant heritability. Our results regarding ACE confirm the findings in other populations.

The influence of maternal BMI and age in twin pregnancies on insulin resistance in the offspring

Abstract: OBJECTIVE —There is strong evidence that low birth weight is associated with glucose intolerance and diabetes in adults. We have carried out a twin study to distinguish among maternal influences, which affect both twins; fetoplacental influences, which are unique to each twin; and the genetic factors that may underlie this association. RESEARCH DESIGN AND METHODS —We identified a sample of 423 twin pairs (250 monozygotic and 173 dizygotic) from the East Flanders Prospective Twin Survey who were born between 1964 and 1982. Data collected in this study included the mother’s body composition and weight gain during pregnancy, the twins’ birth weights, and gestational age. The twins (aged 18–34 years) attended a research center for measurement of height, weight, and waist-to-hip ratio as well as fasting glucose, proinsulin, and insulin concentrations. RESULTS —Among twin pairs discordant for birth weight, we found little evidence that the lighter twin had abnormal glucose-insulin metabolism in adult life. However, both a low prepregnancy maternal BMI and older maternal age at delivery were associated with hyperinsulinemia and evidence of insulin resistance in the offspring. Fasting insulin increased by 1.3% (95% CI 0.1–2.6%) per unit fall in maternal BMI and by 1.1% (0.02–2.0%) per year increase in maternal age. These associations were independent of the twins’ BMI and waist-to-hip ratio and their zygosity. CONCLUSIONS —These novel findings suggest that in twin pregnancies, maternal factors are more important than fetoplacental factors in determining glucose-insulin metabolism in the offspring.

Blood pressure, serum total cholesterol and contraceptive pill use in 17-year-old girls

Abstract: Background Many studies have analysed the relation between cardiovascular risk factors and oral contraceptive use in adult women, whereas information on the possible health effects of oral contraceptive use during adolescence is lacking. Design The effect of current contraceptive pill use on blood pressure and serum total cholesterol concentration was studied in a cross-sectional sample of 120 adolescent girls with a mean age of 17.4 years. Methods After the girls had rested for 5 minutes in the sitting position, trained study nurses measured blood pressure three times consecutively using a mercury sphygmomanometer. The nurses also administered a questionnaire gathering information on the use of oral contraceptives, smoking and parental social class. In the morning blood samples were taken for the measurement of serum total cholesterol. Results Mean age (± SD) was 17.4 ± 0.8 years. Blood pressure averaged (± SD) 108.7 ± 9.9 systolic and 68.0 ± 8.2 mmHg diastolic. Serum total cholesterol was 4.5 ± 0.7 mmol/l. Forty-nine girls (41%) were taking the contraceptive pill. Of these, 44 (90%) were on a combination of ethinyloestradiol (20-35 μg) and a progestogen, four (8%) on anti-androgens (35 μg) and one (2%) only on a progestogen. After adjustment for age, body mass index, smoking and alcohol status systolic blood pressure was 4.6 mmHg higher (95% CI 1.2-8.1; P<0.001) in current pill users than in girls not currently on the pill (111.4 versus 106.8 mmHg). Adjusted for the aforementioned covariates, diastolic blood pressure was not related to pill use (68.2 versus 67.8 mmHg; P = 0.7). Serum total cholesterol was 0.43 mmol/l (95% CI 0.18-0.60; P = 0.001) higher among girls using oral contraceptives (4.7 versus 4.3 mmol/l), irrespective of whether or not the model was adjusted for age, body mass index, smoking and alcohol status. Conclusions In 17-year-old girls, the use of oral contraceptives was associated with a nearly 5 mmHg higher systolic blood pressure and a 0.4 mmol/l higher level of serum total cholesterol. The long-term prognostic implications of our findings remain to be elucidated.

Physical exercise and coronary artery disease.

