Atherogenic LDL Cholesterol Research Articles

Abstract 440: Role Of Retinoid X Receptor In Regulating Pcsk9 Transcription In The Liver And Atherosclerosis

Nonalcoholic fatty liver diseases ( NALFD) are associated with high cardiovascular disease ( CVD ) risk. The demand for novel CVD treatments leads to the recent discovery of the Proprotein Convertase Subtilisin Kexin 9 ( PCSK9 ), which promotes the degradation of low-density lipoprotein receptor ( LDLR ) to increase atherogenic lipoprotein LDL cholesterol ( LDL-C ) levels. Targeting PCSK9 shows promising benefits in mitigating CVD and NAFLD. However, the underlying mechanism causing the NAFLD-associated PCSK9 induction is still unclear. Our findings fill the critical knowledge gap by elucidating that Retinoid X Receptor alpha ( RXRα ) is essential to regulate the transcription of PCSK9 in the liver. Our preliminary data showed that hepatic depletion of RXRα leads to hepatic steatosis. To reveal the underlying mechanism by which hepatic RXRα deficiency promotes NAFLD development, we carried out the RNA-seq analysis. The Gene Set Enrichment Analysis ( GSEA ) of RNA-seq data showed the expected downregulation of PPARα signaling genes and the unexpected upregulation of cholesterol pathway genes in the liver of RXRα hepatocyte-specific knockout ( hepKO ) mice. One of the significantly upregulated genes in the cholesterol pathway is PCSK9, which induction in the liver of RXRα hepKO mice can be abolished by AAV8-mediated overexpression of RXRα. Consistently, we observed the increased cholesterol and LDL-C in the plasma of RXRα hepKO mice, and hepatic overexpression of RXRα can significantly reduce the plasma cholesterol and LDL-C levels. Recently, we identified a previously unrecognized acetylation residue of RXRα, which controls the heterodimerization between RXRα and PPARα. The inhibitory effects of constitutively acetylated RXRα mutant further indicate that acetylation of RXRα is essential for preventing the induction of PCSK9 in the liver of RXRα hepKO mice. Interestingly, we also observed the decreased acetylation of RXRα in the liver of high-fat diet ( HFD )-fed mice and human NAFLD patients. These results suggest that RXRα acetylation is required for regulating the PPARα-mediated repression of PCSK9 transcription in the liver, and impaired RXRα acetylation in the NAFLD liver results in increased PCSK9 and atherosclerosis risk.

*Lipoprotein X hyperlipidemia and Its Complications in a Patient with Primary Sclerosing Cholangitis

Lead Author's Financial Disclosures Nothing to disclose. Study Funding None. Background/Synopsis We reviewed a case of a young man referred for management of severe hypercholesterolemia and bilateral palpebral xanthelasma. This is intended to highlight key features in diagnosis and management of severe hypercholesterolemia due to LpX from biliary obstructive disease. Objective/Purpose To review clinical management of severe hypercholesterolemia due to LpX. Methods Clinical management at tertiary care lipid program. Results A 22-year-old slim male with history of Wilson's disease, Crohn's disease, and primary sclerosing cholangitis (PSC) was referred for management of severe hypercholesterolemia and progressive symmetric palpebral xanthelasmas. There is no family history of severe hypercholesterolemia or premature atherosclerotic cardiovascular disease (ASCVD), nor were any other secondary causes identified. He was successfully treated with cholestyramine for pruritis which resulted in marked total cholesterol reduction and increased triglyceride (TG) level. Conclusions Very severe hypercholesterolemia with total cholesterol levels >500 mg/dL is a rare condition. Levels this high are typically associated with homozygous familial hypercholesterolemia (FH) due to an increased level of atherogenic LDL cholesterol (LDL-C). However, other causes need to be considered in the right clinical context, such as lipoprotein fraction lipoprotein X (LpX) in an individual with obstructive biliary disease. LpX is a consequence of ``spillover'' of hepatic free cholesterol (FC)/phospholipid complexes in disc- shaped lipoproteins which do not contain apoB. Consequently, there is wide discordance between apoB and the calculated LDL-C and high serum FC levels. The diagnosis is typically made in the right clinical context without FC measurement since this test is not commercially available. Hypercholesterolemia due to LpX is not associated with increased ASCVD risk, but its presence can be a marker of the severity of liver disease and cause other medical complications including hyperviscosity syndrome, pulmonary embolism and cholesteroloma.Our patient's marked increase in total cholesterol without severe increase in apoB suggested progression of PSC and prompted referral back to his primary Hepatology team. Additional cholesterol-lowering pharmacotherapy is not indicated for hypercholesterolemia due to LpX without hyperviscosity. Nothing to disclose.

