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Biomedical subjects

T A Miettinen

Publications and source records attributed to T A Miettinen.

At least 19 recordsLinked to original sources
PubMed2006

Postprandial behavior of plasma squalene and non-cholesterol sterols in men with varying cholesterol absorption.

BACKGROUND: The purpose of this study was to investigate, whether low vs. high absorption of cholesterol affects the postprandial lipid clearance (squalene as the surrogate marker) and postprandial cholesterol metabolism evaluated with plasma levels of cholesterol absorption (cholestanol and plant sterols) and synthesis markers (desmosterol and lathosterol). METHODS: Fifteen normo- or mildly hypercholesterolemic men were divided into low or high cholesterol absorbers on the basis of plasma cholestanol to cholesterol ratio and they volunteered to an oral fat load test containing fat 35 g/m(2) body surface. RESULTS: Plasma squalene to cholesterol ratio did not differ between the groups throughout the postprandial follow-up of 8 h. The level differences in the plasma absorption and synthesis markers seen at baseline remained between the groups, so that in high absorbers the absorption markers remained high and synthesis markers low throughout the postprandial follow-up. The postprandial response curves of desmosterol (p<0.05) and lathosterol (p=0.052) to cholestanol decreased linearly in the low, but not in the high absorbers. CONCLUSIONS: Low vs. high absorption of cholesterol does not affect the first 8-h postprandial lipid clearance. The metabolic profile of cholesterol is maintained postprandially. The postprandial decrease in cholesterol synthesis differs in low vs. high absorbers especially through the desmosterol pathway.

Absorption↗
PubMed2006

Plant stanol and sterol esters in prevention of cardiovascular diseases: a review.

Plant sterol and stanol esters have been introduced as an additional dietary means to lower serum total and LDL cholesterol concentration. In short-term studies they lower LDL cholesterol by 10%, and according to a meta-analysis by Malcolm Law the incidence of coronary heart disease is considered to be reduced by over 20% in long-term use of these products. Plant stanol and sterol esters are not identical sterols; they have different metabolic effects and their long-term efficacy seems to be different. The present review deals with the differences of the sterols and discusses what is known of their role in preventing the cardiovascular diseases.

Cardiovascular Diseases↗
PubMed2005

Ester percentages of plant sterols and cholesterol in chylomicrons and VLDL of humans with low and high sterol absorption.

Ester percentages of cholesterol and non-cholesterol sterols were measured in chylomicrons and very low density lipoproteins (VLDL) in 15 subjects. Our hypothesis was that in humans, in contrast to animal experiments, plant sterols in chylomicrons are esterified similarly to cholesterol. In fact, the mean ester percentage of chylomicron sitosterol (approximately 40%), but not of campesterol ( approximately 51%), was lower than that of cholesterol (approximately 54%) in the whole study population. In high cholesterol absorbers (high serum total campesterol, > or = 2.8 mmol/mol of cholesterol), the ester percentages of sitosterol and other non-cholesterol sterols were similar to that of cholesterol in chylomicrons, and the percentages tended to be higher than those in low absorbers. In contrast to chylomicrons, the ester percentages of sterols in VLDL tended to be lower in the high than low absorbers. In conclusion, percentages of plant sterol esters are not consistently lower than those of cholesterol in chylomicrons.

Absorption↗
PubMed2003

Impact of midlife weight change on mortality and quality of life in old age. Prospective cohort study.

OBJECTIVE: To examine the effects of weight change during midlife on long-term mortality risk and quality of life in old age. DESIGN: Prospective cohort study with a 26-y follow-up. SUBJECTS: Socioeconomically homogeneous sample of 1657 men (born 1919-1934) who had attended health checks during the 1960s, were healthy and professionally active in 1974, and could recall their weight at the age of 25 y. MAIN OUTCOME MEASURES: Total mortality 1974-2000, scales of the RAND-36 (SF-36) health survey in 91% (n=1147) of the survivors in 2000. RESULTS: Body weight increased from 25 y of age until midlife, but not thereafter. During the 26-y follow-up, 392 men (23.7% of the initial 1974 cohort) died. Weight at 25 y of age did not predict death, but the adjusted mortality risk was significantly increased in the highest quartile of midlife weight gain (>/=15.0 kg) compared with lower quartiles (RR 1.39, 95% CI 1.12-1.73). In 2000, multivariate analyses (adjusted for body weight at the age of 25 y and in 2000, age, smoking, alcohol and subjective health and physical fitness in 1974) showed impairment in all eight RAND-36 scales (statistically significantly in seven) with increasing weight gain in midlife. CONCLUSION: In this homogeneous male cohort, only the largest weight gain from 25 y of age to midlife predicted long-term mortality. Weight gain sensitively affected later health-related quality of life, and zero weight gain up to midlife was associated with the best quality of life in old age.

