Impaired Reverse Cholesterol Transport is Associated with Changes in Fatty Acid Profile in Children and Adolescents with Abdominal Obesity.

BACKGROUND: Abdominal obesity is an important cardiovascular disease risk factor. Plasma fatty acids display a complex network of both pro and antiatherogenic effects. High density lipoproteins (HDL) carry out the antiatherogenic pathway called reverse cholesterol transport (RCT), which involves cellular cholesterol efflux (CCE), and lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities. OBJECTIVES: Our aim was to characterize RCT and its relation to fatty acids present in plasma in pediatric abdominal obesity. METHODS: Seventeen children and adolescents with abdominal obesity and 17 healthy controls were studied. Anthropometric parameters were registered. Glucose, insulin, lipid levels, CCE employing THP-1 cells, LCAT and CETP activities, plus fatty acids in apo B-depleted plasma were measured. RESULTS: The obese group showed a more atherogenic lipid profile, plus lower CCE (Mean±Standard Deviation) (6 ± 2 vs. 7 ± 2%; P < 0.05) and LCAT activity (11 ± 3 vs. 15 ±5 umol/dL.h; P < 0.05). With respect to fatty acids, the obese group showed higher myristic (1.1 ± 0.3 vs. 0.7 ± 0.3; P < 0.01) and palmitic acids (21.5 ± 2.8 vs. 19.6 ± 1.9; P < 0.05) in addition to lower linoleic acid (26.4 ± 3.3 vs. 29.9 ± 2.6; P < 0.01). Arachidonic acid correlated with CCE (r = 0.37; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05), palmitioleic acid with CCE (r = -0.35; P < 0.05), linoleic acid with CCE (r = 0.37; P < 0.05), lauric acid with LCAT (r = 0.49; P < 0.05), myristic acid with LCAT (r = -0.37; P < 0.05) ecoisatrienoic acid with CCE (r = 0.40; P < 0.05) and lignoseric acid with LCAT (r = -0.5; P < 0.01). CONCLUSIONS: Children and adolescents with abdominal obesity presented impaired RCT, which was associated with modifications in proinflammatory fatty acids, such as palmitoleic and myristic, thus contributing to increased cardiovascular disease risk.

Impaired HDL-associated enzymes and proteins in children and adolescents with weight disorders and their association with novel cardiometabolic indexes.

BACKGROUND AND AIMS: Overweight/obesity (OW/OB) is associated with modifications in lipoprotein (Lp)-associated enzymes and proteins, such as cholesteryl ester transfer protein (CETP), Lp-associated phospholipase A2 (LpPLA2) and paraoxonase (PON)1. No evidence is available regarding underweight (UW). The following indexes have been proposed to better assess atherogenic risk related to weight alterations: triglycerides-glucose index (TyG), visceral adiposity index (VAI) and height-corrected lipid accumulation product (HLAP). AIM: To analyze the presence of alterations in Lp-associated enzymes and proteins in children and adolescents with UW and OW/OB and their relation to novel cardiometabolic indexes. METHODS AND RESULTS: Thirty male children and adolescents with UW, 66 with normal weight (NW) and 30 with OW/OB were included. Anthropometric parameters, glucose, Lp profile and the activities of CETP, LpPLA2 and PON1 were evaluated. Body mass index (BMI)-z, TyG, VAI and HLAP were calculated. UW and NW showed lower CETP activity than OW/OB (Mean ± SD) (218 ± 38vs.224 ± 26vs.237 ± 26%/mL.h; p < 0.05). UW and OW/OB showed lower PON1 activity than NW (318 ± 170vs.409 ± 200vs.310 ± 184 nmol/mL.min; p < 0.05). TyG was higher in OW/OB than UW (p < 0.01), whilst both HLAP (p < 0.05) and VAI (p < 0.01) followed a linear trend across weight categories. After adjusting for age and BMI-z, TyG was an independent predictor of CETP (r2 = 0.25, ß = -0.22, p < 0.01) and LpPLA2 (r2 = 0.21,ß = -0.21,p < 0.05), while VAI (r2 = 0.21,ß = -0.32,p < 0.01) and HLAP (r2 = 0.20,ß = -0.31,p < 0.01) of CETP. CONCLUSIONS: Both UW and OW/OB showed impaired antioxidant PON1 activity. Moreover, TyG, VAI and HLAP were all capable of predicting alterations in crucial modulators of Lp metabolism and vascular inflammation in children and adolescents with varying degrees of alterations in body weight.

Poor glycemic control in type 2 diabetes enhances functional and compositional alterations of small, dense HDL3c.

High-density lipoprotein (HDL) possesses multiple biological activities; small, dense HDL3c particles displaying distinct lipidomic composition exert potent antiatherogenic activities which can be compromised in dyslipidemic, hyperglycemic insulin-resistant states. However, it remains indeterminate (i) whether such functional HDL deficiency is related to altered HDL composition, and (ii) whether it originates from atherogenic dyslipidemia, dysglycemia, or both. In the present work we analyzed compositional characteristics of HDL subpopulations and functional activity of small, dense HDL3c particles in treatment-naïve patients with well-controlled (n=10) and poorly-controlled (n=8) type 2 diabetes (T2D) and in normolipidemic age- and sex-matched controls (n=11). Our data reveal that patients with both well- and poorly-controlled T2D displayed dyslipidemia and low-grade inflammation associated with altered HDL composition. Such compositional alterations in small, dense HDL subfractions were specifically correlated with plasma HbA1c levels. Further analysis using a lipidomic approach revealed that small, dense HDL3c particles from T2D patients with poor glycemic control displayed additional modifications of their chemical composition. In parallel, antioxidative activity of HDL3c towards oxidation of low-density lipoprotein was diminished. These findings indicate that defective functionality of small, dense HDL particles in patients with T2D is not only affected by the presence of atherogenic dyslipidemia, but also by the level of glycemic control, reflecting compositional alterations of HDL.

