Hypercholesterolemia Low-density Lipoprotein Research Articles

Long-Term Evaluation of Lipid Profile Changes in Olympic Athletes.

Dyslipidemia is a major contributor to the development of atherosclerotic cardiovascular disease. Despite high level of physical activity, athletes are not immune from dyslipidemia, but longitudinal data on the variation of lipids are currently lacking. We sought to assess lipid profile changes over time in Olympic athletes practicing different sports disciplines (power, skills, endurance, and mixed). We enrolled 957 consecutive athletes evaluated from London 2012 to Beijing 2022 Olympic Games. Dyslipidemia was defined as low-density lipoprotein (LDL) ≥115mg/dl, high-density lipoprotein (HDL) <40mg/dl for males, or HDL <50mg/dl for females. Hypertriglyceridemia was defined as triglycerides >150mg/dl. At the follow-up, a variation of ±40mg/dl for LDL, ±6mg/dl for HDL, and ±50mg/dl for triglycerides was considered relevant. Athletes with follow-up <10months or taking lower lipid agents were excluded. Follow-up was completed in 717 athletes (74.9%), with a mean duration of 55.6months. Mean age was 27.2 ± 4.8years old, 54.6% were male (n = 392). Overall, 19.8% (n = 142) athletes were dyslipidemic at both blood tests, being older, practicing nonendurance sports, and predominantly male. In 69.3% (n = 129) of those with elevated LDL at t0, altered values were confirmed at follow-up, while the same occurred in 36.5% (n = 15) with hypo-HDL and 5.3% (n = 1) in those with elevated triglycerides. Weight and fat mass percentage modifications did not affect lipid profile variation. LDL hypercholesterolemia tends to persist over time especially among male, older, and nonendurance athletes. LDL hypercholesterolemia detection in athletes should prompt early preventive intervention to reduce the risk of future development of atherosclerotic disease.

Comparison of the five different definitions of equol producers: The relationship between blood and urine equol concentrations and blood parameters in 466 healthy men and women

Background and aimsNo studies have compared various definitions of “equol producers” until now. Therefore, we aimed to explore the accuracy of five different definitions of equol producers (EQP) and their associations with health benefits. MethodsThis is a cross-sectional study of 466 healthy Japanese men and women aged between 22 and 88 years. Equol producer proportions were calculated from their serum and urine isoflavone concentrations using five commonly used definitions. We then examined their accuracy, and associations with the blood parameters. ResultsProportions of equol ranged from 29 % in the most stringent definition to 47.6 % in the most sensitive definition. EQP identified under all definitions had significantly low serum PSA11PSA: prostate specific antigen. levels compared to nonequol producers (NEQP). The most stringent definition, which is defined as the urinary equol level of 1.0 μM and above, corresponded to the highest median serum equol level and was associated with better health outcomes. Male EQP identified by this definition seemed to have reduced risk of LDL22LDL: low density lipoprotein-hypercholesterolemia by 50 %, and female EQP identified by this definition seemed to have lower risk of high hs-CRP,33CRP: C-reactive protein compared to NEQP. Both the first and second stringent definition, which is defined as the serum equol level of 1.0 ng/mL and above, was associated with lower thyroid stimulating hormone level. ConclusionsMore stringent definitions were associated with better parameters in general. Combined with the dietary inquires, a reliable definition for equol producer is crucial to evaluate the health benefits of equol.

Associations of adipokines and metabolic hormones with low-density lipoprotein hypercholesterolemia in men and women under 45 years of age.

