Association of Severity of Lower Extremity Arterial Disease and Overactive Bladder Syndrome: A Cross Sectional Study.

PURPOSE: The aim of this study aim is to clarify the relationship between Overactive bladder syndrome (OAB) and severity of lower extremity ischemia by using Fontaine classification system. MATERIALS AND METHODS: Patients who were diagnosed with lower extremity arterial disease were enrolled into the study. The Fontaine score of each patient was taken and all patients completed the validated Turkish version of OAB-V8 questionnaire. Body mass index, serum creatinine, blood urea nitrogen, cholesterol and fasting plasma glucose levels were measured. The patients were divided into two groups. Patients with OAB-V8 score above 8 were enrolled into group 1 and patients with OAB-V8 score under 8 were enrolled into group 2. RESULTS: At the end of study period, 181 patients who met the  inclusion criteria were enrolled into the study.  Patients with OAB ? 8 score (n= 79) were compared with  patients with OAB < 8 score (n= 102). The mean age and the mean BMI were significantly higher in patients with OAB ? 8 (P = .001 and P = .001, respectively). Also, HDL- cholesterol level was found significantly lower in group 1 patients  (P= .001). Multivariate regression analysis showed that presence of Fontaine score ? class 2b, age ? 60 years, BMI ? 30 kg/m2 , and HDL-cholesterol levels < 60 mg/dL were predictive factors for OAB. CONCLUSION: The present study  demonstrated that incidence of OAB is higher in patients with severe lower extremity ischemic symptoms, older age, high BMI, and lower HDL-cholesterol level.

Hypoalphalipoproteinemia and BRAFV600E Mutation Are Major Predictors of Aortic Infiltration in the Erdheim-Chester Disease.

Objective- Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by the infiltration of multiple tissues with lipid-laden histiocytes. Cardiovascular involvement is frequent in ECD and leads to a severe prognosis. The objective of this study was to determine whether an alteration of lipid metabolism participates in the lipid accumulation in histiocytes and the cardiovascular involvement in ECD. Approach and Results- An analysis of plasma lipid levels indicated that male ECD patients carrying the BRAFV600E (B-Raf proto-oncogene, serine/threonine kinase) mutation exhibited hypoalphalipoproteinemia, as demonstrated by low plasma HDL-C (high-density lipoprotein cholesterol) levels. Capacity of sera from male BRAFV600E ECD patients to mediate free cholesterol efflux from human macrophages was reduced compared with control individuals. Cardiovascular involvement was detected in 84% of the ECD patients, and we reported that the presence of the BRAFV600E mutation and hypoalphalipoproteinemia is an independent determinant of aortic infiltration in ECD. Phenotyping of blood CD14+ cells, the precursors of histiocytes, enabled the identification of a specific inflammatory signature associated with aortic infiltration which was partially affected by the HDL phenotype. Finally, the treatment with vemurafenib, an inhibitor of the BRAFV600E mutation, restored the defective sera cholesterol efflux capacity and reduced the aortic infiltration. Conclusions- Our findings indicate that hypoalphalipoproteinemia in male ECD patients carrying the BRAFV600E mutation favors the formation of lipid-laden histiocytes. In addition, we identified the BRAF status and the HDL phenotype as independent determinants of the aortic involvement in ECD with a potential role of HDL in modulating the infiltration of blood CD14+ cells into the aorta.

Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans.

OBJECTIVE: Studies into the role of LRP1 (low-density lipoprotein receptor-related protein 1) in human lipid metabolism are scarce. Although it is known that a common variant in LRP1 (rs116133520) is significantly associated with HDL-C (high-density lipoprotein cholesterol), the mechanism underlying this observation is unclear. In this study, we set out to study the functional effects of 2 rare LRP1 variants identified in subjects with extremely low HDL-C levels. APPROACH AND RESULTS: In 2 subjects with HDL-C below the first percentile for age and sex and moderately elevated triglycerides, we identified 2 rare variants in LRP1: p.Val3244Ile and p.Glu3983Asp. Both variants decrease LRP1 expression and stability. We show in a series of translational experiments that these variants culminate in reduced trafficking of ABCA1 (ATP-binding cassette A1) to the cell membrane. This is accompanied by an increase in cell surface expression of SR-B1 (scavenger receptor class B type 1). Combined these effects may contribute to low HDL-C levels in our study subjects. Supporting these findings, we provide epidemiological evidence that rs116133520 is associated with apo (apolipoprotein) A1 but not with apoB levels. CONCLUSIONS: This study provides the first evidence that rare variants in LRP1 are associated with changes in human lipid metabolism. Specifically, this study shows that LRP1 may affect HDL metabolism by virtue of its effect on both ABCA1 and SR-B1.