Associations between disease activity, markers of HDL functionality and arterial stiffness in patients with rheumatoid arthritis.

BACKGROUND AND AIMS: Rheumatoid arthritis (RA) is a chronic, inflammatory disease associated with increased risk of cardiovascular disease (CVD). Measures of HDL metabolism/function were shown to be altered in RA patients with high disease activity. We aimed at evaluating the effect of HDL characteristics on arterial stiffness in RA patients classified according to the inflammatory disease activity. METHODS: RA patients were classified according to disease activity (DAS-28) into active RA (n = 27; DAS-28 > 3.2) and inactive RA patients (n = 17; DAS-28 < 3.2). A control group of healthy individuals was also studied (n = 33). Clinical and biochemical characteristics, cholesteryl ester transfer protein (CETP) and paraoxonase 1 (phenylacetate and paraoxonase) activities and carotid-femoral pulse wave velocity (cf-PWV) were determined. RESULTS: Anthropometric characteristics were similar in all groups. In accordance with the inflammatory status, active RA patients presented elevated hsCRP levels (p < 0.001). There were no differences in the lipid profile between groups. Similarly, features of insulin resistance were absent in RA patients (p = non-significant). Active RA patients presented higher CETP activity than the other two groups (p = 0.026). Phenylacetate and paraoxonase activities were altered in active RA patients in comparison with the other groups (p = 0.034 and p = 0.041, respectively). Cf-PWV was significantly higher in active RA patients in comparison with controls, following adjustment by age (p = 0.030). Age (ßst = 0.468, p = 0.013) and apo A-I levels (ßst = -0.405, p = 0.029) were independent predictors of cf-PWV in a model including hsCRP, HOMA-IR, and phenylacetate activity (r(2) = 0.42). CONCLUSIONS: High DAS-28 identifies patients with alterations in HDL characteristics. Plasma levels of apo A-I can be used as a marker of arterial stiffness in RA.

Vascular reactivity and biomarkers of endothelial function in healthy subjects exposed to acute hypobaric hypoxia.

AIMS: The aim of this study was to evaluate the effects of acute hypobaric hypoxia (HH) on vascular reactivity and biochemical markers associated with endothelial function (EF). MAIN METHODS: Ten healthy subjects were exposed to a simulated altitude of 4,000 meters above sea level for 4 hours in a hypobaric chamber. Vascular reactivity was measured by the flow-mediated vasodilatation (FMVD) test. Endothelin-1, high sensitive-C reactive protein (hsCRP), vascular cell adhesion molecule 1, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), paraoxonase and adiponectin levels, and FMVD were evaluated before and after the exposure. KEY FINDINGS: Subjects were young (age: 32±6 years), lean [body mass index: 23.9±2.0kg/m(2), waist circumference: 77(IQR: 72-80) cm], and presented normal clinical and biochemical parameters. No significant changes were evidenced in FMVD in response to HH (pre: 0.45 (0.20-0.70) vs. during: 0.50 (0.20-1.22) mm; p=0.594). On the other hand, endothelin-1 (+54%, p<0.05), hsCRP (+37%, p<0.001), IL-6 (+75%, p<0.05), TNF-α (+75%, p<0.05), and adiponectin (-39%, p<0.01) levels were significantly altered post-HH. FMVD was increased in 7 subjects, and it was decreased in 3 individuals during HH exposure. Interestingly, when EF biomarkers were compared between these two subgroups of subjects, only post exposure-adiponectin levels were significantly different (49±5 vs. 38±6µg/ml, respectively, p<0.05). SIGNIFICANCE: HH exposure had an effect on endothelin-1, adiponectin, hsCRP, IL-6, and TNF-α concentration. However, adiponectin was the only biomarker associated with an altered vascular reactivity.

CONDITIONING FACTORS FOR HIGH CARDIOVASCULAR RISK IN PATIENTS WITH CUSHING SYNDROME.