Statins repress needle-like carbon nanotube- or cholesterol crystal-stimulated IL-1β production by inhibiting the uptake of crystals by macrophages

Statins are 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors that lower atherogenic LDL-cholesterol levels. Statins exert clinically relevant anti-inflammatory effects; however, the underlying molecular mechanism remains unclear. Studies have shown that endogenous and exogenous pathogenic crystals, such as cholesterol and monosodium urate (MSU), and needle-like nanomaterials, such as multi-wall carbon nanotubes (MWCNT), induce the production of IL-1β and play a critical role in the development of crystal-associated sterile inflammatory pathologies. In this study, we evaluated the effect of statins on crystal-induced IL-1β production in macrophages. We found that various statins, including pitavastatin, atorvastatin, fluvastatin, and lovastatin, but not squalene synthase inhibitor, repressed IL-1β release upon MWCNT stimulation. In addition, IL-1β production induced by cholesterol crystals and MSU crystals, but not by ATP or nigericin, was diminished. MWCNT-stimulated IL-1β release was dependent on the expression of NLRP3, but not AIM2, NLRC4, or MEFV. Statin-induced repression was accompanied by reduced levels of mature caspase-1 and decreased uptake of MWCNT into cells. Supplementation of mevalonate, geranylgeranyl pyrophosphate, or farnesyl pyrophosphate prevented the reduction in IL-1β release, suggesting a crucial role of protein prenylation, but not cholesterol synthesis. The statin-induced repression of MWCNT-elicited IL-1β release was observed in THP-1-derived and mouse peritoneal macrophages, but not in bone marrow-derived macrophages where statins act in synergy with lipopolysaccharide to enhance the expression of IL-1β precursor protein. In summary, we describe a novel anti-inflammatory mechanism through which statins repress mature IL-1β release induced by pathogenic crystals and nanoneedles by inhibiting the internalization of crystals by macrophages.

The role of statins in the differentiation and function of bone cells.

Statins are 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors blocking cholesterol biosynthesis in hepatic cells, thereby causing an increase in low-density lipoprotein (LDL) receptors resulting in enhanced uptake and clearance of atherogenic LDL-cholesterol (LDL-C) from the blood. Accordingly, statins decrease the risk of developing atherosclerosis and its acute complications, such as acute myocardial infarction and ischaemic stroke. Besides the LDL-C-lowering impact, statins also have other so-called pleiotropic effects. Among them, the ability to modulate differentiation and function of bone cells and exert direct effects on osteosynthesis factors. Specifically, earlier studies have shown that statins cause in vitro and in vivo osteogenic differentiation. The most relevant papers on the bone-related 'pleiotropic' effects of statins were selected following literature search in databases and were reveiwed. Statins increase the expression of many mediators involved in bone metabolism including bone morphogenetic protein-2 (BMP-2), glucocorticoids, transforming growth factor-beta (TGF-β), alkaline phosphatase (ALP), type I collagen and collagenase-1. As a result, they enhance bone formation and improve bone mineral density by modulating osteoblast and osteoclast differentiation. This review summarizes the literature exploring bone-related 'pleiotropic' effects of statins and suggests an anabolic role in the bone tissue for this drug class. Accordingly, current knowledge encourages further clinical trials to assess the therapeutic potential of statins in the treatment of bone disorders, such as arthritis and osteoporosis.

