Correlation between HDL2, HDL3 and serum ferritin levels with fatty liver and NAFLD activity score (NAS) in liver histology of organ donors.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most important liver diseases. High-density lipoprotein (HDL) has anti-atherogenic properties and its reduction can be associated with fatty liver. Serum ferritin levels are usually elevated in patients with NAFLD. This study aimed to evaluate the correlation between HDL subtypes and serum ferritin levels with evidence of NAFLD in liver histology of organ donors. METHODS: One hundred organ donor patients who were eligible for the study were included in the study and ferritin; HDL2 and HDL3 were measured in blood samples. Donated liver tissue biopsy specimens were evaluated for fatty liver and NAFLD activity score (NAS). In addition, AST and ALT were measured in recipients 24 h after transplant. All data abstracted and analyzed statistically. RESULTS: Serum HDL2 levels and HDL2/HDL3 ratio in patients with NAS > 1 were significantly lower (P < 0.05). Serum levels of HDL3 and ferritin were not significantly associated with NAS >1 (P > 0.05). In addition, serum ferritin > 1000 ng/ml in organ donors associated with increased AST and ALT levels 24 h after transplantation in the liver organ recipient. CONCLUSIONS: Lower HDL2 values and HDL2/HDL3 ratio were associated with increased NAFLD activity score, but HDL3 and ferritin did not show such a relationship. In addition, higher levels of ferritin in organ donors may be associated with increased AST and ALT 24 h after liver transplantation in the organ recipient.

Changes in plasma HDL and its subcomponents HDL2b and HDL3 regulate inflammatory response by modulating SOCS1 signaling to affect severity degree and prognosis of sepsis.

OBJECTIVES: To explore if SOCS1 is regulated by plasma HDL and its subcomponents HDL2b and HDL3 to affect inflammatory reaction then to influence the severity degree and prognosis of sepsis. METHODS: One hundred sepsis patients in ICU and 85 normal control persons from October 2018 to October 2019 in our hospital were enrolled. Adult male C57BL/6 mice were used to establish sepsis model by CLP method. HDL, CRP, and WBC count of human were measured using an auto-analyzer. Plasma HDL, IL-1ß, and TNF-α proteins levels of mice were measured with ELISA. Microfluidic chip was used for plasma HDL2b and HDL3 detections. SOCS1 in liver and spleen of mice were measured by qRT-PCR. The relationship between plasma HDL//HDL2b and inflammatory indices/SOCS1 in liver/spleen was analyzed with spearman correlation coefficient method. The sepsis patients/mice were divided into non-survival and survival groups. The sepsis patients were divided into severe and mild sepsis patients based on the SOFA score or divided into high and low score groups according to the APACHE II score. The sepsis mice were divided into high and low score group based on the modified sepsis severity score criterion. RESULTS: Plasma HDL and HDL2b levels were significantly declined (P < 0.01), while HDL3 was normal in both sepsis patients and mice (P > 0.05). Plasma HDL and HDL2b were negatively associated with the serum CRP concentration and positively correlated with the prognosis and severity in sepsis patients (P < 0.05). Moreover, the downregulated plasma HDL but not HDL2b was negatively related to increased SOCS1 mRNA levels in liver and spleen of mice, which were positively connected with TNF-α and IL-1ß protein levels (P < 0.05). CONCLUSIONS: Plasma HDL is downregulated in sepsis, which may facilitate inflammatory reaction then activate the SOCS1 signaling to regulate the severity and affect prognosis of sepsis. The decline of plasma HDL2b content could aggravate the severity and poor prognosis of sepsis through facilitating inflammatory reaction. The plasma HDL3 is not involved in sepsis. The more and further explorations may be needed.

Association of proportion of the HDL-cholesterol subclasses HDL-2b and HDL-3 and macrovascular events among patients undergoing hemodialysis.

Altered high-density lipoprotein cholesterol (HDL-C) subclass distribution in hemodialysis (HD) patients is well documented. Aim of this study is to investigate the relationship between HDL-C subclass distribution and macrovascular events in patients undergoing HD. A total of 164 prevalent HD patients and 71 healthy individuals in one hospital-facilitated clinic were enrolled from May 2019 to July 2019 and individual HD patients was follow-up for one year. Macrovascular events (cerebral stroke, coronary heart disease) were recorded in the study period. The HDL-2b, HDL-3 proportions and biochemical parameters were measured. Pearson correlation test and logistic regression analysis were used to examine correlation and odds ratio (OR). 144 HD patients completed one-year follow-up. Cohort with macrovascular events revealed significantly lower HDL-2b and higher HDL-3 subclass proportions compared to those without events. By multivariable adjustment, HDL-3 subclass proportion revealed significantly increase risk for these events (OR 1.17, 95% CI 1.02-1.41, P = 0.044). HDL-2b subclass was significantly higher and HDL-3 subclass was significantly lower in the HD cohort under the hs-CRP level of < 3 mg/L compared to higher hs-CRP level. In conclusion, HDL-2b and HDL-3 subclasses distributions were associated with macrovascular events in HD patients. Proinflammatory status influences the distribution of HDL-2b and HDL-3 subclasses in HD patients.

