Response to antihypertensive therapy in older patients with sustained and nonsustained systolic hypertension. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators.

BACKGROUND: The goal of the present study was to assess the effect of antihypertensive therapy on clinic (CBP) and ambulatory (ABP) blood pressures, on ECG voltages, and on the incidence of stroke and cardiovascular events in older patients with sustained and nonsustained systolic hypertension. METHODS AND RESULTS: Patients who were >/=60 years old, with systolic CBP of 160 to 219 mm Hg and diastolic CBP of <95 mm Hg, were randomized into the double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) Trial. Treatment consisted of nitrendipine, with the possible addition of enalapril, hydrochlorothiazide, or both. Patients enrolled in the Ambulatory Blood Pressure Monitoring Side Project were classified according to daytime systolic ABP into 1 of 3 subgroups: nonsustained hypertension (<140 mm Hg), mild sustained hypertension (140 to 159 mm Hg), and moderate sustained hypertension (>/=160 mm Hg). At baseline, patients with nonsustained hypertension had smaller ECG voltages (P<0.001) and, during follow-up, a lower incidence of stroke (P<0.05) and of cardiovascular complications (P=0.01) than other groups. Active treatment reduced ABP and CBP in patients with sustained hypertension but only CBP in patients with nonsustained hypertension (P<0.001). The influence of active treatment on ECG voltages (P<0.05) and on the incidence of stroke (P<0.05) and cardiovascular events (P=0.06) was more favorable than that of placebo only in patients with moderate sustained hypertension. CONCLUSIONS: Patients with sustained hypertension had higher ECG voltages and rates of cardiovascular complications than did patients with nonsustained hypertension. The favorable effects of active treatment on these outcomes were only statistically significant in patients with moderate sustained hypertension.

Associations of fasting blood glucose with cholesterol absorption and synthesis in nondiabetic middle-aged men.

NIDDM and the metabolic syndrome are characterized by a low serum, HDL cholesterol content and a high triglyceride level, whereas total and LDL cholesterol concentrations are not necessarily elevated. Variable results have been reported on cholesterol absorption, elimination, and synthesis in NIDDM, but no studies are available on subjects within the normal range of blood glucose. From serum samples collected in 1985 from 203 nondiabetic men aged 51-66 years, we examined lipids, cholesterol precursors (reflecting cholesterol synthesis), and plant sterols and cholestanol (reflecting cholesterol absorption) in relation to fasting blood glucose. The findings prompted us (in 1993) to further examine 11 men from the highest and lowest glucose thirds of 203 nondiabetic men by additional dietary, serum, and fecal analyses for absorption, elimination, and synthesis of cholesterol and insulin sensitivity. In 1985, blood glucose was significantly related to LDL apolipoprotein B (P = 0.05) but not to LDL cholesterol (P = 0.19). Significantly higher serum lathosterol and desmosterol-to-cholesterol proportions and lower plant sterol and cholestanol proportions in the highest rather than the lowest glucose thirds suggested that the subjects with high normal blood glucose had decreased absorption and enhanced synthesis of cholesterol. In 1993, men with the lowest glucose versus those with the highest glucose had a lower waist-to-hip ratio, plasma HbA1c, fasting and postload insulin and glucose values, and a higher insulin sensitivity index. In agreement with the 1985 non-cholesterol sterol data, direct analyses of cholesterol metabolism showed further higher cholesterol absorption efficiency (P = 0.03) and serum plant sterol and cholestanol proportions (P < 0.001). Despite a slightly lower dietary cholesterol intake, cholesterol synthesis (P = 0.02) and serum lathosterol (P < 0.01) and desmosterol (P < 0.01) proportions were lowest in men with the lowest glucose third. We conclude that noncholesterol sterols in serum exhibits a long-lasting correlation with blood glucose level in a nondiabetic male population. Low intestinal absorption and high synthesis of cholesterol characterize men with high normal blood glucose. Differences in cholesterol metabolism could be due to underlying insulin effects associated with obesity-like fat distribution and may thus imply novel aspects in the metabolic interrelation between insulin and cholesterol in humans.