The significance of circulating progenitor cells with osteogenic activity in the of atherosclerosis development in patients with type 2 diabetes mellitus

BACKGROUND: There is an interaction between cell-mediated pathway of the vessel calcification and atherosclerosis processes. In some studies the relation beeen circulating osteogenic progenitor cells and cardiovascular diseases was shown. Though its role in the development of cerebrovascular diseases (CVD) in Type 2 diabetes mellitus (T2DM) remains unknown.
 AIM: To study the level of circulating endothelial (CD34 + VEGFR2 +) and osteogenic (CD34 + OCN +) progenitor cells in patients with CVD and T2DM. 
 METHODS: We observed patients with CVD (coronary artery disease and / or chronic limb threatening ischemia) with T2DM and without T2DM. Patients with CVD and T2DM were included in group 1 patients with CVD and without T2D were included in group 2. The level of CD34 + VEGFR2 cells and CD34 + OCN+ cells was determined by flow cytometry.There were no differences in the age, gender, lipid profile, body mass index, creatinine clearance, myocardial revascularization and lower limb revascularization between the 2 groups.The level of CD34 + VEGFR2 cells and CD34 + OCN+ cells was determined by flow cytometry. The number of cells was determined by a percentage of the number of CD34+ cells.
 RESULTS: We observed 71 patients (38 women, mean age 67 years [62, 74]). Forty six patients were included in group 1 (28 women, mean age 68 years [63;75], 25 patients (10 women, 66 years [55;72]) were included in group 2. We found that in patients with CVD and T2DM demonstrated higher amounts of CD34+OCN+ cells than CD34+VEGFR2+ cells. (29.7% [26.2;36.1] and 11.8% [9.57;17.2], p0.001). In the 1st group observed higher amounts of CD34+OCN+ cells, than in the 2d group (29.7 [26.2;36.1] и 25.6 [17.3;30.7] соответственно; p=0.035). Positive correlation was established between amount of CD34+OCN+ cells and atherogenic lipid fraction, LDL (r=0.4; р=0.032) and total cholesterol (r=0.27; р=0.05) in patients of group 1.While SYNTAX score tertiles and amount of CD34+OCN+ cells (r = 0.50, p=0.021) were the positive correlation. Between coronary artery calcium score and amount of CD34+OCN+ cells (r = 0.49, p=0.034) was the positive correlation.
 CONCLUSIONS: Acquired results may indicate the active role of CD34+OCN+ endothelial progenitor cells in atherosclerosis and vascular calcification in patients with T2DM.

Adropin: An endocrine link between the biological clock and cholesterol homeostasis

ObjectiveIdentify determinants of plasma adropin concentrations, a secreted peptide translated from the Energy Homeostasis Associated (ENHO) gene linked to metabolic control and vascular function. MethodsAssociations between plasma adropin concentrations, demographics (sex, age, BMI) and circulating biomarkers of lipid and glucose metabolism were assessed in plasma obtained after an overnight fast in humans. The regulation of adropin expression was then assessed in silico, in cultured human cells, and in animal models. ResultsIn humans, plasma adropin concentrations are inversely related to atherogenic LDL-cholesterol (LDL-C) levels in men (n = 349), but not in women (n = 401). Analysis of hepatic Enho expression in male mice suggests control by the biological clock. Expression is rhythmic, peaking during maximal food consumption in the dark correlating with transcriptional activation by RORα/γ. The nadir in the light phase coincides with the rest phase and repression by Rev-erb. Plasma adropin concentrations in nonhuman primates (rhesus monkeys) also exhibit peaks coinciding with feeding times (07:00 h, 15:00 h). The ROR inverse agonists SR1001 and the 7-oxygenated sterols 7-β-hydroxysterol and 7-ketocholesterol, or the Rev-erb agonist SR9009, suppress ENHO expression in cultured human HepG2 cells. Consumption of high-cholesterol diets suppress expression of the adropin transcript in mouse liver. However, adropin over expression does not prevent hypercholesterolemia resulting from a high cholesterol diet and/or LDL receptor mutations. ConclusionsIn humans, associations between plasma adropin concentrations and LDL-C suggest a link with hepatic lipid metabolism. Mouse studies suggest that the relationship between adropin and cholesterol metabolism is unidirectional, and predominantly involves suppression of adropin expression by cholesterol and 7-oxygenated sterols. Sensing of fatty acids, cholesterol and oxysterols by the RORα/γ ligand-binding domain suggests a plausible functional link between adropin expression and cellular lipid metabolism. Furthermore, the nuclear receptors RORα/γ and Rev-erb may couple adropin synthesis with circadian rhythms in carbohydrate and lipid metabolism.