A homogeneous assay to determine high-density lipoprotein subclass cholesterol in serum.

Existing methods to measure high-density lipoprotein cholesterol (HDL-C) subclasses (HDL2-C and HDL3-C) are complex and require proficiency, and thus there is a need for a convenient, homogeneous assay to determine HDL-C subclasses in serum. Here, cholesterol reactivities in lipoprotein fractions [HDL2, HDL3, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL)] toward polyethylene glycol (PEG)-modified enzymes were determined in the presence of varying concentrations of dextran sulfate and magnesium nitrate. Particle sizes formed in the lipoprotein fractions were measured by dynamic light scattering. We optimized the concentrations of dextran sulfate and magnesium nitrate before assay with PEG-modified enzymes to provide selectivity for HDL3-C. On addition of dextran sulfate and magnesium nitrate, the sizes of particles of HDL2, LDL, and VLDL increased, but the size of HDL3 fraction particles remained constant, allowing only HDL3-C to participate in coupled reactions with the PEG-modified enzymes. In serum from both healthy volunteers and patients with type 2 diabetes, a good correlation was observed between the proposed assay and ultracentrifugation in the determination of HDL-C subclasses. The assay proposed here enables convenient and accurate determination of HDL-C subclasses in serum on a general automatic analyzer and enables low-cost routine diagnosis without preprocessing.

Clinical-epidemiological analysis of HDL2 and HDL3 subfractions in adults from Maracaibo city, Venezuela. / Análisis clínico-epidemiológico de las subfracciones HDL2 y HDL3 en adultos de la ciudad de Maracaibo, Venezuela.

OBJECTIVE: To carry out a clinical-epidemiological analysis of high-density lipoprotein cholesterol subfractions (HDL-C) in adults from Maracaibo, Venezuela. MATERIALS AND METHODS: A descriptive and cross-sectional study of the database from the Metbolic Syndrome Prevalence in Maracaibo Study was carried out. HDL3 and HDL2 serum concentration, as well as the HDL2/HDL3 ratio, were determined in 359 individuals of both sexes, over 18 years of age. Values obtained were evaluated according to sociodemographic, clinical and biochemical characteristics. RESULTS: Mean population age was 39.4 ± 15.2 years, and 51.5% were female. Differences in HDL-C subfraction levels were only observed in those subjects with low HDL-C levels. Women with hypertriglyceridemia showed significantly lower serum HDL3 and HDL2 concentrations than those with normal triglycerides (p=0.033), as well as a lower HDL3 level and HDL2 / HDL3 ratio in those with higher levels of ultra-sensitive C-reactive protein (us-CRP) (p<0.001). A significantly lower concentration of HDL2 was observed in men with some degree of hypertension (p=0.031), insulin resistance (p=0.050) and metabolic syndrome (p=0.003); while those with elevated us-CRP showed a lower concentration of HDL3 (p=0.011). CONCLUSION: HDL-C subfractions show varying clinical-epidemiological behavior in adults from Maracaibo. Lower serum levels are observed in men, differences only in those with low HDL-C; and no predominance of any subclass was observed according to sociodemographic, clinical and biochemical characteristics.

OBJETIVO: Realizar un análisis clínico-epidemiológico de las subfracciones de colesterol unido a lipoproteinas de alta densidad (HDL-C, por sus siglas en inglés) en adultos de la ciudad de Maracaibo, Venezuela. MATERIALES Y MÉTODOS: Se realizó un estudio descriptivo y transversal de la base de datos del Estudio de Prevalencia de Síndrome Metabólico de Maracaibo, que incluyó 359 individuos de ambos sexos, mayores de 18 años, a quienes se les determinó la concentración sérica de HDL3 y HDL2, así como el índice HDL2/HDL3; evaluando sus niveles según características sociodemográficas, clínicas y bioquímicas. RESULTADOS: La edad promedio de la población era 39,4 ± 15,2 años, y 51,5% era de sexo femenino. Solo se observaron diferencias en los niveles de HDL-C en aquellos sujetos con HDL-C bajas. Las mujeres con hipertriacilgliceridemia mostraron concentraciones séricas de HDL3 y HDL2 significativamente menores con respecto a aquellas con triacilglicéridos normales (p = 0,033); asimismo, se encontró una concentración menor de HDL3 y relación HDL2/HDL3 en aquellas con proteína C reactiva ultrasensible (PCR-us) elevada (p < 0,001). En hombres, se evidenció una concentración significativamente menor de HDL2 en aquellos con algún grado de hipertensión arterial (p = 0,031), insulinorresistencia (p = 0,050) y síndrome metabólico (p = 0,003); mientras que aquellos con PCR-us elevada mostraron una menor concentración de HDL3 (p = 0,011). CONCLUSIÓN: Las subfracciones de HDL-C muestran un comportamiento clínico epidemiológico variable en adultos de la población de Maracaibo, con promedios más bajos en los hombres, diferencias en los niveles únicamente en aquellos con HDL-C bajas, y sin predominio de alguna subclase según las características sociodemográficas, clínicas y bioquímicas.

