Decreasing the Cholesterol Burden in Heterozygous Familial Hypercholesterolemia Children by Dietary Plant Stanol Esters.

This review covers the current knowledge about plant stanol esters as a dietary treatment option for heterozygous familial hypercholesterolemia (he-FH) children. The current estimation of the prevalence of he-FH is about one out of 200⁻250 persons. In this autosomal dominant disease, the concentration of plasma low-density lipoprotein cholesterol (LDL-C) is strongly elevated since birth. Quantitative coronary angiography among he-FH patients has revealed that stenosing atherosclerotic plaques start to develop in he-FH males in their twenties and in he-FH females in their thirties, and that the magnitude of the plaque burden predicts future coronary events. The cumulative exposure of coronary arteries to the lifelong LDL-C elevation can be estimated by calculating the LDL-C burden (LDL-C level × years), and it can also be used to demonstrate the usefulness of dietary stanol ester treatment. Thus, when compared with untreated he-FH patients, the LDL-C burden of using statin from the age of 10 is 15% less, and if he-FH patients starts to use dietary stanol from six years onwards and a combination of statin and dietary stanol from 10 years onwards, the LDL-C burden is 21% less compared to non-treated he-FH patients. We consider dietary stanol treatment of he-FH children as a part of the LDL-C-lowering treatment package as safe and cost-effective, and particularly applicable for the family-centered care of the entire he-FH families.

Omega 3 fatty acids induce a marked reduction of apolipoprotein B48 when added to fluvastatin in patients with type 2 diabetes and mixed hyperlipidemia: a preliminary report.

BACKGROUND: Mixed hyperlipidemia is common in patients with diabetes. Statins, the choice drugs, are effective at reducing lipoproteins that contain apolipoprotein B100, but they fail to exert good control over intestinal lipoproteins, which have an atherogenic potential. We describe the effect of prescription omega 3 fatty acids on the intestinal lipoproteins in patients with type 2 diabetes who were already receiving fluvastatin 80 mg per day. METHODS: Patients with type 2 diabetes and mixed hyperlipidemia were recruited. Fasting lipid profile was taken when patients were treated with diet, diet plus 80 mg of fluvastatin and diet plus fluvastatin 80 mg and 4 g of prescription omega 3 fatty acids. The intestinal lipoproteins were quantified by the fasting concentration of apolipoprotein B48 using a commercial ELISA. RESULTS: The addition of 4 g of prescription omega 3 was followed by significant reductions in the levels of triglycerides, VLDL triglycerides and the triglyceride/HDL cholesterol ratio, and an increase in HDL cholesterol (P < 0.05). Fluvastatin induced a reduction of 26% in B100 (P < 0.05) and 14% in B48 (NS). However, the addition of omega 3 fatty acids enhanced this reduction to 32% in B100 (NS) and up to 36% in B48 (P < 0.05). CONCLUSION: Our preliminary findings therefore suggest an additional benefit on postprandial atherogenic particles when omega 3 fatty acids are added to standard treatment with fluvastatin.

Dietary supplementation with an extract of lycopene-rich tomatoes does not reduce atherosclerosis in Watanabe Heritable Hyperlipidemic rabbits.

Tomatoes are rich in lycopene and other carotenoids which have shown beneficial effects on CVD in epidemiological and intervention studies. In the present study the effect of an extract of lycopene-rich tomatoes, Lyc-O-Mato on atherosclerosis was studies in Watanabe Heritable Hyperlipidemic rabbits. The rabbits were fed a control diet, a control diet supplemented with the tomato extract or a control diet supplemented with a mixture of plant oils for 16 weeks. Lycopene was detected only in plasma of rabbits receiving tomato extract. The tomato extract had no effect on cholesterol and triacylglycerol levels measured in total plasma, lipoprotein fractions and on aortic atherosclerosis evaluated biochemically and by microscopy. Oxidation of lipids in unfractionated plasma also was unaffected by the intake of tomato extract. In conclusion, the tomato extract increased plasma levels of lycopene in rabbits, but had no effect on hypercholesterolaemia, oxidation of plasma lipids or aortic atherosclerosis.