A promoter variant of the APOA5 gene increases atherogenic LDL levels and arterial stiffness in hypertriglyceridemic patients.

Hypertriglyceridemia is recognized as an independent risk factor for coronary artery disease. The apolipoprotein A5 gene (APOA5) is a key regulator of triglyceride levels. We aimed to evaluate the associations of single nucleotide polymorphisms (SNPs) in APOA5, including -1131T>C and c.553G>T, with hypertriglyceridemia, apoA5 concentrations, atherogenic LDL cholesterol levels, and arterial stiffness in hypertriglyceridemic patients. The study population included 599 hypertriglyceridemic patients (case) and 1,549 untreated normotriglyceridemic subjects (control). We genotyped two APOA5 variants, -1131T>C (rs662799) and c.553G>T (rs2075291). The frequencies of the CC genotype of -1131T>C (0.165) and the T allele of c.553G>T (0.119) were significantly higher in hypertriglyceridemic patients than in normotriglyceridemic subjects (0.061 and 0.070, respectively; all p<0.001). In the control and case groups, both the -1131T>C and c.553G>T variants were associated with higher triglyceride and lower HDL cholesterol levels. Controls with the -1131CC variant had lower apoA5 concentrations than controls with the -1131TT variant. Similar effects of the -1131T>C variant on apoA5 were observed in the cases. In the hypertriglyceridemic group, the -1131T>C variant was associated with a smaller LDL particle size, higher levels of oxidized LDL and malondialdehyde, and higher brachial-ankle pulse wave velocity. The -1131T>C and c.553G>T polymorphisms were associated with hypertriglyceridemia in the study population, but only the -1131T>C polymorphism directly affected apoA5 concentrations. Hypertriglyceridemic patients carrying the APOA5 -1131T>C polymorphism exhibited increased atherogenic LDL levels and arterial stiffness, probably due to an effect of the -1131T>C polymorphism on apoA5 concentrations.

Hypolipidemic effect of mannans from C. albicans serotypes a and B in acute hyperlipidemia in mice

Mannans, which are biological macromolecules of polysaccharide origin and function as immunomodulators, have been shown to stimulate macrophages in vivo by interaction with the mannose receptor. Thus, they can be used to stimulate macrophages in order to effectively remove circulating atherogenic lipoproteins. Our primary aim was to evaluate the hypolipidemic potential of mannans from C. albicans serotype A (mannan A) and serotype B (mannan B) in a murine model of hyperlipidemia. Mannan A and mannan B were shown to significantly (p<0.05) stimulate both the proliferation (p <0.05) and nitric oxide production of murine peritoneal macrophages in vitro. Pre-treatment of CBA/Lac mice with mannan A prior to induction of hyperlipidemia significantly (p<0.001) reduced serum atherogenic LDL-cholesterol, total cholesterol, and triglycerides. Mannan B exhibited a similar, but more potent, hypolipidemic effect. Electron microscopic analysis of liver revealed a significant (p<0.001) decrease in the volume of lipid droplets when hyperlipidemic mice were pretreated by both mannans. In conclusion, our findings would suggest that both polysaccharide-based biological macromolecules evaluated in the present study, specifically, the natural immunomodulators (mannans A and B), appeared to function as effective lipid-lowering macromolecules, which could potentially serve as adjunct therapy to more conventional hypolipidemic medications such as a statin drug.