Análisis clínico-epidemiológico de las subfracciones HDL2 y HDL3 en adultos de la ciudad de Maracaibo, Venezuela / Clinical-epidemiological analysis of HDL2 and HDL3 subfractions in adults from Maracaibo city, Venezuela

RESUMEN Objetivo: Realizar un análisis clínico-epidemiológico de las subfracciones de colesterol unido a lipoproteinas de alta densidad (HDL-C, por sus siglas en inglés) en adultos de la ciudad de Maracaibo, Venezuela. Materiales y métodos: Se realizó un estudio descriptivo y transversal de la base de datos del Estudio de Prevalencia de Síndrome Metabólico de Maracaibo, que incluyó 359 individuos de ambos sexos, mayores de 18 años, a quienes se les determinó la concentración sérica de HDL3 y HDL2, así como el índice HDL2/HDL3; evaluando sus niveles según características sociodemográficas, clínicas y bioquímicas. Resultados: La edad promedio de la población era 39,4 ± 15,2 años, y 51,5% era de sexo femenino. Solo se observaron diferencias en los niveles de HDL-C en aquellos sujetos con HDL-C bajas. Las mujeres con hipertriacilgliceridemia mostraron concentraciones séricas de HDL3 y HDL2 significativamente menores con respecto a aquellas con triacilglicéridos normales (p=0,033); asimismo, se encontró una concentración menor de HDL3 y relación HDL2/HDL3 en aquellas con proteína C reactiva ultrasensible (PCR-us) elevada (p<0,001). En hombres, se evidenció una concentración significativamente menor de HDL2 en aquellos con algún grado de hipertensión arterial (p=0,031), insulinorresistencia (p=0,050) y síndrome metabólico (p=0,003); mientras que aquellos con PCR-us elevada mostraron una menor concentración de HDL3 (p=0,011). Conclusión: Las subfracciones de HDL-C muestran un comportamiento clínico epidemiológico variable en adultos de la población de Maracaibo, con promedios más bajos en los hombres, diferencias en los niveles únicamente en aquellos con HDL-C bajas, y sin predominio de alguna subclase según las características sociodemográficas, clínicas y bioquímicas.

ABSTRACT Objective: To carry out a clinical-epidemiological analysis of high-density lipoprotein cholesterol subfractions (HDL-C) in adults from Maracaibo, Venezuela. Materials and methods: A descriptive and cross-sectional study of the database from the Metbolic Syndrome Prevalence in Maracaibo Study was carried out. HDL3 and HDL2 serum concentration, as well as the HDL2/HDL3 ratio, were determined in 359 individuals of both sexes, over 18 years of age. Values obtained were evaluated according to sociodemographic, clinical and biochemical characteristics. Results: Mean population age was 39.4 ± 15.2 years, and 51.5% were female. Differences in HDL-C subfraction levels were only observed in those subjects with low HDL-C levels. Women with hypertriglyceridemia showed significantly lower serum HDL3 and HDL2 concentrations than those with normal triglycerides (p=0.033), as well as a lower HDL3 level and HDL2 / HDL3 ratio in those with higher levels of ultra-sensitive C-reactive protein (us-CRP) (p<0.001). A significantly lower concentration of HDL2 was observed in men with some degree of hypertension (p=0.031), insulin resistance (p=0.050) and metabolic syndrome (p=0.003); while those with elevated us-CRP showed a lower concentration of HDL3 (p=0.011). Conclusion: HDL-C subfractions show varying clinical-epidemiological behavior in adults from Maracaibo. Lower serum levels are observed in men, differences only in those with low HDL-C; and no predominance of any subclass was observed according to sociodemographic, clinical and biochemical characteristics.

HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure.

