Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.

In healthy individuals, acute changes in cholesterol intake produce modest changes in plasma cholesterol levels. A striking exception occurs in sitosterolemia, an autosomal recessive disorder characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis. We identified seven different mutations in two adjacent, oppositely oriented genes that encode new members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter family (six mutations in ABCG8 and one in ABCG5) in nine patients with sitosterolemia. The two genes are expressed at highest levels in liver and intestine and, in mice, cholesterol feeding up-regulates expressions of both genes. These data suggest that ABCG5 and ABCG8 normally cooperate to limit intestinal absorption and to promote biliary excretion of sterols, and that mutated forms of these transporters predispose to sterol accumulation and atherosclerosis.

Familial hypercholesterolemia (one form of familial type II hyperlipoproteinemia). A study of its biochemical, genetic and clinical presentation in childhood.

Primary hyperbetalipoproteinemia (type II hyperlipoproteinemia) is a common disorder associated with premature vascular disease. It is frequently due to genetic abnormalities, some of which are expressed in childhood. We have examined the manner in which that form of hyperbetalipoproteinemia known as familial hypercholesterolemia may be expressed in 236 children aged 1-19 born of 90 matings in which one parent had hyperbetalipoproteinemia of this variety and one parent did not.Two Gaussian populations were fitted to the distribution of both low density lipoprotein cholesterol (C(LDL)) and plasma cholesterol (C) in these children and a likelihood ratio test strongly favored a two over a one population model for both C(LDL) (X(2) = 18.41, P < 0.0005) and C (X(2) = 7.81, P < 0.025). 45% of the children were in the population identified as affected; their mean C(LDL) was 229. The remaining 55% were in the normal population with a mean C(LDL) of 110 which was indistinguishable from that of an unrelated control population, aged 1-19. On the basis of an assumed frequency of hyperbetalipoproteinemia in the general population of 5%, the Edwards' test indicated that a polygenic model of inheritance was highly unlikely (expected, 22%; observed, 45%). The segregation ratio obtained from the derived intersection between the two population curves (C(LDL), 164 mg/100 ml; C, 235 mg/100 ml) was 45/55 (abnormal/normal). The percentage of abnormal children in the first decade (52%) significantly exceeded that in the second (39%) (P < 0.01). The ratios (II/N) were 50/47 and 55/84 in the offspring of affected female and male parents, respectively (X(2) = 3.819, 0.05 < P < 0.10). Only 10% of hyperbetalipoproteinemic children were considered to have hyperglyceridemia. These children, frequently, but not invariably, had a parent with hyperglyceridemia in addition to hyperbetalipoproteinemia (P < 0.05). None of the affected children who were examined had ischemic heart disease (IHD) and 7% had tendon xanthomas. Half of the parents (mean age, 37.4 yr) who were examined had IHD and three-quarters had xanthomas. The data agree well with the hypothesis that hyperbetalipoproteinemia is inherited as a monogenic trait with early expression in these children. More than one genetic defect within the group is not excluded, but retrospective analyses of the 345 first-degree adult relatives of the affected parents indicated that most of the abnormal parents probably represented familial hypercholesterolemia, rather than combined hyperlipidemia, the other most generally recognized form of familial hyperbetalipoproteinemia.

Mapping a gene involved in regulating dietary cholesterol absorption. The sitosterolemia locus is found at chromosome 2p21.

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body as well as the body's ability to selectively exclude other dietary sterols are poorly understood. Studies of the rare autosomal recessively inherited disease sitosterolemia (OMIM 210250) may shed some light on these processes. Patients suffering from this disease appear to hyperabsorb both cholesterol and plant sterols from the intestine. Additionally, there is failure of the liver's ability to preferentially and rapidly excrete these non-cholesterol sterols into bile. Consequently, people who suffer from this disease have very elevated plasma plant sterol levels and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. Identification of this gene defect may therefore throw light on regulation of net dietary cholesterol absorption and lead to an advancement in the management of this important cardiovascular risk factor. By studying 10 well-characterized families with this disorder, we have localized the genetic defect to chromosome 2p21, between microsatellite markers D2S1788 and D2S1352 (maximum lodscore 4.49, theta = 0.0).

Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia.