The effect of ciprofibrate on flow-mediated dilation and inflammatory markers in patients with combined hyperlipidemia.

Impairment of flow-mediated dilation (FMD) has been shown to be associated with hypercholesterolemia and hypertriglyceridemia and reduction of cholesterol and/or triglyceride levels can improve FMD. In hyperlipidemia the role of inflammatory substances on endothelial function requires further clarification. In patients with combined hyperlipidemia (n = 29), the capacity of FMD was weaker whereas the levels of interleukin (IL)-lalpha, tumor necrosis factor alpha (TNFalpha), soluble intercellular adhesion molecule (sICAM), and fibrinogen were higher compared to normolipemic controls with normal FMD adjusted for age and sex. Patients were randomized to a diet-only or to a ciprofibrate treatment group. After 8 weeks FMD levels rose significantly both in the diet-only (10.2%) and the ciprofibrate treatment (79.4%) groups. In the diet-only group improvement of FMD was significantly associated with the reduction of triglyceride (by 15.9%) and cholesterol (6.9%) levels. The much larger improvement of FMD due to ciprofibrate therapy was accompanied by significant reductions of cholesterol (by 14.4%), fibrinogen, IL-1alpha, and sICAM levels and by significant increase of high-density lipoprotein (HDL) cholesterol concentration, but the change in FMD correlated only with the reduction of the cholesterol level. In line with previous data the authors emphasize that improvement of FMD in patients with combined hyperlipidemia treated with diet and/or ciprofibrate is linked directly to the reduction of cholesterol and triglyceride concentrations rather than to changes in the level of the investigated inflammatory markers.

Familial combined hyperlipidemia in a North Indian kindred.

Familial combined hyperlipidemia is the most common genetic hyperlipidemia and is responsible for premature coronary artery disease. It is genetically heterogenous and no single diagnostic marker exists. The authors report an affected North Indian kindred spanning three successive generations with a possible autosomal dominant pattern of inheritance and all of them had combined dyslipidemia [elevated total cholesterol, predominantly the low density lipoprotein (LDL) fraction and elevated triglycerides]. The proband, a 4-month-old male baby, was incidentally discovered to have a lipaemic serum and so further evaluated. Both the index case and his maternal grandmother, a non-obese diabetic (type 2) with hypertension, had an atherogenic lipoprotein phenotype. Lipaemia retinalis was documented in this baby but xanthomas and coronary artery disease were not noted in the kindred. The present case report highlights the failure of dietary therapy in the proband and explores new options.

Docosahexaenoic acid restores endothelial function in children with hyperlipidemia: results from the EARLY study.

OBJECTIVE: The primary objective of this study was to determine whether the National Cholesterol Education Program Step II (NCEP-II) diet or supplementation with docosahexaenoic acid (DHA) with the diet, affects endothelial function in children with familial hypercholesterolemia (FH) or the phenotype of familial combined hyperlipidemia (FCH). As secondary endpoints, the influence of diet and DHA supplementation on lipid profiles as well as biomarkers for oxidative stress and inflammation, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, were all evaluated. METHODS: In a double-blind, placebo-controlled, randomized, crossover study design, 20 children (ages 9-19 years) with FH (n = 12) and FCH (n = 8) received nutritional counseling based on the National Cholesterol Education Program Step II (NCEP-II) and food guide pyramid dietary guidelines for 6 weeks. They were then randomly assigned to supplementation with docosahexaenoic acid (DHA 1.2 g/d) or placebo for 6 weeks, followed by a washout phase of 6 weeks and crossover phase of 6 weeks while continuing the NCEP-II diet. Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery was determined by high-resolution ultrasound. Plasma levels of total cholesterol, triglycerides and lipoprotein classes (LDL, HDL, VLDL) were measured by ultracentrifugation and enzymatic methods, plasma F2 isoprostanes by gas chromatography/mass spectrometry, urinary 8-OH-2' deoxyguanosine by liquid chromatography, high sensitivity C-reactive protein by immunonephelometry and ADMA by liquid chromatography. RESULTS: FMD increased significantly after DHA supplementation compared to baseline (p < 0.001), diet alone (p < 0.002), placebo (p < 0.012) and washout (p < 0.001) phases of the study without affecting biomarkers for oxidative stress, inflammation or ADMA. DHA supplementation was associated with increased levels of total cholesterol (p < 0.01), LDL- and HDL cholesterol concentrations (p < 0.001) compared to the NCEP-II diet. CONCLUSION: This study demonstrates that DHA supplementation restores endothelial-dependent FMD in hyperlipidemic children. The endothelium may thus be a therapeutic target for DHA. This is consistent with a hypothesis of increasing NO bioavailability, with the potential for preventing the progression of early coronary heart disease in high-risk children.