Abstract: Hypertension, hypercholesterolaemia, smoking and diabetes are firmly established risk factors for coronary artery disease and cardiovascular morbidity and mortality in general. In contrast, physical inactivity has encountered more difficulties to be accepted as a risk factor for which several reasons can be invoked. Unlike the so-called major risk factors, physical activity is more difficult to quantify. Furthermore, it involves occupational and leisure-time activities with variable dynamic and static components, which may have different effects on health. Studies have used various questionnaires and sometimes interviews relating to the subject’s physical activity at work, at leisure time or both over different periods of time. Most authors accept that the estimation of physical activity by questionnaire or interview is a poor but nevertheless useful and possibly the best available tool. A number of other studies have measured physical fitness through maximal or submaximal exercise testing, but it should be realized that the relationship between physical activity and physical fitness is of a low order1,2. Research in twins revealed that about half of the variance in fitness results from genetic composition3. Furthermore, even adequate dynamic physical training will only lead to an on average 15% increase in exercise performance, and there is evidence that also this effect is partly genetically determined4. The optimal tool to establish a causal relationship between a risk factor and disease incidence is a randomized, controlled intervention trial. Needless to say that it is nearly impossible to organize such a trial with regard to the role of exercise in primary prevention, as well for practical as for financial reasons. Such trials, however, have been performed in secondary prevention. The next best method is the prospective followup of cohorts with assessment of physical activity or fitness at baseline, or even changes in activity or fitness over time. Although a causal relationship can not be proven, a number of causality criteria have been postulated for such observational studies, i.e. strength and plausibility of the relationship; appropriate temporal sequence; specificity; consistency; and biological gradient. Another criterium is the independence of the association from the effect of other risk factors, such as blood pressure and lipids. However, this criterium may be scientifically relevant, but, with regard to public health, the mechanisms by which physical activity would improve health are of lesser importance. Nevertheless, the analyses should account for other confounding variables such as age, gender, body mass or fatness, and should exclude pre-existing disease unless e.g. one is studying the effects of physical activity in patients with coronary artery disease. Also the pitfall of latent disease, which may lead to lesser activity or fitness and be associated with an increased incidence of morbidity and mortality, has to be avoided, e.g. by excluding the first few years of follow-up from the analyses. Finally, observational studies cannot control for selection bias with regard to physical activity. In this review the role of physical activity and of physical fitness will be considered in both primary and secondary prevention of coronary heart disease events. We will only include studies which did at least control for demographic characteristics because of their influence on both physical activity or fitness and disease incidence. Coronary heart disease will be the primary end-point of interest in this review, but relevant studies in which cardiovascular events or mortality have Address for correspondence: Prof. R. Fagard, MD, PhD, U.Z. Gasthuisberg – Hypertensie. Herestraat 49, B-3000 Leuven, Belgium. Tel.: +32 16 34 87 07. Fax: +32 16 34 37 66. E-mail: robert.fagard@ uz.kuleuven.ac.be

Stimulation of collagen gel contraction by angiotensin II and III in cardiac fibroblasts

Abstract: Keywords: angiotensin II, angiotensin III, collagen gel contraction, cardiac fibroblasts Abstract Objective The aim of the present study was to investigate whether angiotensin II (Ang II), angiotensin III (Ang III) or Ang II (2-8), angiotensin IV (Ang IV) or Ang II (3-8) and Ang II (1-7), Ang II (4-8), Ang II (5-8) and Ang II (1-4) can stimulate collagen gel contraction in cardiac fibroblasts in serum-free conditions. Methods Cardiac fibroblasts (from male adult Wistar rats) from passage 2 were cultured to confluency and added to a hydrated collagen gel in a Dulbecco's Modified Eagle's Medium, with or without foetal bovine serum, for one, two or three days. The area of the collagen gels embedded with cardiac fibroblasts was determined by a densitometric analysis. Collagen gel contraction was characterised by a decrease in the gel area. Results Ang II dose-dependently stimulated the contraction of collagen mediated by cardiac fibroblasts after one, two or three days of incubation in a serum-free medium. Telmisartan completely blocked the Ang II-induced collagen contraction by cardiac fibroblasts. PD 123319 and des-Asp 1

Characteristics of conventional blood pressure in studies on the predictive power of ambulatory blood pressure.