Adult↗
PubMed2003

Synthesis and absorption markers of cholesterol in serum and lipoproteins during a large dose of statin treatment.

BACKGROUND: Serum contains noncholesterol sterols, which are reliable markers of cholesterol metabolism, but their presence and importance in different lipoproteins have been insufficiently studied. MATERIALS AND METHODS: Serum and lipoprotein cholesterol precursors squalene, cholestanol, desmosterol and lathosterol (markers of cholesterol synthesis) and cholestanol and plant sterols (markers of cholesterol absorption), and absorption efficacy and absolute synthesis of cholesterol were studied at baseline and during 6-month atorvastatin (80 mg day(-1)) treatment by the sterol balance technique in men with type 2 diabetes. RESULTS: At baseline, approximately 14% of serum squalene was transported by VLDL, 12% by IDL, 40% by LDL and 30% by HDL. The respective values for the noncholesterol sterols were approximately 8, 4, 61 and 26%. The squalene to cholesterol ratios were highest in VLDL and IDL, those of cholestanol, desmosterol and absorption marker sterols were gradually higher, and that of lathosterol lower from VLDL to HDL. Atorvastatin reduced LDL cholesterol by approximately 50%, decreased the absolute cholesterol synthesis and turnover by approximately 40%, but increased significantly the fractional and mass absorption of cholesterol. In accordance with the fecal data, the ratios of the precursor sterols to cholesterol were reduced (-50%), but those of squalene (+48%) and the absorption sterols increased (e.g. 2.6-fold for sitosterol) similarly in each lipoprotein, but progressively from VLDL to HDL. CONCLUSIONS: Effective lowering of LDL cholesterol by large dose of statin is associated with decreased synthesis and turnover of cholesterol and increased fractional and mass absorption of cholesterol. These changes are detectable by noncholesterol sterols in serum and in different lipoprotein fractions.

Aged↗
PubMed2002

Baseline intestinal absorption and synthesis of cholesterol regulate its response to hypolipidaemic treatments in coronary patients.

Baseline cholesterol metabolism was hypothesized to regulate responses of cholesterol synthesis and absorption, and serum cholesterol lowering to hypolipidaemic treatment. Thus, serum cholesterol and non-cholesterol sterols were measured before and during long-term simvastatin treatment (inhibition of cholesterol synthesis) and subsequent combination of statin with plant stanol ester margarine (inhibition of cholesterol absorption) consumption in subjects with low (n=15) and high (n=15) absorption of cholesterol, defined by respective low and high baseline ratios of serum cholestanol to cholesterol. Cholesterol synthesis (defined by precursors of cholesterol) was markedly reduced by the long-term statin treatment in both groups, but more extensively in the low than high absorption group (P<0.05), yet the respective serum cholesterol reductions were similar. From among the absorption markers, sitosterol and cholestanol ratios were correspondingly increased more in the low than in the high absorption group. Plant stanol ester margarine consumption, combined with chronic statin treatment, further lowered the serum cholesterol level (P<0.001) only in the high absorption group. The sum of cholesterol absorption markers was reduced more (P<0.05) in the high than in the low absorption group, while the non-significant serum cholesterol reduction of the low absorption group was associated with relatively high increase of cholesterol synthesis. Thus, stanol ester margarine combined with chronic simvastatin treatment reduces cholesterol absorption and serum cholesterol more consistently in subjects with high than low baseline absorption of cholesterol. The profile of baseline cholesterol metabolism determines the changes in synthesis and absorption of cholesterol to hypolipidaemic treatments, but affects less differently serum cholesterol level.

Aged↗
PubMed2002

Effects of gender, apolipoprotein E phenotype and cholesterol-lowering by plant stanol esters in children: the STRIP study. Special Turku Coronary Risk Factor Intervention Project.