Effects of walnut consumption on plasma fatty acids and lipoproteins in combined hyperlipidemia.

BACKGROUND: Epidemiologic studies show an inverse relation between nut consumption and coronary heart disease. OBJECTIVE: We determined the effects of walnut intake on plasma fatty acids, lipoproteins, and lipoprotein subclasses in patients with combined hyperlipidemia. DESIGN: Participants sequentially adhered to the following diets: 1) a habitual diet (HD), 2) a habitual diet plus walnuts (HD+W), 3) a low-fat diet (LFD), and 4) a low-fat diet plus walnuts (LFD+W). RESULTS: In 13 postmenopausal women and 5 men ( +/- SD age 60 +/- 8 y), walnut supplementation did not increase body weight despite increased energy intake and the LFD caused weight loss (1.3 +/- 0.5 kg; P < 0.01). When comparing the HD with the HD+W, linoleic acid concentrations increased from 29.94 +/- 1.14% to 36.85 +/- 1.13% and alpha-linolenic acid concentrations increased from 0.78 +/- 0.04% to 1.56 +/- 0.11%. During the LFD+W, plasma total cholesterol concentrations decreased by 0.58 +/- 0.16 mmol/L when compared with the HD and by 0.46 +/- 0.14 mmol/L when compared with the LFD. LDL-cholesterol concentrations decreased by 0.46 +/- 0.15 mmol/L when compared with the LFD. Measurements of lipoprotein subclasses and particle size suggested that walnut supplementation lowered cholesterol preferentially in small LDL (46.1 +/- 1.9% compared with 33.4 +/- 4.3%, HD compared with HD+W, respectively; P < 0.01). HDL-cholesterol concentrations decreased from 1.27 +/- 0.07 mmol/L during the HD to 1.14 +/- 0.07 mmol/L during the HD+W and to 1.11 +/- 0.08 mmol/L during the LFD. The decrease was seen primarily in the large HDL particles. CONCLUSIONS: Walnut supplementation may beneficially alter lipid distribution among various lipoprotein subclasses even when total plasma lipids do not change. This may be an additional mechanism underlying the antiatherogenic properties of nut intake.

The effect of four-year hypolipidaemic treatment on the intimal thickness of the common carotid artery in patients with familiar hyperlipidaemia.