Blood levels of antioxidants during age-related macular degeneration treatment by rheohaemapheresis.

Rheohaemapheresis treatment influences rheological markers and most likely improves metabolism in affected retinal areas, resulting not only in absorption of soft drusen but also reduction or complete disappearance of drusenoid retinal pigment epithelium detachments. However, the character of the treatment process has raised suspicion that there is a decrease not only in cholesterol but also in antioxidants, such as vitamin E and vitamin A. Twenty-three patients with the progressive dry form of age-related macular degeneration were each treated with 8 procedures of rheohaemapheresis. We measured levels of vitamin E (α-tocopherol), the vitamin E/cholesterol ratio in serum and lipoproteins (VLDL, LDL, HDL). Vitamin E in erythrocyte membrane and serum vitamin A (retinol) were also measured. These parameters were determined before and after rheohaemapheresis. Erythrocyte superoxide dismutase, erythrocyte glutathione peroxidase and serum malondialdehyde were analysed as markers of antioxidant activity and lipid peroxidation, respectively. In serum, the VLDL and LDL fraction ratios of vitamin E/cholesterol increased significantly. Additionally, the HDL fraction ratio showed an increase but this was not statistically significant. The patients showed no clinical signs of vitamin E deficiency, and their serum concentrations of vitamin E did not differ from normal values. The results show that rheohaemapheresis in addition to causing a significant reduction in atherogenic LDL cholesterol, may have favourable additive anti-atherogenic effects due to a relative increase in the content of vitamin E in the lipoprotein fractions.

Effect of water cooking on free phytosterol levels in beans and vegetables

Plant sterols (phytosterols) are known to decrease plasma cholesterol, mainly the atherogenic LDL cholesterol. In an earlier study, the thermal stability of phytosterols in vegetable oils was reported. The aim of this present work was to investigate the potential effect of cooking (30 min in boiling water), for eight plant products (broad bean, celery, cabbage, courgette, carrot, cauliflower, onion, pepper), on the free phytosterol level. Sitosterol was the most abundant sterol, followed by campesterol. After cooking, the level of total sterols was higher in all vegetables than that before cooking, if dry matter is considered. Acid hydrolysis (active for glycosylated phytosterols) yielded a higher sterol value than alkaline hydrolysis alone (active for esterified phytosterols). This indicated that studied vegetables contained appreciable amounts of steryl glycosides. Their cooking induced higher values of free phytosterols. Cooked vegetables could give better protection against cardiovascular diseases thanks to higher phytosterol levels.

Bisphosphonates and atherosclerosis: why?

The increasing knowledge on bone calcification processes has revealed some similarities with vascular tissue, where calcifications of arteries and cardiac valves contribute to several cardiovascular problems, such as heart failure, systolic hypertension, and myocardial and peripheral ischemic disease. Bisphosphonates have been used extensively for over two decades for the treatment of diseases associated with excessive bone resorption, i.e., osteoporosis, osteolytic bone metastasis, hypercalcemia and Paget's disease, by blocking osteoclastic function. Etidronate, pamidronate and clodronate has been shown to inhibit the development of experimental atherosclerosis, and proposed mechanisms for this action include inhibition of arterial calcification and lipid accumulation, degradation of atherogenic LDL-cholesterol and reduced foam cell formation. Bisphosphonates inhibit various enzymes involved in cholesterol biosynthesis and suppress macrophages in atheromatous lesions. The possibility of pharmacological agents that effectively treat both osteoporosis and atherosclerosis is attractive, however, current evidence is not conclusive and further research is necessary to confirm these actions in the clinical setting.