Effects of vitamin E on the toxicity of oxidized LDL on endothelial cells in vitro in smokers vs nonsmokers on diets rich in fish.

OBJECTIVE: To clarify whether supplementation of vitamin E can alter the low density lipoprotein (LDL) oxidation properties and thereby affect endothelial cell function and prostacyclin production in smokers compared to nonsmokers on diets rich in fish in a pilot study. DESIGN: The LDL of six smokers and six nonsmokers on habitual high fish diet was isolated before and after an 8-week supplementation of vitamin E (800 IU/day). LDL was oxidized by incubation with CuSO4. Cytotoxicity of LDL oxidized to different degrees on endothelial cells was investigated in vitro in these two groups. SETTING: Helsinki University Central Hospital; Institute of Biomedicine, Pharmacology, University of Helsinki. RESULTS: At baseline, the rate of oxidation was higher in nonsmokers than in smokers. The lag phase increased significantly after the supplementation of vitamin E both in smokers and nonsmokers. Native LDL dose dependently tended to reduce the viability of endothelial cells in vitro more markedly when isolated from smokers than from nonsmokers. Vitamin E supplementation had no beneficial effect on the cytotoxicity of oxidized LDLs in endothelial cell culture. On the other hand, simultaneous administration of Trolox, the water-soluble analogue of vitamin E, attenuated the LDL cytotoxicity on endothelial cells. The vitamin E supplementation to LDL donors attenuated the increase in prostacyclin production both in smokers and nonsmokers. CONCLUSION: Supplementation of LDL donors (healthy male volunteers on habitual fish diet) with vitamin E increased the lag phase of LDL oxidation, but, on the other hand, did not influence in vitro cytotoxicity of LDL, or prostacyclin production.

Subgroup and per-protocol analysis of the randomized European Trial on Isolated Systolic Hypertension in the Elderly.

BACKGROUND: In 1989, the European Working Party on High Blood Pressure in the Elderly started the double-blind, placebo-controlled, Systolic Hypertension in Europe Trial to test the hypothesis that antihypertensive drug treatment would reduce the incidence of fatal and nonfatal stroke in older patients with isolated systolic hypertension. This report addresses whether the benefit of antihypertensive treatment varied according to sex, previous cardiovascular complications, age, initial blood pressure (BP), and smoking or drinking habits in an intention-to-treat analysis and explores whether the morbidity and mortality results were consistent in a per-protocol analysis. METHODS: After stratification for center, sex, and cardiovascular complications, 4695 patients 60 years of age or older with a systolic BP of 160 to 219 mm Hg and diastolic BP less than 95 mm Hg were randomized. Active treatment consisted of nitrendipine (10-40 mg/d), with the possible addition of enalapril maleate (5-20 mg/d) and/or hydrochlorothiazide (12.5-25 mg/d), titrated or combined to reduce the sitting systolic BP by at least 20 mm Hg, to below 150 mm Hg. In the control group, matching placebo tablets were employed similarly. RESULTS: In the intention-to-treat analysis, male sex, previous cardiovascular complications, older age, higher systolic BP, and smoking at randomization were positively and independently correlated with cardiovascular risk. Furthermore, for total (P = .009) and cardiovascular (P = .09) mortality, the benefit of antihypertensive drug treatment weakened with advancing age; for total mortality (P = .05), the benefit increased with higher systolic BP at entry, while for fatal and nonfatal stroke (P = .01), it was most evident in nonsmokers (92.5% of all patients). In the perprotocol analysis, active treatment reduced total mortality by 24% (P = .05), reduced all fatal and nonfatal cardiovascular end points by 32% (P<.001), reduced all strokes by 44% (P = .004), reduced nonfatal strokes by 48% (P = .005), and reduced all cardiac end points, including sudden death, by 26% (P = .05). CONCLUSIONS: In elderly patients with isolated systolic hypertension, stepwise antihypertensive drug treatment, starting with the dihydropyridine calcium channel blocker nitrendipine, improves prognosis. The per-protocol analysis suggested that treating 1000 patients for 5 years would prevent 24 deaths, 54 major cardiovascular end points, 29 strokes, or 25 cardiac end points. The effects of antihypertensive drug treatment on total and cardiovascular mortality may be attenuated in very old patients.

