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Purpose: To evaluate any association of specific subtypes of dyslipidemia with increments of preoperative tear size and with structural integrity after arthroscopic rotator cuff repair (ARCR)., Methods: One surgeon's consecutive patients who underwent ARCR from January 2011 to June 2018 were reviewed. The inclusion criteria were minimum 1-year follow-up ultrasonography, blood tests, physical examination, and provision of informed consent. The exclusion criteria were incomplete laboratory tests, history of acute trauma, previous shoulder surgery, isolated subscapularis tendon tear, inappropriate radiographs, no 1-year follow-up ultrasonography, and medication with lipid-lowering drugs. Associated preoperative factors for the increments of tear size and for retear after ARCR were determined using logistic regression analysis. Statistical significance was set at P < .05., Results: Of the 502 ARCR patients from the study period, 195 patients (195 shoulders), with a mean age of 60.5 ± 7.5 years, met the inclusion and exclusion criteria. Age (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.1-1.3), diabetes (OR, 3.6; 95% CI, 1.7-7.5), and hypo-high-density lipoproteinemia (hypo-HDLemia) (OR, 2.9; 95% CI, 1.5-5.6) were significantly associated with increments of preoperative tear size (P ≤ .01). Diabetes (OR, 3.0; 95% CI, 1.3-6.6), critical shoulder angle (OR, 2.0; 95% CI, 1.4-3.0), and tear size (OR, 2.1; 95% CI, 1.3-3.4) were significantly associated with retear after ARCR in overall study subjects (P = .01). Diabetes (OR, 3.8; 95% CI, 1.3-11.4), hypo-HDLemia (OR, 3.0; 95% CI, 1.1-8.8), and critical shoulder angle (OR, 1.5; 95% CI, 1.1-2.3) had significant associations with retear after ARCR in patients with a large to massive preoperative tear size (P ≤ .04)., Conclusions: Preoperative hypo-HDLemia (high-density lipoprotein level < 40 mg/dL in male patients and < 50 mg/dL in female patients) has a significant association with the increments of preoperative tear size and with retear after ARCR in large- to massive-sized rotator cuff tears., Level of Evidence: Level IV, case series., (Copyright © 2020 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.)

Objective In patients with acute coronary syndrome (ACS), low high-density lipoprotein cholesterol (HDL-C) levels in samples collected after an overnight fast are diagnostic indicators and well-established predictors of adverse outcomes. However, the relationship between the HDL-C levels in samples collected just after arrival (early HDL-C) and in-hospital mortality remains unknown. The purposes of the present ACS study were to (1) evaluate the association between the early HDL-C levels of patients and in-hospital mortality and (2) compare the early HDL-C level with other well-known determinants associated with in-hospital mortality. Methods This retrospective study surveyed 638 consecutive ACS patients and then assessed the possible determinants of in-hospital mortality. All initial blood samples, including that for early HDL-C, were drawn within one hour of arrival. Results In the present study, the overall in-hospital mortality was 5.9%. A multivariable analysis showed that a low early HDL-C [odds ratio (OR) 2.53, 95% confidence interval (CI) 1.14-5.62], elevated troponin T (OR 4.40, 95% CI 1.26-15.29) and high Killip class (OR 15.41, 95% CI 7.29-32.59) were independent predictors of in-hospital mortality. A Kaplan-Meier survival analysis indicated that there the in-hospital outcome for the low early HDL-C group was significantly worse than that for the high early HDL-C group (age- and gender-adjusted hazard ratio 2.40, 95% CI 1.15-5.00, p=0.02). Conclusion ACS patients with low early HDL-C levels had higher in-hospital mortalities than those who did not have low early HDL-C levels. In addition to the already well-known determinants, low early HDL-C should also be considered as an independent predictor of in-hospital mortality in ACS patients who present to a cardiac care unit.

Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4 ng/mL (124.9;243.3); heterozygotes, 180.3 ng/mL (127.6;251.5) and controls, 190.4 ng/mL (146.7;264.4); P for trend = 0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Postpartum depression (PPD) is a psychiatric complication of childbirth affecting 10-20% of new mothers and has negative impact on both mother and infant. Serum lipid levels have been related to depressive disorders, but very limited literatures are available regarding the lipid levels in women with postpartum depression. The present study is aimed to examine the association of serum lipids with the development of postpartum depressive symptoms. This is a cross sectional study conducted at a tertiary care hospital in South India. Women who came for postpartum check-up at 6th week post-delivery were screened for PPD (September 2014-October 2015). Women with depressive symptoms were assessed using EPDS (Edinburgh Postnatal Depression Scale). The study involved 186 cases and 250 controls matched for age and BMI. Serum levels of lipid parameters were estimated through spectrophotometry and the atherogenic indices were calculated in all the subjects. Low serum levels of Total Cholesterol (TC) and High Density Lipoprotein cholesterol (HDL-c) were significantly low in PPD women with severe depressive symptoms. The study recorded a significant negative correlation between HDL-c and the EPDS score in PPD women (r = -0.140, p = 0.05). Interestingly, the study also observed a significant negative correlation between Body Mass Index (BMI) and EPDS scores in case group (r = -0.146, p = 0.047), whereas a positive correlation between the same in controls (r = 0.187, p = 0.004). Our study demonstrated that low levels of serum HDL-c is correlated with the development of severe depressive symptoms in postpartum women. Study highlights the role of lipids in the development of postpartum depressive symptoms.

Although the short-term effects of fasting or energy deficit on hypothalamic neuropeptide circuitries are now better understood, the effects of long-term energy deficit and refeeding remain to be elucidated. We showed that after a long-term energy deficit, mice exhibited persistent hypoleptinemia following the refeeding period despite restoration of fat mass, ovarian activity, and feeding behavior. We aimed to examine the hypothalamic adaptations after 10 weeks of energy deficit and after 10 further weeks of nutritional recovery. To do so, we assessed the mRNA levels of the leptin receptor and the main orexigenic and anorexigenic peptides, and their receptors regulated by leptin. Markers of hypothalamic inflammation were assessed as leptin can also participate in this phenomenon. Long-term time-restricted feeding and separation induced significant increase in mRNA levels of hypothalamic orexigenic peptides, while both Y1 and Y5 receptor mRNAs were downregulated. No changes occurred in the mRNA levels of orexin (OX), melanin-concentrating hormone, pro-opiomelanocortin, 26RFa (26-amino acid RF-amide peptide), and their receptors despite an increase in the expression of melanocortin receptors (MC3-R and MC4-R) and OXR1 (OX receptor 1). The refeeding period induced an overexpression of leptin receptor mRNA in the hypothalamus. The other assessed mRNA levels were normalized except for Y2, Y5, MC3-R, and MC4-R, which remained upregulated. No convincing changes were observed in neuroinflammatory markers, even if interleukin-1β mRNA levels were increased in parallel with those of Iba1 (ionized calcium-binding adaptor molecule 1), a marker of microglial activation. Normalization of leptin-regulated functions and hypothalamic gene expressions in refed mice with low plasma leptin levels could be sustained by recalibration of hypothalamic sensitivity to leptin., (© 2016 S. Karger AG, Basel.)