Aim To study the adipokine profile in young people with hypercholesterolemia and low-density lipoproteins (LDL) and to evaluate the relationship between concentrations of LDL cholesterol (LDL-C) and metabolic hormones in men and women younger than 45 years.Material and methods This study included 304 subjects (group 1, 56 men with LDL-C concentration &lt;2.1 mmol/l; group 2, 87 men with LDL-C concentration ≥4.2 mmol/l; group 3, 90 women with LDL-C concentration &lt;2.1 mmol/l; and group 4, 71 women with LDL-C concentration ≥4.2 mmol/l). Serum concentrations of total cholesterol (C), triglycerides (TG), high-density lipoprotein C, and glucose were measured by an enzymatic assay with ThermoFisher Scientific kits and a KonelabPrime 30i biochemical analyzer. LDL-C was calculated using the Friedewald's formula. Concentrations of amylin, C-peptide, ghrelin, glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 (GLP-1), glucagon, interleukin 6, insulin, leptin, monocyte chemotactic protein 1 (MCP-1), pancreatic polypeptide (PP), peptide YY (PYY), tumor necrosis factor alpha (TNF-α), adiponectin, adipsin, lipocalin-2, plasminogen activator inhibitor 1 (PAI-1), and resistin were measured by multiplex analysis (Human Metabolic Hormone V3 and Human Adipokine Panel 1 panels).Results The groups differed in traditional cardiometabolic risk factors. In the male and female patient groups with LDL-C ≥4.2 mmol/l, the prevalence of impaired fasting glucose, incidence of insulin resistance, TG, and TC were higher than in subjects with LDL-C &lt;2.1 mmol/l. The odds for the presence of LDL hypercholesterolemia (LDL-C ≥4.2 mmol/l) were significantly associated with increased concentrations of C-peptide and lipocalin-2 in men and with increased concentrations of lipocalin-2 and decreased concentrations of GLP-1 in women (р&lt;0.05).Conclusion Increased concentrations of LDL-C in young people were associated with changes in the adipokine profile and with the presence of metabolic syndrome components. These results were confirmed by changes in blood concentrations of metabolic markers that characterize disorders of metabolic processes.

Association between Dietary Diversity and Sociopsychological Factors and the Onset of Dyslipidemia after the Great East Japan Earthquake: Fukushima Health Management Survey.

This study aimed to clarify the relationship between the onset of low-density lipoprotein hypercholesterolemia (hyper-LDLemia), high-density lipoprotein hypocholesterolemia (hypo-HDLemia), and hyper-triglyceridemia (hyper-TGemia) and lifestyle/socio-psychological factors among Fukushima evacuation area residents after the Great East Japan Earthquake. Participants included 11,274 non-hyper-LDLemia, 16,581 non-hypo-HDLemia, and 12,653 non-hyper-TGemia cases in the Fiscal Year (FY) 2011. In FY2011, these participants underwent a health checkup and responded to a mental health and lifestyle survey. The onset of each disease was followed through FY2017. The evacuation experience was positively associated with the risk of hyper-LDLemia, hypo-HDLemia, or hyper-TGemia. Conversely, the middle high dietary diversity score was negatively associated with the onset of hyper-TGemia. Moreover, low sleep satisfaction was positively associated with hypo-HDLemia and hyper-TGemia. The "almost never" exercise habit was positively associated with hypo-HDLemia. Current smoking and audible nuclear power plant explosions were positively associated with the risk of hyper-TGemia. Drinking habits exhibited a negative association with the onset of hyper-LDLemia, hypo-HDLemia, and hyper-TGemia. The results of this study indicate the need for continuous improvement in lifestyle, as well as efforts to eliminate the impact of disasters to prevent the onset of dyslipidemia among disaster evacuees.

Efficacy of Anti-Vascular Endothelial Growth Factor Treatment in Neovascular Age-Related Macular Degeneration and Systemic Cardiovascular Risk Factors.

This study evaluates whether the presence of cardiovascular risk factors (CRFs) affects functional and morphological responses to anti–vascular endothelial growth factor (VEGF) therapy in patients with neovascular age-related macular degeneration (nAMD). Retrospective analysis included 98 treatment-naïve eyes followed for at least 12 months. Patients received intravitreal injections of ranibizumab or aflibercept with the dosage and regimen set according to each manufacturer’s recommendations for their product. Parameters evaluated at each follow-up visit included best-corrected visual acuity and central retinal thickness. Additionally, the presence of the following CRFs was evaluated: male sex, age of older than 70 years, history of current or past smoking, systemic arterial hypertension, diabetes mellitus, total hypercholesterolemia, low-density lipoprotein hypercholesterolemia, high-density lipoprotein concentration of 45 mg/dL or less, atherogenic dyslipidemia, family history of cardiovascular disease, and chronic kidney disease. A statistically significant better letter gain in visual acuity (p = 0.012) and greater percentage of responders (p = 0.035)—that is patients in whom best corrected visual acuity was stabilized or improved at 12 months—were noted among patients without a diagnosis of arterial hypertension. A statistically significant better mean visual improvement was also achieved in patients with higher total cholesterol plasma levels (p = 0.004), but this finding was not reflected in the significantly higher percentage of responders. The presence of remaining analyzed risk factors did not substantially affect the results of treatment. Systemic arterial hypertension is an independent factor leading to a poor functional outcome following anti-VEGF therapy in patients with nAMD. Effects of anti-VEGF treatment in patients with high total cholesterol levels should be analyzed in further research.

