Associations of the CYP7A1 Gene Polymorphisms Located in the Promoter and Enhancer Regions with the Risk of Acute Coronary Syndrome, Plasma Cholesterol, and the Incidence of Diabetes.

Cholesterol-7-alpha hydroxylase (CYP7A1) is a key enzyme in the synthesis of bile salts, and its activity can contribute to determining cholesterol levels and, consequently, the risk of developing coronary atherosclerotic disease. We evaluated whether seven (rs3808607 G/T, rs9297994 G/A, rs10504255 A/G, rs8192870 G/T, rs2081687 C/T, rs1457043 C/T, and rs10107182 C/T) polymorphisms located in the promoter and enhancer regions of the CYP7A1 gene, which have not been sufficiently explored, are candidates of risk markers of acute coronary syndrome (ACS) in the Mexican population. These polymorphisms were determined in a group of 1317 patients with ACS and 1046 control subjects. The results showed that, under different inheritance models, the alleles rs9297994 G, rs10504255 G, rs8192870 T, rs2081687 T, and rs10107182 C were significantly associated with an increased risk of ACS (pC < 0.05). In addition, the incidence of dyslipidemia among patients with ACS, notably high total cholesterol and LDL-cholesterol, and low HDL-cholesterol plasma levels, were more frequent in carriers of the same five risk alleles associated with ACS (p < 0.05). There was also an unexpected increased incidence of type 2 diabetes mellitus (T2DM) in patients with ACS who are homozygous for the rs2081687 T, rs9297944 G, rs10504255 G, and rs10107182 C alleles of the CYP7A1 gene, suggesting that such gene variants enhance the development of coronary complications in patients with diabetes (p < 0.05). In summary, our study demonstrated that five polymorphisms situated in the promoter and enhancer regions of the CYP7A1 gene are associated with the risk of ACS and higher incidences of dyslipidemia and T2DM in Mexican patients with ACS.

Total Outflow of High-Density Lipoprotein-Cholesteryl Esters from Plasma Is Decreased in a Model of 3/4 Renal Mass Reduction.

(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein metabolism is still controversial. To understand the role of the kidneys in regulating the HDL lipid content, we determined the turnover of HDL-cholesteryl esters in rabbits with a three-quarter renal mass reduction. (2) Methods: HDL subclass characterization was conducted, and the kinetics of plasma HDL-cholesteryl esters, labeled with tritium, were studied in rabbits with a 75% reduction in functional renal mass (Ntx). (3) Results: The reduced renal mass triggered the enrichment of cholesterol, specifically cholesteryl esters, in HDL subclasses. The exchange of cholesteryl esters between HDL and apo B-containing lipoproteins (VLDL/LDL) was not significantly modified in Ntx rabbits. Moreover, the cholesteryl esters of HDL and VLDL/LDL fluxes from the plasmatic compartment tended to decrease, but they only reached statistical significance when both fluxes were added to the Nxt group. Accordingly, the fractional catabolic rate (FCR) of the HDL-cholesteryl esters was lower in Ntx rabbits, concomitantly with its accumulation in HDL subclasses, probably because of the reduced mass of renal cells requiring this lipid from lipoproteins.

DNA Methylation of the IL-17A Gene Promoter Is Associated with Subclinical Atherosclerosis and Coronary Artery Disease: The Genetics of Atherosclerotic Disease Mexican Study.

The interleukin-17 (IL-17) has a crucial role during inflammation and has been associated with cardiovascular diseases, but its role in epigenetics is still poorly understood. Therefore, the aim of this study was to evaluate the DNA methylation status of the IL-17A gene promoter to establish whether it may represent a risk factor for subclinical atherosclerosis (SA) or clinical coronary artery disease (CAD). We included 38 patients with premature CAD (pCAD), 48 individuals with SA, and 43 healthy controls. Methylation in the CpG region of the IL-17A gene promoter was assessed via methylation-specific polymerase chain reaction (MSP). Individuals with SA showed increased methylation levels compared to healthy controls and pCAD patients, with p < 0.001 for both. Logistic regression analysis showed that high methylation levels represent a significant risk for SA (OR = 5.68, 95% CI = 2.38-14.03, p < 0.001). Moreover, low methylation levels of the IL-17A gene promoter DNA represent a risk for symptomatic pCAD when compared with SA patients (OR = 0.16, 95% CI = 0.06-0.41, p < 0.001). Our data suggest that the increased DNA methylation of the IL-17A gene promoter is a risk factor for SA but may be a protection factor for progression from SA to symptomatic CAD.