Abstract: BACKGROUND It is commonly believed that the associations of left ventricular mass and cardiovascular morbidity/mortality with blood pressure are stronger for 24-h ambulatory pressure than for conventional clinic or casual pressure. METHODS The investigation comprised a review of relevant studies, with particular emphasis on the characteristics of the conventional blood pressure measurement. RESULTS A review of 21 studies on left ventricular mass, published between 1982 and 1993, showed that the relationship between mass and blood pressure was stronger for ambulatory blood pressure than for clinic blood pressure but that the methodology and conditions of the conventional blood pressure measurements were poorly described or standardized in several reports. Between 1983 and 2001, seven studies showed that ambulatory blood pressure was superior to conventional blood pressure with regard to the prediction of cardiovascular morbidity and/or mortality. From published data and requests for additional information, it appears that recommendations for the measurement of conventional blood pressure have been reasonably well observed, although the number of measurements has not always been adequate. CONCLUSIONS Whereas the quality of the conventional blood pressure measurements left much to be desired in the studies on left ventricular mass, the quality appeared to be reasonably good in outcome studies, even though the published details were often incomplete.

Withdrawal from treatment in the Syst-Eur Trial.

Abstract: Objective To investigate the reasons for withdrawal fromdouble-blind randomized trials, and the reasons forchanging treatment within a randomized therapeutic group.Design The Syst-Eur trial, in which 4695 older patientswith systolic hypertension were randomized to active orplacebo treatment.Methods The reasons for withdrawal from the trial wereexamined, both for patient-initiated and investigator-initiated withdrawals. In addition, the reasons for stoppingthe first-line treatment (nitrendipine), the second-linetreatments (enalapril and hydrochlorothiazide) and thecorresponding placebos, were determined.Results A total of 135 patients (6%) were withdrawn by theinvestigators from placebo treatment because their bloodpressure was too high, and, similarly, 36 (1.6%) throughpatient initiation. The corresponding results for the activelytreated patients were 14 (0.6%) and 7 (0.3%). Very fewpatients were withdrawn from the trial because of theadverse effects of treatment. However, 39 (4%) stoppedtaking active nitrendipine because of ankle oedema,compared with 4 (0.5%) on placebo. Similarly, 28 versusthree stopped due to flushing. Forty-one (10%) stoppedtaking enalapril because of cough, against eight (2%) forenalapril placebo. In all, 15.0% stopped active nitrendipine,20.2% enalapril and 6.3% hydrochlorothiazide, versusplacebo 7.1, 9.1 and 5.1%.Conclusions The numbers withdrawn from the trial foradverse treatment consequences were small incomparison to the cardiovascular benefits. Neverthelessthe numbers stopping individual treatments were higherthan expected. J Hypertens 20:339–346 & 2002 LippincottWilliams & Wilkins.

The drive to identify genetic factors influencing left ventricular mass responses to antihypertensive treatment.

Abstract: Left ventricular hypertrophy (LVH) is a major and independent risk factor for cardiovascular morbidity and mortality [1], even among normotensive subjects [2]. In addition, several studies indicate that a reduction of left ventricular mass (LVM) over time is associated with a better outcome in the following years [3,4]. Therefore, it would be of interest to treat hypertensive patients with LVH with drugs that decrease LVM more compared to other drugs. The conclusion from an early meta-analysis, which was mainly based on uncontrolled studies, that converting enzyme inhibitors are superior to other ®rst-line antihypertensive agents in this respect [5], was not con®rmed in a later meta-analysis in which the in ̄uence of the main drug classes on LVM was analysed with respect for the comparative design of the original studies [6]. More recently, a large prospective randomized clinical trial found that LVM was reduced to a similar extent by the converting enzyme inhibitor, enalapril, and the long-acting dihydropyridine calcium channel blocker, amlodipine [7]. As no drug class appears to be superior with regard to the regression of LVH in general, it would be of interest to ®nd out whether the response of LVM to a particular drug can be predicted in the individual patient. Polymorphisms in genes involved in the renin±angiotensin±aldosterone system (RAAS) might be candidates for such predictions.