BACKGROUND: Cholesterol lowering in patients with above-average cholesterol levels has been shown to reduce the progression of atherosclerosis. We assess the effects of lipid lowering therapy on the progression of early, preintrusive carotid arterial atherosclerosis in high risk patients with familial hyperlipidaemia free of symptomatic cardiovascular disease. METHODS: Fifty-two patients with familial hyperlipidaemia by were treated by diet and various hypolipidaemic drugs. Eighteen individuals were not taking hypolipidaemic drugs. In a prospective study by B-mode ultrasound we assessed the intima-media thickness of the distal common carotid arterial (CCA) far wall at baseline and after 4 years. RESULTS: In a subgroup of 25 patients with familial hypercholesterolaemia there was a significant decrease in total and LDL cholesterol and reduction in the intima-media thickness (IMT) of the common carotid artery from 0.78+/-0.22 mm to 0.69+/-0.17 mm (p=0.004). In a subgroup of 27 patients with familial combined hyperlipidaemia significant decreases in total and LDL cholesterol and triglycerides were associated with a decrease in the IMT of common carotid. artery from 0.72+/-0.22 mm to 0.67+/-0.15 mm (p=0.044). In 18 individuals, who were not taking hypolipidaemic drugs, there were no significant changes in the levels of cholesterol and triglycerides and in the IMT of the common carotid artery (increase from 0.58+/-0.18 mm to 0.62+/-0.13 mm, p>0.05). CONCLUSIONS: Lipid-lowering therapy in patients with familial hyperlipidaemia free of symptomatic cardiovascular disease reverses the progression of early, preintrusive atherosclerosis of the carotid artery. It is a beneficial sign indicating the possibility for atherosclerosis regression.

[Effect of nutrition on combined hyperlipidemia]. / Effet de la nutrition sur l'hyperlipidémie combinée.

Recent studies had underlined the expected effects of dietary changes in combined hyperlipidemia. Weight reduction is useful, but long term effect is usually moderate (10% reduction of cholesterol and 30% of triglycerides). There is no support to limit the intake of complex carbohydrates at 55% of the total calorie intake even in case of high triglyceride levels. The reduction of fat intake up to 30% of the total daily calorie intake is recommended but the quantity of saturated, mono or polyunsaturated flat is still discussed. Monoinsaturated fatty acid intake are now strongly recommended. Thus the Mediterranean diet appears to be very well adapted to the treatment of combined hyperlipidemia.

Changes in plasma triacylglycerol concentrations among free-living hyperlipidemic men adopting different carbohydrate intakes over 2 y: the Dietary Alternatives Study.

We reported previously that low-fat, high-carbohydrate diets containing < 26% of energy as fat and > 57% of energy as carbohydrate induce hypertriacylglycerolemia (hypertriglyceridemia) in hypercholesterolemic but not in combined hyperlipidemic (CHL) subjects. Because subjects may not consistently adhere to an assigned diet long term, we examined the extent to which plasma triacylglycerols (triglycerides) increase at four consistently reported carbohydrate intakes at intervals of up to 2 y. Three hundred seventy-two subjects reported consistent carbohydrate intakes of < 45%, 45-51.9%, 52-59.9%, or > or = 60% of energy on food records for 3, 12, and 24 mo. Among hypercholesterolemic subjects reporting a carbohydrate intake > or = 60% of energy, triacylglycerols increased by 0.25, 0.18, and 0.27 mmol/L (22, 16, and 24 mg/dL) over baseline at 3, 12, and 24 mo, respectively (P < 0.01 in each instance), and 0.32 mmol/L (28 mg/dL) above the group with a carbohydrate intake 52-59.9% of energy (P < 0.05) after 3 mo. No statistically significant effects were observed among CHL subjects, but compared with baseline, triacylglycerols decreased during the first 3 mo (-0.29 to -0.04 mmol/L, or -26 to -4 mg/dL), were unchanged over 12 mo, and were increased after 24 mo in three of four carbohydrate intake strata (0.27-0.36 mmol/L, or 24-32 mg/dL). These data confirm our previous observation that a moderately but not extremely low-fat, high-carbohydrate diet can be used long-term without deleterious effects on plasma triacylglycerols in the management of hypercholesterolemia, whereas CHL is unaffected by the amount of carbohydrate ingested.

Benefits and risks of modifying maternal fat intake in pregnancy and lactation.