Zucker fa/fa rats easily develop dyslipidemia and obesity. Restructured pork (RP) is a suitable matrix for including functional ingredients. The effects of glucomannan- RP or glucomannan plus spirulina-enriched RP on plasma lipid/lipoprotein levels, cytochrome P450 7A1 (CYP7A1) expression, and arylesterase activity in growing fa/fa rats fed high-energy, high-fat cholesterol-enriched diets were tested. Groups of six rats each received diet containing 15% control-RP (C), 15% glucomannan-RP diet (G), 15% glucomannan + spirulina-RP diet (GS), and same diets enriched with 2.4% cholesterol and 0.49% cholic acid (cholesterol-enriched control (HC), cholesterol-enriched glucomannan (HG), and cholesterol-enriched glucomannan + spirulina (HGS) diets) over a 7-week period. C diet induced obesity, severe hyperglycemia, moderate hypercholesterolemia, and hypertriglyceridemia. Those facts were not significantly modified by G or GS diets. G diet increased CYP7A1 expression but decreased the total cholesterol/high density lipoproteins (HDL)-cholesterol ratio (p < 0.05) vs. C diet. GS vs. G diet increased (p < 0.05) CYP7A1 expression. HC vs. C diet reduced food intake, body weight gain, and plasma glucose (p < 0.01) but increased cholesterolemia (p < 0.01), lipidemia (plasma cholesterol plus triglycerides) (p < 0.001), cholesterol/triglyceride ratio in very low density lipoproteins (VLDL), and HDL (p < 0.05), cholesterol transported by VLDL and intermediate density lipoproteins (IDL) + low density lipoproteins (LDL), total cholesterol/HDL-cholesterol ratio and CYP7A1 expression (at least p < 0.05). HG and HGS diets vs. HC noticeably reduced lipidemia (p < 0.001), normalized VLDL and IDL + LDL lipid composition, and increased CYP7A1 expression (p < 0.01) but did not modify the cholesterol/HDL-cholesterol ratio. HGS vs. HG decreased triglyceridemia, the triglyceride-glucose (TyG) index and increased arylesterase/HDL-cholesterol activity (p < 0.05). In conclusion, G- and GS-RP act as functional foods and notably blocked the dietary cholesterol effects. In addition, HGS-RP improved the glucomannan hypolipidemic effects, increased arylesterase/HDL-cholesterol activity, and decreased insulin resistance.

In order to assess the progression of carotid-artery disease in type 2 diabetic cohort (n=207 patients), the dynamic change in carotid intima-media thickness (CIMT) and the occurrence of plaques were followed for a period of 31.35±10.59 months. The mean CIMT at the beginning of the study was 0.9178±0.1447 mm, with a maximal value of 1.1210±0.2366 mm. The maximal value of CIMT changed by 0.07 mm/year. Progression of CIMT was noted in 86.8% and its regression in 7.8% of patients. The occurrence of carotid plaques was detected in 41.8% of patients. Multiple regression analysis revealed the maximal value of CIMT to be associated with diastolic blood pressure, despite mean CIMT being predicted by body mass index. The presence of peripheral arterial disease and hypo-high-density lipoproteinemia were found to be predictors for the occurrence of carotid plaques. Our data have clinical implications in predicting risk factors for the progression of carotid-artery disease in type 2 diabetic patients for their appropriate management.

Background: The levels of serum low-density lipoproteins (LDL) have been implicated in the inflammatory cascade in a murine model of asthma. Recent findings suggest that LDL may modulate the inflammatory state of the asthmatic airways in humans., Objective: We explored whether LDL subclasses are associated with the occurrence and severity of asthma., Methods: 24 asthmatics (M/F: 11/13) and 24 healthy individuals, with normal BMI and absence of metabolic syndrome, matched for age and gender. Serum concentrations of LDL subclasses were distributed as seven bands (LDL-1 and -2 defined as large, least pro-inflammatory LDL, and LDL-3 to -7 defined as small, most pro-inflammatory LDL), using the LipoPrint(©) System (Quantimetrix Corporation, Redondo Beach, CA, USA)., Results: LDL-1 was similar in the two groups (56 ± 16% vs. 53 ± 11, p = NS), while LDL-2 was significantly lower in asthmatics as compared to controls (35 ± 8% vs. 43 ± 10%, p = 0.0074). LDL-3 levels were two-fold higher in the asthmatics, but the difference did not reach the statistical significance (8 ± 7.3% vs. 4 ± 3%, p = NS). Smaller subclasses LDL-4 to LDL-7 were undetectable in controls. In asthmatics, LDL-1 was positively associated with VC% predicted (r = +0.572, p = 0.0035) and FEV1% predicted (r = +0.492, p = 0.0146). LDL-3 was inversely correlated with both VC% predicted (r = -0.535, p = 0.0071) and FEV1% predicted (r = -0.465, p = 0.0222)., Conclusions: The findings of this pilot study suggest a role of LDL in asthma, and advocate for larger studies to confirm the association between asthma and dyslipidemia., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Severe hypo-high-density lipoprotein (HDL) cholesterolemia is defined by serum values less than 20mg/dl. Few acquired cases, without serious underlying disease, have been reported., Case: An asymptomatic 75-y-old man was admitted for evaluation of low serum HDL-cholesterol (HDL-C) levels (2-8 mg/dl). The record of periodic medical examinations revealed that a sudden decrease had occurred 5 y ago. Mild anemia and proteinuria were noted but the liver and thyroid function tests were normal. β-Quantification revealed a relatively low HDL-C (10.8 mg/dl) and the serum lecithin cholesterol acyltransferase (LCAT) activity was low (29.4 nmol/ml/h). Unexpectedly, serum HDL-C levels recovered 2 y after hospital discharge. In addition, the serum LCAT activity, hemoglobin concentrations, and urine protein tests all returned to within the reference interval. Subsequent examinations could not clarify the cause of the sudden onset and spontaneous recovery of the extremely low HDL-C., Conclusions: We describe an unusual case of acquired HDL-C deficiency in a 75-y-old man that did not have serious pre-existing disease. Recently, extremely low HDL-C levels in patients with the nephrotic syndrome, associated with acquired LCAT deficiency, have been reported. The present case might illustrate a milder form of this disorder, because the clinical findings show many similarities., (© 2013.)

