[Primary prevention in hypertension--how to explain mortality differences between therapeutic regimes?].
Explore the source record for details and available documents.
Biomedical subjects
Publications and source records attributed to G Olsson.
Explore the source record for details and available documents.
1. The effects of mental stress induced by a colour word conflict test (CWT; n = 9) or 3 h infusions of placebo or adrenaline (0.4 nmol min-1 kg-1; n = 9) on platelet function in vivo were studied in 16 healthy male volunteers. 2. Platelet function was assessed by a filtragometry technique, which reflects aggregability in vivo, and by measurements of the plasma levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4). 3. Adrenaline and CWT induced marked cardiovascular responses as expected. Venous plasma adrenaline increased from 0.1-0.2 nmol/l at rest to 4.87 +/- 0.42 nmol/l during adrenaline infusion and to 0.46 +/- 0.10 nmol/l during CWT. 4. Filtragometry measurements were reproducible within individuals with coefficients of variation of 7.9% during placebo infusion and 5.4% for resting measurements between days. 5. Platelet aggregability, as measured by filtragometry, was similarly increased during both adrenaline infusion (P less than 0.05) and CWT (P less than 0.01). 6. The coefficients of variation for beta-TG and PF4 levels were 17.3% for log beta-TG and 27.9% for log PF4 between days, but could not be calculated for within-day variability. Both beta-TG (P less than 0.05) and PF4 (P less than 0.01) levels decreased time-dependently during placebo infusion, indicating that long resting periods (hours) are needed to attain basal levels. Artefactual results could not be identified by evaluating beta TG/PF4 ratios. 7. beta-TG and PF4 levels did not decrease time-dependently during adrenaline infusion. There were no significant changes of beta-TG or PF4 during CWT.(ABSTRACT TRUNCATED AT 250 WORDS)
Explore the source record for details and available documents.
1. Effects of 3 h infusions of adrenaline (0.4 nmol kg-1 min-1) or placebo and of mental stress evoked by a colour word test (CWT) on adrenergic receptor function were investigated in healthy men. Responses of heart rate, blood pressure, plasma catecholamines, plasma cyclic AMP and plasma free fatty acids (FFA) were evaluated during infusions and CWT. In vitro beta 2-adrenoceptor numbers [( 125I]-HYP binding) and function (isoprenaline induced cyclic AMP accumulation) were studied on lymphocytes in all experiments. alpha 2-adrenoceptor binding [( 3H]-yohimbine and adrenaline) to intact platelets was evaluated in the infusion experiments only. 2. Placebo infusion evoked no major alterations of any parameter. 3. Adrenaline infusion raised venous plasma adrenaline levels to 4-5 nmol l-1, increased heart rate by 14 +/- 3 beats min-1 and plasma cyclic AMP by 17 +/- 3 nmol l-1, and decreased diastolic blood pressure by 15 +/- 5 mm Hg. These responses persisted throughout the infusion. Plasma FFA levels, on the other hand, increased at 30 min of infusion (from 236 +/- 44 to 717 +/- 92 mumol l-1) and returned to basal levels after 3 h of infusion. 4. In vitro, lymphocytes showed increased beta 2-responsiveness after 30 min of adrenaline infusion (delta cyclic AMP increased from 1.86 +/- 0.24 to 3.06 +/- 0.58 pmol/10(6) cells), but a decreased response (0.47 +/- 0.10 pmol/10(6) cells) after 3 h of infusion. [125I]-HYP binding to lymphocyte membranes showed a three-fold increase of Bmax at 30 min of adrenaline infusion followed by a return to basal values after 3 h of infusion. [125I]-HYP binding reflected the functional responsiveness of the lymphocytes in vitro poorly. alpha 2-adrenoceptors on platelets were not altered with regard to Bmax or Kd for [3H]-yohimbine binding or Ki for adrenaline displacement of [3H]-yohimbine binding. 5. CWT evoked marked circulatory changes, a four-fold increase in plasma adrenaline and a 60% increase in beta 2-adrenoceptor binding sites without changes in functional responsiveness of the lymphocytes. 6. We conclude that exposure to high physiological levels of adrenaline in vivo alters lymphocyte beta-adrenoceptor responsiveness in a biphasic manner, with an early increase followed by a later decrease, but that most beta-adrenoceptor mediated responses to adrenaline in vivo remain intact. Lymphocyte alterations may reflect recruitment of cells into the circulation during sympathoadrenal stimulation. Platelet alpha 2-adrenoceptors are apparently not easily subjected to agonist induced dynamic receptor regulation.(ABSTRACT TRUNCATED AT 400 WORDS)
Explore the source record for details and available documents.