BACKGROUND & AIMS: High-density lipoprotein cholesterol (HDL-C) levels are reduced in patients with chronic liver disease and inversely correlate with disease severity. During acute conditions such as sepsis, HDL-C levels decrease rapidly and HDL particles undergo profound changes in their composition and function. We aimed to determine whether indices of HDL quantity and quality associate with progression and survival in patients with advanced liver disease. METHODS: HDL-related biomarkers were studied in 508 patients with compensated or decompensated cirrhosis (including acute-on-chronic liver failure [ACLF]) and 40 age- and gender-matched controls. Specifically, we studied levels of HDL-C, its subclasses HDL2-C and HDL3-C, and apolipoprotein A1 (apoA-I), as well as HDL cholesterol efflux capacity as a metric of HDL functionality. RESULTS: Baseline levels of HDL-C and apoA-I were significantly lower in patients with stable cirrhosis compared to controls and were further decreased in patients with acute decompensation (AD) and ACLF. In stable cirrhosis (n = 228), both HDL-C and apoA-I predicted the development of liver-related complications independently of model for end-stage liver disease (MELD) score. In patients with AD, with or without ACLF (n = 280), both HDL-C and apoA-I were MELD-independent predictors of 90-day mortality. On ROC analysis, both HDL-C and apoA-I had high diagnostic accuracy for 90-day mortality in patients with AD (AUROCs of 0.79 and 0.80, respectively, similar to that of MELD 0.81). On Kaplan-Meier analysis, HDL-C <17 mg/dl and apoA-I <50 mg/dl indicated poor short-term survival. The prognostic accuracy of HDL-C was validated in a large external validation cohort of 985 patients with portal hypertension due to advanced chronic liver disease (AUROCs HDL-C: 0.81 vs. MELD: 0.77). CONCLUSION: HDL-related biomarkers are robust predictors of disease progression and survival in chronic liver failure. LAY SUMMARY: People who suffer from cirrhosis (scarring of the liver) have low levels of cholesterol carried by high-density lipoproteins (HDL-C). These alterations are connected to inflammation, which is a problem in severe liver disease. Herein, we show that reduced levels of HDL-C and apolipoprotein A-I (apoA-I, the main protein carried by HDL) are closely linked to the severity of liver failure, its complications and survival. Both HDL-C and apoA-I can be easily measured in clinical laboratories and are as good as currently used prognostic scores calculated from several laboratory values by complex formulas.

Comparing Data-Independent Acquisition and Parallel Reaction Monitoring in Their Abilities To Differentiate High-Density Lipoprotein Subclasses.

High-density lipoprotein (HDL) is a diverse group of particles with multiple cardioprotective functions. HDL proteome follows HDL particle complexity. Many proteins were described in HDL, but consistent quantification of HDL protein cargo is still a challenge. To address this issue, the aim of this work was to compare data-independent acquisition (DIA) and parallel reaction monitoring (PRM) methodologies in their abilities to differentiate HDL subclasses through their proteomes. To this end, we first evaluated the analytical performances of DIA and PRM using labeled peptides in pooled digested HDL as a biological matrix. Next, we compared the quantification capabilities of the two methodologies for 24 proteins found in HDL2 and HDL3 from 19 apparently healthy subjects. DIA and PRM exhibited comparable linearity, accuracy, and precision. Moreover, both methodologies worked equally well, differentiating HDL subclasses' proteomes with high precision. Our findings may help to understand HDL functional diversity.

Higher High Density Lipoprotein 2 (HDL2) to Total HDL Cholesterol Ratio Is Associated with a Lower Risk for Incident Hypertension.

BACKGROUND: Recent studies have suggested that high density lipoprotein (HDL) cholesterol is inversely associated with the development of hypertension. We aimed to determine the association between different HDL cholesterol subclasses and risk of future hypertension. METHODS: A total of 270 Japanese Americans (130 men, 140 women) without hypertension between the ages of 34 to 75 years were enrolled. Blood pressure was measured with a mercury sphygmomanometer, and average blood pressure was calculated. Incident hypertension was determined 5 to 6 and 10 to 11 years after enrollment. HDL2, HDL3, and total HDL cholesterol were measured at baseline. RESULTS: During 10 years of follow-up, the cumulative incidence of hypertension was 28.1% (76/270). In univariate analysis, age, diabetes, waist circumference, systolic and diastolic blood pressure, fasting glucose, insulin resistance index, total and low density lipoprotein cholesterol, and visceral adipose tissue were significant predictors for incident hypertension. Among the HDL cholesterol subclass, HDL2 cholesterol was inversely associated with hypertension incidence, but both total and HDL3 cholesterol were not. In addition, HDL2/HDL cholesterol was inversely associated with future hypertension risk. In multivariate analysis, age (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.26 to 2.31; P=0.001), systolic blood pressure (OR, 1.83; 95% CI, 1.31 to 2.56; P<0.001), and HDL2/HDL cholesterol (OR, 0.71; 95% CI, 0.52 to 0.98; P=0.035), were associated with future development of hypertension. CONCLUSION: A higher proportion of HDL2 cholesterol among total HDL cholesterol predicted a lower risk for incident hypertension. However, concentrations of total HDL, HDL2, and HDL3 cholesterol were not independent predictors of incident hypertension.

High-Density Lipoprotein Particles, Cell-Cholesterol Efflux, and Coronary Heart Disease Risk.