Ambulatory monitoring uncorrected for placebo overestimates long-term antihypertensive action. Systolic Hypertension in Europe (SYST-EUR) Trial Investigators.

This study compares blood pressure (BP) changes during active antihypertensive treatment and placebo as assessed by conventional and ambulatory BP measurement. Older patients (> or = 60 years, n=337) with isolated systolic hypertension by conventional sphygmomanometry at the clinic were randomized to placebo or active treatment consisting of nitrendipine (10 to 40 mg/d), with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d). At baseline, clinic systolic/diastolic BP averaged 175/86 mm Hg and 24-hour and daytime ambulatory BPs averaged 148/80 and 154/85 mm Hg, respectively. After 13 months (median) of active treatment, clinic BP had dropped by 22.7/7.0 mm Hg and 24-hour and daytime BPs by 10.5/4.5 and 9.7/4.3 mm Hg, respectively (P<.001 for all). However, clinic (9.8/1.6 mm Hg), 24-hour (2.1/1.1 mm Hg), and daytime (2.9/1.0 mm Hg) BPs decreased also during placebo (P<.05, except for daytime diastolic BP); these decreases represented 43%/23%, 20%/24%, and 30%/23% of the corresponding BP fall during active treatment. After subtraction of placebo effects, the net BP reductions during active treatment averaged only 12.9/5.4, 8.3/3.4, and 6.8/3.2 mm Hg for clinic, 24-hour, and daytime BPs, respectively. The effect of active treatment was also subject to diurnal variation (P<.05). Changes during placebo in hourly systolic and diastolic BP means amounted to (median) 21% (range, -1% to 42%) and 25% (-3% to 72%), respectively, of the corresponding changes during active treatment. In conclusion, expressed in millimeters of mercury, the effect of antihypertensive treatment on BP is larger with conventional than with ambulatory measurement. Regardless of whether BP is measured by conventional sphygmomanometry or ambulatory monitoring, a substantial proportion of the long-term BP changes observed during active treatment may be attributed to placebo effects. Thus, ambulatory monitoring uncorrected for placebo or control observations, like conventional sphygmomanometry, overestimates BP responses in clinical trials of long duration.

Serum concentration and metabolism of cholesterol during rapeseed oil and squalene feeding.

The effect of rapeseed oil with and without added squalene was studied on serum lipids and cholesterol metabolism. Dietary rapeseed oil reduced LDL cholesterol by 10%, increased cholesterol precursors and plant sterols, and decreased cholestanol in serum during a 6-wk baseline period from initial values. Addition of 1 g squalene in rapeseed oil for 9 wk caused net increases in serum total, VLDL-, IDL-, and LDL-cholesterol concentrations by 12%, 34%, 28%, and 12%, respectively; squalene by five times; and cholesterol precursor sterols by up to 60%. Fecal squalene was 15% of the dietary intake, cholesterol absorption was unchanged, fecal neutral sterols were significantly increased, whereas, in contrast to the precursor sterols, the increase in cholesterol synthesis was insignificant. LDL apolipoprotein B was increased by 14% with unchanged removal but enhanced transport of LDL apolipoprotein B. A negative correlation between the changes in LDL apolipoprotein B removal and LDL cholesterol suggests that LDL receptor activity was down-regulated, allowing more of the LDL precursor lipoproteins to be converted to LDL. A subsequent 6-wk period on 0.5 g squalene/d normalized serum sterols.

Dietary sitostanol related to absorption, synthesis and serum level of cholesterol in different apolipoprotein E phenotypes.