Diagnosis and treatment of high density lipoprotein deficiency.

Low serum high density lipoprotein cholesterol level (HDL-C) <40 mg/dL in men and <50 mg/dL in women is a significant independent risk factor for cardiovascular disease (CVD), and is often observed in patients with hypertriglyceridemia, obesity, insulin resistance, and diabetes. Patients with marked deficiency of HDL-C (<20 mg/dL) in the absence of secondary causes are much less common (<1% of the population). These patients may have homozygous, compound heterozygous, or heterozygous defects involving the apolipoprotein (APO)AI, ABCA1, or lecithin:cholesterol acyl transferase genes, associated with apo A-I deficiency, apoA-I variants, Tangier disease , familial lecithin:cholesteryl ester acyltransferase deficiency, and fish eye disease. There is marked variability in laboratory and clinical presentation, and DNA analysis is necessary for diagnosis. These patients can develop premature CVD, neuropathy, kidney failure, neuropathy, hepatosplenomegaly and anemia. Treatment should be directed at optimizing all non-HDL risk factors.

Impact of hypoalphalipoproteinemia on quality of life in Taiwanese women with central obesity.

PURPOSE: To investigate the relationship between health-related quality of life (HRQoL) and different cutoff value of low level of high-density lipoprotein cholesterol (HDL-C) in Taiwanese women with different definition of obesity. METHODS: Prospective observational study in women with central obesity was conducted in Taipei City Hospital. A total of 572 women were screened at our clinic, and 227 of them with a body mass index ≧27 kg/m2 defined by the Department of Health in Taiwan and weight circumference ≧80 cm were eligible for the study. We defined two groups as group A-low HDL (HDL-C < 40 mg/dL) and group B-high HDL (HDL-C < 50 mg/dL) according to different definition of hypoalphalipoproteinemia in obese women. RESULTS: Significantly reduced HRQoL score was noted in group A-low HDL compared to group A-high HDL (HDL-C ≧ 40 mg/dL), but not between group B-low HDL and group B-high HDL (HDL-C ≧ 50 mg/dL). Positively correlation was noted between HDL-C level and physical domain of HRQoL score. HDL-C contributes independently to physical domain of HRQoL score after controlling for other factors. Decreased leptin and adiponectin level were noted in hypoalphalipoproteinemia groups. CONCLUSION: Taiwanese obese women with hypoalphalipoproteinemia have adverse impact on HRQoL, especially when the HDL-C level is lower than 40 mg/dL. Both hypoalphalipoproteinemia and hypertension accounted for a great variance to lower scores of physical domain of HRQoL with positively correlation with HDL-C level observed. Decreased leptin and adiponectin were also observed in hypoalphalipoproteinemia group, which implied increased cardiovascular risk. HDL-C level may deem as another indicator for HRQoL in women with central obesity.

Cardiometabolic risk factors and quality of life in severely obese children and adolescents in The Netherlands.

BACKGROUND: The prevalence of severe obesity in children and adolescents is increasing. However, little is known about cardiometabolic risk factors and quality of life of children with severe obesity.Therefore, the aim of this study was to assess the demographic characteristics and the prevalence of cardiometabolic risk factors and quality of life in severely obese children and adolescents undergoing intensive inpatient treatment for obesity. METHODS: Data were collected between August 2009 and April 2011 on 16 children (8-13y) and 64 adolescents (13-19y) with severe obesity (SDS-BMI >= 3.0 or SDS-BMI >= 2.3 and comorbidity) participating in an RCT evaluating two intensive inpatient treatment programs for obesity. Demographic, anthropometric, clinical characteristics and two components of the EuroQol for the assessment of quality of life are described. RESULTS: Eighty percent of participants in this study had at least one cardiometabolic risk factor in addition to severe obesity. Low HDL-cholesterol and hypertension were most prevalent (65.0% respectively 31.2%). The highest significant correlations were found between SDS-BMI and SDS-waist circumference, fasting plasma insulin and HOMA-IR (correlation coefficients respectively 0.80, 0.49, and 0.48). With regard to quality of life, the mean utility score of the participants was 0.79 on a scale of 0.0 to 1.0 on the EuroQol questionnaire and their mean individual valuation was 69.1 on a scale of 0 to100. CONCLUSION: Cardiometabolic risk factors are already highly prevalent in this group of severely obese children and adolescents. The score of 69.1 found for quality of life in this study suggests that participants experience important limitations in their quality of life. However, quality of life is not associated with the prevalence of cardiometabolic risk factors. TRIAL REGISTRATION: Netherlands Trial Register (NTR1678, registered 20-Feb-2009).