Objective- The cell-cholesterol efflux capacity of HDL (high-density lipoprotein) is inversely associated with coronary heart disease risk. ABCA1 (ATP-binding cassette transporter A1) plays a crucial role in cholesterol efflux from macrophages to preß-1-HDL. We tested the hypothesis that coronary heart disease patients have functionally abnormal preß-1-HDL. Approach and Results- HDL cell-cholesterol efflux capacity via the ABCA1 and the SR-BI (scavenger receptor class B type I) pathways, HDL antioxidative capacity, apo (apolipoprotein) A-I-containing HDL particles, and inflammatory- and oxidative-stress markers were measured in a case-control study of 100 coronary heart disease cases and 100 sex-matched controls. There were significant positive correlations between ABCA1-dependent cholesterol efflux and the levels of small lipid-poor preß-1 particles ( R2=0.535) and between SR-BI-dependent cholesterol efflux and the levels of large lipid-rich (α-1+α-2) HDL particles ( R2=0.712). Cases had significantly higher (87%) preß-1 concentrations than controls, but the functionality of their preß-1 particles (preß-1 concentration normalized ABCA1-dependent efflux capacity) was significantly lower (-31%). Cases had significantly lower (-12%) mean concentration of large HDL particles, but the functionality of their particles (α-1+α-2 concentration normalized SR-BI-dependent efflux capacity) was significantly higher (22%) compared with that of controls. HDL antioxidative capacity was significantly lower (-16%) in cases than in controls. There were no significant correlations between either preß-1 functionality or large HDL particle functionality with HDL antioxidative capacity or the concentrations of inflammatory- and oxidative-stress markers. Conclusions- HDL cell-cholesterol efflux capacity is significantly influenced by both the concentration and the functionality of specific HDL particles participating in cell-cholesterol efflux. Coronary heart disease patients have higher than normal preß-1 concentrations with decreased functionality and lower than normal large HDL particle concentrations with enhanced functionality.

Featured Article: Depletion of HDL3 high density lipoprotein and altered functionality of HDL2 in blood from sickle cell patients.

In sickle cell disease (SCD), alterations of cholesterol metabolism is in part related to abnormal levels and activity of plasma proteins such as lecithin cholesterol acyltransferase (LCAT), and apolipoprotein A-I (ApoA-I). In addition, the size distribution of ApoA-I high density lipoproteins (HDL) differs from normal blood. The ratio of the amount of HDL2 particle relative to the smaller higher density pre-ß HDL (HDL3) particle was shifted toward HDL2. This lipoprotein imbalance is exacerbated during acute vaso-occlusive episodes (VOE) as the relative levels of HDL3 decrease. HDL3 deficiency in SCD plasma was found to relate to a slower ApoA-I exchange rate, which suggests an impaired ABCA1-mediated cholesterol efflux in SCD. HDL2 isolated from SCD plasma displayed an antioxidant capacity normally associated with HDL3, providing evidence for a change in function of HDL2 in SCD as compared to HDL2 in normal plasma. Although SCD plasma is depleted in HDL3, this altered capacity of HDL2 could account for the lack of difference in pro-inflammatory HDL levels in SCD as compared to normal. Exposure of human umbilical vein endothelial cells to HDL2 isolated from SCD plasma resulted in higher mRNA levels of the acute phase protein long pentraxin 3 (PTX3) as compared to incubation with HDL2 from control plasma. Addition of the heme-scavenger hemopexin protein prevented increased expression of PTX3 in sickle HDL2-treated cells. These findings suggest that ApoA-I lipoprotein composition and functions are altered in SCD plasma, and that whole blood transfusion may be considered as a blood replacement therapy in SCD. Impact statement Our study adds to the growing evidence that the dysfunctional red blood cell (RBC) in sickle cell disease (SCD) affects the plasma environment, which contributes significantly in the vasculopathy that defines the disease. Remodeling of anti-inflammatory high density lipoprotein (HDL) to pro-inflammatory entities can occur during the acute phase response. SCD plasma is depleted of the pre-ß particle (HDL3), which is essential for stimulation of reverse cholesterol from macrophages, and the function of the larger HDL2 particle is altered. These dysfunctions are exacerbated during vaso-occlusive episodes. Interaction of lipoproteins with endothelium increases formation of inflammatory mediators, a process counteracted by the heme-scavenger hemopexin. This links hemolysis to lipoprotein-mediated inflammation in SCD, and hemopexin treatment could be considered. The use of RBC concentrates in transfusion therapy of SCD patients underestimates the importance of the dysfunctional plasma compartment, and transfusion of whole blood or plasma may be warranted.

Dapagliflozin decreases small dense low-density lipoprotein-cholesterol and increases high-density lipoprotein 2-cholesterol in patients with type 2 diabetes: comparison with sitagliptin.