OBJECTIVE: To characterize the alterations in carbohydrate and lipoprotein metabolism, to evaluate markers of lipoprotein functionality, and to identify the presence of novel atherogenic risk factors in patients with Cushing syndrome (CS) in comparison with sex- and age-matched controls. METHODS: In an open, cross-sectional study, 32 nontreated patients with active CS were consecutively recruited from the Endocrinology Service at "José de San Martín" Clinical Hospital, University of Buenos Aires, Argentina, between April 11, 2010 and December 11, 2012. The patients were compared with sex- and age-matched controls. RESULTS: Versus controls, patients with CS presented with excess weight, central obesity, and hypercortisolism. They also exhibited an insulin-resistant state, with high resistin levels (median [interquartile range], 16 [10 to 22] ng/mL versus 6 [5 to 9] ng/mL; P<.0001), a more atherogenic lipoprotein profile, high oxidized low-density lipoprotein levels (oxLDL; mean ± SD, 100 ± 31 U/L versus 75 ± 32 U/L; P<.05) and high sensitive C-reactive protein levels (median [interquartile range], 1.2 [0.6 to 3.1] mg/L versus 0.6 [0.3 to 1.1] mg/L; P<.05), and increased leukocyte count (mean ± SD, 9.5 ± 2.6 × 10(3) cells/µL versus 6.5 ± 1.4 × 10(3) cells/µL; P<.0001). Multivariate analyses showed that the increase in waist circumference was associated with both the diagnosis of CS and the degree of insulin resistance. Resistin concentration was related to a greater extent to the diagnosis of CS than to homeostasis model assessment-insulin resistance. Triglyceride and oxLDL levels were only significantly associated with the diagnosis of CS. CONCLUSION: Hypercortisolism is related to the increase observed in triglycerides and oxLDL levels, and, in combination with insulin resistance, acts to increase waist circumference and amplify the inflammatory process, key factors for the development of cardiovascular disease.

Altered lipidome and antioxidative activity of small, dense HDL in normolipidemic rheumatoid arthritis: relevance of inflammation.

OBJECTIVE: High-density lipoprotein (HDL) particles exert potent antiatherogenic activities, including antioxidative actions, which are relevant to attenuation of atherosclerosis progression. Such activities are enriched in small, dense HDL and can be compromised under conditions of chronic inflammation like rheumatoid arthritis (RA). However, structure-function relationships of HDL largely remain indeterminate. METHODS: The relationships between HDL structure and function were evaluated in normolipidemic patients with active RA (DAS28 > 3.2; n = 12) and in normolipidemic age-matched controls (n = 10). Small, dense HDL3b and 3c particles were isolated from plasma or serum by density gradient ultracentrifugation and their physicochemical characteristics, lipidome (by LC/MS/MS) and antioxidative function (as protection of normolipidemic LDL from free radical-induced oxidation) were evaluated. RESULTS: As expected, active RA patients featured significantly elevated plasma levels of high-sensitivity C-reactive protein (hsCRP; p < 0.001) and serum amyloid A (SAA; p < 0.01) relative to controls. Antioxidative activity and weight % chemical composition of small, dense HDL did not differ between RA patients and controls (p > 0.05), whereas HDL phosphosphingolipidome was significantly altered in RA. Subgroup analyses revealed that RA patients featuring high levels of inflammation (hsCRP>10 mg/l) possessed small, dense HDL with reduced antioxidative activities (p < 0.01). Furthermore, antioxidative activity of HDL was inversely correlated with plasma hsCRP (p < 0.01). CONCLUSIONS: These data revealed that (i) despite normolipidemic state, the lipidome of small, dense HDL was altered in RA and (ii) high levels of inflammation can be responsible for the functional deficiency of small, dense HDL in RA.

Liver Med23 ablation improves glucose and lipid metabolism through modulating FOXO1 activity.

Mediator complex is a molecular hub integrating signaling, transcription factors, and RNA polymerase II (RNAPII) machinery. Mediator MED23 is involved in adipogenesis and smooth muscle cell differentiation, suggesting its role in energy homeostasis. Here, through the generation and analysis of a liver-specific Med23-knockout mouse, we found that liver Med23 deletion improved glucose and lipid metabolism, as well as insulin responsiveness, and prevented diet-induced obesity. Remarkably, acute hepatic Med23 knockdown in db/db mice significantly improved the lipid profile and glucose tolerance. Mechanistically, MED23 participates in gluconeogenesis and cholesterol synthesis through modulating the transcriptional activity of FOXO1, a key metabolic transcription factor. Indeed, hepatic Med23 deletion impaired the Mediator and RNAPII recruitment and attenuated the expression of FOXO1 target genes. Moreover, this functional interaction between FOXO1 and MED23 is evolutionarily conserved, as the in vivo activities of dFOXO in larval fat body and in adult wing can be partially blocked by Med23 knockdown in Drosophila. Collectively, our data revealed Mediator MED23 as a novel regulator for energy homeostasis, suggesting potential therapeutic strategies against metabolic diseases.

Physical activity and cardiometabolic risk in male children and adolescents: the Balcarce study.

AIMS: This study aims to evaluate the relationship between the amount of physical activity and different traditional and novel cardiometabolic risk factors, as well as atheroprotective agents, in male children and adolescents. MAIN METHODS: Cross-sectional study. A total of 337 male children and adolescents aged 7-14 years old from the rural city of Balcarce, Buenos Aires, Argentina were studied. KEY FINDINGS: The main finding of the present study was that, in male children and adolescents, physical activity was inversely associated with lipoprotein-associated phospholipase A2 (Lp-PLA2) activity (r=-0.39, p<0.001) and with cholesteryl ester transfer protein activity (r=-0.23, p<0.05) apart from other proatherogenic agents after adjusting for age and BMI. Strikingly, among the parameters evaluated, overweight, hyperglycemia and Lp-PLA2 activity resulted to be independently related to physical activity as shown by stepwise regression analysis. SIGNIFICANCE: The strong negative association between exercise and Lp-PLA2 activity and the fact that the latter resulted to be the unique continuous variable that persisted associated with physical activity would add an additional benefit of exercise in early prevention of vascular inflammation and atherogenesis.