Effects of small amounts of sitosterol, sitostanol and sitostanol esters (< 1 g/day of free sterols) dissolved in rapeseed oil (RSO) were studied on serum lipids and cholesterol metabolism in patients with primary hypercholesterolemia and different apolipoprotein E phenotypes on an RSO diet. One of the four groups was an RSO-fed control. Serum total and LDL cholesterol reductions were small in different plant sterol-fed groups, tended to be highest in the sitostanol ester group (-7%), but were significantly reduced by about 5% in the combined plant sterol groups. The reductions were -8% in the subjects with epsilon 4 allele and insignificant in those with apo E3/3 phenotype. Cholesterol precursor sterols in serum, markers of cholesterol synthesis, were increased only in the subjects with epsilon 4 allele. Cholesterol absorption was reduced by 7%, being 31% in the subjects with epsilon 4 allele, and fecal elimination of cholesterol was increased, a finding also indicating increased cholesterol synthesis. The changes in cholesterol absorption were related to those in fecal plant sterols (change in dietary intake) and serum total and LDL cholesterol (P = 0.04, 0.01 and 0.05, respectively). Thus, small amounts of dietary plant sterols (< 1 g/day), especially sitostanol esters dissolved in dietary fats, decrease serum total and LDL cholesterol by a proportional decrease in cholesterol absorption which, in turn, is associated with a compensatory increase in cholesterol synthesis. The effects are most consistent in subjects with epsilon 4 allele, but for effective hypocholesterolemic treatment dietary amount of sitostanol ester should exceed 1 g/day.

Cholesterol absorption and synthesis during pravastatin, gemfibrozil and their combination.

The study evaluates cholesterol metabolism off and on treatment with pravastatin (P), gemfibrozil (G) and their combination (PG) in 38 middle-age hyperlipidemic primary care patients with serum cholesterol > 6 mmol/l and serum triglycerides < 4 mmol/l after a low-fat low-cholesterol diet. The subjects were randomized to P (40 mg/g), G (1200 mg/day), PG (40 + 1200 mg/day) or placebo for 12 weeks. We analyzed serum lipids, apolipoproteins A-I, B and E, serum cholesterol precursors (markers of cholesterol synthesis), serum plant sterols and cholestanol (markers of cholesterol absorption) and cholesterol metabolism by the sterol balance technique and cholesterol absorption efficiency. P alone or in combination with G lowered apoprotein E concentration, and serum cholesterol levels by inhibiting cholesterol synthesis measured by the precursor/cholesterol proportions with inconsistent change in fecal output of cholesterol. G alone decreased bile acid synthesis and increased biliary cholesterol secretion which were associated with reduced cholesterol absorption efficiency and the serum plant sterol and cholestanol proportions, and increased synthesis of cholesterol as measured both by the sterol balance technique and the precursor sterol proportions. A combination of PG also lowered LDL cholesterol similarly but triglyceride-rich lipoproteins significantly more than P alone, and otherwise inhibited the changes caused by G in cholesterol metabolism except that the precursor sterol proportions still indicated reduced cholesterol synthesis. Overall, the changes of the cholesterol precursor proportions were negatively related to that of cholesterol absorption efficiency and positively to that of cholesterol synthesis. The respective plant sterol and cholestanol values correlated oppositely to cholesterol absorption efficiency and synthesis. Serum precursor sterols reflected changes in cholesterol synthesis more sensitively than the sterol balance technique, even though only the latter method can quantitate cholesterol synthesis.

Apolipoprotein E phenotype and cholesterol metabolism in familial hypercholesterolemia.

Serum lipids, lipoproteins, cholesterol absorption and parameters of cholesterol metabolism were related to apolipoprotein E phenotypes in 38 patients with familial xanthomatous hypercholesterolemia. Serum lipids and lipoproteins were similar in 2 most frequent apo E phenotypes E 3/3 and E 4/3. Coronary artery disease was not related to the apo E phenotypes. Cholesterol absorption efficiency was significantly lower in the apo E 3/3 patients than in the apo E 4/3 group. A high serum level of cholesterol precursor lathosterol, a high lathosterol/sitosterol ratio and sterol balance data suggest that cholesterol synthesis may be slightly higher in the apo E 3/3 than E 4/3 group. The findings indicate that the genetically determined apo E polymorphism contributes to cholesterol absorption efficiency in FH patients, but serum total and lipoprotein cholesterol levels are poorly related to apo E isoforms.

Blood pressure and mortality during an up to 32-year follow-up.