BACKGROUND: Sitosterolemia is a recessively inherited disorder that results from mutations in either ABCG5 or G8 proteins, with hyperabsorption of dietary sterols and decreased hepatic excretion of plant sterols and cholesterol. As a consequence of markedly elevated plasma and tissue sitosterol and campesterol levels, premature atherosclerosis develops. METHODS AND RESULTS: In this multicenter, double-blind, randomized, placebo-controlled study, we examined whether treatment with ezetimibe, an inhibitor of cholesterol absorption, reduces plant sterol levels in patients with sitosterolemia. After a 3-week placebo run-in, 37 patients were randomized to receive placebo (n=7) or ezetimibe 10 mg/d (n=30) for 8 weeks. Sitosterol concentrations decreased by 21% (P<0.001) in patients treated with ezetimibe compared with a nonsignificant 4% rise in those on placebo (between-group P<0.001). The reduction in sitosterol from baseline was progressive, with further decline observed at each subsequent biweekly visit. Campesterol also progressively declined, with a mean decrease after 8 weeks of 24% with ezetimibe and a mean increase of 3% with placebo treatment (between-group P<0.001). Reductions in plant sterol concentrations were similar irrespective of whether patients were undergoing concomitant treatment with resin or statin. Reductions in total sterols and apolipoprotein B were also observed. Ezetimibe was well tolerated, with no serious treatment-related adverse events or discontinuations due to adverse events being reported. CONCLUSIONS: Ezetimibe produced significant and progressive reductions in plasma plant sterol concentrations in patients with sitosterolemia, consistent with the hypothesis that ezetimibe inhibits the intestinal absorption of plant sterols as well as cholesterol, leading to reductions in plasma concentrations.

Plasma dehydroepiandrosterone and dehydroepiandrosterone sulfate in patients undergoing diagnostic coronary angiography.

Serum levels of DHEA sulfate are inversely associated with cardiovascular death in men, and urinary dehydroepiandrosterone (DHEA) levels are inversely associated with clinical manifestations of coronary artery disease. These observations may be related to the antiproliferative effects of DHEA, resulting in inhibition of atherosclerotic intimal hyperplasia. To examine the relation between these steroids and a direct measure of coronary atherosclerosis, plasma DHEA and DHEA sulfate levels were determined in 206 middle-aged patients (103 men, 103 women) undergoing elective coronary angiography. Plasma DHEA sulfate levels were lower in men with at least one stenosis greater than or equal to 50% compared with those without any stenosis greater than or equal to 50% (4.9 +/- 2.7 versus 6.1 +/- 3.5 nmol/ml, p = 0.05). Levels of DHEA sulfate were also inversely related to the number of diseased coronary vessels (r = -0.20, p = 0.05) and a continuous measure of the extent of coronary atherosclerosis (r = -0.25, p = 0.01) in men. The association between DHEA sulfate levels and extent of coronary artery disease was independent of age and other conventional risk factors for coronary disease. In women, there was no association between plasma DHEA or DHEA sulfate levels and coronary disease. These data demonstrate a consistent, independent, inverse, dose-response relation between plasma DHEA sulfate levels and angiographically defined coronary atherosclerosis in men. Plasma DHEA sulfate may be another important and potentially modifiable risk factor for the development and progression of coronary atherosclerosis.

Risk factors in siblings of people with premature coronary heart disease.

Prior studies of the contribution of coronary disease risk factors to familial aggregation of premature coronary disease may have underestimated risk factors by relying on self-reported risk factor prevalence levels or, when risk factors have been measured, by using cut points in excess of the 90th percentile. To determine the actual prevalence of hyperlipidemia, hypertension and diabetes, and the awareness of these coronary risk factors in unaffected family members, 150 apparently coronary disease-free siblings of 86 people who had documented coronary disease before 60 years of age were studied. All subjects participated in a 1 day screening preceded by a self-administered risk factor questionnaire and a personal interview. Participation of both the index patients and siblings exceeded 86%. With the use of nationally established recommendations for blood pressure and lipids, which are based on coronary disease risk curves, screening revealed that 48% of brothers and 41% of sisters were hypertensive, 45% of brothers and 22% of sisters had a lipid abnormality, 38% of siblings were current cigarette smokers and 4.7% were diabetic. Two or more risk factors were present in 42% of brothers and 26% of sisters. More than 75% of siblings had one or more risk factors that would require intervention. When compared with a race-, gender- and age-matched reference population from the Lipid Research Clinics Prevalence Study, distributions for blood pressure and for total and low density lipoprotein cholesterol were higher for the siblings in every gender and age group.(ABSTRACT TRUNCATED AT 250 WORDS)

A genetic model for control of hypertriglyceridemia and apolipoprotein B levels in the Johns Hopkins colony of St. Thomas Hospital rabbits.