La rosuvastatina atenúa la progresión de la estenosis aórtica generada por hipertensión arterial, independientemente de sus efectos hipolipemiantes / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects

Introducción Existe evidencia epidemiológica que vincula factores de riesgo cardiovascular con la estenosis valvular aórtica. Recientemente se ha demostrado el desarrollo de estenosis valvular aórtica en un modelo de hipertensión arterial en animales. Planteamos la hipótesis de que el tratamiento con rosuvastatina modifica esta transformación. Objetivo Evaluar el efecto de la rosuvastatina sobre el desarrollo de estenosis valvular aórtica. Material y métodos Se instrumentaron conejos NZ machos (n = 43) con el modelo 1-riñón 1-clip de Goldblatt para generar hipertensión arterial. Los animales fueron aleatorizados a: HT (n = 17) que no recibió otro tratamiento, HT+R (n = 14) tratado con rosuvastatina 2,5 mg/kg/día y HT+R+C (n = 12) tratado con rosuvastatina 2,5 mg/kg/día + suplemento de colesterol dietético para mantener los niveles basales de colesterol plasmático. Un grupo control (GC) fue sometido a cirugía simulada (n = 15). Las características de la válvula aórtica se midieron por ecografía en condiciones basales y a los 3 y a los 6 meses de hipertensión arterial. Resultados A los 6 meses de seguimiento, los incrementos de PAS y PAD fueron más elevados en HT (49% y 40%, respectivamente; p < 0,001) en comparación con los grupos tratados con rosuvastatina (PAS = 23% y 25%; PAD = 28% y 26%; p < 0,001 para HT+R y HT+R+C, respectivamente). El colesterol total se redujo el 45,7% (p < 0,01) sólo en HT+R. El espesor valvar se incrementó en HT (0,50 ± 0,01 vs. 0,62 ± 0,02 mm; p < 0,01), sin mostrar diferencias en HT+R y HT+R+C. Finalmente, el área valvular aórtica mostró una reducción en HT (0,277 ± 0,024 vs. 0,208 ± 0,014 cm²; p < 0,05), sin cambios en HT+R y HT+R+C y un aumento no significativo en el GC (0,264 ± 0,022 vs. 0,32 ± 0,016 cm²; p = 0,07). Conclusiones La rosuvastatina atenúa la progresión de la estenosis valvular aórtica generada por hipertensión arterial. Esta protección podría ser mediada por efectos no hipolipemiantes de estas drogas.

Background There is epidemiological evidence associating cardiovascular risk factors with aortic valve stenosis. The development of aortic valve stenosis has been recently demonstrated in a hypertensive animal model. We hypothesize that treatment with rosuvastatin modifies this transformation. Objective To evaluate the effect of rosuvastatin on the development of aortic valve stenosis. Material and Methods Hypertension was induced in 43 male NZ rabbits by a onekidney, one-clip Goldblatt procedure. The animals were randomly assigned to 3 groups: HT (n=17) without treatment; HT+R (n=14) treated with rosuvastatin 2.5 mg/kg/day and HT+R+C (n=12) treated with rosuvastatin 2.5 mg/kg/day + cholesterol-enriched diet to keep baseline cholesterol levels. A control group (CG) underwent sham surgery (n=15). The characteristics of the aortic valve were measured by echocardiography at baseline, 3 and 6 months after inducing hypertension. Results After 6 months of follow-up, SBP and DBP presented greater increase in the group HT (49% and 40%, respectively; p<0.001) compared to groups treated with rosuvastatin (SBP = 23% and 25%; DBP = 28% and 26%; p <0.001 for HT+R and HT+R+C, respectively). Total cholesterol decreased by 45.7% (p <0.01) only in HT+R group. The aortic valve became thickened in the HT group (0.50 ± 0.01 vs. 0.62± 0.02 mm; p <0.01); there were no significant differences in HT+R and HT+R+C. Finally, the aortic valve area was reduced in HT (0.277 ± 0.024 vs. 0.208 ± 0.014 cm² ; p <0.05), had no differences in HT+R and HT+R+C, and presented a non-significant increase in CG (0.264 ± 0.022 vs. 0.32± 0.016 cm²; p=0.07). Conclusions Rosuvastatin slows the progression of aortic valve stenosis caused by hypertension. This protection might be independent of the lipid-lowering effect of the drug.