Factors Associated with High Blood Pressure in People Living with HIV at the National Teaching Hospital Hubert Koutoukou Maga and Cotonou Teaching Hospital of the Armed Forces

In Benin Republic, few data are available on the prevalence and determinants of arterial hypertension (AH) in people living with the human immunodeficiency virus (PLWHA). The present study was conducted in two outpatient treatment centers for PLWHA in Cotonou and was conducted from June 19 to July 04, 2019 with 314 PLWHA. We performed descriptive statistics and logistic regression for the estimates. The prevalence of high blood pressure (HBP) among PLWHA was 41.4% [CI (95%): (35.9 - 47)]. In univariate analysis: age, smoking, alcoholism, physical inactivity, family history of hypertension, personal history of diabetes, obesity, and total and LDL (low density lipoprotein) hypercholesterolemia were significantly associated with HBP. No association was found with duration of HIV (human immunodeficiency virus) infection, time to ARV (antiretrovirals) exposure, and treatment regimen. In multivariate analysis, age, sex, smoking, family history of hypertension, and total hypercholesterolemia remained associated with HBP. In conclusion, the prevalence of HBP in PLWHA was very high compared with the results in the general population, and the same risk factors described in the general population were found but with a more marked hypertense potential.

Associations between metabolic syndrome and reduced lung function in young people

To reveal possible associations between metabolic syndrome (MS) and reduced lung function. In 2013-016, a cross-sectional survey was conducted in 908 Novosibirsk dwellers, which included spirometry to evaluate external respiratory function (ERF). For the detection of MS, the investigators used the 2009 All-Russian Research Society of Cardiologists criteria: waist circumference (WC) > 80 cm for women and >94 cm for men in combination with two of the following criteria: blood pressure (BP) ≥130/85 mm Hg, triglycerides (TG) ≥1.7 mmol/l, high-density lipoproteins (HDL) cholesterol <1.0 mmol/l for men and <1.2 mmol/l for women, low-density lipoprotein (LDL) cholesterol >3.0 mmol/l, and glucose ≥6.1 mmol/l. The mean values of WC were significantly greater with a forced expiratory volume in one second (FEV1) <80% than those with a FEV1 of ≥80% in both men (p=0.002) and women (p=0.050); in women, the mean values of WS were higher than those with a FEV1/forced vital capacity (FVC) <70% than those with a FEV1/FVC of ≥70% (p=0.047); the mean systolic and diastolic BP levels were significantly more with reductions in FEV1 and FVC, and the level of HDL cholesterol was significantly lower than that with a FEV1 of < 80% in men only. Significant correlations were found between FEV1 and all components of MS in men, between the majority of components of MS and FVC in men, between WC, BP, and FEV1/FVC in men and women, between plasma glucose levels and FEV1/FVC in women. Linear regression analysis revealed significant inverse correlations of FEV1 with TG, glucose, BP; those of FVC with TG, glucose; at the same time a positive association with HDL cholesterol in men, and only a negative correlation of FEV1/FVC with WC. The revealed associations between MS and reduced lung function can most likely be explained by the greater prevalence of both MS and its components (hypertension, hypertriglyceridemia, hyperglycemia, LDL hypercholesterolemia) among Novosibirsk men. This is consistent with the assertion that the decline in ERF, particularly FEV1, may be a marker of future cardiovascular disease morbidity and mortality.