The present primary prevention study aimed at investigating whether metoprolol given as initial antihypertensive treatment would lower cardiovascular complications of high blood pressure to a greater extent than thiazide diuretics. Patients were randomized to metoprolol (n = 1,609, 8,110 patient-years) or a thiazide diuretic (n = 1,625, 8,070 patient-years). At randomization, 535 patients in the metoprolol group and 524 patients in the diuretic group were classified as smokers. Blood pressure control during follow-up was equally effective regardless of smoking habits at randomization. Cardiovascular and coronary heart disease mortality was three to four times higher in smokers than in nonsmokers, underlining the importance of smoking as a risk factor. Total and cardiovascular mortality were significantly lower for the metoprolol group than for the thiazide diuretic group in the whole study population (p = 0.028 and p = 0.012), as well as in smokers (p = 0.013 and p = 0.016). Coronary heart disease mortality was significantly lower for patients on metoprolol than for patients on diuretics in the whole study population (p = 0.048) as well as in smokers (p = 0.021). The results suggest that initial antihypertensive therapy with metoprolol is associated with a lesser incidence of total, cardiovascular, and coronary heart disease mortality as compared with initial diuretic treatment, both in the whole study population and in smokers. The favorable effect of metoprolol must be mediated via mechanisms other than the blood pressure-lowering effect of metoprolol because equal blood pressure control was achieved with both types of medication, irrespective of smoking habits at randomization.
Explore the source record for details and available documents.
The present study of primary prevention in white men aged 40 to 64 years attempts to investigate whether a beta-blocker given as initial antihypertensive treatment would lower total mortality to a greater extent than thiazide diuretics. Patients were randomized to metoprolol (n = 1609, 8110 patient-years) or a thiazide diuretic (n = 1625, 8070 patient-years). The median follow-up time was 4.2 years. The mean dose of metoprolol was 174 mg/d, and of thiazide diuretics, 46 mg/d of hydrochlorothiazide or 4.4 mg/d of bendroflumethiazide. Identical control of blood pressure was achieved using a fixed therapeutic schedule. Total mortality was significantly lower for metoprolol than for thiazide diuretics because of fewer deaths from coronary heart disease and stroke. Total mortality was also significantly lower in smokers randomized to metoprolol. The benefit demonstrated in patients treated with metoprolol seems to have important implications for clinical practice.
The effect of therapy on exercise performance during a 3-year follow-up after acute myocardial infarction (AMI) was evaluated in a double-blind randomized comparison between 154 patients given metoprolol (100 mg twice daily) and 147 patients given placebo. Exercise tests were performed 1.5, 6, 12, 24 and 36 months after AMI. Maximal accomplished workloads were similar in the 2 groups throughout follow-up. Maximal heart rate was significantly higher in the placebo-treated group throughout the study (p less than 0.001). At the 6-week test more patients in the placebo group terminated exercise due to angina pectoris (40 vs 25%, p less than 0.05) and showed exercise-induced ST-depressions (38 vs 27%, p = 0.05) compared with the metoprolol group. Exercise-induced ventricular arrhythmias were significantly more common in the placebo group during the initial 6 months. Death, another AMI or both were significantly reduced by metoprolol treatment in patients with exercise-induced ST depression greater than or equal to 1 mm at the 6-week test. In a multiple logistic regression analysis maximal accomplished workload at 6 weeks (p less than 0.026), male sex (relative risk [rr] = 3.57, p = 0.016), previous AMI (rr = 3.07, p = 0.001), therapy with placebo (rr = 2.14, p = 0.007) and left ventricular failure (rr = 2.04, p = 0.023) were shown to carry independent prognostic information as well as exercise-induced ST-depression (greater than or equal to 1 mm) in placebo-treated patients (rr = 2.70, p = 0.01).