The St. Thomas Hospital (STH) rabbit has been previously shown to have a Mendelian form of hypertriglyceridemia, accompanied by accelerated atherosclerosis, and these animals may serve as a useful model for human dyslipoproteinemia syndromes. Here we describe the establishment of a new colony of these STH animals, and present genetic analysis of triglyceride (TG) and apolipoprotein B (apoB) levels. Segregation analysis of TG in 39 STH animals and 24 controls gave evidence of Mendelian segregation for an allele leading to both elevated TG levels and increased variability in these levels. Predicted means from the most parsimonious model for the Johns Hopkins STH colony were quite similar to that seen in the original London colony, and this model accounted for 80% of the variation in TG seen in the sample. This hypertriglyceridemia locus indirectly influenced the mean apoB levels in these rabbits, and segregation analysis of mean apoB levels suggested a second locus controlling apoB levels. Analysis of residual apoB levels (adjusted for predicted effects of the hypertriglyceridemia locus) revealed clearer evidence for a second locus controlling mean apoB levels in this colony. Arguments for two distinct genetic mechanisms operating in these STH animals are presented.

Comparison of the effects of lean red meat vs lean white meat on serum lipid levels among free-living persons with hypercholesterolemia: a long-term, randomized clinical trial.

BACKGROUND: Patients with hypercholesterolemia are often counseled to limit or eliminate intake of red meats, despite evidence that lean red meats (LRMs) are not hypercholesterolemic in comparison with lean white meats (LWMs). The objective of this study was to evaluate the long-term effects on serum lipids of incorporating LRM (beef, veal, and pork) vs LWM (poultry and fish) into a National Cholesterol Education Program (NCEP) Step I diet in free-living individuals with hypercholesterolemia. METHODS: Subjects included 191 men and women with a serum low-density lipoprotein cholesterol level of 3.37 to 4.92 mmol/L (130-190 mg/dL) and triglyceride level less than 3.96 mmol/L (350 mg/dL). After a 4-week baseline phase, subjects were counseled to follow an NCEP Step I diet including 170 g (6 oz) of lean meat per day, 5 to 7 days per week. Based on random assignment, subjects were instructed to consume at least 80% of their meat in the form of LRM or LWM. Fasting serum lipid levels were assessed 4, 12, 20, 28, and 36 weeks after randomization. RESULTS: After randomization, mean concentrations of total cholesterol (6.09 mmol/L [235.7 mg/dL] vs 6.08 mmol/L [235.2 mg/dL]) and low-density lipoprotein cholesterol (3.99 mmol/L [154.1 mg/dL] vs4.01 mmol/L [154.7 mg/dL]) were nearly identical in the LRM and LWM groups (1%-3% below baseline) during treatment. Mean triglyceride levels remained similar to baseline values and high-density lipoprotein cholesterol concentrations increased by approximately 2% in both groups. CONCLUSIONS: The NCEP Step I diets containing primarily LRM or LWM produced similar reductions in low-density lipoprotein cholesterol and elevations in high-density lipoprotein cholesterol levels, which were maintained throughout 36 weeks of treatment.

Existence of multiple peaks in plasma ethinyl estradiol and norethindrone after oral administration of a contraceptive pill.

Previous measurements of plasma ethinyl estradiol (EE2) and norethindrone (NE) over 24 h after oral administration of a contraceptive pill have demonstrated a single steroid peak occurring 1-2 h after pill ingestion, with a gradual decline over the next 22 h. In the present study plasma concentrations of EE2 and NE were measured 0, 0.5, 0.75, 1, 2, 4, 12, and 24 h after oral ingestion of a contraceptive pill containing 35 micrograms EE2 and 1 mg NE at 0, 3, 6, and 9 months of use in 58 normal healthy women. Contrary to previous reports, analysis of the 464 steroid curves (58 subjects x 4 time periods x 2 steroids) revealed the presence of multiple hormone peaks. Two peaks of EE2 were identified in 44.8% of women during the first pill cycle and in 75.9%, 55.2%, and 67.2% of women after 3, 6, and 9 months of pill use. Two hormone peaks of NE were observed in 29.3% of women during the first cycle and in 36.2%, 50%, and 44.8% at 3, 6, and 9 months, respectively. Existence of these multiple peaks at the frequency observed has not previously been reported. Further quantification of the frequency and magnitude of these peaks could be helpful in explaining differences in biological responses associated with pill use.