Prevalence of metabolic syndrome in 25-45-year-old Novosibirsk dwellers

To study the prevalence of metabolic syndrome (MS) and its components in a 25-45-year-old Novosibirsk population. The Novosibirsk Research Institute of Internal and Preventive Medicine conducted a cross-sectional population-based survey in one of the typical districts of Novosibirsk in 2013-2015. The survey covered 346 men and 408 women. The criteria of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP-ATP III, 2001), the International Diabetes Federation (IDF, 2005), the Joint Interim Statement (JIS, 2009), and the All-Russian Research Society of Cardiologists (ARRSC, 2009) were used to detect MS. According to the ARRSC criteria, MS was recorded if a waist circumference (WC) was >80 cm for women and >94 cm for men in conjunction with 2 of the following criteria: a blood pressure ≥130/85 mm Hg, triglycerides (TG) ≥1.7 mmol/l, high-density lipoprotein (HDL) cholesterol <1.0 mmol/l for men and <1.2 mmol/l for women, low-density lipoprotein (LDL) cholesterol >3.0 mmol/l, and plasma glucose level ≥6.1 mmol/l. According to the 2009 ARRSC criteria, the prevalence of abdominal obesity, hypertension, hypertriglyceridemia, HDL hypocholestrolemia, LDL hypercholesterolemia, and high plasma glucose level was 42.6, 33.5, 17.5, 24.3, 64.8, and 29%, respectively. The prevalence of MS in 25-45-year-old Novosibirsk people was 17% (19.9% in men and 14.5% in women) according to the 2001 NCEP-ATP III, 27% (29.5% in men and 24.5% in women) according to the 2005 IDF criteria, 30% (35.8% in men and 25% in women) according to the 2009 JIS criteria, and 29.3% (33.2% in men and 26% in women) according to the 2009 ARRSC criteria, this was higher among men than women. There was an increase in the prevalence of MS with age. The highest prevalence of MS was 30 and 29.3% when using the 2009 JIS and the 2009 ARRSC criteria, respectively. Whatever the criterion was used, MS was more frequently recorded in men than women.

Energy Dense, Protein Restricted Diet Increases Adiposity and Perturbs Metabolism in Young, Genetically Lean Pigs

Animal models of obesity and metabolic dysregulation during growth (or childhood) are lacking. Our objective was to increase adiposity and induce metabolic syndrome in young, genetically lean pigs. Pre-pubertal female pigs, age 35 d, were fed a high-energy diet (HED; n = 12), containing 15% tallow, 35% refined sugars and 9.1–12.9% crude protein, or a control corn-based diet (n = 11) with 12.2–19.2% crude protein for 16 wk. Initially, HED pigs self-regulated energy intake similar to controls, but by wk 5, consumed more (P<0.001) energy per kg body weight. At wk 15, pigs were subjected to an oral glucose tolerance test (OGTT); blood glucose increased (P<0.05) in control pigs and returned to baseline levels within 60 min. HED pigs were hyperglycemic at time 0, and blood glucose did not return to baseline (P = 0.01), even 4 h post-challenge. During OGTT, glucose area under the curve (AUC) was higher and insulin AUC was lower in HED pigs compared to controls (P = 0.001). Chronic HED intake increased (P<0.05) subcutaneous, intramuscular, and perirenal fat deposition, and induced hyperglycemia, hypoinsulinemia, and low-density lipoprotein hypercholesterolemia. A subset of HED pigs (n = 7) was transitioned back to a control diet for an additional six weeks. These pigs were subjected to an additional OGTT at 22 wk. Glucose AUC and insulin AUC did not improve, supporting that dietary intervention was not sufficient to recover glucose tolerance or insulin production. These data suggest a HED may be used to increase adiposity and disrupt glucose homeostasis in young, growing pigs.

The lipoproteins selections aphereses with LDL Lipopak 400

The lipid lowering is one of the main ways to achieve reduction of the atherosclerosis progress. In the rare patients with homozygous familial hypercholesterolemia low density lipoprotein cholesterol apheresis should be performed as these patients usually have extremely high low density lipoprotein cholesterol concentrations and these patients usually do not, or only insufficiently, respond to statin therapy.