Differences between markers of atherogenic lipoproteins in predicting high cardiovascular risk and subclinical atherosclerosis in asymptomatic men

Objective: As main markers of atherogenic lipoproteins, apolipoprotein B (apoB), non-HDL cholesterol (non-HDLC), and LDL cholesterol (LDLC) do not seem equipotent to predict cardiovascular complications, we have compared simultaneously their capacity to predict high cardiovascular risk and subclinical atherosclerosis in a primary prevention population. Methods: In 723 asymptomatic men, we measured apoB, non-HDLC, and LDLC, and we determined concomitantly coronary heart disease (CHD) risk equivalent defined by National Cholesterol Education Program guidelines, ultrasound-assessed extra-coronary plaques at multiple sites, and electron beam computed tomography-assessed high coronary calcium. Results: Odds ratios (95% confidence interval) per standard deviation of apoB, non-HDLC, and LDLC of having: (i) CHD risk equivalent were 1.90 (1.53–2.37), 1.78 (1.43–2.21), 1.47 (1.19–1.81); (ii) extra-coronary plaques were 1.37 (1.16–1.61), 1.31 (1.11–1.56), 1.19 (1.01–1.39); (iii) high coronary calcium were 1.35 (1.09–1.68), 1.33 (1.07–1.64), 1.26 (1.01–1.39), respectively. Risk factors and treatment did not confound the above associations, except triglycerides for which adjustment weakened the risk predictions of lipids and annihilated lipids differences in predicting CHD risk equivalent and atherosclerosis markers. Conclusions: ApoB was the best predictor, non-HDLC the second best predictor, and LDLC the poorest predictor of high cardiovascular risk and subclinical extra-coronary and coronary atherosclerosis, and triglycerides participated to these differences.

RELATIONSHIP BETWEEN POSTPRANDIAL LIPEMIA AND LDL PARTICLE SIZE DURING A KETOGENIC DIET IN MEN

Individuals exhibiting a predominance of small dense LDL-cholesterol (LDL) particles have been termed “pattern B”, which is associated with a greater than three-fold risk of coronary heart disease in men. This atherogenic phenotype may be partially driven by a delayed clearance of triacylglycerols (TAG) after a fat-rich meal (i.e., abnormal postprandial lipemia). Thus, a reduction in postprandial lipemia should result in a shift to a larger LDL particle profile. PURPOSE This study determined factors related to changes in peak LDL diameter resulting from a ketogenic diet, which was previously shown by our laboratory to result in decreased postprandial lipemia. METHODS Twenty-five healthy men consumed a ketogenic diet for six weeks. Fasting blood draws and an oral fat tolerance test were performed before and after the diet. Relationships between the change in peak LDL diameter and changes in blood lipids, insulin, and percent body fat were assessed. RESULTS The ketogenic diet resulted in significant (P < 0.05) changes in fasting serum TAG (−39%), postprandial lipemia (−33%), insulin (−40%), percent body fat (−11%), and peak LDL diameter (+1.8%). There were no significant changes in total cholesterol, LDL or HDL. There was a significant relationship between peak LDL particle diameter and fasting TAG (r = 0.41) at the start of the study. The only variable significantly related to the change in peak LDL diameter was the change in fasting TAG (r = 0.41) and the change in postprandial lipemia (r = 0.50). Thus, approximately 25% of the variance in peak LDL diameter responses to a ketogenic diet was accounted for by changes in postprandial lipemia. CONCLUSION These data indicate that a ketogenic diet has favorable effects on postprandial lipemia and peak LDL size in men and provides support for the notion that an impaired ability to clear circulating TAG after a meal contributes to a small atherogenic LDL profile. Sponsored by a grant from the Atkins Foundation, New York, NY

Hepatic lipase: a marker for cardiovascular disease risk and response to therapy.