La rosuvastatina atenúa la progresión de la estenosis aórtica generada por hipertensión arterial, independientemente de sus efectos hipolipemiantes / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects

Introducción Existe evidencia epidemiológica que vincula factores de riesgo cardiovascular con la estenosis valvular aórtica. Recientemente se ha demostrado el desarrollo de estenosis valvular aórtica en un modelo de hipertensión arterial en animales. Planteamos la hipótesis de que el tratamiento con rosuvastatina modifica esta transformación. Objetivo Evaluar el efecto de la rosuvastatina sobre el desarrollo de estenosis valvular aórtica. Material y métodos Se instrumentaron conejos NZ machos (n = 43) con el modelo 1-riñón 1-clip de Goldblatt para generar hipertensión arterial. Los animales fueron aleatorizados a: HT (n = 17) que no recibió otro tratamiento, HT+R (n = 14) tratado con rosuvastatina 2,5 mg/kg/día y HT+R+C (n = 12) tratado con rosuvastatina 2,5 mg/kg/día + suplemento de colesterol dietético para mantener los niveles basales de colesterol plasmático. Un grupo control (GC) fue sometido a cirugía simulada (n = 15). Las características de la válvula aórtica se midieron por ecografía en condiciones basales y a los 3 y a los 6 meses de hipertensión arterial. Resultados A los 6 meses de seguimiento, los incrementos de PAS y PAD fueron más elevados en HT (49% y 40%, respectivamente; p < 0,001) en comparación con los grupos tratados con rosuvastatina (PAS = 23% y 25%; PAD = 28% y 26%; p < 0,001 para HT+R y HT+R+C, respectivamente). El colesterol total se redujo el 45,7% (p < 0,01) sólo en HT+R. El espesor valvar se incrementó en HT (0,50 ± 0,01 vs. 0,62 ± 0,02 mm; p < 0,01), sin mostrar diferencias en HT+R y HT+R+C. Finalmente, el área valvular aórtica mostró una reducción en HT (0,277 ± 0,024 vs. 0,208 ± 0,014 cm²; p < 0,05), sin cambios en HT+R y HT+R+C y un aumento no significativo en el GC (0,264 ± 0,022 vs. 0,32 ± 0,016 cm²; p = 0,07). Conclusiones La rosuvastatina atenúa la progresión de la estenosis valvular aórtica generada por hipertensión arterial. Esta protección podría ser mediada por efectos no hipolipemiantes de estas drogas.(AU)

Background There is epidemiological evidence associating cardiovascular risk factors with aortic valve stenosis. The development of aortic valve stenosis has been recently demonstrated in a hypertensive animal model. We hypothesize that treatment with rosuvastatin modifies this transformation. Objective To evaluate the effect of rosuvastatin on the development of aortic valve stenosis. Material and Methods Hypertension was induced in 43 male NZ rabbits by a onekidney, one-clip Goldblatt procedure. The animals were randomly assigned to 3 groups: HT (n=17) without treatment; HT+R (n=14) treated with rosuvastatin 2.5 mg/kg/day and HT+R+C (n=12) treated with rosuvastatin 2.5 mg/kg/day + cholesterol-enriched diet to keep baseline cholesterol levels. A control group (CG) underwent sham surgery (n=15). The characteristics of the aortic valve were measured by echocardiography at baseline, 3 and 6 months after inducing hypertension. Results After 6 months of follow-up, SBP and DBP presented greater increase in the group HT (49% and 40%, respectively; p<0.001) compared to groups treated with rosuvastatin (SBP = 23% and 25%; DBP = 28% and 26%; p <0.001 for HT+R and HT+R+C, respectively). Total cholesterol decreased by 45.7% (p <0.01) only in HT+R group. The aortic valve became thickened in the HT group (0.50 ± 0.01 vs. 0.62± 0.02 mm; p <0.01); there were no significant differences in HT+R and HT+R+C. Finally, the aortic valve area was reduced in HT (0.277 ± 0.024 vs. 0.208 ± 0.014 cm² ; p <0.05), had no differences in HT+R and HT+R+C, and presented a non-significant increase in CG (0.264 ± 0.022 vs. 0.32± 0.016 cm²; p=0.07). Conclusions Rosuvastatin slows the progression of aortic valve stenosis caused by hypertension. This protection might be independent of the lipid-lowering effect of the drug.(AU)

La rosuvastatina atenúa la progresión de la estenosis aórtica generada por hipertensión arterial, independientemente de sus efectos hipolipemiantes / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects / Rosuvastatin Slows the Progression of Aortic Stenosis Caused by Hypertension Regardless of Its Lipid-Lowering Effects

Introducción Existe evidencia epidemiológica que vincula factores de riesgo cardiovascular con la estenosis valvular aórtica. Recientemente se ha demostrado el desarrollo de estenosis valvular aórtica en un modelo de hipertensión arterial en animales. Planteamos la hipótesis de que el tratamiento con rosuvastatina modifica esta transformación. Objetivo Evaluar el efecto de la rosuvastatina sobre el desarrollo de estenosis valvular aórtica. Material y métodos Se instrumentaron conejos NZ machos (n = 43) con el modelo 1-riñón 1-clip de Goldblatt para generar hipertensión arterial. Los animales fueron aleatorizados a: HT (n = 17) que no recibió otro tratamiento, HT+R (n = 14) tratado con rosuvastatina 2,5 mg/kg/día y HT+R+C (n = 12) tratado con rosuvastatina 2,5 mg/kg/día + suplemento de colesterol dietético para mantener los niveles basales de colesterol plasmático. Un grupo control (GC) fue sometido a cirugía simulada (n = 15). Las características de la válvula aórtica se midieron por ecografía en condiciones basales y a los 3 y a los 6 meses de hipertensión arterial. Resultados A los 6 meses de seguimiento, los incrementos de PAS y PAD fueron más elevados en HT (49% y 40%, respectivamente; p < 0,001) en comparación con los grupos tratados con rosuvastatina (PAS = 23% y 25%; PAD = 28% y 26%; p < 0,001 para HT+R y HT+R+C, respectivamente). El colesterol total se redujo el 45,7% (p < 0,01) sólo en HT+R. El espesor valvar se incrementó en HT (0,50 ñ 0,01 vs. 0,62 ñ 0,02 mm; p < 0,01), sin mostrar diferencias en HT+R y HT+R+C. Finalmente, el área valvular aórtica mostró una reducción en HT (0,277 ñ 0,024 vs. 0,208 ñ 0,014 cm²; p < 0,05), sin cambios en HT+R y HT+R+C y un aumento no significativo en el GC (0,264 ñ 0,022 vs. 0,32 ñ 0,016 cm²; p = 0,07). Conclusiones La rosuvastatina atenúa la progresión de la estenosis valvular aórtica generada por hipertensión arterial. Esta protección podría ser mediada por efectos no hipolipemiantes de estas drogas.(AU)