Mipomersen: evidence-based review of its potential in the treatment of homozygous and severe heterozygous familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal-dominant inherited disease with a prevalence of one in 500 (heterozygous) to one in 1,000,000 (homozygous). Mutations of the low-density lipoprotein (LDL) receptor gene, the apolipoprotein B100 gene, or the PCSK9 gene may be responsible for the disease. The resulting LDL hypercholesterolemia results in premature atherosclerosis as early as childhood (homozygous FH) or in adulthood (heterozygous FH). Current treatment modalities include lifestyle modification, combination drug therapy (statin-based), and apheresis. Mipomersen is an antisense oligonucleotide which inhibits apolipoprotein B production independent of LDL receptor function and thus works in homozygous FH, heterozygous FH, and other forms of hypercholesterolemia. Mipomersen is given 200 mg/week subcutaneously. Phase III studies indicate that the LDL cholesterol concentration can be reduced by 25%–47%, lipoprotein(a) levels by 20%–40%, and triglyceride concentrations by approximately 10%. In general, mipomersen has no effect on high-density lipoprotein cholesterol concentrations. Although there is considerable interindividual variability, the observed lipid effects are largely independent of age, gender, concomitant statin therapy, and underlying dyslipoproteinemia. The most common side effects are injection site reactions (70%–100%), flu-like symptoms (29%–46%), and elevated transaminases associated with an increased liver fat content (6%–15%). Mipomersen may be an interesting addon drug in patients with heterozygous or homozygous FH not reaching treatment goals, either because baseline values are very high or because high-dose statins are not tolerated.

Plasma PCSK9 preferentially reduces liver LDL receptors in mice

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the expression of LDL receptor (LDLR) protein. Gain-of-function mutations in PCSK9 cause hypercholesterolemia, and loss-of-function mutations result in lower plasma LDL-cholesterol. Here, we investigate the kinetics and metabolism of circulating PCSK9 relative to tissue levels of LDLRs. The administration of recombinant human PCSK9 (32 microg) to mice by a single injection reduced hepatic LDLRs by approximately 90% within 60 min, and the receptor levels returned to normal within 6 h. The half-life of the PCSK9 was estimated to be approximately 5 min. Continuous infusion of PCSK9 (32 microg/h) into wild-type mice caused a approximately 90% reduction in hepatic LDLRs within 2 h and no associated change in the level of LDLR in the adrenals. Parallel studies were performed using a catalytically inactive form of PCSK9, PCSK9(S386A), and similar results were obtained. Infusion of PCSK9(D374Y), a gain-of-function mutation, resulted in accelerated clearance of the mutant PCSK9 and a greater reduction in hepatic LDLRs. Combined, these data suggest that exogenously administrated PCSK9 in plasma preferentially reduces LDLR protein levels in liver at concentrations found in human plasma and that PCSK9's action on the LDLR is not dependent on catalytic activity in vivo.

A matched comparison of serum lipids between hemodialysis patients and nondialysis morbid controls

The high incidence of cardiac and vascular disease in maintenance hemodialysis (MHD) patients has heightened interest in many investigations concerning the serum lipid levels of these patients. The prevalence and laboratory characteristics of serum lipid concentrations in MHD patients, however, are far from clear. We hypothesized that serum lipids are significantly lower in MHD patients compared to their matched nondialysis counterparts. We compared 2-year averaged serum levels of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoproteins (HDL), and triglycerides in 285 MHD patients to the same averaged measurements during the same period of time in 285 nondialyzed outpatients from the same geographic area, whose lipid panels were measured in the same laboratory. Matching factors were sex, race and/or ethnicity, diabetes mellitus, and age (+/- 5 years). The MHD patients and their matched controls were 55.6 +/- 13.5 (SD) and 56.3 +/- 13.0 years old, respectively. Each group contained 51% women, 31% African Americans, 52% Hispanics, and 37% diabetics; 16% of MHD patients and 38% of controls were receiving statins. Body mass index (BMI) was significantly lower in MHD patients than in controls (26.2 vs. 31.5 kg/m2; p < 0.001). Serum cholesterol levels were significantly lower in MHD patients than in control subjects including after adjustment for BMI and statin use (TC, -51; LDL, -39; and HDL, -10 mg/dL; p < 0.001). Using conditional logistic regression for matched data and after controlling for BMI and statins, all odds ratios for predetermined hypercholesterolemic, but not hypertriglyceridemic, levels were significantly and substantially lower than 1.00, indicating much lower likelihood of hypercholesterolemia in MHD patients. Total and LDL hypercholesterolemia, although very common in nondialysis ambulatory outpatients, are substantially less prevalent in the MHD population, whereas hypertriglyceridemia is approximately equally prevalent between these populations.