Eicosapentaenoic and Docosahexaenoic Acid Supplementation Increases HDL Content in n-3 Fatty Acids and Improves Endothelial Function in Hypertriglyceridemic Patients.

High-density lipoproteins (HDLs) are known to enhance vascular function through different mechanisms, including the delivery of functional lipids to endothelial cells. Therefore, we hypothesized that omega-3 (n-3) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) content of HDLs would improve the beneficial vascular effects of these lipoproteins. To explore this hypothesis, we performed a placebo-controlled crossover clinical trial in 18 hypertriglyceridemic patients without clinical symptoms of coronary heart disease who received highly purified EPA 460 mg and DHA 380 mg, twice a day for 5 weeks or placebo. After 5 weeks of treatment, patients followed a 4-week washout period before crossover. HDLs were isolated using sequential ultracentrifugation for characterization and determination of fatty acid content. Our results showed that n-3 supplementation induced a significant decrease in body mass index, waist circumference as well as triglycerides and HDL-triglyceride plasma concentrations, whilst HDL-cholesterol and HDL-phospholipids significantly increased. On the other hand, HDL, EPA, and DHA content increased by 131% and 62%, respectively, whereas 3 omega-6 fatty acids significantly decreased in HDL structures. In addition, the EPA-to-arachidonic acid (AA) ratio increased more than twice within HDLs suggesting an improvement in their anti-inflammatory properties. All HDL-fatty acid modifications did not affect the size distribution or the stability of these lipoproteins and were concomitant with a significant increase in endothelial function assessed using a flow-mediated dilatation test (FMD) after n-3 supplementation. However, endothelial function was not improved in vitro using a model of rat aortic rings co-incubated with HDLs before or after treatment with n-3. These results suggest a beneficial effect of n-3 on endothelial function through a mechanism independent of HDL composition. In conclusion, we demonstrated that EPA and DHA supplementation for 5 weeks improved vascular function in hypertriglyceridemic patients, and induced enrichment of HDLs with EPA and DHA to the detriment of some n-6 fatty acids. The significant increase in the EPA-to-AA ratio in HDLs is indicative of a more anti-inflammatory profile of these lipoproteins.

HDL as Bidirectional Lipid Vectors: Time for New Paradigms.

The anti-atherogenic properties of high-density lipoproteins (HDL) have been explained mainly by reverse cholesterol transport (RCT) from peripheral tissues to the liver. The RCT seems to agree with most of the negative epidemiological correlations between HDL cholesterol levels and coronary artery disease. However, therapies designed to increase HDL cholesterol failed to reduce cardiovascular risk, despite their capacity to improve cholesterol efflux, the first stage of RCT. Therefore, the cardioprotective role of HDL may not be explained by RCT, and it is time for new paradigms about the physiological function of these lipoproteins. It should be considered that the main HDL apolipoprotein, apo AI, has been highly conserved throughout evolution. Consequently, these lipoproteins play an essential physiological role beyond their capacity to protect against atherosclerosis. We propose HDL as bidirectional lipid vectors carrying lipids from and to tissues according to their local context. Lipid influx mediated by HDL appears to be particularly important for tissue repair right on site where the damage occurs, including arteries during the first stages of atherosclerosis. In contrast, the HDL-lipid efflux is relevant for secretory cells where the fusion of intracellular vesicles drastically enlarges the cytoplasmic membrane with the potential consequence of impairment of cell function. In such circumstances, HDL could deliver some functional lipids and pick up not only cholesterol but an integral part of the membrane in excess, restoring the viability of the secretory cells. This hypothesis is congruent with the beneficial effects of HDL against atherosclerosis as well as with their capacity to induce insulin secretion and merits experimental exploration.

Trp Fluorescence Redshift during HDL Apolipoprotein Denaturation Is Increased in Patients with Coronary Syndrome in Acute Phase: A New Assay to Evaluate HDL Stability.