Nutrient intake and blood pressure in the Dietary Intervention Study in Children.

Delineating the role that diet plays in blood pressure levels in children is important for guiding dietary recommendations for the prevention of hypertension. The purpose of this study was to investigate relationships between dietary nutrients and blood pressure in children. Data were analyzed from 662 participants in the Dietary Intervention Study in Children who had elevated low-density lipoprotein cholesterol and were aged 8 to 11 years at baseline. Three 24-hour dietary recalls, systolic pressure, diastolic pressure, height, and weight were obtained at baseline, 1 year, and 3 years. Nutrients analyzed were the micronutrients calcium, magnesium, and potassium; the macronutrients protein, carbohydrates, total fat, saturated fat, polyunsaturated fat, and monounsaturated fat; dietary cholesterol; and total dietary fiber. Baseline and 3-year longitudinal relationships were examined through multivariate models on diastolic and systolic pressures separately, controlling for height, weight, sex, and total caloric intake. The following associations were found in longitudinal analyses: analyzing each nutrient separately, for systolic pressure, inverse associations with calcium (P < .05); magnesium, potassium, and protein (all P < .01); and fiber (P < .05), and direct associations with total fat and monounsaturated fat (both P < .05); for diastolic pressure, inverse associations with calcium (P < .01); magnesium and potassium (both P < .05), protein (P < .01); and carbohydrates and fiber (both P < .05), and direct associations with polyunsaturated fat (P < .01) and monounsaturated fat (P < .05). Analyzing all nutrients simultaneously, for systolic pressure, direct association with total fat (P < .01); for diastolic pressure, inverse associations with calcium (P < .01) and fiber (P < .05), and direct association with total and monounsaturated fats (both P < .05). Results from this sample of children with elevated low-density lipoprotein cholesterol indicate that dietary calcium, fiber, and fat may be important determinants of blood pressure level in children.

Long-term follow-up of hypopituitary patients treated with human growth hormone.

Thirty-six former human growth hormone (hGH) recipients underwent comprehensive physical, endocrine and lipoprotein evaluations as adults. Treatment was associated with a decrease in height standard deviation score (SDS) in males from 4.0 pretreatment to 2.1 as adults, and in females from 4.2 to 2.5. Males showed a better growth response to treatment than did females. Plasma somatomedin-C levels were subnormal in 30 patients, but were higher in isolated growth-hormone-deficient patients than in others. Three men and 1 woman showed evidence suggesting a disturbance in pulsatile gonadotropin release despite the previous documentation of normal serum gonadotropin levels. Hypertriglyceridemia was not observed, and the women's plasma cholesterol levels were unremarkable. Men, however, showed higher-than-expected total cholesterol, LDL-cholesterol, and HDL-cholesterol concentrations. The last finding may explain the lack of increased cardiovascular morbidity in this group.

Influence of genetic polymorphisms on responsiveness to dietary fat and cholesterol.

Genes influence quantitative variations in plasma lipoprotein concentrations. For example, intake of dietary saturated fat and cholesterol raises the average serum cholesterol concentration, leading to a higher risk of coronary artery disease in populations. However, not all individuals within the population are susceptible: genetic factors appear to render individuals either "dietary responsive" or "dietary nonresponsive." In this review, we focus on current knowledge about the influence of genetic polymorphisms in certain genes on the lipoprotein response to dietary fat and cholesterol. Our preliminary studies in the Dietary Intervention Study in Children suggest a significant dose-response relation between the decrease in LDL cholesterol from baseline to 36 mo of follow-up in both the intervention group (who consumed a low-fat, low-cholesterol diet) and the usual care group (who consumed a regular diet) and the presence of the APOA1*A allele at the M1 site and the + site at the M2 site of the gene encoding apolipoprotein (apo) A-I. The DNA polymorphisms on the genes encoding apo A-IV, apo B, apo C-III, apo E, lipoprotein lipase, cholesteryl ester transfer protein, lecithin:cholesterol acyltransferase (phosphatidylcholine-sterol O:-acyltransferase), and LDL receptor were found by others to be associated with the plasma lipoprotein response to dietary intervention. Possible mechanisms involved in these effects are discussed and certain discrepancies in the literature about some genetic effects on responsiveness are analyzed. An improved understanding of the influence of specific genes on lipoprotein responsiveness to dietary fat and cholesterol may allow us to identify and counsel certain individuals to avoid high-fat diets so that they may reduce their risk of developing hyperlipidemia and coronary artery disease.