Lack of cholesterol-lowering effect of graded doses of cholestyramine in children with Alagille syndrome: a pilot study.

There is controversy about the potential risk of sustained high concentrations of cholesterol and triglyceride in patients with cholestatic chronic liver disease. However, it is currently accepted that cholesterol-lowering therapy may reduce morbidity and mortality rates in hypercholesterolemic patients without preexisting coronary heart disease, as well as in those with coronary heart disease. The objective of this study was to evaluate the effect of cholestyramine on the serum lipid profile of a group of children with Alagille syndrome and hypercholesterolemia. Five children with Alagille syndrome and basal serum cholesterol concentrations greater than 230 mg/dL were included. Total serum cholesterol, triglyceride, low-density, and high-density lipoprotein cholesterol concentrations were measured on days 0, 10, 20, and 30 after the administration of oral cholestyramine 100, 250, and 500 mg(kg.d), respectively. Lipid fractions were reported as mean +/- 1 SD. Statistical analysis was performed with Friedman analysis of variance. The basal values and those of the three 10-day subsequent 100-, 250-, and 500-mg(kg.d) cholestyramine periods were as follows: total cholesterol: 327.6 +/- 77.1, 305.4 +/- 52.1, 290.6 +/- 24.1, and 320.6 +/- 32.3, respectively (P = 0.668); triglyceride: 136.4 +/- 14.6, 144.8 +/- 41.3, 161 +/- 30.9, and 165.4 +/- 40.7, respectively (P = 0.356); low-density lipoprotein cholesterol: 245.4 +/- 57.8, 239.8 +/- 48.6, 242.2 +/- 68.6, and 246.4 +/- 49.5, respectively (P = 0.782); and high-density lipoprotein cholesterol: 44.4 +/- 11.2, 41.8 +/- 12.8, 44.6.2 +/- 13.2, and 47 +/- 8.5, respectively (P = 0.431). Under the conditions of the current study, no significant effect of variable doses of cholestyramine could be demonstrated on the serum lipid profile of a series of children with Alagille syndrome. While the controversy on the potential atherogenic risk of low-density lipoprotein hypercholesterolemia in patients with chronic liver disease persists, new, prospective pharmacologic or nutritional trials are required.

The autosomal recessive hypercholesterolemia (ARH) protein interfaces directly with the clathrin-coat machinery.

The low density lipoprotein (LDL) receptor plays a pivotal role in cholesterol metabolism. Inherited mutations that disturb the activity of the receptor lead to elevations in plasma cholesterol levels and early-onset coronary atherosclerosis. Defects in either the LDL receptor or apolipoprotein B, the proteinaceous component of LDL particles that binds the LDL receptor, elevate circulating LDL-cholesterol levels in an autosomal-dominant fashion, with heterozygotes displaying values between homozygous and normal individuals. Rarely, similar clinical phenotypes occur with a recessive pattern of inheritance, and several genetic lesions in the autosomal recessive hypercholesterolemia (ARH) gene on chromosome 1 have been mapped in this class of patients. ARH has an N-terminal phosphotyrosine-binding (PTB) domain evolutionarily related to that found in Disabled-2 and numb, two endocytic proteins. PTB domains bind to the consensus sequence FXNPXY, corresponding to the internalization motif of the LDL receptor. We show here that in addition to the FXNPXY sequence, ARH binds directly to soluble clathrin trimers and to clathrin adaptors by a mode involving the independently folded appendage domain of the beta subunit. At steady state, ARH colocalizes with endocytic proteins in HeLa cells, and the LDL receptor fluxes through peripheral ARH-positive sites before delivery to early endosomes. Because ARH also binds directly to phosphoinositides, which regulate clathrin bud assembly at the cell surface, our data suggest that in ARH patients, defective sorting adaptor function in hepatocytes leads to faulty LDL receptor traffic and hypercholesterolemia.