High-density lipoproteins' (HDL) stability is a determinant of their residence times in plasma and consequently an important parameter that influences the beneficial properties of these lipoproteins. Since there are no accessible procedures for this purpose, here, we describe the methodological conditions to assess the stability of the HDL based on the redshift of the fluorescence spectrum of tryptophans contained in the structure of HDL-apolipoproteins during incubation with urea 8M. Along the HDL denaturation kinetics, the main variations of fluorescence were observed at the wavelengths of 330, 344, and 365 nm at room temperature. Therefore, HDL denaturation was estimated using the tryptophan (Trp)-ratio of fluorescence intensity (rfi) at such wavelengths. By setting 100% of the measurable denaturation at 26 h, HDL reached 50% after 8 h of incubation with urea. Then, for further analyses we determined the percentage of HDL denaturation at 8 h as an estimation of the stability of these lipoproteins. To explore the potential usefulness of this test, we analyzed the stability of HDL isolated from the plasma of 24 patients diagnosed with acute coronary syndrome (ACS). These HDL presented significantly higher percentages of denaturation (64.9% (58.7-78.4)) than HDLs of healthy individuals (23.3% (20.3-27.0)). These results indicate that HDL in ACS are less stable than in control subjects. Moreover, the percentage of denaturation of HDL correlated with body mass index and aspartate transaminase plasma activity. Furthermore, apo-I, HDL-cholesterol, HDL-triglycerides, and apo A-I-to-triglycerides ratio correlated with the percentage of HDL denaturation, suggesting that the lipoprotein composition is a main determinant of HDL stability. Finally, the percentage of HDL denaturation is the parameter that predicted the presence of ACS as determined by a machine learning procedure and logistic regression analysis. In conclusion, we established the methodological conditions to assess the stability of HDL by a fluorescence-based method that merits exploration in prospective studies for evaluating the coronary artery disease risk.

Microencapsulated Pomegranate Modifies the Composition and Function of High-Density Lipoproteins (HDL) in New Zealand Rabbits.

Previous studies demonstrated that pomegranate, which is a source of several bioactive molecules, induces modifications of high-density lipoproteins (HDL) lipid composition and functionality. However, it remains unclear whether the beneficial effects of pomegranate are related to improvement in the lipid components of HDL. Therefore, in this placebo-controlled study, we characterized the size and lipid composition of HDL subclasses and assessed the functionality of these lipoproteins after 30 days of supplementation with a pomegranate microencapsulated (MiPo) in New Zealand white rabbits. We observed a significant decrease in plasma cholesterol, triglycerides, and non-HDL sphingomyelin, as well as increases in HDL cholesterol and HDL phospholipids after supplementation with MiPo. Concomitantly, the triglycerides of the five HDL subclasses isolated by electrophoresis significantly decreased, whereas phospholipids, cholesterol, and sphingomyelin of HDL subclasses, as well as the HDL size distribution remained unchanged. Of particular interest, the triglycerides content of HDL, estimated by the triglycerides-to-phospholipids ratio, decreased significantly after MiPo supplementation. The modification on the lipid content after the supplementation was associated with an increased resistance of HDL to oxidation as determined by the conjugated dienes formation catalyzed by Cu2+. Accordingly, paraoxonase-1 (PON1) activity determined with phenylacetate as substrate increased after MiPo. The effect of HDL on endothelial function was analyzed by the response to increasing doses of acetylcholine of aorta rings co-incubated with the lipoproteins in an isolated organ bath. The HDL from rabbits that received placebo partially inhibited the endothelium-dependent vasodilation. In contrast, the negative effect of HDL on endothelial function was reverted by MiPo supplementation. These results show that the beneficial effects of pomegranate are mediated at least in part by improving the functionality of HDL, probably via the reduction of the content of triglycerides in these lipoproteins.

Bone Morphogenetic Protein-2 and Osteopontin Gene Expression in Epicardial Adipose Tissue from Patients with Coronary Artery Disease Is Associated with the Presence of Calcified Atherosclerotic Plaques.

PURPOSE: It has been proposed that the cardiovascular effects of obesity are related to epicardial adipose tissue (EAT), which seems to play an active role on the development and calcification of atherosclerotic plaques, but the mechanisms are still unknown. Therefore, the aim of this study was to determine whether the EAT expresses the genes of calcifying factors and whether such expression is associated with the body mass index (BMI) and with the presence of coronary artery calcium (CAC) in patients with coronary artery disease (CAD). PATIENTS AND METHODS: Forty-three patients with CAD were enrolled specifically for this study, and their CAC score and EAT volume were determined by computed tomography. As the group of comparison, 41 patients with aortic valve stenosis and CAC = 0 were included (control group). A representative subgroup of 16 CAD patients and 23 controls were selected to obtain EAT biopsies during the chirurgical procedure from the atrio-interventricular groove. The mRNA expression of bone morphogenetic protein-2 and -4 (BMP-2, BMP-4), osteopontin (OPN), osteonectin (ON), and osteoprotegerin (OPG) in EAT was determined by qPCR. RESULTS: The gene expression of OPN and BMP-2 was 70% and 52% higher in the EAT from CAD patients than that in controls, respectively, whereas the expression of OPG, ON, and BMP-4 was similar in both groups. The EAT volume positively correlated with OPG and with the BMI, suggesting a relationship of obesity with local higher expression of calcifying genes in the coronary territory. The logistic regression analysis showed that high levels of both OPN and BMP-2 increased about 6 and 8 times the odds of coronary calcification (CAC score > 0), respectively. CONCLUSION: EAT correlated with BMI and expressed the mRNA of calcifying genes but only OPN and BMP-2 expression was higher in CAD patients. Higher levels of both OPN and BMP-2 statistically determined the presence of calcium in coronary arteries of CAD patients.