Context: Familial combined hypolipidemia causes a global reduction of plasma lipoproteins. Its clinical correlates and metabolic implications have not been well defined., Objective: The objective of the study was to investigate the genetic, clinical, and metabolic characteristics of a cohort of subjects with familial combined hypolipidemia., Design: The design of the study included candidate gene screening and the comparison of the clinical and metabolic characteristics between carrier and noncarrier individuals., Setting: The study was conducted in a general community., Subjects: Participants in the study included individuals belonging to nine families with familial combined hypolipidemia identified in a small town (Campodimele) as well as from other 352 subjects living in the same community., Main Outcomes Measures: Serum concentrations of lipoproteins, Angiopoietin-like 3 (Angptl3) proteins, and noncholesterol sterols were measured., Results: The ANGPTL3 S17X mutation was found in all probands, 20 affected family members, and 32 individuals of the community. Two additional frame shift mutations, FsE96del and FsS122, were also identified in two hypocholesterolemic individuals. Homozygotes for the ANGPTL3 S17X mutation had no circulating Angptl3 and a marked reduction of all plasma lipids (P < 0.001). Heterozygotes had 42% reduction in Angptl3 level compared with noncarriers (P < 0.0001) but a significant reduction of only total cholesterol and high-density lipoprotein cholesterol. No differences were observed in the plasma noncholesterol sterols between carriers and noncarriers. No association between familial combined hypolipidemia and the risk of hepatic or cardiovascular diseases were detected., Conclusions: Familial combined hypolipidemia segregates as a recessive trait so that apolipoprotein B- and apolipoprotein A-I-containing lipoproteins are comprehensively affected only by the total deficiency of Angptl3. Familial combined hypolipidemia does not perturb whole-body cholesterol homeostasis and is not associated with adverse clinical sequelae.

The aim of this study was to investigate the association between leukocyte subtype counts and hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia. Logistic regressions using hyper-LDL cholesterolemia, hypertriglyceridemia, and hypo-HDL cholesterolemia as a dependent variable and total leukocyte, basophil, eosinophil, neutrophil, lymphocyte, and monocyte counts as an independent variable were calculated adjusting for age, body mass index (BMI), high-sensitivity C-reactive protein (hs-CRP), smoking, drinking, and physical activity in apparently healthy Japanese men (1,803) and women (1,150). The odds ratio (OR) of hyper-LDL cholesterolemia for total leukocyte, eosinophil, and lymphocyte counts, the OR of hypertriglyceridemia for total leukocyte, eosinophil, neutrophil, and lymphocyte counts, and the OR of hypo-HDL cholesterolemia for total leukocyte, neutrophil, and lymphocyte counts were significant in men, and the OR of hyper-LDL cholesterolemia, for lymphocyte count, and the OR of hypo-HDL cholesterolemia for eosinophil count were significant in women. Lymphocyte count was significantly associated with hyper-LDL cholesterolemia independently of hs-CRP in apparently healthy Japanese.

Objective: To demonstrate that hypolipidemia is a typical feature of the mouse model of amyotrophic lateral sclerosis (ALS) and to assess the association between hypolipidemia and disease stage, dietary intake, and sex., Methods: We compared daily dietary intake, body weight, and serumlipid and glucose levels in ALS mice and wild-type controls at different stages of the disease., Findings: Total cholesterol low-density lipoprotein (LDL) and LDL/high-density lipoprotein (HDL) ratio were significantly lower in ALS mice compared with controls. Subgroup analysis revealed that the incidence of hypolipidemia was significantly greater in male, but not female, ALS mice compared with control mice and that hypolipidemia was present at the presymptomatic stage of the disease. This hypolipidemia can be found without a decrease in the serum levels of other energy sources, such as glucose, in the presymptomatic stage., Conclusions: Hypolipidemia is present at the presymptomatic stage of the ALS mouse model in the absence of malnutrition, significant neuromuscular degeneration or regeneration, and respiratory difficulty. Our findings suggest that hypolipidemia might be associated with the pathomechanism of ALS and/or lipid-specific metabolism rather than simply an epiphenomenon of neuromuscular degeneration or energy imbalance.

Objectives: To study the resistance of HDL particles to direct oxidation in respect to the distribution of HDL particles., Design and Methods: We studied HDL composition, subclass distribution, and the kinetics of CuSO4-induced oxidation of total HDL and HDL3 in vitro in 36 low-HDL-C subjects and in 41 control subjects with normal HDL-C., Results: The resistance of HDL3 to oxidation, as assessed from the propagation rate was significantly higher than that of total HDL. The propagation rate and diene formation during HDL oxidation in vitro was attenuated in HDL derived from low-HDL-C subjects. Propagation rate and maximal diene formation during total HDL oxidation correlated significantly with HDL mean particle size. The propagation rate of total HDL oxidation in vitro displayed a significant positive association with HDL2 particle mass and HDL mean particle size by multiple regression analyses., Conclusions: These observations highlight that the distribution of HDL subpopulations has important implications for the potential of HDL as an anti-oxidant source.

We report a novel apolipoprotein A-I (apoA-I) mutation identified in a 64-year-old patient with marked plasma high density lipoprotein (HDL) cholesterol (4 mg/dl) and apoA-I (5mg/dl) deficiency, prior myocardial infarction, and moderate corneal opacities. Coronary angiography revealed extensive atherosclerosis in all three major vessels. Genomic DNA sequencing of the proband revealed a homozygous novel deletion of two successive adenine residues in codon 138 in the apoA-I gene, resulting in a frameshift mutation at amino acid residues 138-178, which we have designated as apoA-I Tomioka. His elder brother was also homozygous for apoA-I Tomioka with marked HDL cholesterol and apoA-I deficiency, but had no clinical evidence of coronary heart disease. Other family members including three siblings and two sons were heterozygous for the mutation, and had approximately 50% of normal plasma HDL cholesterol, and apoA-I. Analysis of apoA-I-containing HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I HDL particles in the homozygotes, while in heterozygotes, the mean concentrations of apoA-I in large alpha-1 and very small prebeta-1 HDL subpopulations were significantly decreased at about 35% of normal. Thus, apoA-I Tomioka, a novel deletion mutation in codon 138 of the apoA-I gene, is the causative defect in this case of HDL deficiency.

Objective: Lipoproteins modulate vascular cell function in inflammation. In this study, we analyzed whether plasma concentrations of lipoproteins and apolipoproteins in human sepsis are related to patient survival and the activation of blood monocytes and platelets., Design: Observational study., Setting: Medical and surgical intensive care units (ICU) of a university hospital., Patients: 151 consecutive patients after sepsis criteria had been met for the first time., Interventions: None., Measurements: Plasma lipoproteins, apolipoproteins, platelet CD62P-expression, monocyte HLA-DR-expression, SAPS II-scores (Simplified Acute Physiology Score) and 30-day-mortality were recorded., Results: Total cholesterol, high-density-lipoprotein (HDL) and low-density-lipoprotein (LDL) cholesterol, apolipoprotein (apo)-AI and apo-B were all found to be significantly lower in non-survivors than in survivors. In contrast to other (apo)lipoproteins, apo-AI and HDL cholesterol further decreased in non-survivors during the ICU stay. Logistic regression analysis revealed apo-AI to be an independent predictor of 30-day-mortality. A significant inverse correlation was found for apo-AI/HDL-cholesterol and platelet activation. Later in the course of the disease, HLA-DR expression on monocytes correlated positively to apo-AI and apo-CI concentrations and inversely to the apo-E concentration., Conclusion: Low apo-AI is independently related to 30-day mortality in human sepsis and the decrease in apo-AI/HDL cholesterol correlates to increased platelet activation. Moreover, changes in apolipoproteins supposed to modulate lipopolysaccharide effects, such as apo-CI and apo-E, correlate to monocyte activation.