Hepatic lipase plays a key role in the metabolism of pro-atherogenic and anti-atherogenic lipoproteins affecting their plasma level as well as their physico-chemical properties. However, controversial evidence exists concerning whether hepatic lipase is pro or anti-atherogenic. The goal of this review is to summarize recent evidence that connects the enzyme to cardiovascular disease. The potential impact of genetic determinants of hepatic lipase activity in modulating both the development of coronary and carotid atherosclerosis will be discussed based on hepatic lipase proposed roles in lipoprotein metabolism. Twenty to 30% of individual variation of hepatic lipase activity is accounted for by the presence of a common polymorphism in the promoter region (-514 C to T) of the hepatic lipase gene (LIPC). This polymorphism, via its impact on hepatic lipase synthesis and activity, appears to contribute to (1) individual susceptibility to cardiovascular disease: the presence of the T allele (low hepatic lipase activity) may carry a marginally increased risk of atherosclerosis; (2) carotid plaque composition and individual susceptibility to cerebrovascular events: the presence of the C allele (high hepatic lipase activity) is associated with increased carotid intima-media thickness and abundance of macrophages in the carotid plaque (unstable plaque); and (3) response of cardiovascular disease patients to lipid-lowering therapy: patients with the CC genotype have the greatest clinical benefit from intensive lipid-lowering therapy. Convincing evidence shows that hepatic lipase plays a key role in remnant lipoprotein catabolism as well as in remodeling of LDL and HDL particles. The anti or pro-atherogenic role of hepatic lipase is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. increased LDL cholesterol levels) as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism. Characterization of patients by their LIPC genotype will contribute to a better definition of individual risk of coronary and cerebrovascular events, specifically in patients with qualitative (small, atherogenic LDL and low HDL2 cholesterol) rather than quantitative lipid abnormalities for whom the routine lipid profile may underestimate the risk of coronary and cerebrovascular disease.

The Impact of Egg Limitations on Coronary Heart Disease Risk: Do the Numbers Add Up?

For over 25 years eggs have been the icon for the fat, cholesterol and caloric excesses in the American diet, and the message to limit eggs to lower heart disease risk has been widely circulated. The “dietary cholesterol equals blood cholesterol” view is a standard of dietary recommendations, yet few consider whether the evidence justifies such restrictions. Over 50 years of cholesterol-feeding studies show that dietary cholesterol does have a small effect on plasma cholesterol concentrations. The 167 cholesterol feeding studies in over 3,500 subjects in the literature indicate that a 100 mg change in dietary cholesterol changes plasma total cholesterol by 2.2 mg/dL.Today we recognize that dietary effects on plasma cholesterol must be viewed from effects on the atherogenic LDL cholesterol as well as anti-atherogenic HDL cholesterol since the ratio of LDL:HDL cholesterol is a major determinant of heart disease risk. Cholesterol feeding studies demonstrate that dietary cholesterol increases both LDL and HDL cholesterol with little change in the LDL:HDL ratio. Addition of 100 mg cholesterol per day to the diet increases total cholesterol with a 1.9 mg/dL increase in LDL cholesterol and a 0.4 mg/dL increase in HDL cholesterol. On average, the LDL:HDL ratio change per 100 mg/day change in dietary cholesterol is from 2.60 to 2.61, which would be predicted to have little effect on heart disease risk. These data help explain the epidemiological studies showing that dietary cholesterol is not related to coronary heart disease incidence or mortality across or within populations.

Lipoproteins and other clinical-chemistry parameters under the conditions of lacto-ovo-vegetarian nutrition

The aim of this study was to examine concentration and composition of lipoproteins and levels of apolipoproteins in serum of 46 lacto-ovo-vegetarians in comparison with 49 non-vegetarians. Other clinical-chemistry parameters were also included in this study. Both male and female lacto-ovo-vegetarians showed a favourable lipoprotein profile characterized by low concentrations of atherogenic LDL-cholesterol, low ratios of cholesterol/HDL-cholesterol, LDL-cholesterol/ HDL-cholesterol and a high ratio HDL 2-cholesterol/HDL 3-chol-esterol. The favourable lipoprotein profile of vegetarians manifested as a low ratio of apolipoprotein B/apolipoprotein A-I and a low concentration of lipoprotein particles containing apolipoprotein B together with apo C-III. These parameters were significantly different between the vegetarians and the non-vegetarians. The α-tocopherol/LDL-cholesterol molar ratio was significantly higher in vegetarians in comparison with non-vegetarians which may be important with respect to protection against atherosclerosis. Total and free carnitine concentrations were reduced in serum of lacto-ovo-vegetarians. However this small reduction does not reflect a carnitine deficiency. The favourable serum lipoprotein profile among vegetarians observed in this study may result not only from nutritional conditions but also from special life-style factors within this group.