Microencapsulated Pomegranate Reverts High-Density Lipoprotein (HDL)-Induced Endothelial Dysfunction and Reduces Postprandial Triglyceridemia in Women with Acute Coronary Syndrome.

(1) Background: the composition of high-density lipoproteins (HDL) becomes altered during the postprandial state, probably affecting their functionality vis-à-vis the endothelium. Since acute coronary syndrome (ACS) in women is frequently associated with endothelial dysfunction, it is likely that HDL are unable to improve artery vasodilation in these patients. Therefore, we characterized HDL from women with ACS in fasting and postprandial conditions. We also determined whether microencapsulated pomegranate (MiPo) reverts the HDL abnormalities, since previous studies have suggested that this fruit improves HDL functionality. (2) Methods: Eleven women with a history of ACS were supplemented daily with 20 g of MiPo, for 30 days. Plasma samples were obtained during fasting and at different times, after a lipid load test to determine the lipid profile and paraoxonase-1 (PON1) activity. HDL were isolated by sequential ultracentrifugation to determine their size distribution and to assess their effect on endothelial function, by using an in vitro model of rat aorta rings. (3) Results: MiPo improved the lipid profile and increased PON1 activity, as previously reported, with fresh pomegranate juice. After supplementation with MiPo, the incremental area under the curve of triglycerides decreased to half of the initial values. The HDL distribution shifted from large HDL to intermediate and small-size particles during the postprandial period in the basal conditions, whereas such a shift was no longer observed after MiPo supplementation. Consistently, HDL isolated from postprandial plasma samples hindered the vasodilation of aorta rings, and this endothelial dysfunction was reverted after MiPo consumption. (4) Conclusions: MiPo exhibited the same beneficial effects on the lipid profile and PON1 activity as the previously reported fresh pomegranate. In addition, MiPo supplementation reverted the negative effects of HDL on endothelial function generated during the postprandial period in women with ACS.

Atorvastatin and Fenofibrate Increase the Content of Unsaturated Acyl Chains in HDL and Modify In Vivo Kinetics of HDL-Cholesteryl Esters in New Zealand White Rabbits.

Previous studies demonstrated modifications of high-density lipoproteins (HDL) structure and apolipoprotein (apo) A-I catabolism induced by the atorvastatin and fenofibrate combination. However, it remains unknown whether such structural and metabolic changes of HDL were related to an improvement of the HDL-cholesteryl esters (HDL-CE) metabolism. Therefore, we determined the structure of HDL and performed kinetic studies of HDL-CE radiolabeled with tritium in rabbits treated with atorvastatin, fenofibrate, and a combination of both drugs. The atorvastatin and fenofibrate combination increased the HDL size and the cholesterol and phospholipid plasma concentrations of the largest HDL subclasses. Moreover, the relative amount of unsaturated fatty acids contained in HDL increased, in detriment of saturated fatty acids as determined by gas chromatography-mass spectrometry. The transfers of cholesteryl esters (CE) from HDL to very low-density lipoproteins/low-density lipoproteins (VLDL/LDL) and vice versa were enhanced with atorvastatin, alone or in combination. Moreover, the direct elimination of CE from plasma via VLDL/LDL decreased with fenofibrate, whereas the direct elimination of CE via HDL augmented with the combination treatment. Taken together, the rise of unsaturated fatty acid content and the size increase of HDL, suggest that atorvastatin and fenofibrate induce more fluid HDL particles, which in turn favor an enhanced CE exchange between HDL and VLDL/LDL. Our results contribute to a better understanding of the relationship between the structure and function of HDL during the use of anti-dyslipidemic drugs.