Background There is epidemiological evidence associating cardiovascular risk factors with aortic valve stenosis. The development of aortic valve stenosis has been recently demonstrated in a hypertensive animal model. We hypothesize that treatment with rosuvastatin modifies this transformation. Objective To evaluate the effect of rosuvastatin on the development of aortic valve stenosis. Material and Methods Hypertension was induced in 43 male NZ rabbits by a onekidney, one-clip Goldblatt procedure. The animals were randomly assigned to 3 groups: HT (n=17) without treatment; HT+R (n=14) treated with rosuvastatin 2.5 mg/kg/day and HT+R+C (n=12) treated with rosuvastatin 2.5 mg/kg/day + cholesterol-enriched diet to keep baseline cholesterol levels. A control group (CG) underwent sham surgery (n=15). The characteristics of the aortic valve were measured by echocardiography at baseline, 3 and 6 months after inducing hypertension. Results After 6 months of follow-up, SBP and DBP presented greater increase in the group HT (49% and 40%, respectively; p<0.001) compared to groups treated with rosuvastatin (SBP = 23% and 25%; DBP = 28% and 26%; p <0.001 for HT+R and HT+R+C, respectively). Total cholesterol decreased by 45.7% (p <0.01) only in HT+R group. The aortic valve became thickened in the HT group (0.50 ñ 0.01 vs. 0.62ñ 0.02 mm; p <0.01); there were no significant differences in HT+R and HT+R+C. Finally, the aortic valve area was reduced in HT (0.277 ñ 0.024 vs. 0.208 ñ 0.014 cm² ; p <0.05), had no differences in HT+R and HT+R+C, and presented a non-significant increase in CG (0.264 ñ 0.022 vs. 0.32ñ 0.016 cm²; p=0.07). Conclusions Rosuvastatin slows the progression of aortic valve stenosis caused by hypertension. This protection might be independent of the lipid-lowering effect of the drug.(AU)

Atherogenic alterations in hypertriglyceridemic patients would not depend on insulin resistance.

BACKGROUND AND AIMS: Several studies have been carried out to characterize the different alterations associated with hypertriglyceridemia (HTG) and to identify this dyslipemia as an independent risk factor for cardiovascular disease (CVD). HTG is frequently, but not always, associated with insulin resistance (IR). The present study was aimed to evaluate if the alterations observed in biomarkers of CVD were similar in HTG states independently of IR. METHODS: HTG was defined as triglycerides ≥1.69 mmol/l and IR as HOMA-IR ≥3.1. HTG-IR patients (n=15) were compared with HTG subjects without IR (WIR) (n=15) and with normotriglyceridemic (NTG)-WIR individuals (n=30). RESULTS: Both HTG groups shared the increment in VLDL-C and non-HDL-C, HDL enrichment in triglycerides and depletion in phospholipids, the decrease in adiponectin concentration, and the increase in CETP activity. HDL-C and VCAM-1 levels were altered only in HTG-IR patients in comparison with the other groups, while oxidized LDL was only higher in HTG-IR than the control group. Multiple regression analysis identified triglycerides as the independent predictor of HDL-C, CETP activity and oxidized LDL levels. CONCLUSION: The increase in triglycerides is the major determinant factor of the atherogenic modifications observed, while IR would be an amplifier factor.

HDL-associated enzymes and proteins in hemodialysis patients.

OBJECTIVES: To evaluate HDL-associated proteins and enzymes and their relation with lipoprotein profile and inflammatory markers in chronic renal patients on hemodialysis. DESIGN AND METHODS: We studied 53 patients under hemodialysis and 32 healthy subjects as controls. We compared plasma lipids, Apoprotein-AI and hs-CRP, as a marker of chronic inflammation. We evaluated proteins and enzymes associated to HDL, involved in several points of lipoprotein metabolism: CETP, paraoxonase and LpPLA2 activities. Hepatic lipase was measured in postheparin plasma. RESULTS: Patients showed higher triglycerides and lower LDL-, HDL- and total-cholesterol than controls (p<0.05). Also, in comparison with controls, Apoprotein-AI, paraoxonase and hepatic lipase were lower, while CETP was higher (p<0.03). LpPLA2 did not show changes between groups. CONCLUSION: Beyond plasma lipid-lipoprotein profile, other factors could contribute to induce a pro-oxidative and pro-inflammatory status. The protective role of HDL does not only depend on its concentration, but also on its functionality.