BACKGROUND: The sodium-glucose co-transporter-2 (SGLT-2) inhibitors have been reported to increase both low-density lipoprotein (LDL) and high-density lipoprotein (HDL)-cholesterol (C). This study aimed to determine how SGLT-2 inhibitors affect LDL and HDL-C subspecies. METHODS: This single center, open-label, randomized, prospective study included 80 patients with type 2 diabetes taking prescribed oral hypoglycemic agents. Patients were allocated to receive dapagliflozin (n = 40) or sitagliptin (n = 40) as add-on treatment. Fasting blood samples were collected before and 12 weeks after this intervention. Small dense (sd) LDL-C, large buoyant (lb) LDL-C, HDL2-C, and HDL3-C levels were determined using our established homogeneous assays. Statistical comparison of blood parameters before and after treatment was performed using the paired t test. RESULTS: Dapagliflozin and sitagliptin comparably decreased HbA1c (0.75 and 0.63%, respectively). Dapagliflozin significantly decreased body weight, systolic blood pressure, plasma triglycerides and liver transaminases, and increased adiponectin; sitagliptin did not alter these measurements. LDL-C and apolipoprotein (apo) B were not significantly changed by dapagliflozin, whereas HDL-C and apo AI were increased. Dapagliflozin did not alter concentrations of LDL-C, but sd LDL-C decreased by 20% and lb LDL-C increased by 18%. Marked elevation in lb LDL-C (53%) was observed in individuals (n = 20) whose LDL-C was elevated by dapagliflozin. However, sd LDL-C remained suppressed (20%). Dapagliflozin increased HDL2-C by 18% without affecting HDL3-C. Sitagliptin did not alter plasma lipids or lipoprotein subspecies. CONCLUSIONS: A SGLT-2 inhibitor, dapagliflozin suppresses potent atherogenic sd LDL-C and increased HDL2-C, a favorable cardiometabolic marker. Although LDL-C levels are elevated by treatment with dapagliflozin, this was due to increased concentrations of the less atherogenic lb LDL-C. However, these findings were not observed after treatment with dipeptidyl peptidase-4 inhibitor, sitagliptin. Trial registration UMIN Clinical Trials Registry (UMIN000020984).

A case-control study on reduced HDL2b in patients with polycystic ovarian syndrome.

High-density lipoprotein (HDL) is an important factor associated with the increasing risk of future ischaemic heart disease. In this study, we analyzed serum HDL2b level in the patients with polycystic ovary syndrome (PCOS). Total of 60 female patients with PCOS was enrolled for assessment and another 60 non-PCOS females with matched age and weight were selected as control. A highly sensitive microfluidic chip was employed to analyze the serum HDL subfractions. Serum HDL2b and HDL2b/HDL ratio were decreased in PCOS group than those in the control group (p < 0.05). Pearson correlation analysis revealed that serum HDL2b level was negatively correlated with body mass index, waist circumference, waist-to-hip ratio, INS0, HOMA-IR, T, estradiol, triglyceride (TG) and low-density lipoprotein (LDL)-C; and the ratio of HDL2b/HDL was negatively correlated with T, TG and LDL-C. Stepwise multiple regression analyses showed a reverse correlation for HDL2b and its ratio to HDL with hyperandrogenism. The results suggested that a reduction of serum HDL2b and its ratio to total serum HDL in PCOS patients by using the microfluidic chip method assessment. Hyperandrogenism was the main factor to affect HDL2b and its ratio to total HDL in PCOS patients, and it might increase the incidence of atherosclerosis as well as the risk of coronary heart disease.

High-density lipoprotein profile in newly-diagnosed lower extremity artery disease in Slovak population without diabetes mellitus.

OBJECTIVE: To assess the relationship of high density lipoprotein subfractions to newly-diagnosed lower extremity artery disease (LEAD) in individuals without diabetes mellitus and without hypolipidemic therapy. METHODS: This cross-sectional study involves 106 subjects: 51 had newly diagnosed LEAD and no diabetes anamnesis and were not on hypolipidemic therapy; and 55 controls were without clinical presentation of LEAD and were normolipidemic. Analysis of HDL subclasses was performed by an innovative electrophoresis method on polyacrylamide gel (PAG), the Lipoprint HDL System. RESULTS: In LEAD subjects, total HDL-C levels as well as HDL2 (intermediate-to-large particles) subfraction levels were decreased (p<0.0001 and p<0.019 respectively). Interestingly the HDL3 (small particles) subfraction was significantly higher and lost its proportional relationship within the HDL cholesterol fraction (p<0.025, p<0.01 respectively). CONCLUSION: These findings pointed out that: (i) the reduction of HDL-C and especially HDL2 subpopulation opposite to the increase of small HDL3 subclass may be considered as important predictors of cardiovascular diseases. (ii) there are undisputable advantages of using Lipoprint HDL to identify HDL subfractions; the presence of high concentration of small HDL in patients with PAD/LEAD emphasizes that the potentially proatherogenic subclass of HDL family is linked to small HDL.