BACKGROUND: Elevated blood pressure is an established risk factor of cardiovascular diseases, but there is a constant debate whether the association is continuous or with a threshold. METHODS: During the 1960s (1964 onwards), 3,267 initially healthy male business executives (born 1919-1934) participated in voluntary health check-ups with measurements of cardiovascular disease risk factors. At baseline none of the men were on antihypertensive medication. Mortality follow-up was performed using national registers up to 31 December, 1995. Follow-up total and cardiovascular mortality was related to systolic (by 10 mmHg) and diastolic (by 5 mmHg, Korotkoff's 4th phase) blood pressure at baseline. Analyses were adjusted for age, body mass index, smoking and serum cholesterol. RESULTS: During an up to 32-year follow-up, there were 701 deaths, 234 (33.4%) of them due to coronary heart disease, 49 (7.0%) to stroke, 42 (6.0%) to other cardiovascular diseases and 204 (29.1%) to cancer. Total mortality curves of the whole cohort (all age groups) were flat until 131-140 mmHg (systolic) and 81-85 (diastolic) and increased thereafter. Among men who smoked and had baseline serum cholesterol > 6.5 mmol/l (n = 986), the risk of death increased progressively with systolic blood pressure, whereas among non-smoking normocholesterolaemic men (n = 504) the association was J-shaped, i.e. higher mortality at < or = 110 mmHg than between 111-150 mmHg and a more consistent rise from 151-160 mmHg. The curves were essentially similar for cardiovascular mortality. The results were supported by analyses where major cardiovascular risk factors were controlled. CONCLUSION: During a truly long-term follow-up, the relationship between systolic blood pressure and mortality was initially flat up to 131-140 mmHg although a linear relationship is suggested in men with other cardiovascular risk factors.

Excess mortality associated with increased pulse pressure among middle-aged men and women is explained by high systolic blood pressure.

OBJECTIVE: To assess the risk of death from coronary heart disease, stroke, all cardiovascular diseases and all-cause mortality associated with pulse pressure among the middle-aged population. METHODS AND DESIGN: A prospective 15-year follow-up cohort study was conducted of two independent cross-sectional random samples of the population who participated in baseline surveys in 1972 or 1977. Each survey included a self-administered questionnaire with questions on smoking and antihypertensive drug treatment, measurements of height, weight and blood pressure and the determination of the serum cholesterol concentration. Multivariate analyses were performed by using Cox proportional hazard models. SETTING: The provinces of North Karelia and Kuopio in eastern Finland PARTICIPANTS: Men and women aged 45-64 years with no history of myocardial infarction or stroke at the time of the baseline survey were selected. In total 4333 men and 5270 women took part in this follow-up study. RESULTS: The relative risk of coronary heart disease, stroke, cardiovascular disease and all-cause mortality increased with the increasing pulse pressure in individuals aged 45-64 years independent of the diastolic blood pressure level. Only in women with diastolic blood pressure > or = 95 mmHg was the relative risk of fatal stroke not statistically significant. After adjustment for systolic blood pressure, the positive association between mortality and increasing pulse pressure disappeared. CONCLUSION: Increasing pulse pressure is a predictor of death from coronary heart disease, stroke, cardiovascular disease and all causes in men and women aged 45-64 years, but the increase in risk is entirely associated with the increase in systolic blood pressure.

Associations of orthostatic blood pressure fall in older patients with isolated systolic hypertension. Syst-Eur Investigators.