Hypertension and high serum cholesterol level are important risk factors for atherosclerosis and coronary heart disease. In the present study we tested the hypothesis whether high sodium intake, when given in combination with Western type high-fat diet, induces endothelial dysfunction and promotes atherosclerosis. Furthermore, the role and enzyme sources of increased oxidative stress were examined. Low-density lipoprotein receptor-deficient mice (LDLR(-/-)) and control C57Bl/6 mice received either high-fat, normal-sodium diet (fat 18% and cholesterol 0.5%; NaCl 0.7%; w/w) or high-fat, high-sodium diet (7% NaCl w/w) for 12 weeks. Superoxide formation was assessed by lucigenin enhanced chemiluminescence, endothelial functions were examined ex vivo, and atherosclerotic lesions from the aorta were assessed by light microscopy. High-fat, high-sodium diet increased systolic blood pressure in LDLR(-/-) mice but not in C57Bl/6 mice, whereas it induced cardiac hypertrophy in both mouse strains. Dietary combination of fat and sodium induced endothelial dysfunction in LDLR(-/-) mice. Preincubation with a superoxide scavenger Tiron normalized endothelial dysfunction, whereas the hydrogen peroxide scavenger catalase did not alter endothelial function. High sodium intake induced superoxide formation in LDLR(-/-) mice on high-fat diet. Stimulation of muscarinic receptors in the endothelial cells by acetylcholine increased superoxide generation, whereas preincubation with the nitric oxide synthase (NOS) inhibitor L-arginine methyl ester or endothelium removal reduced superoxide production. Inhibition of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase by apocynin decreased vascular superoxide formation whereas the xanthine oxidase inhibitor oxypurinol did not significantly affect oxidative stress in LDLR(-/-) mice. In conclusion, the detrimental effects of dietary sodium on endothelial function and progression of atherosclerosis in LDLR(-/-) mice on high-fat diet are mediated by increased ROS formation mainly through uncoupled NOS and NADPH oxidase. The present study also underscores the importance of superoxide and endothelial NOS uncoupling in the pathogenesis of endothelial dysfunction.

Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon -2, Q[-2]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small alpha-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow alpha migrating apoA-IV- and apoE-containing HDL, while in the eight heterozygotes, there was loss of large alpha-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II alpha-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.

Traumatic brain injury (TBI) acts as an inducer of the inflammatory reaction expressed by the release of pro-inflammatory cytokines (interleukin-1beta [IL-1beta], interleukin-6 [IL-6] and interleukin-8 [IL-8]), and causes metabolic alterations in the early, post-traumatic state, either in the brain or/and the systemic circulation. The metabolic changes involve carbohydrates, proteins and lipids. We focused on the serum lipid profile, the impact of trauma on lipoproteins, and their subsequent effects, on inflammation. We investigated the role of cytokines and serum lipids, in patient outcome, reviewing 30-day mortality and the Glasgow Coma Scale (GCS). A total of 75 patients with severe or moderate TBI (GCS

Objective: Reduced plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) are a significant risk factor for cardiovascular disease. Mechanisms that regulate HDL-C concentrations represent an important area of investigation., Methods and Results: Comparative transcriptome analyses of monocyte-derived macrophages (MDM) from a large population of low HDL-C subjects and age- and sex-matched controls revealed a cluster of inflammatory genes highly expressed in low HDL-C subjects. The expression levels of peroxisome proliferator activated receptor (PPAR) gamma and several antioxidant metallothionein genes were decreased in MDM from all low HDL-C groups compared with controls, as was the expression of other genes regulated by PPARgamma, including CD36, adipocyte fatty acid binding protein (FABP4), and adipophilin (ADFP). In contrast, PPARdelta expression was increased in MDM from low HDL-C groups. Quantitative RT-PCR corroborated all major findings from the microarray analysis in two separate patient cohorts. Expression of several inflammatory cytokine genes including interleukin 1beta, interleukin 8, and tumor necrosis factor alpha were highly increased in low HDL-C subjects., Conclusions: The activated proinflammatory state of monocytes and MDM in low HDL-C subjects constitutes a novel parameter of risk associated with HDL deficiency, related to altered expression of metallothionein genes and the reciprocal regulation of PPARgamma and PPARdelta.

Monogenic high density lipoprotein (HDL) deficiency, because of defects in the genes of apolipoprotein A-I (apoA-I), adenosine triphosphate binding cassette transporter A1 (ABCA1) or lecithin:cholesterol acyltransferase (LCAT), can be assumed in patients with HDL cholesterol levels below the fifth percentile within a given population. As in a first step underlying diseases should be excluded. Patients with a virtual absence of HDL must undergo careful physical examination to unravel the clinical hallmarks of certain HDL deficiency syndromes. In addition, family studies should be initiated, to demonstrate the vertical transmission of the low HDL cholesterol phenotype. Definitive diagnosis requires specialized biochemical tests and the demonstration of a functionally-relevant mutation in one of the three discussed candidate genes. As yet no routinely used drug is able to increase HDL cholesterol levels in patients with familial low HDL cholesterol so that prevention of cardiovascular disease in these patients must be focused on the avoidance and treatment of additional risk factors.

Clinical, experimental and epidemiological research has shown the undeniable causal relationship between low HDL plasma concentrations and cardiovascular disease. Low HDL levels are present in about 10% of the general population and represent the most frequent form of dyslipidemia in patients with coronary disease. Reduced HDL concentrations seem to be unable to eliminate efficiently the cholesterol excess at vascular wall level, contributing to the onset of the inflammatory response that typically occurs in the pathogenesis of atherosclerosis right from its earliest stages. The results of numerous studies quite convincingly suggest that HDL is capable of exerting anti-inflammatory activity either directly or by modulating the expression of a number of acute phase proteins. Although the therapeutic options currently available for raising HDL levels still show modest efficacy, both in experimental and pre-clinical fields, genetic investigation and specifically aimed pharmacological treatment have produced more encouraging results, shedding some light on the concrete possibility of being able to treat this disease in the very near future.

Relationship between presence of coronary heart disease (CHD), coronary risk factors (parameters of lipid transport system and hypertension) and disturbances of microcirculation was studied in patients with myeloproliferative blood disease Polycythemia Vera (PV). Probability of tissue (including blood vessel wall) cholesterol accumulation was estimated by measurement of its content in skin surface layers. PV patients (n=55, including 27 patients with CHD) had predominant hypolipoproteinemia with normal proportion of various lipoprotein classes. Absence of substantial increase of skin surface cholesterol content both in patients with and without CHD was considered to be a sign of low probability of the presence of severe atherosclerotic processes. However patients with CHD had substantially more pronounced disturbances of microcirculation. Basing on these data the authors suggest that CHD in PV patients had non-lipoprotein genesis and present discussion of alternative mechanisms of vascular changes.