The National Cholesterol Education Program recommends that healthy Americans aged > 2 y reduce energy intake to maintain ideal body weight, saturated fat to 10% of energy, fat intake to 30% of energy, and cholesterol consumption to < 300 mg/d. Although these guidelines exclude pregnant or lactating women, nursing infants, and very young children, women with gestational diabetes, preeclampsia, and familial hyperlipidemias may benefit from them. In a normal pregnancy, serum cholesterol and triglycerides rise 25-40% and 200-400%, respectively. Multiparous middle-aged women may have an increased incidence of angina and cholesterol gallstones from the hypercholesterolemia of pregnancy. Few studies support the safety of maternal low-fat diets for the developing fetus or demonstrate benefits to the mother. Polyunsaturated fatty acids lower serum lipids, and n-3 fatty acids may improve some obstetric complications. Arachidonic acid (20:4) and docosahexaenoic acid (22:6) may benefit the psychomotor and visual development of children.

Plasma carnitine and lipid-lowering drugs.

Oral carnitine has been reported to have a lipid-lowering effect with concomitant elevation of high density lipoprotein cholesterol (HDL-C) levels in normo- and hyperlipidemic individuals. Unexpectedly, basal carnitine concentrations were found to be abnormally high in subjects receiving a combination of probucol (1 g/day) and clofibrate (2 g/day), and who also had reduced HDL-C levels. Changes in plasma carnitine levels were found to correlate with clofibrate therapy and to be readily reversible with cessation of this drug. These increases of circulating carnitine were not accompanied by a rise in HDL-C.

Effects of guar gum on plasma lipoproteins and apolipoproteins C-II and C-III in patients affected by familial combined hyperlipoproteinemia.

In recent years, guar gum has been shown to be a potent hypocholesterolemic agent. The effects of this fiber on triglycerides are less clear. In order to evaluate the influence of guar supplementation on plasma lipoproteins and apolipoprotein C-II (apoC-II) and apolipoprotein C-III (apoC-III) isoforms (apoC-III2, apoC-III1, apoC-III0), 16 g/day of guar gum were administered to 12 outpatients affected by familial combined hyperlipoproteinemia for a period of 60 days. Mean total cholesterol and triglyceride levels significantly decreased after 15 days of treatment and persisted reduced at the 30th and 60th day of guar supplementation. While low-density lipoprotein cholesterol paralleled the reduction of total plasma cholesterol, we did not observe any change in the cholesterol content of high-density lipoprotein (HDL) subfractions (HDL2 and HDL3) during the study. A redistribution of the relative content of very low-density lipoprotein apoC-III isoforms with a significant increase of apoC-III1 and a decrease of apoC-III0 was observed after 15, 30, and 60 days of guar gum administration. The results show that guar gum reduces not only cholesterol but also triglyceride levels in patients affected by familial combined hyperlipoproteinemia. Further studies are needed to confirm the suggestion that the different distribution of very low-density lipoprotein apoC-III isoforms induced by guar supplementation may influence the behavior of plasma triglycerides.

[Diagnosis, clinical features and treatment of hyperlipidemias in children]. / Diagnose, Klinik und Therapie der Hyperlipidämien im Kindesalter.

Hyperlipidemias represent one of the most important risk factors for the development of premature atherosclerotic disease. If prevention of ischaemic cardiovascular disease, which is responsible for about 50% of the deaths in Western Europe, should be successful, diagnosis and treatment of hyperlipidemic states should start as early as possible. A short overview concerning the composition and the metabolism of the lipoproteins is given and theoretical and practical aspects for the classification of the different forms of hyperlipoproteinemia during childhood are pointed out. Laboratory determinations are described and therapeutic approaches of the main pediatric hyperlipidemias are given: polygenetic and combined familial hyperlipidemias should be treated by diet alone, whereas familial hypercholesterolemias request drug treatment: cholestyramine, given in doses between 4 and 8 g seems to be the drug of choice. Possible future aspects of drug treatment are discussed, even those who are shown to increase the number of LDL-receptors, which are blocked in that disease. Finally, efforts are emphasized to screen all children of families, in which premature heart disease or hypercholesterolemia occur.