Association of common variants in JAK2 gene with reduced risk of metabolic syndrome and related disorders.

BACKGROUND: Disturbances in leptin and insulin signaling pathways are related to obesity and metabolic syndrome (MS) with increased risk of diabetes and cardiovascular disease. Janus kinase 2 (JAK2) is a tyrosine kinase involved in the activation of mechanisms that mediate leptin and insulin actions. We conducted a population cross-sectional study to explore the association between two common variants in JAK2 gene and MS related traits in 724 Argentinean healthy male subjects. METHODS: A total of 724 unrelated men aged 37.11 ± 10.91 yr were included in a cross-sectional study. Physical examination, anthropometric measurements and biochemical analysis were determined by a standardized protocol. rs7849191 and rs3780378 were genotyped. Analyses were done separately for each SNP and followed up by haplotype analysis. RESULTS: rs7849191 and rs3780378 were both associated with reduced risk of MS [p = 0.005; OR (95%CI) = 0.52 (0.33-0.80) and p = 0.006; OR (95% CI) = 0.59 (0.40-0.86) respectively, assuming a dominant model]. rs3780378 T allele was associated with triglyceridemia values under 150 mg/dl [p = 0.007; OR (95%CI) = 0.610 (0.429-0.868)] and TT carriers showed lower triglycerides (p = 0.017), triglycerides/HDL-C ratio (p = 0.022) and lipid accumulation product (p = 0.007) compared to allele C carriers. The two-SNPs-haplotype analysis was consistent with single locus analysis. CONCLUSIONS: It was found for the first time, significant associations of JAK2 common variants and related haplotypes with reduced risk of MS. These findings could be explained by the role of JAK2 in insulin and/or leptin signaling.

Association of lipoprotein-associated phospholipase A2 activity with components of the metabolic syndrome in apparently healthy boys.

BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) has been proposed as a biomarker of risk of cardiovascular disease (CVD). OBJECTIVE: To determine the association between Lp-PLA(2) activity and BMI, insulin-resistance, components of the metabolic syndrome (MS), and lifestyle behaviors in healthy adolescent boys. METHODS: Data were collected cross-sectionally from 164 adolescents from an amateur rugby club. BMI, blood pressure (BP), Tanner stages, glucose, insulin, lipids, and Lp-PLA(2) activity were measured. Questionnaires for lifestyle behaviors were completed. RESULTS: Approximately 26% of the adolescents were obese and 23% overweight. There was a univariate association between Lp-PLA(2) and BMI (r=0.16;p=0.042), triglycerides (r=0.26;p=0.001), LDL-C (r=0.46;p<0.001), apo B (r=0.55;p<0.001), whereas waist circumference , BP, glucose, HOMA-IR, and HDL-C were not correlated. None of the lifestyle behaviors were significantly correlated with Lp-PLA(2). In order to analyze Lp-PLA(2) association with known CVD risk conditions, adolescents were categorized according to overweight/obesity and to the presence of metabolic syndrome. Conversely, as it was for LDL-C and apo B concentration, Lp-PLA(2) activity was not higher in adolescents with obesity. Multiple regression analysis showed that apo B was significantly associated with Lp-PLA(2) adjusted for age, BMI, triglycerides and LDL-C (R2=0.32). CONCLUSION: Lp-PLA(2) activity was only associated with apo B adjusted for several confounding variables, suggesting that its clinical utility to identify individuals at risk for CVD does not surpass LDL-C and apo B in healthy adolescents. As plaque morphology may change with age, associations of Lp-PLA(2) with CVD may likewise vary with age.

Low plasma triiodothyronine levels in heart failure are associated with a reduced anabolic state and membrane damage.

BACKGROUND: Low plasma triiodothyronine (T(3)) levels are considered a prognostic predictor of death in heart failure (HF) patients. AIM: To study an association between plasma T(3) levels and several cardiac, neurohormonal, and metabolic markers of HF. METHODS: A total of 133 ambulatory HF patients (114 males; mean age 63.2 years) with left ventricular ejection fraction <40% were enrolled. TSH, total tetraiodothyronine (T(4)) and T(3), N-terminal pro-brain natriuretic peptide (NT-proBNP), and other cardiac and metabolic parameters were measured. The lowest tertile of T(3) (group 1) was compared against the two upper ones (group 2). RESULTS: In simple logistic regression, the lowest T(3) tertile was associated with more advanced HF disease status: older (age: odds ratio (OR)=1.05; confidence interval (CI) 95% 1.01-1.09, P=0.004), lower functional capacity (walking test: OR=0.996; CI 95% 0.993-0.999, P=0.008), higher NT-proBNP (OR=1.64; CI 95% 1.19-2.27, P=0.003) and adiponectin levels (OR=1.07; CI 95% 1.02-1.11, P=0.004), lower DHEAS log-transformed (OR=0.50; CI 95% 0.31-0.80, P=0.004), and the presence of lower phase angle values as measured by body bioelectrical impedance analysis (OR=3.18; CI 95% 1.50-6.71, P=0.04) and worse renal function (OR=0.96; CI 95% 0.94-0.98, P=0.003). T(3) levels in the lowest tertile were independently associated with low phase angle values (OR=2.95, CI 95% 1.16-7.50, P=0.02) and the log transformation of DHEAS (OR=0.56; CI 95% 0.32-0.97, P=0.04). CONCLUSION: We have demonstrated an association between plasma T(3) levels in the lower range and other deranged hormonal and metabolic parameters in HF patients.