Effects of direct adsorption of lipoproteins apheresis on lipoproteins, low-density lipoprotein subtypes, and hemorheology in hypercholesterolemic patients with coronary artery disease.

Direct adsorption of lipoproteins (DALI) apheresis has been shown to reduce effectively low-density lipoprotein (LDL) cholesterol and lipoprotein (a) concentrations. However, the effects on nontraditional risk indicators such as hemorheology and LDL subtypes have not been investigated so far. Five patients (2 women, 3 men, age 53 +/- 8 years) with coronary artery disease and severe LDL hypercholesterolemia regularly treated with other LDL apheresis devices entered the study and were then treated with DALI for the first time. Hemorheological and lipoprotein parameters were measured before and immediately after the initial DALI apheresis as well as before the fourth DALI apheresis. Compared to baseline (before the first DALI apheresis), the following parameters were significantly improved (p < 0.05) after the first DALI apheresis: LDL cholesterol (69 +/- 28 versus 208 +/- 82 mg/dl) and cholesterol in each LDL subfraction as well as plasma viscosity (1.23 +/- 0.04 versus 1.37 +/- 0.06 mPa), C-reactive protein, native blood viscosity, red cell aggregation, and red cell deformability. When parameters before the fourth DALI apheresis were compared to baseline, LDL cholesterol was still lower, and red cell deformability was still improved while cholesterol in each subfraction showed a statistical trend to lower concentrations (0.08 < p < 0.14). In conclusion, DALI apheresis not only reduces LDL cholesterol but also induced a significant reduction of cholesterol in all LDL subfractions and improved various hemorheological parameters.

Identification of recurrent and novel mutations in the LDL receptor gene in Japanese familial hypercholesterolemia

We used the denaturing gradient gel electrophoresis (DGGE) method to investigate 120 Japanese patients with familial hypercholesterolemia (FH) for mutations in the promoter region and the 18 exons and their flanking intron sequence of the low density lipoprotein (LDL) receptor gene. Fourteen aberrant DGGE patterns were found, and the underlying mutations were characterized by DNA sequencing. Five novel missense mutations (C317S, F382L A410T, L547V, and E693K), two nonsense mutations (W512X and K790X), four frameshift mutation (355del7, 1246ins5, 1687ins1, and 2035ins1), one splicing mutation (1845+2 TC), and two inframe mutations (661ins21 and 1115del9/ins6) were identified. Six of these mutations (L547V, E693K, W512X, 355del7, 1687ins1, and 20354ins1) have not been described before in FH. These newly identified mutations cosegregated in their family members with defective LDL receptor activity and hypercholesterolemia, and are thought to be causal for the FH phenotype. These results demonstrate that there is a broad spectrum of mutations in the LDL receptor gene in the Japanese population. Hum Mutat 14:87, 1999. © 1999 Wiley-Liss, Inc.

Identification of recurrent and novel mutations in the LDL receptor gene in Japanese familial hypercholesterolemia Communicated by: Haig H. Kazazian Online Citation: Human Mutation, Mutation in Brief #248 (1999) Online http://journals.wiley.com/1059-7794/pdf/mutation/248.pdf

We used the denaturing gradient gel electrophoresis (DGGE) method to investigate 120 Japanese patients with familial hypercholesterolemia (FH) for mutations in the promoter region and the 18 exons and their flanking intron sequence of the low density lipoprotein (LDL) receptor gene. Fourteen aberrant DGGE patterns were found, and the underlying mutations were characterized by DNA sequencing. Five novel missense mutations (C317S, F382L A410T, L547V, and E693K), two nonsense mutations (W512X and K790X), four frameshift mutation (355del7, 1246ins5, 1687ins1, and 2035ins1), one splicing mutation (1845+2 T→C), and two inframe mutations (661ins21 and 1115del9/ins6) were identified. Six of these mutations (L547V, E693K, W512X, 355del7, 1687ins1, and 20354ins1) have not been described before in FH. These newly identified mutations cosegregated in their family members with defective LDL receptor activity and hypercholesterolemia, and are thought to be causal for the FH phenotype. These results demonstrate that there is a broad spectrum of mutations in the LDL receptor gene in the Japanese population. Hum Mutat 14:87, 1999. © 1999 Wiley-Liss, Inc.