HDL deficiency due to a new insertion mutation (ApoA-INashua) and review of the literature.

A 61-year-old white man of European ancestry with significant coronary heart disease since age 42 years and marked high-density lipoprotein (HDL) deficiency (HDL cholesterol 1 mg/dL) was evaluated. His fasting low-density lipoprotein cholesterol level was 42 mg/dL, and his triglycerides were 417 mg/dL on therapy with rosuvastatin 40 mg/day, ezetimibe 10 mg/day, fenofibrate 145 mg/day, and extended-release niacin 2 g/day. Further analysis of his plasma revealed an apolipoprotein (apo) A-I level of 23.5 mg/dL (approximately 20% of normal), and the absence of small alpha-4 HDL, medium alpha-3 HDL, and very large alpha-1 HDL, with only very small pre-beta-1 HDL and large alpha-2 HDL being present. APOA-I gene sequencing revealed a novel heterozygous in-frame insertion mutation with duplication of nucleotides 1535 through 1552 inserted at position 1553, causing a new amino acid glycine at codon 157 and a duplication of amino acids alanine, arginine, alanine, histidine, and leucine at codons 158-162. This novel apoA-I mutation results in the formation of apoA-I that appears to have abnormal lipid binding properties, resulting in impaired reverse cholesterol transport, probable enhanced clearance, and premature coronary heart disease.

[Diagnostic criteria for hypoalphalipoproteinemia and the threshold associated with cardiovascular protection in a Mexican Mestizo population]. / Criterio diagnóstico para hipoalfalipoproteinemia y punto de corte asociado con protección cardiovascular en una población mestiza mexicana.

BACKGROUND AND OBJECTIVES: In the Mexican Mestizo and Indian populations it is unknown the diagnostic criteria (DC) and associated risk of myocardial infarction (MI) for the HDL-cholesterol (HDL-c). We aimed to establish, in a Mexican adult population without cardiovascular risk factors, their HDL-c concentrations, the DC for hypoalphalipoproteinemia and prevalence base on the percentile-10 and the risk associated with MI, as well as the threshold (TH) associated with cardiovascular protection. SUBJECTS AND METHODS: In 826 adult Mestizos, 98 Indians and 155 Mestizos with MI for the first time the average HDL-c serum concentrations were determined. Then the percentile and statistical analysis were carried out. RESULTS: The average HDL-c (mg/dl) concentrations for Mestizos and Indians were 43.2 and 37.2 and the ones inferior to the percentile-10 were <30 and <26, respectively. In Mestizos, HDL-c concentrations of ≤ 35 mg/dl (odds ratio [OR] 1.91, 95% confidence interval [95%CI] 1.3-2.8, P=.001) were associated with MI and those >35 (OR 0.52, IC 95% 0.36-0.76, P=.001) were associated with a cardiovascular protection of 52%. The hypoalphalipoproteinemia prevalences in Mestizos and Indians were: for the percentile-10 DC 9 and 11% and for the TH associated with MI ≤ 35, 26 and 54%, respectively. CONCLUSIONS: The Indians average HDL-c concentration was significantly lower (P<.003) than for Mestizos. The established DC showed that the hypoalphalipoproteinemia prevalences in both populations were similar to those for other open populations. In Mestizos, HDL-c concentrations > 35 mg/dl are protective for MI, but it will be necessary to establish this TH for the Indian population. Each population should establish its own DC for hypoalphalipoproteinemia.

Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3.

BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) affects lipid metabolism by inhibiting the activity of lipoprotein and endothelial lipases. Angptl3 knockout mice have marked hypolipidemia, and heterozygous carriers of ANGPLT3, loss-of-function mutations were found among individuals in the lowest quartile of plasma triglycerides in population studies. Recently, 4 related individuals with primary hypolipidemia were found to be compound heterozygotes for ANGPTL3 loss-of-function mutations. METHODS AND RESULTS: We resequenced ANGPTL3 in 4 members of 3 kindreds originally identified for very low levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (0.97±0.16 and 0.56±0.20 mmol/L, respectively) in whom no mutations of known candidate genes for monogenic hypobetalipoproteinemia and hypoalphalipoproteinemia had been detected. These subjects were found to be homozygous or compound heterozygous for ANGPTL3 loss-of-function mutations (p.G400VfsX5, p.I19LfsX22/p.N147X) associated with the absence of ANGPTL3 in plasma. They had reduced plasma levels of triglyceride-containing lipoproteins and of HDL particles that contained only apolipoprotein A-I and pre-ß-high-density lipoprotein. In addition, their apolipoprotein B-depleted sera had a reduced capacity to promote cell cholesterol efflux through the various pathways (ABCA1-, SR-BI-, and ABCG1-mediated efflux); however, these subjects had no clinical evidence of accelerated atherosclerosis. Heterozygous carriers of the ANGPTL3 mutations had low plasma ANGPTL3 and moderately reduced low-density lipoprotein cholesterol (2.52±0.38 mmol/L) but normal plasma high-density lipoprotein cholesterol. CONCLUSIONS: Complete ANGPTL3 deficiency caused by loss-of-function mutations of ANGPTL3 is associated with a recessive hypolipidemia characterized by a reduction of apolipoprotein B and apolipoprotein A-I-containing lipoproteins, changes in subclasses of high-density lipoprotein, and reduced cholesterol efflux potential of serum. Partial ANGPTL3 deficiency is associated only with a moderate reduction of low-density lipoprotein.

High prevalence of low high-density lipoprotein cholesterol concentrations and other dyslipidemic phenotypes in an Iranian population.

OBJECTIVE: This study was designed to determine the prevalence of different atherogenic dyslipidemic phenotypes, especially decreased serum high-density lipoprotein cholesterol (HDL-C) in an Iranian population and its relationship to other coronary artery disease (CAD) risk factor. METHODS: The prevalence of lipid abnormalities was assessed in 2941 people, including 1396 males and 1545 females, aged more than 20 years. The population is representative of Iranian urban adults living in northwestern Iran. In addition to isolated forms of hypertriglyceridemia, hypercholesterolemia, and hypoalphalipoproteinemia, some dyslipidemic phenotypes including hypertriglyceridemia/low high-density lipoprotein (HDL) combination, mixed dyslipidemias, and severe dyslipidemias were assessed. RESULTS: The most prevalent abnormality was low HDL cholesterol (HDL-C; 73% including 63% for men and 93.3% for women). Hypertriglyceridemia (>150 mg/dL) was the second most prevalent abnormality (40.6%). Increased total cholesterol (>200 mg/dL) was observed in 35.4% of the subjects. The combination of hypertriglyceridemia and low HDL-C was observed in 9.9% of the population. Fifty eight percent of the low HDL-C cases were not accompanied with hypertriglyceridemia, and 24.4% of hypertriglyceridemic subjects had low HDL-C. Among subjects younger than 30 years, 19% had hypercholesterolemia, 13% had isolated low HDL-C less than 35 mg/dL, and 63% had HDL-C less than 40 mg/dL. Unexpectedly, except for the hypertriglyceridemia/low HDL-C pattern, which was more common in males, the other abnormal lipid profiles were more common in females. CONCLUSION: The prevalence of dyslipidemia, especially low HDL cholesterol, in Iranian adults is very high. Urgent preventive programs and changes in lifestyle are needed in this area.

No evidence of increased risk for certain highly atherogenic lipoprotein phenotypes in HIV-infected patients.

BACKGROUND: There is a need to assess whether human immunodeficiency virus (HIV)-infected patients are more likely than noninfected individuals to have any of the specific lipoprotein combination profiles identified as the best predictors of future cardiovascular disease in the general population. METHODS: One hundred five infected patients, randomly selected from a Mexican HIV clinic, and 105 age- and gender-matched noninfected community volunteers, were enrolled to study the prevalence of each of three highly atherogenic lipoprotein phenotypes [high apolipoprotein (Apo)B/ApoA-I ratio, hypertriglyceridemia with high ApoB and hypoalphalipoproteinemia with high ApoB], and the relationship between time of exposure to antiretroviral therapy (ART) drug class and lipid changes. RESULTS: The highly atherogenic lipoprotein phenotypes were similarly frequent in both groups. There was a nonsignificant increased risk of dyslipidemia with longer exposure to any of the ART drug classes, although this hazard seems to be greater in patients with central fat accumulation. CONCLUSIONS: No evidence of increased risk for certain highly atherogenic lipoprotein phenotypes in HIV-infected patients was found. More than one pathogenic mechanism for ART-associated dyslipidemia is postulated.