AIM: To evaluate the effects of gender, apolipoprotein E phenotype and cholesterol absorption and synthesis (estimated as serum plant sterol and cholesterol precursor sterol concentrations) on the cholesterol-lowering effect of plant stanol esters in children. METHODS: Eighty-one healthy, normocholesterolaemic 6-y-old children (45 boys) were recruited from the Special Turku Coronary Risk Factor Intervention Project (STRIP), a randomized prospective trial aiming at atherosclerosis prevention in childhood. This placebo-controlled, double-blind, cross-over study comprised two 3-mo study periods and a 6-wk wash-out period. During the study periods, 20 g of the children's daily dietary fat intake was replaced with plant stanol ester margarine or control margarine. RESULTS: In boys, plant stanol esters reduced serum total and low-density lipoprotein cholesterol concentrations by 6% (0.09 to 0.42 mmol/L) and 9% (0.09 to 0.36 mmol/L), respectively (p < 0.01 for both). In girls, the decreases in concentrations were 4% (0.03 to 0.38 mmol/L) and 6% (0.02 to 0.32 mmol/l) (p < 0.05 for both). The response rate did not differ between the genders. Serum total and low-density lipoprotein cholesterol concentrations decreased by 6% and 8% (p < 0.01 for both), respectively, in both children with the apolipoprotein E 3/4 or 4/4 (apoE4+) phenotype and the apolipoprotein E 2/3 or 3/3 (apoE4-) phenotype. Cholesterol absorption decreased both in the apoE4+ children and in the apoE4- children, but cholesterol synthesis consistently increased in the apoE4+ children only. CONCLUSION: Plant stanol esters reduce serum cholesterol concentration in healthy children irrespective of their gender or apoE4 phenotype.

Apolipoproteins E↗
PubMed2002

LDL cholesterol lowering by bile acid malabsorption during inhibited synthesis and absorption of cholesterol in hypercholesterolemic coronary subjects.

BACKGROUND AND AIMS: Recent large-scale trials have consistently documented the fact that a 25-35% reduction in low-density lipoprotein cholesterol (LDL-C) can delay the progression of atherosclerosis. This raises the question as to how much it is possible to reduce serum cholesterol using feasible therapies. The aim of this study was to investigate the cholesterol-lowering efficacy of a triple therapy combining bile acid malabsorption with the inhibition of cholesterol synthesis and absorption. METHODS AND RESULTS: Eleven consecutive hypercholesterolemic coronary patients from Lipid Clinics on a low-fat, low-cholesterol baseline diet added simvastatin (20 mg/day) for three months, and then dietary plant stanol ester margarine (2.25 g of stanols/day) for eight weeks; finally, cholestyramine 8 g/day was added for another eight weeks. This was a before-after trial, in which the results of each period were compared with baseline and those of the previous period. Serum lipids were quantitated using commercial kits, and serum sterols by means of gas-liquid chromatography. Simvastatin lowered LDL-C by 39% (p < 0.001), and additional stanol ester margarine by a further 13% (p < 0.05). The triple treatment led to 67% reduction from baseline (p < 0.001), with all LDL-C values being < 2.6 mmol/L, and increased high-density lipoprotein cholesterol (HDL-C) by 15% (p < 0.01). It also increased the serum lathosterol/cholesterol ratio (p < 0.01), thus indicating an upregulation of cholesterol synthesis, and increased the serum sitosterol ratio (p < 0.01) despite the simultaneous consumption of plant stanols. CONCLUSIONS: The massive reduction in LDL and increase in HDL-C obtained using our triple therapy suggests that the combination of stanol ester with only moderate doses of statin and resin makes it possible to control LDL-C levels effectively in hypercholesterolemic subjects.

Aged↗
PubMed2001

Acute effect of dietary stanyl ester dose on post-absorptive alpha-tocopherol, beta-carotene, retinol and retinyl palmitate concentrations.

Stanyl esters dissolved in margarine inhibit cholesterol absorption, lower sterol absorption in general, and lower serum total cholesterol, LDL-cholesterol and plant sterol levels. To find out whether stanyl esters inhibit absorption of fat-soluble vitamins and beta-carotene in acute experiments, we performed two fat-tolerance tests fortified with vitamins (retinol 0.9-3.7 mg, alpha-tocopherol 70-581 mg), beta-carotene (25-150 mg) and squalene (0.5 g) with and without 1 g of stanyl ester added to the test meal in ten healthy men. The concentrations or areas under the curves (AUC) of cholesterol, triacylglycerols, squalene and alpha-tocopherol, beta-carotene and retinyl palmitate showed typical postprandial changes in serum, chylomicrons, VLDL and VLDL infranatant (intermediate-density lipoproteins, LDL and HDL) over 24 h after the test meal without stanyl esters, and they were not affected by the addition of stanyl esters. The post-absorptive serum campesterol concentration and campesterol : cholesterol were significantly lowered at 6-9 h by stanyl ester supplementation, reflecting reduced sterol absorption efficiency. Changes in vitamin and beta-carotene AUC did not correlate with the given doses. In conclusion, the present study shows that stanyl esters dissolved in margarine do not detectably interfere in a short-term study with the absorption of alpha-tocopherol, beta-carotene or retinol measured by a 24 h oral fat-load test.