OBJECTIVES: To investigate the associations of the orthostatic blood pressure changes in older patients with isolated systolic hypertension. METHODS: A total of 2716 patients, 917 men and 1799 women, aged > or = 60 years, were examined at three separate outpatient visits whilst receiving placebo during the single-blind run-in phase of the Syst-Eur trial. The orthostatic blood pressure changes were calculated by subtracting the average of two blood pressure readings with the patient in the supine position from the mean of two readings obtained after the patient had stood for 2 min. An orthostatic blood pressure drop by at least 20 mmHg systolic or 10 mmHg diastolic was considered exaggerated. RESULTS: For the three run-in visits combined, the supine blood pressure was 175 +/- 13 mmHg systolic and 86 +/- 6 mmHg diastolic (means +/- SD). With the patients standing the systolic blood pressure was 5 +/- 12 mmHg lower, whereas the diastolic blood pressure was 2 +/- 7 mmHg higher. An exaggerated fall in systolic blood pressure was observed on at least 1 visit in 21.0% of the patients and on all three visits in 2.5%. The corresponding values for diastolic blood pressure were 9.7 and 0.4%. The orthostatic fall in systolic blood pressure increased with previous antihypertensive treatment, age and smoking, but decreased with a higher sitting pulse rate and usual alcohol consumption versus none. The rise in diastolic blood pressure upon standing was higher in women than in men, was curvilinearly associated with age and increased with the sitting diastolic blood pressure. By multiple logistic regression analysis, the odds of having a persistent or occasional exaggerated orthostatic fall in systolic blood pressure were 22% higher in women than in men. The odds increased with previous antihypertensive treatment (by 42%), age (by 1.4%/year), electrocardiographic left ventricular mass (by 15%/mV) and sitting systolic blood pressure (by 0.9%/mmHg), but decreased with sitting pulse rate (by 1.9%/beat per min). An exaggerated orthostatic fall in diastolic blood pressure was 30% more likely in men; the likelihood increased with age (by 6.4%/year) and decreased with sitting diastolic blood pressure (by 6.6%/mmHg). CONCLUSION: An exaggerated orthostatic blood pressure fall in older patients with isolated systolic hypertension is associated mainly with gender, age and blood pressure level. Previous antihypertensive treatment, a lower pulse rate and a lower electrocardiographic left ventricular mass were also associated with an exaggerated orthostatic fall in systolic blood pressure.

Quality of life of elderly patients with isolated systolic hypertension: baseline data from the Syst-Eur trial. Syst-Eur Trial Investigators.

OBJECTIVE: To describe measures of quality of life of elderly patients with isolated systolic hypertension at entry to a placebo-controlled randomized trial of antihypertensive treatment and to investigate factors associated with these. DESIGN: Cross-sectional analyses at entry to a randomized controlled trial. SETTING: Patients attending hypertension clinics or general practitioners' surgeries at 30 centres in 10 European countries. PATIENTS: Six hundred and thirty-one patients aged 60 years or more, with a sitting systolic blood pressure during the run-in phase of 160-219 mmHg, a sitting diastolic blood pressure below 95 mmHg and a standing systolic blood pressure of 140 mmHg or more. MAIN OUTCOME MEASURES: Cognitive function tests (Reitan Trail Making A and B), Brief Assessment Index (a measure of depressed mood) and four subscales from the Sickness Impact Profile (Ambulation, Social Interaction, Sleep and Rest and Housework). RESULTS: Poor quality of life was generally associated with increasing age, previous treatment with antihypertensive drugs, presence of cardiovascular complications and, among women, high diastolic blood pressure, higher consumption of alcohol and high body mass index. CONCLUSIONS: At entry to the trial there was considerable heterogeneity of patients in terms of measures of quality of life and cognitive performance. It remains to be determined whether these influence subsequent quality of life during randomized treatment.

Correlates of cognitive status of old patients with isolated systolic hypertension: the Syst-Eur Vascular Dementia Project.

OBJECTIVE: To assess cognitive functions and their correlates for a dementia-free cohort of old patients with isolated systolic hypertension. DESIGN: Cross-sectional data from the randomization period of the European Trial in Elderly with Systolic Hypertension (Syst-Eur Vascular Dementia Project). SETTING: Sixteen European countries and Israel. PARTICIPANTS: We studied 2252 patients aged 60-100 years (mean 70). MAIN OUTCOME MEASURES: Mini Mental State Examination (MMSE) and Spearman correlation of MMSE scores to demographic data or blood pressure. RESULTS: The MMSE was successfully completed for 1474 women and 751 men. The baseline blood pressure averaged 173 +/- 10/86 +/- 6 mmHg (means +/- SD). Median age at which education of patients at school had stopped was 15 years. Men and women who consumed alcohol (28%) had median intakes of 8 and 3 g/day, respectively. The median MMSE score was 29 (range 15-30). The maximum score of 30 was attained by 609 (30%) subjects. Fifty-nine (3%) patients had a MMSE score of 23 or less. The MMSE score decreased with advancing age (r = -0.21, P < 0.001). Both for men and for women, it was positively correlated to the level of education (r = 0.30 and r = 0.32, P < 0.001). For women after adjustment for age and the level of education, the score was correlated negatively to systolic blood pressure (r = -0.07, P < 0.05) but positively to intake of alcohol (r = 0.06, P < 0.05). CONCLUSION: In a cohort of elderly patients with isolated systolic hypertension, baseline cognitive function measured in terms of the MMSE score was high, probably due to selective recruitment of patients who were not clinically demented. Blood pressure was a weak contributor to cognitive status compared with age and level of education. Baseline cognitive function of women was negatively and independently correlated to systolic blood pressure.

