Hannu Vanhanen

Reduction of Serum Cholesterol with Sitostanol-Ester Margarine in a Mildly Hypercholesterolemic Population

BACKGROUND Dietary plant sterols, especially sitostanol, reduce serum cholesterol by inhibiting cholesterol absorption. Soluble sitostanol may be more effective than a less soluble preparation. We tested the tolerability and cholesterol-lowering effect of margarine containing sitostanol ester in a population with mild hypercholesterolemia. METHODS We conducted a one-year, randomized, double-blind study in 153 randomly selected subjects with mild hypercholesterolemia. Fifty-one consumed margarine without sitostanol ester (the control group), and 102 consumed margarine containing sitostanol ester (1.8 or 2.6 g of sitostanol per day). RESULTS The margarine containing sitostanol ester was well tolerated. The mean one-year reduction in serum cholesterol was 10.2 percent in the sitostanol group, as compared with an increase of 0.1 percent in the control group. The difference in the change in serum cholesterol concentration between the two groups was -24 mg per deciliter (95 percent confidence interval, -17 to -32; P < 0.001). The respective reductions in low-density lipoprotein (LDL) cholesterol were 14.1 percent in the sitostanol group and 1.1 percent in the control group. The difference in the change in LDL cholesterol concentration between the two groups was -21 mg per deciliter (95 percent confidence interval, -14 to -29; P < 0.001). Neither serum triglyceride nor high-density lipoprotein cholesterol concentrations were affected by sitostanol. Serum campesterol, a dietary plant sterol whose levels reflect cholesterol absorption, was decreased by 36 percent in the sitostanol group, and the reduction was directly correlated with the reduction in total cholesterol (r = 0.57, P < 0.001). CONCLUSIONS Substituting sitostanol-ester margarine for part of the daily fat intake in subjects with mild hypercholesterolemia was effective in lowering serum total cholesterol and LDL cholesterol.

Effect of statins on C-reactive protein in patients with coronary artery disease

patients who had SCLC-LEMS with a matched group of patients who had SCLC only. Survival data were available for 15 SCLC-LEMS patients seen in a neuromuscular clinic since 1987. All had biopsyproven SCLC, typical clinical and electromyographic features of LEMS, and raised titres of anti-P/Q-type voltagegated calcium channel antibodies detectable by RIA. Hospital records were available for SCLC patients who had no neurological illness and who had participated in randomised SCLC treatment trials between 1988 and 1997 at the Middlesex and University College Hospitals, London, UK. We matched each of the 15 SCLC-LEMS patients with five or six SCLC-only patients (n=81) for sex, age at SCLC diagnosis, tumour extent (limited or extensive), and treatment (chemotherapy of radiotherapy). Computer matching was done by medical staff masked to the SCLCLEMS patients’ survival data. Three SCLC-LEMS patients had extensive disease at tumour diagnosis; four did not receive specific tumour treatment because they died soon after diagnosis. With one exception, symptoms of LEMS predated the diagnosis of SCLC (range 0·3–4·7 years). At the time of the study, four SCLC-LEMS patients were alive with no evidence of tumour recurrence after a median of 6 years (range 1·5–8·5) since tumour detection and treatment. Kaplan-Meier survival estimates (figure) show a significantly shorter median survival time from the diagnosis of SCLC in SCLC-only patients (10 months) than in the SCLC-LEMS patients (17·3 months, p=0·048, Log-rank test). Factors contributing to this better survival rate in SCLC-LEMS might be a slower rate of growth in tumours that provoke LEMS, or lead-time bias, in that once LEMS is diagnosed, the vigilance for associated lung cancer may be increased. In SCLC-LEMS, however, tumour macrophage infiltration is greater and MHC class I antigen expression less in patients with SCLC only, which implies more tumour-cell destruction in LEMS. Moreover, the time between onset of LEMS and clinical presentation of the tumour can be longer than would be predicted from the estimated ratio of tumour growth on the basis of radiographic analysis of non-LEMS patients. These observations and our survival data support the view that the autoimmune response in LEMS retards tumour growth. Therefore, the recognition of LEMS in any patients with SCLC could have important implications for long-term outcome after antitumour therapy.

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, elimination, and synthesis related to LDL kinetics during varying fat intake in men with different apoprotein E phenotypes.

Cholesterol absorption, fecal elimination, and synthesis and low density lipoprotein (LDL) metabolism were measured in 29 middle-aged men while on their normal diet and a diet low in fat and cholesterol, and the obtained values were related to apoprotein (apo) E phenotypes. Basal cholesterol absorption efficiency was positively related to production rate (PR) for LDL apo B and negatively to cholesterol synthesis (measured by fecal steroids and dietary cholesterol), which in turn was negatively associated with the LDL level and positively with the fractional removal (FCR) of LDL apo B. The apo E subscript (e.g., E2/2 = 1, E2/3 = 2, etc.) was positively associated with cholesterol absorption and the LDL apo B and cholesterol levels and negatively with cholesterol synthesis and FCR for LDL apo B. Effective bile acid and cholesterol synthesis, fecal elimination of cholesterol, removal of LDL apo B, and low cholesterol absorption characterized men with the epsilon 2 allele. Reduction of dietary fat and cholesterol intakes lowered LDL cholesterol levels and cholesterol absorption but increased cholesterol synthesis proportionally to the apo E subscript; the FCR and PR for LDL apo B were significantly increased and decreased, respectively. The decrease in absorption was related to enhanced removal of LDL apo B and synthesis of cholesterol. During the modified diet, cholesterol metabolism was poorly related to LDL, apo E phenotypes, and LDL apo B kinetics. A positive correlation of cholesterol absorption with dietary fat intake in combined studies suggests that a dietary fat reduction-associated decrease in LDL cholesterol is at least partly caused by reduced cholesterol absorption.(ABSTRACT TRUNCATED AT 250 WORDS)