Atorvastatin and Fenofibrate Exert Opposite Effects on the Vascularization and Characteristics of Visceral Adipose Tissue in New Zealand White Rabbits.

Statins may precipitate the onset of type 2 diabetes (T2D) in high-risk patients. In contrast, only the subset of individuals with insulin resistance and/or diabetes receives cardiovascular benefits with fibrates. In this context, previous observations from our laboratory suggested that atorvastatin induced an increase in visceral adipose tissue (VAT), whereas fenofibrate had the opposite effects in rabbits. Therefore, we determined the mass, morphology, and vascularization of VAT in New Zealand white rabbits (n = 6/group) that received 0.33 or 2.6 mg/kg/d of atorvastatin or fenofibrate, respectively, during 2 months. As expected, the cholesterol from the atorvastatin group was lower after treatment, while triglycerides decreased in the fenofibrate group. The mass of VAT from the fenofibrate group was 46% lower compared to the controls, meanwhile atorvastatin was associated with a larger diameter of adipocytes (+65%) than that of the control and fenofibrate groups. Fibroblast growth factor 2 (FGF2) gene expression was lower in the fenofibrate group than in the control group (-54%). By contrast, vascular endothelial growth factor A (VEGF-A) gene expression in fenofibrate-treated rabbits was 110% higher than in the control group. In agreement with the gene expression, the marker of angiogenesis platelet endothelial cell adhesion molecule 1 was slightly but significantly higher (+10%) in rabbits treated with fenofibrate than in controls, as determined by immunohistochemistry. These results suggest that fenofibrate is associated with a favorable remodeling of VAT, that is, reduced mass and increased vascularization in normolipemic rabbits; in contrast, atorvastatin induced a nonfavorable remodeling of VAT. These results may be related to the cardiovascular benefits of fenofibrate and the increased risk of T2D in high-risk patients induced by atorvastatin.

Estudio Descriptivo: Atención y Memoria General en Niños que Practican Ajedrez, Cuenca ­ Ecuador 2015 / Descriptive Research: Attention and General Memory in Children Who Practice Chess Cuenca ­ Ecuador 2015

INTRODUCCIÓN: Los procesos cognitivos permiten el desarrollo del aprendizaje by el ajedrez ha sido tomado como herramienta para lograr este fin. El objetivo de la presente investigación fue medir atención y memoria en niños que practican ajedrez para conocer si estos resultados son superiores a los estándares normales. MÉTODOS: Se realizó un estudio descriptivo de septiembre a noviembre del 2015, la muestra estuvo constituida por 15 niños que practicaban ajedrez en la Federación Deportiva del Azuay con una práctica mínima de 6 meses. Se aplicó el Test de atención y el test de memoria y aprendizaje; se usaron medidas dispersión y tendencia central, los datos fueron procesados utilizando SPSS V25. RESULTADOS: Se obtuvo el índice compuesto de memoria verbal, la media obtenida fue de 108, desviación estándar 10.6, que corresponde a un nivel medio, según la interpretación de los baremos, mientras que en memoria no verbal la media fue de 122, correspondiente a un nivel superior. Los resultados de memoria general muestran que el Índice de memoria compuesta fue de 117, desviación estándar 12.01, indicativos de un nivel medio alto. En atención se obtuvo una media de 60 que también representó un nivel medio alto, según la interpretación del test para el índice de concentración; sin embargo los resultados fueron más dispersos con una desviación estándar 28.48. CONCLUSIONES: El nivel de concentración reveló una tendencia positiva, pero heterogénea; los niveles de memoria estaban altamente desarrollados, especialmente en memoria no verbal y en el componente verbal la captación selectiva de palabras.

BACKGROUND: Cognitive processes allow the development of learning and chess has been considered as a tool to achieve this goal. The aim of this study was to measure attention and memory in children who practice chess and to know if these results are higher than normal standards. METHODS: Descriptive research from September to November of 2015.The data were collected from 15 children who practiced chess for at least six months at the Sports Federation of Azuay. The attention D2 Test and the Test of Memory and Learning were applied. Measurements of central tendency and dispersion were used; data were processed using SPSS V25. RESULTS: The composite index of verbal memory was obtained, with a mean of 108 and a standard deviation of 10.6; this data correspond to a medium level according to the interpretation scales. Non-verbal memory average was 122, corresponding to an upper level. The general memory result shows a Composite Memory Index of 117 with a standard deviation of 12.01, corresponding to high level. In attention an average of 60 was obtained, equivalent to medium high level. We observed more dispersed data than the TOMAL test, with a standard deviation of 28.48. CONCLUSIONS: Concentration level revealed a positive and heterogeneous trend. Memory levels were highly developed, especially in non-verbal memory and word selective reminding.