The East Baltimore study: the relationship of lipids and lipoproteins to selected cardiovascular risk factors in an inner city Black adult population.

Low socioeconomic status, inner city Black adults, aged 20 to 49 yr (24 males and 45 females), were randomly selected from East Baltimore, MD to study plasma lipid and lipoprotein levels. Several factors known to affect these levels also were examined: dietary intake, alcohol intake, degree of obesity (measured by body mass index), physical activity level, smoking, and hormone use. Compared to women, the men consumed 9.3 more calories/kg body weight (p less than 0.005), 273 mg more cholesterol/day (p less than 0.005), and 7% fewer calories as sucrose (p less than 0.01). The P/S ratio of both their diets was 0.5. The men also had a lower body mass index than the women (23.9 kg/m2 versus 29.0; p less than 0.001). Mean lipid and lipoprotein levels were similar in the men and women. However, the men's total cholesterol (167 mg/dl) and low density lipoprotein cholesterol (94 mg/dl) levels were lower than those of adult Blacks in other studies, while the levels of the East Baltimore women were similar to those in other studies. For women, body mass index and high density lipoprotein cholesterol were negatively correlated (p less than 0.01); triglycerides and oral contraceptive use were positively correlated (p less than 0.01). None of the factors studied explained the relatively low total cholesterol and low density lipoprotein cholesterol levels in these inner city Black adult men.

Efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol in children with elevated LDL cholesterol: the Dietary Intervention Study in Children.

BACKGROUND: Few studies have shown the efficacy and safety of lower-fat diets in children. OBJECTIVE: Our objective was to assess the efficacy and safety of lowering dietary intake of total fat, saturated fat, and cholesterol to decrease LDL-cholesterol concentrations in children. DESIGN: A 6-center, randomized controlled clinical trial was carried out in 663 children aged 8-10 y with LDL-cholesterol concentrations greater than the 80th and less than the 98th percentiles for age and sex. The children were randomly assigned to either an intervention group or a usual care group. Behavioral intervention promoted adherence to a diet providing 28% of energy from total fat, <8% from saturated fat,

Dyslipoproteinemia and other risk factors for atherosclerosis in children and adolescents.

The early lesions of atherosclerosis in youth are strongly related to antemortem levels of total and low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol, and triglyceride, to ponderal index and to systolic and diastolic blood pressure. The major apolipoproteins of LDL and high density lipoprotein (HDL), apo B and apo A1, respectively, as well as levels of Lp(a) lipoprotein are often abnormal in children born to a parent with coronary artery disease (CAD). Other risk factors for CAD include obesity, high blood pressure, cigarette smoking, diabetes mellitus, positive family history of CAD and physical inactivity. Children from families with premature CAD, familial dyslipidemia or hypertension, and/or two other risk factors should have a lipoprotein profile determined. The first form of treatment is a diet low in total fat, saturated fat and cholesterol, combined with treatment of overnutrition and obesity, if necessary, and regular habits of aerobic physical activity. Children with inherited disorders of LDL metabolism may require the addition of lipid lowering therapy. The early detection and treatment of youth at risk for premature CAD offers the greatest promise to decrease morbidity and mortality.

Effect of hyperapo B LDL on cholesterol esterification in THP-1 macrophages.