Impact of unhealthy lifestyle behaviors and obesity on cholesteryl ester transfer protein among adolescent males.

BACKGROUND AND AIMS: Cholesteryl ester transfer protein (CETP) has been proposed to be associated with high risk of cardiovascular disease. Increased CETP activity was previously reported in obese adults, although its association with lifestyle behaviors has not been assessed in healthy adolescents. We undertook this study to determine the association between CETP activity and overweight/obesity, insulin resistance markers, components of the metabolic syndrome and lifestyle behaviors in healthy adolescent males. METHODS: Data were collected from 164 adolescents from an amateur rugby club. Body mass index (BMI), blood pressure (BP), Tanner stages, lipids, glucose, insulin and CETP activity were measured. Questionnaires for daily intake of breakfast, sweet drinks, milk, and hours of TV watching were completed. RESULTS: About 26% of the adolescents were obese and 23% overweight. The prevalence of metabolic syndrome was 6.7%. CETP activity was higher in obese than in normal and overweight adolescents (174 ± 35, 141 ± 30, and 149 ± 38%/ml/min, respectively; p <0.001). Univariate correlations showed an inverse association between CETP and HDL-C (r = -0.43; p = 0.018) and positive ones with BMI (r = 0.38; p = 0.007), systolic BP (r = 0.20; p <0.01) triglycerides (r = 0.40; p = 0.001), LDL-C (r = 0.46; p <0.001), TV watching >2 h/day (r = 0.17; p 0.02), and milk intake >3 glasses/day (r = 0.16; p = 0.03). Multivariate analysis showed that triglycerides, LDL-C, HDL-C, TV watching >2 h/day, milk intake >3 glasses/day and BMI were significant independent predictors for CETP (R(2) = 0.41). CONCLUSIONS: Unhealthy lifestyle habits such as TV watching >2 h daily and milk intake higher than three glasses per day and the increase in BMI were shown to be closely associated with high CETP activity in apparently healthy adolescent males. Future longitudinal studies should be performed to confirm these findings.

High LDL levels are associated with increased lipoprotein-associated phospholipase A(2) activity on nitric oxide synthesis and reactive oxygen species formation in human endothelial cells.

OBJECTIVE: To evaluate in vitro the effects of serum and LDL fractions isolated from hypercholesterolemic patients on nitric oxide (NO) synthesis and reactive oxygen species (ROS) production by human umbilical vein endothelial cells (HUVECs). DESIGN AND METHODS: Serum and LDL isolated from subjects with high (n=18) and normal (n=21) LDL-cholesterol levels were analyzed on NO synthesis and ROS production in vitro models of HUVECs. LDL was furthers characterized in their chemical composition and activities of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), cholesteryl ester transfer protein (CETP) and paraoxonase. RESULTS: NO bioavailability was significantly lower and ROS production higher in HUVECs incubated with serum samples from patients with high LDL-cholesterol levels in comparison to control subjects. Moreover, hypercholesterolemic patients presented higher CETP and Lp-PLA(2) activities than control subjects. LDL fractions isolated from patients and controls were not different in their chemical composition, Lp-PLA(2) activity, and their capacity to reduce NO synthesis and increase ROS production. CONCLUSION: Alterations of serum from hypercholesterolemic patients could be due to the increment in LDL concentration, main Lp-PLA(2) carrier, and not to LDL composition or intrinsic Lp-PLA(2) activity.

Does non-alcoholic fatty liver impair alterations of plasma lipoproteins and associated factors in metabolic syndrome?

BACKGROUND: Hepatic steatosis (HS) is closely associated to metabolic syndrome (MS). Both, VLDL-triglyceride oversecretion and intrahepatic deposits, can take place. We evaluated VLDL characteristics, CETP, hepatic lipase (HL), IDL and small dense LDL (sdLDL), in patients with HS associated to MS. METHODS: We studied 3 groups matched by age and sex: 25 MS patients with HS (diagnosed by ultrasonography), 25 MS patients without HS and 25 healthy controls. Main measurements were: lipid profile, free fatty acids, VLDL composition, VLDL size by HPLC, CETP and HL activities, IDL-cholesterol and sdLDL-cholesterol. RESULTS: Patients with HS presented higher triglyceride levels, HOMA-IR and free fatty acids, VLDL mass and VLDL-apoB (p<0.05). No differences in VLDL composition were observed. MS groups presented higher proportion of large VLDL than controls (p<0.05). HS group showed higher CETP than controls (p=0.01) and almost higher than MS without HS (p=0.06). CETP correlated with VLDL-cholesterol content, r=0.48, p<0.005. The increase in sdLDL-cholesterol correlated with CETP (r=0.47) and HL (r=0.56), independent of insulin resistance (p<0.003). CONCLUSION: Despite intrahepatic fat, patients with HS secreted higher number of VLDL particles. CETP would have a remodeling action on VLDL in circulation, enriching it in cholesterol and also favoring, together with HL, the formation of sdLDL.