Low levels of high-density lipoprotein cholesterol (HDL-C) show a consistent relationship with the development of atherosclerosis. The underlying mechanisms are not well understood, but recent studies in subjects with primary hypoalphalipoproteinemia suggest that this could represent a proinflammatory condition. To better assess the link between HDL-C levels and C-reactive protein levels and the possible role of chronic infections as putative mediators of this relationship, we studied a population sample with nonselected causes of hypoalphalipoproteinemia. Eighty-six consecutive patients with HDL-C levels below 40 mg/dL who attend our lipid clinic and 86 control subjects with normal concentrations matched for gender, age, smoking habit, and weight were included in the study. Mean HDL-C levels were 34 +/- 3.9 and 55.4 +/- 8.8 mg/dL for subjects with hypoalphalipoproteinemia and control subjects, respectively. C-reactive protein concentrations were increased in case patients as compared with control subjects (2.13 +/- 2.0 vs 1.52 +/- 1.8 mg/L; P = .025). The prevalence of herpes simplex virus type 1, cytomegalovirus, Chlamydia pneumoniae , and Helicobacter pylori infections did not differ between the 2 groups. Although a possible confounding variable could be a degree of insulin resistance within the group of patients with low HDL-C levels, our results indicate that C-reactive protein levels are increased in subjects with nonselected hypoalphalipoproteinemia and that chronic infections do not appear to mediate this relationship.

Objective: There may be an association between a low serum cholesterol level and dissociative disorders., Method: The subjects of the study were 16 patients with dissociative disorder and 16 normal comparison subjects (two men and 14 women in each group). Total cholesterol, triglyceride, high-density lipoprotein, low-density lipoprotein, and very low density lipoprotein levels were compared., Results: Patients with dissociative disorders had lower serum triglyceride, total cholesterol, low-density lipoprotein, and very low density lipoprotein levels than normal comparison subjects., Conclusions: Low serum lipid concentrations may be related to a high incidence of self-injurious behaviors and borderline features in patients with dissociative disorders.

Low levels of high-density lipoprotein cholesterol (HDL-C) are frequently encountered in patients with coronary artery disease (CAD), most often in combination with elevated triglycerides as part of a dysmetabolic syndrome. Although no large secondary prevention trials with statin therapy with special emphasis on low HDL-C have been performed, some guidance can be extracted from a number of post-hoc analyses on how to treat patients with low levels of HDL-C. In terms of risk reduction, statin therapy appears to be at least as effective in patients with low compared to normal HDL-C levels. Fibrate therapy seems only effective when low HDL-C coincides with a level of low-density lipoprotein cholesterol (LDL-C) in the low-normal range. Before considering combination therapy of statins with fibrates, much emphasis should be put on dietary changes, weight reduction, smoking cessation and regular exercise, since these measures are effective tools to raise HDL-C levels. Moreover, one should be aware of the fact that combination therapy of statins and fibrates is not evidence-based and confers some potential risk of myopathy. Future therapy options may include CETP (cholesterol ester transfer protein) inhibitors, but these agents are still in an experimental phase. As most patients with low HDL-C levels share features of the dysmetabolic syndrome, one could also consider a combination therapy of statins and ACE-inhibitors, since this combination is not only safe, but the individual preventive effects of these compounds appear to be cumulative.

Hypoalphalipoproteinemia (Hypo-A), a lipid disorder characterized by low high-density lipoprotein (HDL)-cholesterol (HDL-C) levels, is frequently associated with an increased risk of suffering future coronary heart disease (CHD). Conversely, hyperalphalipoproteinemia (Hyper-A) is a characterized by high HDL-C concentrations and is possibly associated with longevity and protection against CHD. Whether plasma C-reactive protein (CRP) level, an emerging marker of CHD risk, may be influenced by either extremely low or high HDL-C concentrations is yet to be determined. Plasma levels of lipids and CRP have been measured in 52 middle-aged men and women, clinically free of CHD, including 20 subjects with Hypo-A, 12 with Hyper-A, and 20 healthy normolipemic age-matched controls. CRP levels were the highest in Hypo-A [0.22 mg/dL (interquartile range, 0.15 to 0.44)], the lowest in Hyper-A [0.03 mg/dL (0.02 to 0.07)], and intermediate in the control group [0.10 mg/dL (0.05 to 0.20)]. Differences in plasma CRP concentrations were significant between Hypo-A and the other 2 groups, as well as between Hyper-A and controls. Plasma CRP levels showed a particularly strong correlation with plasma HDL-C concentrations (r = -.66, P <.001). In multivariate models, HDL-C represented the only significant predictor of circulating levels of CRP. In conclusion, in subjects with Hypo-A or Hyper-A, HDL-C levels may account for plasma CRP variations independent of other potential cardiovascular risk factors., (Copyright 2003 Elsevier, Inc. All rights reserved.)

Background and Purpose: Ultrasound-assessed plaque morphology is an independent predictor of ischemic stroke. The purpose of this population-based cross-sectional nested case-control study was to examine the risk factors associated with carotid plaque morphology., Methods: Ultrasonography of the right carotid artery was conducted on 6727 participants in a population health survey (response rate 79%). Plaque echogenicity, defined as reflectance of the emitted ultrasound signal, was scored as echolucent, predominantly echolucent, predominantly echogenic, or echogenic. Information on cardiovascular risk factors in all 216 participants who had carotid stenosis and in 223 control subjects matched by age and sex who did not have carotid stenosis was obtained from measurements of blood pressure, weight, height, and nonfasting blood samples and from a self-administered questionnaire., Results: In both univariate and multivariate analyses, low levels of HDL cholesterol and increasing degree of stenosis were independently associated with an increased risk of having an echolucent plaque. For 1-SD increase in HDL cholesterol, the adjusted odds of being in a lower plaque echogenicity category decreased by approximately 30% (OR 0.69, 95% CI 0.52 to 0.93)., Conclusions: These findings indicate that low levels of HDL cholesterol are associated with an increased risk of having echolucent, rupture-prone atherosclerotic plaques.

Familial high-density lipoprotein (HDL)-deficiency syndromes are caused by mutations of the ABCA1 gene, coding for the ATP-binding cassette transporter 1. We have developed a homogeneous assay based on 52 primer sets to amplify all 50 ABCA1 exons and approximately 1 kb of its promoter. The assay allows for convenient amplification of the gene from genomic DNA and easy mutational analysis through automatic sequencing. It obviates the need to use mRNA preparations, which were difficult to handle and posed a risk to miss splice junction or promoter mutations. The application of the test to the molecular analysis of a new patient with familial HDL-deficiency (Tangier disease) led to a discovery of two novel ABCA1 mutations: C2665del and C4457T.