High-density lipoprotein subfractions and carotid plaque: the Northern Manhattan Study.

OBJECTIVE: The objective of this cross-sectional analysis was to investigate the relation between two major high-density lipoprotein cholesterol (HDL-C) subfractions (HDL2-C and HDL3-C) and carotid plaque in a population based cohort. METHODS: We evaluated 988 stroke-free participants (mean age 66 ± 8 years; 40% men; 66% Hispanic and 34% Non-Hispanic) with available data on HDL subfractions using precipitation method and carotid plaque area and thickness assessed by a high-resolution 2D ultrasound. The associations between HDL-C subfractions and plaque measurements were analyzed by quantile regression. RESULTS: Plaque was present in 56% of the study population. Among those with plaque, the mean ± SD plaque area was 19.40 ± 20.46 mm² and thickness 2.30 ± 4.45 mm. The mean ± SD total HDL-C was 46 ± 14 mg/dl, HDL2-C 14 ± 8 mg/dl, and HDL3-C 32 ± 8 mg/dl. After adjusting for demographics and vascular risk factors, there was an inverse association between HDL3-C and plaque area (per mg/dl: beta = -0.26 at the 75th percentile, p = 0.001 and beta = -0.32 at the 90th percentile, p = 0.02). A positive association was observed between HDL2-C and plaque thickness (per mg/dl; beta = 0.02 at the 90% percentile, p = 0.003). HDL-C was associated with plaque area (per mg/dl: beta = -0.18 at the 90th percentile, p = 0.01), but only among Hispanics. CONCLUSION: In our cohort we observed an inverse association between HDL3-C and plaque area and a positive association between HDL2-C and plaque thickness. HDL-C subfractions may have different contributions to the risk of vascular disease. More studies are needed to fully elucidate HDL-C anti-atherosclerotic functions in order to improve HDL-based treatments in prevention of vascular disease and stroke.

HDL-3 is a superior predictor of carotid artery disease in a case-control cohort of 1725 participants.

BACKGROUND: Recent data suggest that high-density lipoprotein cholesterol (HDL-C) levels are likely not in the causative pathway of atheroprotection, shifting focus from HDL-C to its subfractions and associated proteins. This study's goal was to determine which HDL phenotype was the better predictor of carotid artery disease (CAAD). METHODS AND RESULTS: HDL-2 and HDL-3 were measured in 1725 participants of European ancestry in a prevalent case-control cohort study of CAAD. Stratified analyses were conducted for men (n=1201) and women (n=524). Stepwise linear regression was used to determine whether HDL-C, HDL-2, HDL-3, or apolipoprotein A1 was the best predictor of CAAD, while adjusting for the confounders of censored age, diabetes, and current smoking status. In both men and women, HDL-3 was negatively associated with CAAD (P=0.0011 and 0.033 for men and women, respectively); once HDL-3 was included in the model, no other HDL phenotype was significantly associated with CAAD. Addition of paraoxonase 1 activity to the aforementioned regression model showed a significant and independent (of HDL-3) association with CAAD in men (P=0.001) but not in the smaller female subgroup. CONCLUSIONS: This study is the first to contrast the associations of HDL-2 and HDL-3 with CAAD. We found that HDL-3 levels were more predictive of CAAD status than HDL-2, HDL-C, or apolipoprotein A1. In addition, for men, paraoxonase 1 activity improved the overall model prediction for CAAD independently and additively with HDL-3 levels. Further investigation into the molecular mechanisms through which HDL-3 is associated with protection from CAAD is warranted.

High-density lipoprotein subfractions display proatherogenic properties in overweight and obese children.

BACKGROUND: In adults, obesity-driven inflammation can lead to increased cardiovascular disease (CVD). However, information regarding childhood obesity and its inflammatory sequelae is less well defined. Serum amyloid-A (SAA) is an inflammatory molecule that rapidly associates with high-density lipoproteins (HDLs) and renders them dysfunctional. Therefore, SAA may be a useful biomarker to identify increased CVD potential in overweight and obese children. METHODS: Young Hearts 2000 is a cross-sectional cohort study in which 92 children who were obese were matched for age and sex with 92 overweight and 92 lean children. HDL(2) and HDL(3) (HDL(2&3)) were isolated from plasma by a three-step rapid-ultracentrifugation procedure. SAA was measured in serum and HDL(2&3) by an enzyme-linked immunosorbent assay procedure, and the activities of cholesterol ester transfer protein (CETP) and lecithin cholesteryl acyltransferase (LCAT) were measured by fluorimetric assays. RESULTS: Trends across the groups indicated that SAA increased in serum and HDL(2&3) as BMI increased, as did HDL(2)-CETP and HDL(2)-LCAT activities. CONCLUSION: These results have provided evidence that overweight and obese children are exposed to an inflammatory milieu that impacts the antiatherogenic properties of HDL and that could increase CVD risk. This supports the concept that it is important to target childhood obesity to help minimize future cardiovascular events.