Hyperuricemia is Associated with Increased Apo AI Fractional Catabolic Rates and Dysfunctional HDL in New Zealand Rabbits.

The potential cause-effect relationship between uric acid plasma concentrations and HDL functionality remains elusive. Therefore, this study aimed to explore the effect of oxonic acid (OA)-induced hyperuricemia on the HDL size distribution, lipid content of HDL subclasses, and apo AI turnover, as well as HDL functionality in New Zealand white rabbits. Experimental animals received OA 750 mg/kg/day by oral gavage during 21 days. The HDL-apo AI fractional catabolic rate (FCR) was determined by exogenous labeling with 125I, and HDL subclasses were determined by sequential ultracentrifugation and PAGE. Paraoxonase-1 activity (PON-1) and the effect of HDL on relaxation of aorta rings in vitro were determined as an indication of HDL functionality. Oxonic acid induced a sixfold increase of uricemia (0.84 ± 0.06 vs. 5.24 ± 0.12 mg/dL, P < 0.001), and significant decreases of triglycerides and phospholipids of HDL subclasses, whereas HDL size distribution and HDL-cholesterol remained unchanged. In addition, HDL-apo AI FCR was significantly higher in hyperuricemic rabbits than in the control group (0.03697 ± 0.0038 vs. 0.02605 ± 0.0017 h-1 respectively, P < 0.05). Such structural and metabolic changes were associated with lower levels of PON-1 activities and deleterious effects of HDL particles on endothelium-mediated vasodilation. In conclusion, hyperuricemia is associated with structural and metabolic modifications of HDL that result in impaired functionality of these lipoproteins. Our data strongly suggest that uric acid per se exerts deleterious effects on HDL that contribute to increase the risk of atherosclerosis.

Differential expression of osteopontin, and osteoprotegerin mRNA in epicardial adipose tissue between patients with severe coronary artery disease and aortic valvular stenosis: association with HDL subclasses.

BACKGROUND: Previous studies suggest a relationship of the epicardial adipose tissue (EAT) with progression and calcification of the atherosclerotic plaque; however, it is unknown if this tissue expresses genes that may participate on these processes and if the expression of these genes is regulated by high-density lipoprotein (HDL) subclasses. METHODS: To explore this possibility, we determined the mRNA expression by qPCR of a pro-calcifying gene (osteopontin (OPN)), and two anti-calcifying genes (osteoprotegerin (OPG) and osteonectin (ON)), in biopsies of EAT obtained from 15 patients with coronary artery disease (CAD) determined by angiography, and 15 patients with diagnostic of aortic valve stenosis but without CAD as control group. We determined the distribution and composition of HDL subclasses by electrophoresis and their statistical relationship with the gene expression in EAT. RESULTS: EAT from CAD patients showed a higher expression level of OPN and OPG than control group, whereas ON expression was similar between groups. Large HDL subclasses were cholesterol-poor in CAD patients as estimated by the cholesterol-to-phospholipid ratio. A linear regression model showed an independent association of OPN expression with HDL3a-cholesterol, and OPG expression with the relative proportion of HDL3b protein. Logistic analysis determined that OPN expression was positively associated with the presence of atherosclerotic plaque CONCLUSION: OPN, ON, and OPG genes are transcribed in EAT; to the exception of ON, the level of expression was different in CAD patients and control group, and correlated with some HDL subclasses, suggesting a new role of these lipoproteins.

Increased HDL Size and Enhanced Apo A-I Catabolic Rates Are Associated With Doxorubicin-Induced Proteinuria in New Zealand White Rabbits.