Hyperapobetalipoproteinemia (hyperapo B), a common disorder associated with coronary artery disease, is characterized by an increased number of small, dense, low density lipoprotein (LDL) particles. The cellular mechanisms responsible for early atherosclerosis in hyperapo B are unknown. We tested the hypothesis that hyperapo B LDL may be preferentially metabolized through an LDL receptor independent pathway promoting the accumulation of cellular cholesteryl ester (CE). THP-1 macrophages have little inducible LDL receptor activity after differentiation with phorbol esters and are, therefore, suitable for assessing non-LDL receptor mediated uptake of lipoproteins. LDL isolated from hyperapo B donors was found to have significantly lower total cholesterol to protein ratio (P = 0.03), higher average density (P = 0.0001) and smaller particle diameter (P = 0.016) compared with normal (control) LDL. LDL (250 micrograms lipoprotein-protein/ml) from normal (n = 11) and hyperapo B (n = 18) subjects were incubated for 24 h with THP-1 macrophages. The mean (S.D.) CE accumulation was 6.2 (3.6) for the normal and 6.4 (2.6) for the hyperapo B LDL (P = 0.84). CE accumulation in cells incubated with malondialdehyde modified (MDA) LDL, or without added lipoprotein, was 18.2 (2.0) and 0.6 (0.7), respectively. CE mass accumulation was significantly correlated with time (6-48 h) of incubation and concentration (100-500 micrograms/ml) of LDL protein (P < 0.05); no differences were observed between normal and hyperapo B LDL. Similarly, when the major LDL species was isolated by density gradient ultracentrifugation, mean (S.D.) CE was similar for the normal and hyperapo B LDL (8.7 (1.2) vs. 6.9 (1.5)). There were no differences in the mean (S.D.) incorporation of [14C]oleate into CE (nmol/mg cell protein per 6 h) in THP-1 macrophages incubated with normal or hyperapo B LDL (0.238 (0.045) vs. 0.211 (0.046)); results were comparable in human monocyte-derived (HMD) macrophages (0.298 (0.037) vs. 0.258 (0.022)). Also, mean (S.D.) cellular uptake and degradation (ng 125I/mg cell protein per h) in THP macrophages of normal and hyperapo B LDL were similar (uptake: 18 (14) vs. 12 (6.0); degradation: 58 (32) vs. 44 (8)). In summary: (1) hyperapo B LDL did not stimulate the accumulation of cellular CE via LDL receptor independent pathways in THP-1 macrophages, (2) normal and hyperapo B LDL stimulation of CE synthesis is similar in THP-1 and HMD macrophages and (3) no differences in cellular uptake and degradation of normal and hyperapo B LDL were observed in THP macrophages.

Hyperapobetalipoproteinemia: the major dyslipoproteinemia in patients with chronic renal failure treated with chronic ambulatory peritoneal dialysis.

In the present study, plasma cholesterol, triglyceride, low density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, and the major protein in LDL, apoB, were measured in 28 patients with chronic renal failure treated with hemodialysis and in 28 patients with chronic renal failure treated with chronic ambulatory peritoneal dialysis (CAPD). Elevated plasma triglycerides and reduced HDL cholesterol were frequent in both the hemodialysis and CAPD patients. However LDL levels were significantly higher in the CAPD patients as evident both by LDL cholesterol and LDL apoB. Even so, only one of the CAPD patients was hypercholesterolemic whereas 14 (or 50%) had hyperapobetalipoproteinemia (HyperapoB). Insulin-dependent diabetes was more frequent in the CAPD group but only 2 of the 9 insulin-dependent diabetics in this group had HyperapoB, and therefore, diabetes mellitus cannot account for the difference between the 2 groups. Thus HyperapoB appears to be a prevalent dyslipoproteinemia in CAPD patients and as such might be another factor which places CAPD patients at particularly increased risk of atherosclerosis.

Effect of gemfibrozil in men with primary isolated low high-density lipoprotein cholesterol: a randomized, double-blind, placebo-controlled, crossover study.

PURPOSE: To evaluate the efficacy of gemfibrozil in men with primary isolated low high-density lipoprotein cholesterol (HDL-C) levels. PATIENTS AND METHODS: Fourteen men with low levels of HDL-C but desirable total cholesterol levels received gemfibrozil in a randomized, double-blind, placebo-controlled, crossover trial. The men were placed on a National Cholesterol Education Program Step-Two Diet. They were randomly assigned to receive placebo and gemfibrozil each for 3 months, with a 1-month washout period between phases. RESULTS: Overall, gemfibrozil increased the total HDL-C concentration by 9.2% (p = 0.001), reduced triglyceride (TG) levels by 38% (p < 0.01), and significantly lowered the total cholesterol:HDL-C ratio (p = 0.01). Those with fasting TG levels of 1.07 mmol/L (95 mg/dL) or greater had a significant elevation in the HDL-C level (14.6%, p = 0.005) and a reduction in TG levels (50%, p = 0.002) with gemfibrozil; those with fasting TG levels less than 1.07 mmol/L had a smaller increase in the HDL-C level (4.1%, p > 0.05) and a smaller reduction in TG levels (15%, p = 0.02). There were no significant differences in the plasma levels of low density lipoprotein-cholesterol, HDL2-C, apolipoproteins (apo) A-I and B, or Lp(a). HDL3-C and apo A-II levels rose slightly. The adverse effects attributable to gemfibrozil were minimal. CONCLUSION: In men with desirable total cholesterol levels, gemfibrozil raises HDL-C and lowers TG levels to a similar extent as reported for hyperlipidemic men in the Helsinki Heart Study. These lipid-altering effects were most pronounced in those with the highest fasting TG levels.