Frequency of lipid-lowering therapy after a coronary event in Helsinki, Finland.

The results from a survey in Finland suggest an important treatment gap of lipid-lowering medications. Patients whose coronary artery disease was diagnosed before 1995 were less likely to be on lipid therapy than patients with a more recent diagnosis.

Long-term use of probucol in the multifactorial primary prevention of vascular disease.

Over 1,200 middle-aged men with no apparent vascular disease participated in a 5-year multifactorial primary prevention trial, in which 612 received dietetic, hygienic and--when indicated--pharmacologic treatment for the following risk factors: hyperlipidemia, hypertension, smoking, obesity and abnormal glucose tolerance. Pharmacologic therapy included hypolipidemic agents (mainly probucol and clofibrate) and antihypertensive drugs (mainly diuretics and beta blockers). At the end of the 5 years, results in these men were compared with findings in 610 high risk and 593 low risk control subjects, none of whom had received treatment. Although intervention decreased the mean risk factor status of the treated men by 33%, their 5-year coronary incidence exceeded that of the high risk control subjects (3.1% vs 1.5%). Stroke incidence, however, was markedly reduced in the treated subjects (0% vs 1.3%). Multivariate analysis showed that the coronary events occurred in patients taking beta blockers or clofibrate, while few occurred in those receiving probucol or the diuretics. The decrease in mean serum cholesterol was 15% in men receiving only probucol, and ranged from 0% to 13% in those receiving different drug combinations, including clofibrate plus probucol (11%). Probucol also markedly decreased high density lipoprotein cholesterol levels, especially when combined with clofibrate. It is possible that adverse drug effects offset the probable benefit of an improved risk profile in the treated men, thereby explaining the greater than expected occurrence of cardiac events in this group. The probucol data, however, suggest that it may not be harmful to lower the high density lipoprotein cholesterol level when there is a significant decrease in total cholesterol as well.

Comparison of effects on sleep of lovastatin and pravastatin in hypercholesterolemia.

The effects on sleep of lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor administered as a lipophilic lactone prodrug, and pravastatin, an inhibitor administered in its active, hydrophilic, open-acid form, were compared by polysomnographic sleep monitoring. Twenty-four men with primary hypercholesterolemia (low-density lipoprotein 4 to 7 mmol/liter) each received 2 of the following 3 treatments in a randomized, incomplete block, crossover design study: lovastatin (40 mg/day), pravastatin (40 mg/day), and placebo. Test drug was administered once daily for 4 weeks during each half of the crossover study. Subjective sleep assessments were obtained throughout each treatment period, and polysomnographic recordings were obtained at the end of the 4-week treatment periods. Treatment periods were separated by a 1-week washout. Lovastatin did not differ from placebo regarding any polysomnographic parameter except "number of entries to wake," for which it produced fewer entries (i.e., change was in the direction of improvement). Pravastatin did not differ from placebo regarding any polysomnographic measures, but was associated with worsening in relation to lovastatin in the following parameters: sleep efficiency, entries to wake, percent rapid eye movement sleep, wake time during sleep, and total wake time. For each of these 4 parameters, although neither drug showed marked differences from placebo, the mean change in the lovastatin group was in the direction of improved sleep, whereas the change in the pravastatin group was in the direction of disturbed sleep. Neither lovastatin nor pravastatin had any effect on subjective, qualitative sleep ratings.(ABSTRACT TRUNCATED AT 250 WORDS)

Hypolipidemic effect and mechanism of ketoconazole without and with cholestyramine in familial hypercholesterolemia.