Purpose: To examine the histologic and ultrastructural changes in Bruch's membrane (BM) in apolipoprotein E deficient [ApoE(-)] mice in comparison with age-matched control animals., Methods: Two-month-old (group 1) and 8-month-old (group 2) normal control C57BL/6 mice and 2-month-old (group 3) and 8-month-old (group 4) ApoE(-) mice were studied. All groups of mice were fed a standard rodent diet. The mice were killed, serum lipid levels were determined, and the eyes were ultrastructurally examined using standard techniques to measure the thickness of BM. The area fraction of electron-lucent (EL) particles in BM was quantified using point-counting stereology., Results: The serum cholesterol levels of the ApoE(-) mice were significantly higher than those of the control mice (P = 0.0001). There was a significant thickening and EL particle accumulation in BM associated with age in the control animals. Group 2 had a thicker BM and more EL particle accumulation than group 1 (P = 0.0410 for thickness; P = 0.0042 for particle accumulation). Age-related changes were not seen in ApoE(-) mice; thickness and accumulation were similar in groups 3 and 4 (P = 0.50, thickness; P approximately/= 1.0, accumulation). Significant thickening and accumulation were seen in young ApoE(-) mice (group 3) versus young control animals (group 1; P = 0.008, thickening; P < 0.0001, EL particle accumulation). Group 4 ApoE(-) mice did not have a thicker BM or more EL particles than group 2 control animals (P = 0.2910, thickness; P = 0.35, EL particle accumulation). "Membrane-bounded" material (material between two membranes) was present significantly more frequently in ApoE(-) mice., Conclusions: ApoE(-) mice exhibit accumulation of EL particles at an earlier age and have more membrane-bounded material in BM than control mice. This material has ultrastructural similarities to basal linear deposit, which accumulates in age-related maculopathy.

Objective: To test the hypothesis that postmenopausal women with a history of eclampsia manifest a more high risk lipid profile than postmenopausal women with a history of normal pregnancy., Setting: The Department of Obstetrics and Gynaecology, National University Hospital, Reykjavik, Iceland, and the Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA., Participants: Thirty Icelandic women with a history of eclampsia, aged between 50 and 67 years at the time of re-examination (cases) were individually matched for current age, and for age and parity at index pregnancy, to 30 unrelated Icelandic women with a history of normal pregnancy (controls)., Methods: The participating women completed a health and family history questionnaire and underwent a physical examination. Fasting plasma low density lipoprotein diameter, serum lipids, insulin, and glucose were measured., Results: Mean low density lipoprotein size was significantly smaller and apolipoprotein B concentration was higher in women with prior eclampsia. The percentage of cases receiving blood pressure medication (33%) was significantly greater than controls (6.7%). Thirteen cases had had hypertensive complications in at least one other pregnancy (recurrent subgroup); postmenopausally, these women displayed significantly increased diastolic blood pressures, smaller-sized low density lipoprotein, increased apolipoprotein B, decreased high density lipoprotein2 (HDL2) cholesterol, and increased total cholesterol: HDL cholesterol ratio compared with their controls. Fourteen cases were normotensive in all other pregnancies (nonrecurrent); these showed no differences from their controls., Conclusions: Dyslipoproteinaemia is more prevalent among postmenopausal women with prior eclampsia, especially with recurrent hypertension in pregnancy, than in postmenopausal women with prior normal pregnancies.

Objectives: To assess the effects of nicotinic acid (NA), gemfibrozil and combination therapy on the lipid profile of patients with clinical atherosclerotic disease and isolated hypoalphalipoproteinemia., Background: Isolated hypoalphalipoproteinemia (low high density lipoprotein cholesterol [HDL-C] alone) accounts for a significant percentage of patients with premature atherosclerosis. However, it remains unclear whether currently available pharmacotherapy has the ability to favorably affect the lipid profile and therefore potentially reduce clinical events., Methods: Twenty-three patients with clinically well-defined atherosclerosis and isolated hypoalphalipoproteinemia were prospectively randomized to receive gemfibrozil, NA or combination therapy in an open-label, crossover design trial to assess the effects on serum lipids. Lipid profiles and other relevant laboratory variables were monitored while the patients were on and off pharmacologic lipid-modulating therapy., Results: In those 14 patients able to tolerate all forms of pharmacotherapy, HDL-C of 0.89 +/- 0.17 mmol/liter (34.5 +/- 6.5 mg/dl) increased by 15%, to 1.02 +/- 0.18 mmol/liter (39.7 +/- 7.1 mg/dl), while taking gemfibrozil (1,200 mg/day); by 35%, to 1.20 +/- 0.21 mmol/liter (46.5 +/- 8.1 mg/dl), while taking NA (mean dose 2,250 mg/day); and by 45%, to 1.29 +/- 0.19 mmol/liter (50.0 +/- 7.5 mg/dl), while taking combination therapy of gemfibrozil plus NA (p < 0.001 for all interventions as compared with baseline/washout; p < 0.005 NA vs. gemfibrozil; p < 0.001 combination therapy vs. gemfibrozil alone; p = 0.088 combination therapy vs. NA alone). Statistically significant favorable alterations were also observed with low density lipoprotein cholesterol (LDL-C), LDL-C/HDL-C, non-HDL-C/HDL-C, apolipoprotein (Apo) B and Apo B/Apo A1., Conclusions: In the majority of patients with clinical atherosclerotic disease and isolated hypoalphalipoproteinemia, pharmacologic therapy to raise HDL-C is not only feasible but is also effective with currently available agents, particularly when used in combination.

Rabbits develop a wasting condition in the intestinal stage of Strongyloides papillosus infection. Serum inflammatory cytokine and lipid profiles were investigated in five rabbits infected with S. papillosus and five uninfected pair-fed controls to ascertain whether the disease is inflammatory cytokine-mediated cachexia. Tumor necrosis factor alpha (TNF alpha) was detected in one infected animal at Day 7 after infection. Interleukin (IL)-1 was detected in three infected, and one control, animals at Day 28. IL-6 remained unchanged in both the groups. Infected animals developed hypolipemia, including hypotriglyceridemia in the intestinal stage of infection. Control animals lost body weight in the same manner as the infected animals, but had elevated cholesterols and phospholipids with normal triglyceride concentrations. The results suggested that the wasting condition has no association with cachexia induced by TNF alpha. IL-1 or IL-6, and that hepatic function for lipid synthesis is affected during the intestinal stage of S. papillosus infection.

HIV infection induces an early decrease of cholesterol and a late increase of triglycerides (TG) with a reduction of HDL. These changes are proportional with the lowering of CD4, which reflects the infection's severity. Both the increase of TG synthesis and the decrease of TG catabolism, in relation with a reduction of lipoprotein lipase activity, are responsible of these changes. Moreover, LDL catabolism is enhanced by macrophage scavenger receptors, due to a high proportion of small, dense LDL which are more easily oxidized. Many cytokines (interferon alpha, interleukins, TNF) play probably a pathogenic role in the dyslipidemia. Some HIV patients who received antiproteases may develop lipodystrophy with central obesity, insulino-resistance, glucose intolerance and sometimes diabetes (like in syndrome X). Other patients present a cushingoid, buffalo hump. This complication may be observed also with antiretroviral treatment other than antiproteases. The physiopathology of these findings could be in relation with structural homologies between antiproteases and some important proteins, involved in lipid and adipocyte metabolism. Cardiovascular risk linked to these perturbations is evident. The treatment is not different from the treatment for seronegative, hyperlipidemic patients: struggle against risk factors, diet advices, fibrates or statins. The antiproteases bring huge contribution to the prognosis of AIDS patients but the risk of cardiovascular complications could impair this therapeutic progress. So, it is essential to understand the pathogeny of these complications in order to discover new antiproteases, without these adverse side effects.