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 ⩾ 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.

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.

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.

Isolated diastolic hypertension, pulse pressure, and mean arterial pressure as predictors of mortality during a follow-up of up to 32 years.

Objective To compare mortality associated with various blood pressure components in middle-aged men during up to 32 years of follow-up. Design A prospective cohort study. Setting Helsinki, Finland. Participants We studied 3267 initially healthy men, aged 30–45 years, who participated in health check-ups from 1964 onwards. Main outcome measures Cox regression was used to relate baseline blood pressure components to all-cause (n = 701) and cardiovascular disease (CVD) mortality (n = 325). Results Systolic (SBP) and diastolic (DBP) blood pressures, pulse pressure and mean arterial pressure singly predicted CVD mortality. With SBP 160 mmHg and DBP 90 mmHg as cut-off values, four blood pressure subgroups were identified: normotension (n = 1919), isolated systolic hypertension (ISH, n = 17), isolated diastolic hypertension (IDH, n = 1013), and combined systolic and diastolic hypertension (SDH, n = 318). IDH was subdivided into IDH-1 with SBP 140–159 mmHg (n = 667) and IDH-2 with SBP less than 140 mmHg (n = 346). With normotension as reference, only SDH and IDH-1 predicted CVD mortality [relative risk (RR) 2.71, 95% confidence interval (CI) 2.00 to 3.66, and RR 1.39, 95% CI 1.04 to 1.87, respectively]. Risk with IDH-2 (RR 1.14, 95% CI 0.77 to 1.69) was not statistically significant. SDH and IDH-1, but not IDH-2, were also associated with increased all-cause mortality risk. Use of antihypertensive medication did not explain the results. Conclusion These results demonstrate the often neglected role of SBP in predicting long-term CVD risk in middle-aged men. When SBP is less than 140 mmHg, IDH is not associated with significantly increased risk of mortality. Administrative guidelines, which affect population health, should also take due note of SBP.

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)

Glucose tolerance and blood pressure: long term follow up in middle aged men.

OBJECTIVE--to investigate the role of glucose tolerance in the development of hypertension. DESIGN--Retrospective analysis of the results of a health check up in a group of clinically healthy middle aged men in the late 1960s (median year 1968). The subjects were invited to enter into a primary prevention trial for cardiovascular disease in 1974, when they underwent clinical examination for risk factors. The trial was completed in 1979, when the men were re-examined. Follow up was in 1986. SETTING--Institute of Occupational Health, Helsinki, Finland and second department of medicine, University of Helsinki. SUBJECTS--In all, 3490 men born during 1919-34 participated in a health check up in the late 1960s. In 1974, 1815 of these men who were clinically healthy were entered into a primary prevention trial for cardiovascular disease. On clinical examination 1222 of the men were considered at high risk of cardiovascular disease. Of these, 612 received an intervention and were excluded from the study. A total of 593 men were without risk factors. The study comprised all of the men who did not have an intervention (n = 1203). In 1979, 1120 men were re-examined, and in 1986 945 men attended follow up. There were two groups for analysis: one comprising all subjects and the other comprising only men who were normotensive in 1968 and for whom complete information was available. INTERVENTIONS--By 1979, 103 men were taking antihypertensive drugs, and by 1986, 131 were taking antihypertensive drugs and 12 were taking drugs for hyperglycaemia. MAIN OUTCOME MEASURES--Blood glucose concentration one hour after a glucose load, blood pressure, and body weight were measured in 1968, 1974, and 1979. In 1986 blood pressure and body weight were recorded. RESULTS--Men who were hypertensive in 1986 had significantly higher blood pressures (p less than 0.0001) and (after adjustment for body mass index and alcohol intake) significantly higher blood glucose concentrations one hour after a glucose load at all examinations than those who were normotensive in 1986. Regression analysis showed that the higher the blood glucose concentration after a glucose load in 1968 the higher the blood pressure during the following years. Those men between the second and third tertiles of blood glucose concentration in 1968 had a significantly higher risk of developing hypertension (odds ratio 1.71, 95% confidence interval 1.05 to 2.77) compared with those below the first tertile. CONCLUSION--In this study men who developed hypertension tended to have shown an increased intolerance to glucose up to 18 years before the clinical manifestation of their disorder. Blood glucose concentration one hour after a glucose load was an independent predictor of future hypertension.