Mutation analysis of iduronate-2-sulphatase gene in 24 patients with Hunter syndrome: characterisation of 6 novel mutations. Mutation in brief no. 249. Online.

Hunter syndrome is a rare, X-linked, recessively inherited disease affecting approximately 1 in 132,000 males. The disease is caused by the inability to degrade dermatan sulphate and heparan sulphate due to mutations in the iduronate-2-sulphatase gene (IDS). The mutations causing the disorder are heterogeneous, ranging from small micro-lesions to gross deletions and inversions. We have screened DNA samples from a panel of 24 unrelated Hunter syndrome patients and have identified mutations in 16 individuals. Six mutations represent novel changes in the gene and these include two single base deletions (1264DC and 1632/3DT); two single base insertions (776/8insC and 1082insT); and two missense mutations--Y264N (914T-->G) and Q465P (1518A-->C). An additional two missense mutations and one splice site alteration identified in this study have been described previously. Southern analysis revealed complete or partial gene deletions in a further 7 patients.

Long-term effect of low-density lipoprotein apheresis on plasma lipoproteins and coronary heart disease in native vessels and coronary bypass in severe heterozygous familial hypercholesterolemia

Low-density lipoprotein (LDL) apheresis is a potent treatment for patients with coronary heart disease and severe hereditary forms of LDL hypercholesterolemia not adequately responsive to drug treatment. Until now, the beneficial effect of aggressive reduction of LDL cholesterol by LDL apheresis on the course of coronary heart disease has been demonstrated in one 3-year study and several studies lasting 2 years. We now report on the clinical course, lipoprotein concentrations, coronary angiograms, and side effects in patients undergoing LDL apheresis for as long as 8.6 years. Thirty-four patients (21 men and 13 women) with coronary heart disease and heterozygous familial hypercholesterolemia (FH) not adequately responsive to lipid-lowering drugs received weekly (four patients biweekly) LDL apheresis for 4.6 ± 2.6 years under diet and lipid-lowering drug therapy; after 0.5 to 3 years, simvastatin in the maximal tolerable dose was added. The baseline LDL cholesterol concentration was 6.9 ± 1.6 mmol/L. Combined treatment in the steady state yielded a pretreatment and posttreatment LDL cholesterol concentration of 4.8 ± 0.9 and 1.8 ± 0.4 mmol/L, respectively. The calculated interval mean LDL cholesterol was 3.3 ± 0.6 mmol/L. Evaluation of the coronary angiographies revealed a definite regression of coronary lesions in four patients (11.8%); in 19 patients, there was a cessation of progression. Two patients developed atheromatous lesions in bypass grafts (L.H., 60% stenosis; S.M., occlusion). Of 23 patients elegible for the scoring of anginal symptoms, five (21.7%) reported a reduction of the frequency and severity of angina pectoris. The mean coronary symptom score in 23 patients changed from 1.65 ± 0.83 at baseline to 1.39 ± 0.66 at the end of the study. During the whole observation period, we observed three sudden deaths, one nonfatal myocardial infarction, and five patients requiring hospital admission because of unstable angina pectoris, one of which was followed by a transluminal coronary angioplasty. Aggressive reduction of LDL cholesterol with combined LDL apheresis and drugs induced regression of coronary lesions in four of 34 patients and prevented progression in 29 patients for as long as 8.6 years. The effect on LDL and high-density lipoprotein (HDL) cholesterol and lipoprotein(a) [Lp(a)] was comparable with all three apheresis techniques. Therefore, no obvious difference between the three techniques was found regarding changes in coronary lesions.