Analysis of Variance↗
PubMed2001

Dietary plant sterols alter the serum plant sterol concentration but not the cholesterol precursor sterol concentrations in young children (the STRIP Study). Special Turku Coronary Risk Factor Intervention Project.

Plant sterol supplementation reduces serum cholesterol concentration but may increase serum plant sterol concentrations, especially in children. We determined whether natural dietary plant sterols derived mainly from vegetable oil or margarine in early childhood affect serum concentrations of plant sterols (campesterol and sitosterol) and cholesterol precursor sterols (Delta-8 cholestenol, desmosterol, and lathosterol), reflecting endogenous cholesterol synthesis. We measured the serum sterol concentrations using gas liquid chromatography in 20 healthy 13-mo-old intervention children in a randomized, prospective study designed to decrease exposure of the children to known environmental atherosclerosis risk factors and in 20 control children. The diet of the intervention children was rich in plant sterols due to replacement of milk fat with vegetable fat, whereas the diet of the control children contained only small amounts of plant sterols. The intervention children consumed twice as much plant sterols as the control children (P < 0.001). Their serum concentrations of campesterol and sitosterol were 75% and 44% higher, respectively, than those in the control children (P < 0.001 for both), but serum cholesterol precursor sterol concentrations did not differ between the two groups. We conclude that doubling dietary plant sterol intake almost doubles serum plant sterol concentrations in 13-mo-old children, but has no effect on endogenous cholesterol synthesis. Relative intestinal absorption of natural plant sterols from the diet in early childhood is similar to that in adults.

Arteriosclerosis↗
PubMed2001

Cholesterol absorption, synthesis, and fecal output in postmenopausal women with and without coronary artery disease.

Hypercholesterolemia is a prominent risk factor for coronary artery disease (CAD), yet cholesterol metabolism has not been evaluated in women with CAD. The objective of this study was to determine the interrelations of CAD, serum squalene and sterols, and cholesterol metabolism with each other in postmenopausal women. For this purpose, we measured serum squalene and sterols and fecal steroids (cholesterol and bile acids) and squalene by gas-liquid chromatography and evaluated cholesterol absorption and synthesis in postmenopausal women with CAD (n=29) and age-matched controls (n=20). On similar dietary lipid intake, the cholesterol absorption efficiency and mean serum cholesterol level were comparable, but the squalene-to-cholesterol ratio was higher in cases than in controls. The presence of CAD was inversely associated with fecal total steroids (logistic regression coefficient beta/SE=-2.11, P=0.04) and cholesterol synthesis (beta/SE=-2.14, P=0.04) and turnover (beta/SE=-2.19, P=0.03) after adjustment for dietary cholesterol, family history of CAD, smoking, low and high density lipoprotein cholesterol, and serum triglyceride levels. A high serum squalene ratio was not related to cholesterol synthesis but was inversely related to fecal squalene excretion, which was lower in cases than in controls. In conclusion, the presence of CAD in postmenopausal women is independently associated with altered cholesterol metabolism, as reflected by low synthesis and inefficient elimination of cholesterol.

Adrenergic beta-Antagonists↗
PubMed2001

Apolipoprotein E phenotype regulates cholesterol absorption in healthy 13-month-old children--The STRIP Study.

High serum cholesterol concentration is one of the key risk factors in development of atherosclerosis, which may begin early in life and later progress to symptomatic coronary heart disease. In adults, apoE polymorphism strongly influences cholesterol metabolism, as subjects with apoE 3/4 or 4/4 (collectively called apoE4) phenotype absorb cholesterol effectively and thus also have higher cholesterol absorption-reflecting plant sterol concentrations in serum than subjects with other apoE phenotypes. Because of the inverse correlation of absorption and synthesis of cholesterol, concentrations of cholesterol synthesis-reflecting serum cholesterol precursor sterols are lower in subjects with apoE4 than in subjects with other phenotypes. To analyze whether apoE phenotype affects cholesterol absorption and synthesis in early childhood, we measured serum plant sterol (campesterol and sitosterol) and cholesterol precursor sterol (desmosterol and lathosterol) concentrations in healthy 13-month old children using gas-liquid chromatography. The 36 study children were participants in a randomized prospective trial (the Special Turku Coronary Risk Factor Intervention Project) aimed at decreasing exposure of the children to environmental atherosclerosis risk factors. The 16 apoE4 children had 30% to 50% higher cholesterol-adjusted campesterol and sitosterol concentrations in serum than the 20 apoE 3/3 children (p = 0.002 and p = 0.02, respectively). The concentrations of cholesterol precursor sterols in serum did not differ between the two groups of children. We conclude that the young apoE4 children may absorb cholesterol and plant sterols more effectively than the children with apoE 3/3 phenotype without compensatory reduction in endogenous synthesis of cholesterol.