To determine the frequency of familial hypoalphalipoproteinemia in the general population due to mutation of the apolipoprotein A-I (apo A-I) gene, we analyzed sequence variations in the apo A-I gene. The subjects were 67 children with a low high-density lipoprotein (HDL) cholesterol level (

A decrease in plasma HDL cholesterol concentration is considered as a major cardiovascular risk factor and is a prevalent lipid abnormality among patients with coronary heart disease. This condition is most often observed in the presence of hypertriglyceridaemia, generally linked to the insulin resistance syndrome, but may also be associated to elevated LDL cholesterol level or even be present alone (hypoalphalipoproteinaemia). The decision to treat a patient with low HDL level depends on the individual overall cardiovascular risk which should be evaluated as carefully as possible. The investigation should look for causes which may favour this metabolic condition, such as bad life habits or possible pharmacological interferences.

Human infection with the parasite Schistosoma mansoni is a relatively common occurrence in regions of South America and is associated with liver dysfunction and dyslipoproteinemia. Specifically, the activity of plasma lecithin:cholesterol acyltransferase (LCAT) activity is reduced, the concentration of plasma cholesterol esters falls, phospholipid concentrations are elevated and erythrocyte membranes become cholesterol enriched. Previous studies have utilized rodents (rats and mice) as experimental models to study the dyslipoproteinemia induced by S. mansoni infection. However, the plasma lipoprotein profiles in these animals is very different from humans and infection is not accompanied by decreases in LCAT activity or cholesterol enrichment of their erythrocyte membranes. Here we have evaluated the suitability of the marmoset Callithrix jacchus (sagüi) which is small and readily available in Brazil, as a potential animal model for the study of the dyslipoproteinemia of S. mansoni infections. The plasma lipoprotein compositions and distributions in sagüi, unlike rats or mice, approximate those of man with the LDL representing a major lipoprotein species. The molecular species of phospholipids, cholesterol esters and triglycerides present in sagüi plasma are also very similar to man, whereas those of rats and mice favor the longer chain more unsaturated species, Sagüi, like rodents, can be successfully infected with S. mansoni and after 60 days, this results in a 50% reduction in plasma LCAT activity, an 11% reduction in plasma cholesterol esters, an absolute increase of 46% in plasma phospholipids and an 18% increase in the cholesterol content of erythrocyte membranes. These changes are qualitatively and quantitatively very similar to those previously reported following human infections. Based upon these changes, and the observation that the plasma lipoprotein profile of sagüi and human is similar, we conclude that C. jacchus (sagüi) is an appropriate animal model for the study of dyslipoproteinemia associated with S. mansoni infections.

We investigated the molecular defect causing high density lipoprotein cholesterol (HDL-C) deficiency in a male proband and his family members. Amplification and sequencing of genomic DNA disclosed a novel base-pair substitution at residue 159 in the apolipoprotein (apo) A-I gene. This substitution resulted in the loss of an AviII restriction site and a predicted substitution of leucine with proline at residue 159. Restriction enzyme analysis demonstrated absence of the AviII site in 19 of 40 biological family members. Compared with familial controls, subjects with the apoA-I(Zavalla) variant had reduced HDL-C (1.16 versus 0.27 mmol/L, P<0.0001), apoA-I (38.7 versus 124.4 mg/dL, P<0.0001), and apoA-II (14.3 versus 19.0 mg/dL, P<0.0001) levels. Two subjects who have developed coronary artery disease to date possess additional cardiovascular risk factors. Other heterozygotes for apoA-I(Zavalla) are presently without symptomatic coronary artery disease. This study identifies a monogenic cause of hypoalphalipoproteinemia, with the single base-pair substitution having a dominant effect on the low HDL-C phenotype. In addition, it extends recent observations that HDL-C deficiency states may be more prone to the development of premature coronary artery disease when accompanied by additional cardiovascular risk factors.

Familial hypercholesterolemia (FH), a disease caused by a variety of mutations in the low density lipoprotein receptor (LDLr) gene, leads not only to elevated LDL-cholesterol (C) concentrations but to reduced high density lipoprotein (HDL)-C and apolipoprotein (apo) A-I concentrations as well. The reductions in HDL-C and apoA-I are the consequence of the combined metabolic defects of increased apoA-I catabolism and decreased apoA-I synthesis. The present studies were designed to test the hypothesis that overexpression of human lecithin:cholesterol acyltransferase (hLCAT), a pivotal enzyme involved in HDL metabolism, in LDLr defective rabbits would increase HDL-C and apoA-I concentrations. Two groups of hLCAT transgenic rabbits were established: 1) hLCAT+/LDLr heterozygotes (LDLr+/-) and 2) hLCAT+/LDLr homozygotes (LDLr-/-). Data for hLCAT+ rabbits were compared to those of nontransgenic (hLCAT-) rabbits of the same LDLr status. In LDLr+/- rabbits, HDL-C and apoA-I concentrations (mg/dl), respectively, were significantly greater in hLCAT+ (62 +/- 8, 59 +/- 4) relative to hLCAT- rabbits (21 +/- 1, 26 +/- 2). This was, likewise, the case when hLCAT+/ LDLr-/- (27 +/- 2, 19 +/- 6) and hLCAT-/LDLr-/- (5 +/- 1, 6 +/- 2) rabbits were compared. Kinetic experiments demonstrated that the fractional catabolic rate (FCR, d(-1)) of apoA-I was substantially delayed in hLCAT+ (0.376 +/- 0.025) versus hLCAT- (0.588) LDLr+/- rabbits, as well as in hLCAT+ (0.666 +/- 0.033) versus hLCAT- (1.194 +/- 0.138) LDLr-/- rabbits. ApoA-I production rate (PR, mg x kg x d(-1)) was greater in both hLCAT+/LDLr+/- (10 +/- 2 vs. 6) and hLCAT+/LDLr-/- (9 +/- 1 vs. 4 +/- 1) rabbits. Significant correlations (P < 0.02) were observed between plasma LCAT activity and HDL-C (r = 0.857), apoA-I FCR (r = -0.774), and apoA-I PR (r = 0.771), while HDL-C correlated with both apoA-I FCR (-0.812) and PR (0.751). In summary, these data indicate that hLCAT overexpression in LDLr defective rabbits increases HDL-C and apoA-I concentrations by both decreasing apoA-I catabolism and increasing apoA-I synthesis, thus correcting the metabolic defects responsible for the hypoalphalipoproteinemia observed in LDLr deficiency.

Paraoxonase is a high density lipoprotein (HDL) associated enzyme with a hypothesised role in the protection of low density lipoproteins (LDL) from oxidative stress. The present study examined paraoxonase in several genetically distinct HDL deficiency states. Despite reduction or even absence of detectable HDL, enzyme activity was present in sera from A-I-Pisa, A-I-Helsinki, A-I-Milano and Tangier patients. Both enzyme activities and peptide concentrations were modulated (reduced) but specific activities were broadly similar to controls, suggesting an impact on peptide concentration rather than an inhibition of enzyme activity. Despite the absence of HDL in A-I-Pisa and Tangier subjects, there was no association of paraoxonase with very low density lipoproteins or LDL. Paraoxonase function is maintained in HDL deficient states. It implies that certain HDL-associated anti-atherogenic processes may not be entirely compromised by HDL deficiency. This has important implications for the cardiovascular risk associated with modulated HDL concentrations.