The hypocholesterolemic and metabolic effects of ketoconazole (400 mg/d) alone (inhibits cholesterol synthesis at 14 alpha-demethylation of lanosterol) and in combination with cholestyramine (12 g/d), were studied in nine women with xanthomatous familial hypercholesterolemia (FH). In addition to serum lipoprotein levels, cholesterol precursors, fecal steroids, and cholesterol absorption were measured before and during the drug treatments. Serum total and low-density lipoprotein (LDL)-cholesterol were reduced by 19% and 22% with ketoconazole; the respective changes were 16% and 21% for cholestyramine, and 31% and 41% for the combined ketoconazole and cholestyramine treatment. Serum triglycerides, very-low-density lipoprotein (VLDL)-and high-density lipoprotein (HDL)-cholesterol levels were unchanged. Accumulation of cholesterol precursors in serum suggested that ketoconazole inhibited cholesterol synthesis at delta 8-sterol levels. Serum and fecal lanosterols were increased up to 20-fold and were interrelated. Their maximal serum level was 1.3 mg/DL and the lanosterol contents were negatively related to the serum cholesterol levels. The intestinal absorption and total intestinal fluxes of cholesterol were reduced by 27% and 29%. Cholesterol and bile acid synthesis were decreased by ketoconazole only when combined with cholestyramine. The synthesis of chenodeoxycholic acid was deeply hindered by ketoconazole. Thus, ketoconazole efficiently lowers serum total and LDL-cholesterol levels in FH patients, probably by inhibiting cholesterol synthesis and absorption. Effective biliary and fecal outputs of cholesterol precursors prevent their excessive increase in serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Pravastatin lowers serum cholesterol, cholesterol-precursor sterols, fecal steroids, and cholesterol absorption in man.

Serum lipids, and absorption, intestinal fluxes, fecal elimination, and synthesis of cholesterol were studied before and during 4 weeks of pravastatin treatment at a dose of 40 mg/d in heterozygous familial hypercholesterolemic (FH) patients without (control group, n = 7) and with an ileal bypass (IBP group, n = 6). The drug reduced serum total and low-density lipoprotein (LDL) cholesterol and LDL-apoprotein (apo)B levels up to 34%. Less-consistent decreases in intermediate-density lipoprotein (IDL) and very-low-density lipoprotein (VLDL) cholesterol were also seen. None of the control patients and two of the IBP patients became normolipidemic (LDL less than 4 mmol/L). Marked transient reductions in serum free-methylated-cholesterol precursors, and more-constant decreases in the esterified and total fractions, suggested that cholesterol synthesis was reduced shortly after the start of treatment. The decreases in total lathosterol and methylsterols were more extensive in the IBP group than in the control group. Serum plant sterol levels were slightly increased, with inconsistent elevations of cholestanol. Reduced fecal elimination of cholesterol and its precursors suggests that decreased cholesterol synthesis was mainly due to lowered bile acid production, particularly in the IBP group with markedly enhanced basal bile acid and cholesterol synthesis. The serum and fecal levels of cholesterol precursors, lathosterol in particular, were related to each other and were proportionate to the serum level and fecal elimination of cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of unsaturated and saturated dietary plant sterols on their serum contents.

Rapeseed oil fed to 24 hypercholesterolemic patients (50 g/day) reduced serum cholesterol (-8.5%) and cholestanol concentrations but increased those of campesterol and sitosterol. Continuation of rapeseed oil alone or with added sitosterol (625 mg/day) or sitostanol (630 mg/day) had no further effect on serum cholesterol. Rapeseed oil with sitosterol increased further its own proportion to cholesterol in serum but reduced that of campesterol while rapeseed oil with sitostanol reduced the proportions of both sitosterol and campesterol proportionately to the pretreatment values. The changes in the campesterol and sitosterol proportions were negatively and positively related to each other during the sitosterol and sitostanol additions, respectively. Thus, concentrations of unsaturated plant sterols in serum reflect their dietary intakes, saturated plant sterols are virtually not absorbed, plant sterols interfere with absorption of unsaturated structurally different plant sterols and cholestanol, and plant sterol-induced reduction of sterol absorption may be positively related to absorption efficiency of sterols.