The outcome of postinfarction patients with a history of hypertension who participated in a randomized, double-blind, secondary prevention study with metoprolol or placebo treatment for 3 years has been evaluated. There were 41 patients in the placebo group and 35 patients in the metoprolol group. Elevated blood pressure was treated primarily by the addition of thiazide diuretics. Blood pressures were nearly identical in the two treatment groups. During the 3 years, 11 patients died in the placebo group and seven died in the metoprolol group. Occurrence of nonfatal events was also higher in the placebo than in the treated group: 12 patients vs one patient for reinfarction (p less than 0.005), three patients vs no patients for coronary artery bypass grafting, four patients vs no patients for cerebrovascular events, and one patient vs no patients for lower limb amputation. The total number of patients with any event was 24 vs eight (p less than 0.01). The present results may imply that treatment after infarction with metoprolol reduces nonfatal thromboatherosclerotic complications, especially nonfatal reinfarctions, in patients with a history of hypertension. However, inasmuch as the results were obtained from a retrospective subgroup analysis, they must be interpreted with caution.
In order to investigate whether initial plasma lipid concentrations could be used to distinguish between high and low responders to an atherogenic diet, rabbits were divided into 3 groups according to their plasma concentrations of cholesterol and phospholipids after 4 weeks on a standard rabbit diet. Plasma cholesterol and phospholipid levels were less than 0.5 mM, less than 1.1 mM, respectively, in group 1 (n = 17), greater than 0.5 mM, less than 1.1 mM, in group 2 (n = 13), and greater than 0.5 mM, greater than or equal to 1.1 mM, in group 3 (n = 14). After 7 weeks on a diet containing 0.25% cholesterol and 3% coconut oil, animals in groups 1 and 2 had a lower increase in their plasma lipid levels compared with group 3. Half of each group was then treated with the beta 1-adrenoceptor antagonist metoprolol during the next 14 weeks on the atherogenic diet. At the end of the study, the extent of atherosclerosis both in the aortas and in the coronary arteries of the control animals showed a positive correlation to plasma cholesterol and to plasma phospholipid concentrations integrated over time. The metoprolol-treated animals in groups 1 and 2 had a reduction of atherosclerosis compared with their respective controls. We conclude that subpopulations of rabbits that react differently on an atherogenic diet can be identified by their initial plasma lipid levels, and that metoprolol treatment of low responders to an atherogenic diet significantly reduces atherosclerotic lesions of the aorta.
Intimal lipid concentrations were determined in aortic biopsies obtained during coronary by-pass surgery. In addition serum lipoprotein and apolipoprotein levels were quantitated and their relationships to aortic intimal lipid concentrations were analysed. The possibility to use aortic intimal lipid and serum lipoprotein or apolipoprotein concentrations to predict clinical prognosis following the coronary by-pass operation was also evaluated. Intimal cholesterol, cholesterol ester, phosphatidylcholine and sphingomyelin were intercorrelated, whereas none of these lipid fractions correlated to aortic intimal triglyceride levels. Patients with hypertension had higher aortic intimal cholesterol ester levels than normotensive patients. There was a positive correlation between the number of stenosed coronary arteries and serum apo B or triglyceride levels. In addition there was a negative correlation between the number of stenosed arteries and HDL-cholesterol. Prognosis after the operation was inversely correlated to serum apo A-I levels. Our data do not, however, support the notion that aortic intimal lipid levels can be used to evaluate prognosis after coronary by-pass surgery.
We have established isolation methods and developed electroimmunoassays for rabbit apolipoprotein A-I (apo A-I), apo B, apo C-III and apo E. The assays were used to characterize a hyperlipidemic strain of the British Halflop rabbits (BHL rabbits), obtained after cross-breeding with WHHL rabbits and referred to as modified WHHL rabbits, and to investigate the changes in the apolipoprotein levels induced by feeding normal BHL rabbits an atherogenic diet (0.25% cholesterol and 3% coconut oil). The modified WHHL rabbits were characterized by increased levels of apo B, apo C-III and apo E as well as cholesterol, phospholipids and triacylglycerol as compared to chow-fed BHL rabbits, while the apo A-I levels were only half of those found in the chow-fed animals. The modified WHHL rabbits had virtually no low density lipoprotein (LDL) receptor activity and a low fractional catabolic rate (FCR) of LDL. These results indicate that the modified WHHL rabbit has the homozygous form of the LDL receptor deficiency. The BHL rabbits fed the atherogenic diet showed increased levels of cholesterol, triacylglycerol, apo B, apo C-III and apo E, as compared to those of the chow-fed BHL rabbits. The apo E and apo C-III reached levels in the range of or even higher than those of the modified WHHL rabbits. The apo A-I levels on the other hand did not differ from those of the chow-fed rabbits. Feeding an atherogenic diet led to a decrease in the FCR of LDL to a level similar to that found in the modified WHHL rabbits.