Apolipoproteins E↗
PubMed2001

Familial hypercholesterolaemia in Finland: common, rare and mild mutations of the LDL receptor and their clinical consequences. Finnish FH-group.

Familial hypercholesterolaemia (FH) is an autosomal co-dominantly inherited condition resulting from mutations of the low-density lipoprotein (LDL) receptor which occur in heterozygous form in approximately one in 500 individuals. Clinically, FH is characterized by 2-3-fold elevation of serum LDL cholesterol levels, accelerated development of atherosclerotic vascular disease, and, if untreated, shortened lifespan. The Finnish population, which represents a genetic isolate, offers exceptional possibilities for genetic-epidemiological studies on FH, as a handful of founder gene mutations account for the majority of FH cases in Finland. This review summarizes data from our FH studies carried out since 1985. We wish to emphasize the continuum of genotype-phenotype relationships, the importance of molecular diagnosis, the detection of novel risk factors of vascular disease, and innovations inhibiting cholesterol absorption for the modern treatment of FH.

Age of Onset↗
PubMed2001

Fate of intravenously administered squalene and plant sterols in human subjects.

We have studied metabolism of plant sterols and squalene administered intravenously in the form of lipid emulsion mimicking chylomicrons (CM). The CM-like lipid emulsion was prepared by dissolving squalene in commercially available Intralipid. The emulsion was given as an intravenous bolus injection of 30 ml containing 6.3 mg of cholesterol, 1.9 mg of campesterol, 5.7 mg of sitosterol, 1.6 mg of stigmasterol, 18.1 mg of squalene, and 6 g of triglycerides in six healthy volunteers. Blood samples were drawn from the opposite arm before and serially 2.5 -180 min after the injections. The decay of CM squalene, plant sterols, and triglycerides was monoexponential. The half-life of CM squalene was 74 +/- 8 min, that of campesterol was 37 +/- 5 min (P < 0.01 from squalene), and those of sitosterol, stigmasterol, and triglycerides were 17 +/- 2, 15 +/- 1, and 17 +/- 2 min, respectively (P < 0.01 from squalene and campesterol). The CM squalene concentration still exceeded the baseline level 180 min after injection (P = 0.02), whereas plant sterols and triglycerides returned to the baseline level between 45 and 120 min after injection. The half-lives of squalene and campesterol were positively correlated with their fasting CM concentrations. In addition, VLDL squalene, campesterol, and triglyceride concentrations, VLDL, LDL, and HDL sitosterol concentrations, as well as VLDL and LDL stigmasterol concentrations were increased significantly. Cholesterol concentrations increased in VLDL (P < 0.05), but were unchanged in CM after injection. These data suggest that squalene clearance occurs more slowly than that of plant sterols and triglycerides from CM, and that squalene is more tightly associated with triglyceride-rich lipoproteins than are plant sterols in injected CM-like emulsions.

Adult↗
PubMed2001

Cholesterol absorption inhibition: a strategy for cholesterol-lowering therapy.

A clear relationship has been documented between plasma levels of low-density lipoprotein cholesterol (LDL-C) and the risk of coronary heart disease. LDL-C is believed to be key in the pathogenesis of coronary atherosclerosis, although increasing evidence suggests that low levels of high-density lipoprotein cholesterol and elevated triglyceride levels are contributory factors. Chylomicron remnants formed via the exogenous (dietary and biliary) pathway of cholesterol metabolism may also have atherogenic potential. Dietary modification, especially with plant stanol (sterol) ester margarine, which inhibits cholesterol absorption and improves the fatty acid pattern, lowers LDL-C sufficiently in many hypercholesterolaemic patients, and is also a useful adjunct to pharmacological therapy. Cholesterol absorption inhibitors typically lower LDL-C by 10-20%. Ezetimibe, the first selective cholesterol absorption inhibitor, has been shown to lower LDL-C by approximately 18% following a once-daily 10 mg dose, either as monotherapy or as combination therapy. Combination therapy with selective cholesterol absorption inhibitors such as ezetimibe along with statins or fibrates may allow more patients with hypercholesterolaemia to achieve target LDL-C levels compared with treatment with monotherapy. Ezetimibe may be useful in the management of patients who respond poorly to or are unable to tolerate statins, or in patients with hereditary or drug-induced phytosterolaemia.

Anticholesteremic Agents↗