The catabolism and structure of high-density lipoproteins (HDL) may be the determining factor of their atheroprotective properties. To better understand the role of the kidney in HDL catabolism, here we characterized HDL subclasses and the catabolic rates of apo A-I in a rabbit model of proteinuria. Proteinuria was induced by intravenous administration of doxorubicin in New Zealand white rabbits (n = 10). HDL size and HDL subclass lipids were assessed by electrophoresis of the isolated lipoproteins. The catabolic rate of HDL-apo A-I was evaluated by exogenous radiolabelling with iodine-131. Doxorubicin induced significant proteinuria after 4 weeks (4.47 ± 0.55 vs. 0.30 ± 0.02 g/L of protein in urine, P < 0.001) associated with increased uremia, creatininemia, and cardiotoxicity. Large HDL2b augmented significantly during proteinuria, whereas small HDL3b and HDL3c decreased compared to basal conditions. HDL2b, HDL2a, and HDL3a subclasses were enriched with triacylglycerols in proteinuric animals as determined by the triacylglycerol-to-phospholipid ratio; the cholesterol content in HDL subclasses remained unchanged. The fractional catabolic rate (FCR) of [(131)I]-apo A-I in the proteinuric rabbits was faster (FCR = 0.036 h(-1)) compared to control rabbits group (FCR = 0.026 h(-1), P < 0.05). Apo E increased and apo A-I decreased in HDL, whereas PON-1 activity increased in proteinuric rabbits. Proteinuria was associated with an increased number of large HDL2b particles and a decreased number of small HDL3b and 3c. Proteinuria was also connected to an alteration in HDL subclass lipids, apolipoprotein content of HDL, high paraoxonase-1 activity, and a rise in the fractional catabolic rate of the [(131)I]-apo A-I.

Echocardiographic and Histologic Correlations in Patients with Severe Aortic Stenosis: Influence of Overweight and Obesity.

BACKGROUND: Severe aortic stenosis (AS), leads to pathological left ventricular remodeling that may worsen with concomitant overweight and obesity (OW/O). METHODS: We aimed to prospectively analyze the impact of OW/O on ventricular remodeling in severe AS, by evaluating the percentage of intraendomyocardial fibrosis (PIEF) and the percentage of infiltrating intraendocardial lipid vacuoles (PIELV) and its relationship to global longitudinal strain (GLS) in patients with OW/O. RESULTS: 44 patients with severe AS were included, 13 non-obese (29%) and 31 OW/O (71%), all of them with left ventricular ejection fraction ≥ 55%. GLS was evaluated with 2D speckle tracking. During valve replacement, an endocardial biopsy was obtained, where PIEF and PIELV were analyzed. Patients with higher PIEF and PIELV had greater body mass index (p < 0.0001) and worse GLS (p < 0.0053). A GLS cut-off point < -14% had a sensitivity of 75%, and a specificity of 92.8% to detect important PIEF (AUC: 0.928, 95% confidence interval: 0.798-1.00). On multivariate analysis, OW/O and PIELV were independently associated to the PIEF, and OW/O and PIEF were independently associated to GLS. A high correlation between the amount of PIELV and PIEF were found. CONCLUSION: Patients with severe AS and OW/O have greater PIEF and PIELV, suggesting more pathological remodeling. GLS is useful to detect subclinical myocardial injury and is potentially useful for endomyocardial fibrosis detection. The presence of higher PIELF may be a trigger factor for the development of intraendomyocardial fibrosis.

Atorvastatin and fenofibrate combination induces the predominance of the large HDL subclasses and increased apo AI fractional catabolic rates in New Zealand white rabbits with exogenous hypercholesterolemia.

The anti-atherogenic properties of high-density lipoproteins (HDLs) may be related to their structure and metabolism. The HDL physicochemical characteristics that determine their plasma clearance during treatment with statins and fibrates are not well understood. In this study, we analyzed HDL-apo AI fractional catabolic rates (FCRs), size distributions, and the lipid composition of the HDL subclasses in New Zealand white rabbits with exogenous dyslipidemia that received low doses of atorvastatin and fenofibrate. Hypercholesterolemia decreased only partially with the combination of both drugs. HDL size distribution shifted toward larger particles among the groups of rabbits that received atorvastatin, fenofibrate, or their combination, compared with both the control group and the dyslipidemic group. The HDL subclasses were significantly rich in cholesterol in each of the groups compared with controls. The structural changes noted in the HDL subclasses were not associated with impaired plasma paraoxonase-1 (PON1) activity. The groups receiving monotherapy and the drug combination group were all associated with a higher apo AI FCR value compared with both the dyslipidemic rabbits and the control group. In conclusion, the combination of atorvastatin and fenofibrate induced a more favorable HDL subclass profile than did the individual use of these drugs. Similarly, the apo AI FCR values were augmented in every group receiving drug treatment (either monotherapy or combination therapy) in the setting of hypercholesterolemia. The anti-atherogenic properties of HDLs, excluding their capacity to bind PON1, may be enhanced by the structural and metabolic modifications induced by the combination of atorvastatin and fenofibrate.