In this review we focus on addressing two questions concerning high density lipoproteins (HDL). First, are elevated levels of HDL a desirable clinical plasma endpoint and secondly, if so, can strategies be devised that would allow the identification of agents to elevate HDL. To address the first question we briefly review the human epidemiologic and prospective data that identifies HDL as a risk factor for coronary heart disease (CHD). To introduce HDL elevating strategies, we next provide a brief review of the structural and enzymatic features of HDL followed by a discussion on the current thinking of the metabolic origin of the lipoprotein. We then turn to discussions on the key plasma and cell associated proteins involved in the synthesis, catabolism, and remodeling of HDL by analyzing data derived from human mutations, genetically engineered animal models with altered HDL metabolism and in vitro experimental systems. Lastly, we propose approaches to raise HDL that are either based on identification of small organic molecules or more unconventional approaches such as gene therapy or delivery of biologicals into plasma. This last section is based on an evaluation of the putative mechanism of actions of both old and new HDL elevating compounds. Our review concludes with an optimistic view that agents can be identified which may have promise in the treatment of human hypoalphalipoproteinemia and CHD.

The purpose of this study was to investigate the effect of low high-density-lipoprotein (HDL) combined with hypertriglyceridemia in coronary artery disease (CAD) patients on prostaglandin I2 (PGI2) biological activity in relation to lipid regulating treatment. The inhibitory rate of PGI2 on ADP-induced platelet aggregation was used as the index for PGI2 biological activity. Twenty health individuals served as normal controls. CAD group consisted of 20 patients with low HDL combined with hypertriglyceridemia. The results showed that, before the treatment, the stabilizing effect on PGI2 activity decreased significantly in CAD group when compared with the control group (P < 0.01). One month after the treatment, HDL level in CAD group increased significantly and TG level significantly decreased (P < 0.001). The different effect on PGI2 activity was no longer found between CAD group and control group (P > 0.05), further confirming the protecting effect of HDL on PGI2 biological activity. Low HDL is considered as an important risk factor of CAD, therefore, impaired PGI2 biological activity and increased platelet aggregation might be responsible mechanisms. Furthermore, raising HDL level by lipid regulating treatment could restore the protective effect of HDL on PGI2 and might be helpful in the prevention of the acute coronary syndrome.

Lipid abnormalities are major risk factors for premature coronary artery disease (CAD). However, the type and prevalence of dyslipidemia in these patients have not been well characterised, especially in some ethnic groups. The purpose of the present work was to determine the lipid disorders in patients of Northwestern Greece with premature CAD. The study population comprised of 132 men and 38 women who underwent elective diagnostic arteriography in our University Hospital. Subjects with > or = 1 lesion that narrowed the lumen of any of the 15 coronary artery segments by > or = 70% were considered to be CAD cases (n=108), whereas those with narrowing < 70% were excluded (n=54). Asymptomatic subjects (n=104) matched for age and sex were taken as controls. Compared with the controls, patients with premature CAD had increased serum levels of total cholesterol, LDL cholesterol, triglycerides, Apo B, and Lp(a), and decreased serum levels of HDL cholesterol and Apo A1. A lipoprotein or apolipoprotein abnormality was identified in 89 CAD patients (82.4%). The increased serum Apo B level (> 130 mg/dl) was the most common lipid abnormality observed in 72 patients. However, the most prevalent dyslipidemic phenotypes in our patients were type IIA followed by hypoalpha and hyperApoB. Compared to the control population, CAD patients had increased incidence of IIA and hypoalpha phenotypes. On the contrary, a normal lipoprotein phenotype was more common in the control population compared to CAD patients (56.7% vs. 17.6%, P<0.001). We conclude that the majority of Greek patients with premature CAD exhibit lipid and lipoprotein abnormalities, which to a large extent can be defined by determining the traditional lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides). However, in some cases the value of the quantification of other lipid parameters such as apolipoproteins and Lp(a) should be taken into account.

Objective: Most reported mutations that affect lipoprotein metabolism are found within the coding sequences of genes. Recently, a few mutations that occur within promoter sequences have been detected. These promoter sequence variants are the topic of the present review., Methods: Some of these variants are fairly common genomic variants in the promoter regions for candidate genes in lipoprotein metabolism, such as APOA1, APOC3, LPA, and LPL. It is possible that such regulatory sequence variants can result in chronic, modestly altered levels of expression of qualitatively normal gene products. This might have a cumulative effect on quantitative phenotypes, such as plasma lipoprotein concentrations, over the long term. Such an effect might not be detected by existing clinical, biochemical, and/or physiological assays., Results: At present, the most consistent evidence from several lines of experiments indicates that genomic variation in the APOC3 promoter creates slightly elevated plasma triglyceride concentrations within the physiologic range. This altered expression appears to predispose to hypertriglyceridemia in the presence of secondary factors. Genetic variants that produce small effects on promoter function might thus be one component of the predisposition to complex diseases., Conclusion: The aggregate of many small effects may create or contribute to a background of susceptibility that, under appropriate conditions, leads to development of frank dyslipidemia and atherosclerosis.

Unesterified cholesterol (UC) that is taken up by the liver from lipoproteins is rapidly mixed by exchange with liver UC. Thus, it is not possible to quantitate the transport of UC from different lipoproteins into bile using radiolabeled UC. However, plant sterols do not exchange with UC and are secreted in bile with the same kinetics as UC. To compare the contribution to bile of sterols from different lipoproteins, we perfused isolated rat livers with VLDL, LDL, and HDL that were obtained from patients with hereditary phytosterolemia and were rich in plant sterols. After 30-min recirculating perfusions, hepatic concentrations of plant sterols were not different after different lipoproteins were perfused. However, biliary plant sterol secretion was markedly different: with the perfusion of either VLDL or LDL there was no increase in plant sterols in bile, but with perfusion of HDL, the secretion of plant sterols was increased two- to threefold (P = 0.0005). The increase in biliary plant sterols was detected 5-10 min after HDL was added to perfusates and was similarly large for each of three individual plant sterols that was tracked. Results show that when sterol transport from lipoproteins into bile can be determined, only HDL provides a vehicle for UC elimination in bile that is consistent with its putative function in reverse cholesterol transport.

A non smoking male patient 42 years old complained of pain in the calves after exercise and had a low 'high density'-lipoprotein (HDL) cholesterol serum concentration. Angiography of the leg vessels revealed no abnormalities. Treatment with simvastatin and gemfibrozil did not affect HDL cholesterol concentrations. Blood tests of relatives made familial hypo-alpha-lipoproteinaemia unlikely. It appeared that the patient had used anabolic steroids; these increase hepatic lipase activity leading to a higher metabolism of HDL and reduced HDL cholesterol levels.