Impact of lipid and ACE inhibitor therapy on cardiovascular disease and metabolic abnormalities in the diabetic and hypertensive patient.

Hypertension is often accompanied by a variety of metabolic abnormalities. These metabolic abnormalities include insulin resistance, dyslipidemia and abnormalities of the coagulation-fibrinolytic system predisposing to a procoagulent state. The nexus for all of these abnormalities may be central (visceral) obesity. The dyslipidemia accompanying hypertension consists of low HDL cholesterol, elevated triglyceride levels and an abnormal more atherogenic LDL cholesterol particle. Dyslipidemia interacts with associated hemodynamic (ie, hypertension) and metabolic (ie, increased platelet aggregation and PAI-1 levels) in a multiplicative manner potentiating cardiovascular and renal disease. Accordingly, lipid therapy should be aggressive to attenuate these medical complications of essential hypertension.

Lipid Apheresis by Hemoperfusion: In Vitro Efficacy and Ex Vivo Biocompatibility of a New Low‐Density Lipoprotein Adsorber Compatible with Human Whole Blood

To date, selective extracorporeal low-density lipoprotein (LDL) removal can only be performed from plasma; that is, a plasma-cell separation step using a centrifuge or a plasma membrane separator is necessary initially. This article characterizes a new polyacrylate-based LDL adsorber directly applicable to whole blood. In vitro single-pass hemoperfusion tests using pooled donor blood showed quantitative adsorption of atherogenic LDL-cholesterol (LDL-C) and complete recovery of protective high-density lipoprotein C. Fibrinogen, another independent risk factor of atherosclerosis, was also adsorbed to a lesser extent. Single-pass ex vivo biocompatibility using fresh donor blood on-line was excellent and resulted in minimal cell loss. Neither signs of hemolysis nor activation of monocytes (interleukin-1 production) were detected. Only slight activation of leukocytes (elastase release) and thrombocytes (platelet factor 4 secretion) as well as of coagulation (thrombin-antithrombin complex formation) and complement (C3a, C5a generation) was observed. Under the experimental conditions used, the optimal anticoagulation regimen was 0.5 IU heparin plus 0.375 mg citrate/ml blood. Priming the column with a buffer of pH 7.4 containing heparin, citrate, and Ca2+ is recommended. In conclusion, this new adsorber exhibited selective LDL-C adsorption in vitro combined with excellent ex vivo biocompatibility and thus holds great promise for a successful clinical application in a closed-loop system in patients.

Effect of verapamil on serum lipoproteins in patients with angina pectoris.

Since several beta-blocking agents increase the atherogenic VLDL-triglycerides and decrease the atheroprotective HDL-cholesterol we studied if verapamil also affects these lipoproteins or the most atherogenic LDL-cholesterol. Twelve patients (three females), mean age 56 years, with angina pectoris or hypertension/tachyarrhythmias were treated with verapamil 240-320 mg/day. Serum lipoproteins were measured before and after 6 and 24 weeks of therapy. Initial total serum cholesterol averaged 7.27 mmol/l. After 6 weeks of treatment it decreased by 9%, p less than 0.02. These results remained significant, p less than 0.01 after 24 weeks. The decrease was due to a fall in LDL-cholesterol by 12%, p less than 0.01. The reduction in LDL-cholesterol was correlated to initial LDL-cholesterol concentration, r = -0.73, p less than 0.01. Within LDL there was a parallel decrease in phospholipids, p less than 0.05. There were no changes in total or VLDL-triglycerides or total HDL-cholesterol. In the HDL fraction HDL2 decreased insignificantly but HDL3 cholesterol increased by 12%, p less than 0.05. We conclude that verapamil has a beneficial effect on serum lipoproteins in that it lowers the atherogenic LDL-cholesterol and does not affect the other lipoproteins in an undesirable way.