Adipose Tissue in Metabolic Syndrome: Onset and Progression of Atherosclerosis.

Metabolic syndrome (MetS) should be considered a clinical entity when its different symptoms share a common etiology: obesity/insulin resistance as a result of a multi-organ dysfunction. The main interest in treating MetS as a clinical entity is that the addition of its components drastically increases the risk of atherosclerosis. In MetS, the adipose tissue plays a central role along with an unbalanced gut microbiome, which has become relevant in recent years. Once visceral adipose tissue (VAT) increases, dyslipidemia and endothelial dysfunction follow as additive risk factors. However, when the nonalcoholic fatty liver is present, risk of a cardiovascular event is highly augmented. Epicardial adipose tissue (EAT) seems to increase simultaneously with the VAT. In this context, the former may play a more important role in the development of the atherosclerotic plaque than the latter. Hence, EAT may act as a paracrine tissue vis-à-vis the coronary arteries favoring the local inflammation and the atheroma calcification.

Early endothelial nitrosylation and increased abdominal adiposity in Wistar rats after long-term consumption of food fried in canola oil.

OBJECTIVE: The aim of this study was to establish whether the long-term consumption of reused canola oil contributes to the development of dyslipidemia, obesity, and endothelial function. METHODS: Canola oil was used for one frying cycle (1 FC) of corn flour dough or reused 10 times (10 FC). Rats received chow diet (control) or supplemented with 7% raw oil (RO), 1 FC or 10 FC oil (n = 10 per group). Food consumption, blood pressure (BP), and body weight plasma glucose, plasma lipids were monitored. Vascular reactivity was analyzed using aorta rings stimulated with phenylephrine and acetylcholine. Nitrotyrosine presence in aorta rings was analyzed by immunohistochemistry. RESULTS: After 10 wk of follow-up, visceral adipose tissue was significantly more abundant in 1 FC (7.4 ± 0.6 g) and 10 FC (8.8 ± 0.7 g) than the RO (5.0 ± 0.2 g; P = 0.05 versus 10 FC group) or control group (2.6 ± 0.3 g; P = 0.05 versus all groups). Despite similar plasma cholesterol, triglycerides, and BP among groups, a significantly reduced acetylcholine-induced vascular relaxation was observed in the three groups receiving the oil-supplemented diet (47.2% ± 3.6%, 27.2% ± 7.7%, and 25.9% ± 7.6% of relaxation, for the RO, 1 FC, and 10 FC, respectively; P < 0.05 for all versus 62.4% ± 9.7% of the control group). Endothelial dysfunction was concomitant with the presence of nitrotyrosine residues at a higher extent in the groups that received heated oils compared with the RO group. CONCLUSION: High canola oil intake over 10 wk was associated with increased adipose tissue and early endothelial dysfunction probably induced by peroxinitrite formation. Such deleterious effects were significantly potentiated when the consumed oil had been used repeatedly for frying.

Normal HDL-apo AI turnover and cholesterol enrichment of HDL subclasses in New Zealand rabbits with partial nephrectomy.

OBJECTIVE: The kidney has been proposed to play a central role in apo AI catabolism, suggesting that HDL structure is determined, at least in part, by this organ. Here, we aimed at determining the effects of a renal mass reduction on HDL size distribution, lipid content, and apo AI turnover. METHODS: We characterized HDL subclasses in rabbits with a 75% reduction of functional renal mass (Nptx group), using enzymatic staining of samples separated on polyacrylamide electrophoresis gels, and also performed kinetic studies using radiolabeled HDL-apo AI in this animal model. RESULTS: Creatinine clearance was reduced to 35% after nephrectomy as compared to the basal values, but without increased proteinuria. A slight, but significant modification of the relative HDL size distribution was observed after nephrectomy, whereas cholesterol plasma concentrations gradually augmented from large HDL2b (+54%) to small HDL3b particles (+150%, P<0.05). Cholesteryl esters were the increased fraction; in contrast, free cholesterol phospholipids and triglycerides of HDL subclasses were not affected by nephrectomy. HDL-apo AI fractional catabolic rates were similar to controls. CONCLUSION: Reduction of functional renal mass is associated to enrichment of HDL subclasses with cholesteryl esters. Structural abnormalities were not related to a low apo AI turnover, suggesting renal contribution to HDL remodeling beyond being just a catabolic site for these lipoproteins.