Explore the source record for details and available documents.
In a single-blind study of 6 weeks' duration, 32 patients with stable angina pectoris, who had been receiving controlled-release, Durules, isosorbide-5-mononitrate (Imdur) 60 to 180 mg daily for at least 1 year, were assessed after abrupt withdrawal of the nitrate. After 2 weeks of placebo treatment nitrate therapy was re-instituted, and the patients followed for another 2 weeks. The possibility of development of tolerance and rebound phenomena was also investigated. Three patients experienced severe anginal symptoms necessitating hospitalization when controlled-release isosorbide-5-mononitrate was withdrawn abruptly. Patients complained of more severe anginal symptoms during the placebo period, experienced more frequent anginal attacks and used more glyceryl trinitrate tablets than during active treatment. ST segment changes during exercise were more pronounced with placebo. After controlled-release isosorbide-5-mononitrate was re-introduced, these variables indicated significant improvement. On the other hand, no deterioration occurred in exercise performance during the placebo phase. Responsiveness to glyceryl trinitrate was maintained, as shown by comparisons of exercise tests performed after the long term treatment and during the placebo phase. Controlled-release isosorbide-5-mononitrate retains a beneficial effect in patients with angina pectoris during prolonged use, although some attenuation of the effect is seen. Abrupt withdrawal of the drug is not recommended because of the possibility of severe exacerbation of anginal symptoms, although no clearcut rebound phenomena were seen.
In a randomized double-blind postinfarction study 301 patients were treated with either metoprolol 100 mg b.i.d. (n = 154) or placebo (n = 147) for three years. After the three-year treatment period the study preparation was gradually withdrawn over one week, followed by another 2-7 year follow-up. Mortality and morbidity data were studied both during the intervention period (reported elsewhere) and over the period following withdrawal of study therapy. During the period following the withdrawal of the trial preparation, there were 16 (14%) and 31 (24%) deaths in the previously placebo and metoprolol groups, respectively (P = 0.10). Corresponding figures for reinfarctions and cerebrovascular events were 15 (13%) vs. 12 (9%) and 14 (12%) vs. 9 (7%) (NS). From a Cox regression analysis taking 13 different variables into account, a model describing the risk for subsequent death was constructed. The model identified the following important variables: sex (relative risk (rr) = 2.4), beta-blocker withdrawal (rr = 2.1), performance on exercise test and digitalis treatment (rr = 2.3, P less than 0.05). The present results, as well as those from other studies, seem to favour continuous postinfarction beta blocker therapy provided that there are no severe side-effects from therapy. Digitalis therapy in postinfarction patients in sinus rhythm may have adverse effects on survival during long-term follow-up.
We studied the influence of beta-adrenoceptor blockade on heart rate responses to facial immersion in ice-cooled water after acute myocardial infarction. Forty patients with acute myocardial infarction were randomized to the double-blind therapy with metoprolol 200 mg daily or matching placebo. Therapy was started as soon as possible after admission to hospital and continued for 15 days. After this initial period all patients were treated with beta-blockade during the subsequent 6 months. Repeated investigations of heart rate responses to facial immersion in ice-cooled water and 24-hour ECG-recordings were performed on day 15 (while patients were on study therapy), after 6 weeks, 3 and 6 months. Throughout the 6-month period, facial immersion elicited significant heart rate reductions in both treatment groups. No differences were found between the two groups or between different examinations during follow-up. There was no correlation between heart rate response to facial immersion and frequency of ventricular arrhythmia on a 24-hour monitoring. In conclusion, acute administration of metoprolol in myocardial infarction does not influence the bradycardial response to facial immersion either in the early postinfarction phase or during 6 months' follow-up. There is no relation between bradycardial response to face immersion and frequency of ventricular arrhythmias.
Explore the source record for details and available documents.