[Effect of exercise on high density lipoprotein subpopulations and blood pressure]. / Efecto del ejercicio en subpoblaciones de lipoproteínas de alta densidad y en la presión arterial.

OBJECTIVE: Determine the relationship of exercise with serum levels of apoA-I and HDL2 and HDL3, subpopulations in hypertensive individuals from the city of Armenia - Quindío. METHODS: The interventions were two months of exercise. Blood pressure was taken with the recommendations of the Ministry of Health of Colombia. HDL subpopulations were measured with the method of precipitate ionic and the apoA-I was measured using nephelometry of Bindig site. RESULTS: Descriptive and inferential statistics were used for data analysis. A total of 160 patients of whom 125 remained until the end of the project were gathered, that is, there was a 78.12 % retention, 28 % did the exercise. The analysis showed a highly significant reduction of systolic and diastolic blood pressure, higher in people who did exercise. The HDL were below normal before exercise, significantly increased with exercise but still remained below the reference values, the HDL2 increased significantly, while HDL3 decreased with normal levels of apoA-I. CONCLUSION: This study shows that exercise increases the total HDL, but the most important is that exercise modified the HDL subpopulations in a relationship that favors those which seem to have ateroprotective properties. The evidence of the interrelationship between protective factors provides new arguments for public health actions against the cardiovascular risk and hypertension.

Glycemic control and high-density lipoprotein characteristics in adolescents with type 1 diabetes.

BACKGROUND: Recent evidence suggests that high-density lipoprotein (HDL) physicochemical characteristics and functional capacity may be more important that HDL-C levels in predicting coronary heart disease. There is little data regarding HDL subclasses distribution in youth with type 1 diabetes. OBJECTIVE: To assess the relationships between glycemic control and HDL subclasses distribution, composition, and function in adolescents with type 1 diabetes. METHODS: This cross-sectional study included 52 adolescents with type 1 diabetes aged 12-16 years and 43 age-matched non-diabetic controls. Patients were divided into two groups: one in fair control [hemoglobin A1c (HbA1c) < 9.6%] and the second group with poor glycemic control (HbA1c ≥ 9.6%). In all participants, we determined HDL subclasses distribution, composition, and the ability of plasma and of isolated HDL to promote cellular cholesterol efflux. Levels of soluble adhesion molecules were also measured. RESULTS: Although both groups of patients and the control group had similar HDL-C levels, linear regression analyses showed that compared with non-diabetic subjects, the poor control group had a lower proportion of HDL2b subclass (p = 0.029), triglyceride enriched (p = 0.045), and cholesteryl ester depleted (p = 0.028) HDL particles. Despite these HDL changes, cholesterol efflux was comparable among the three groups. The poor control group also had significantly higher intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 plasma concentrations. CONCLUSIONS: In adolescents with type 1 diabetes, poor glycemic control is associated with abnormalities in HDL subclasses distribution and HDL lipid composition, however, in spite of these HDL changes, the ability of HDL to promote cholesterol efflux remains comparable to that of healthy subjects.

Functionality of postprandial larger HDL2 particles is enhanced following CETP inhibition therapy.

OBJECTIVE: To evaluate the impact of CETP inhibition on the capacity of individual postprandial HDL subspecies to promote key steps of the reverse cholesterol transport pathway. METHODS: The capacity of HDL particles to mediate cellular free cholesterol efflux and selective hepatic uptake of cholesteryl esters was evaluated throughout postprandial phase (0-8 h) following consumption of a standardised mixed meal before and after treatment for 6 weeks with atorvastatin alone (10 mg/d) and subsequently with combination torcetrapib/atorvastatin (60/10 mg/d) in 16 patients displaying low HDL-C levels (<40 mg/dl). RESULTS: The larger HDL2b and HDL2a subfraction displayed a superior capacity to mediate cellular free cholesterol efflux via both SR-BI and ABCG1-dependent pathways than smaller HDL3 subspecies. CETP inhibition specifically enhanced the capacity of HDL2b subfraction for both SR-BI and ABCG1 dependent efflux. However, only the SR-BI-dependent efflux to HDL2b subspecies can be further enhanced during postprandial lipemia following CETP inhibition. Concomitantly, postprandial lipemia was associated with a reduced capacity of total HDL particles to deliver cholesteryl esters to hepatic cells in a drug independent manner. CONCLUSION: CETP inhibition specifically improves postprandial SR-BI and ABCG1-dependent efflux to larger HDL2b subspecies. In addition, CETP inhibition improves HDL-CE delivery to hepatic cells and maintains an efficient direct return of cholesteryl esters to the liver during postprandial lipemia.