Effect of low-dose alcohol use versus abstention on apolipoproteins A-I and B.

An inverse association between low to moderate alcohol consumption and coronary heart disease has been demonstrated in epidemiologic studies of diverse design. An attempt was made to determine if this association might be due to an effect of alcohol on apolipoproteins A-I and B and to determine if low-dose alcohol intake might have a potentially protective effect by this mechanism in persons at increased risk for coronary heart disease. To address this, an eight-week prospective randomized clinical trial of abstention versus low-dose alcohol consumption, defined as one beverage per day, was conducted in white men, aged 21 to 60 years, most of whom were patients of a preventive cardiology program. Apolipoprotein A-I levels had a mean increase of 9 mg/dl in the 28 participants who drank alcohol compared with a mean decline of 5 mg/dl in the 28 participants who abstained (p less than 0.005). This association was independent of other cardiovascular risk factors. Low-density lipoprotein (LDL)-B levels had a mean increase of 7 mg/dl in both arms of the trial (NS). However, the ratio of apolipoprotein A-I to LDL-B increased by 4 percent in the drinkers and decreased 10 percent in the abstainers (p less than 0.03). No significant changes in mean levels of total high-density lipoprotein (HDL)-, HDL2-, or HDL3-cholesterol were observed with this low dose of alcohol. This effect on apolipoprotein A-I suggests a possible mechanism by which low-dose alcohol may lower the risk of coronary heart disease.

Relationship between corticosteroid exposure and plasma lipid levels in heart transplant recipients.

PURPOSE: Accelerated coronary atherosclerosis is a major cause of heart graft failure two years and more after heart transplantation, yet its etiology remains undetermined. We conducted this study to determine the prevalence of coronary risk-associated lipid abnormalities, and the relationship between lipid levels and exposure to corticosteroids and cyclosporine, in heart transplant recipients. PATIENTS AND METHODS: The records of 92 consecutive heart transplant recipients from three different transplantation centers were reviewed. Patients from the three centers varied in age, in corticosteroid regimens, and in the proportion undergoing transplantation for ischemic cardiomyopathy. Although 11 patients were not receiving corticosteroids at the time of the study, all patients had received them immediately after transplantation. In addition to information pertaining to demographics, pretransplant medical history, rejection episodes, drug doses, renal function, and blood glucose levels, data on dietary intake and body weight were collected and plasma lipid levels were measured at the time of record review. RESULTS: A significant number, 48 (52 percent), of heart transplant recipients were above the sex- and age-adjusted 75th percentile, and 35 (38 percent) were above the 90th percentile for total cholesterol in comparison with a general reference population. Similar elevations were found in low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol levels. Bivariate analysis demonstrated cumulative prednisone exposure (r = 0.40, p = 0.0001) and cumulative cyclosporine exposure (r = 0.22, p = 0.04) but not diet or etiology of pretransplant heart disease to be significantly associated with age- or sex-adjusted total cholesterol percentiles. Low-density lipoprotein cholesterol percentiles were also correlated with cumulative prednisone (r = 0.37, p = 0.001) and cumulative cyclosporine exposure (r = 0.24, p = 0.02). Stepwise multiple linear regression analysis, however, demonstrated cumulative prednisone exposure to be the strongest predictor of both total and low-density lipoprotein cholesterol levels and percentiles (p = 0.0001), independent of cumulative cyclosporine exposure and other clinical variables. CONCLUSION: These data suggest that long-term corticosteroid exposure may result in an increased prevalence of unfavorable lipid profiles in heart transplant recipients.