High-flow nasal oxygen versus conventional oxygen therapy in patients with COVID-19 pneumonia and mild hypoxaemia: a randomised controlled trial.

RATIONALE: In patients with COVID-19 pneumonia and mild hypoxaemia, the clinical benefit of high-flow nasal oxygen (HFNO) remains unclear. We aimed to examine whether HFNO compared with conventional oxygen therapy (COT) could prevent escalation of respiratory support in this patient population. METHODS: In this multicentre, randomised, parallel-group, open-label trial, patients with COVID-19 pneumonia and peripheral oxygen saturation (SpO2) ≤92% who required oxygen therapy were randomised to HFNO or COT. The primary outcome was the rate of escalation of respiratory support (ie, continuous positive airway pressure, non-invasive ventilation or invasive mechanical ventilation) within 28 days. Among secondary outcomes, clinical recovery was defined as the improvement in oxygenation (SpO2 ≥96% with fractional inspired oxygen (FiO2) ≤30% or partial pressure of arterial carbon dioxide/FiO2 ratio >300 mm Hg). RESULTS: Among 364 randomised patients, 55 (30.3%) of 181 patients assigned to HFNO and 70 (38.6%) of 181 patients assigned to COT underwent escalation of respiratory support, with no significant difference between groups (absolute risk difference -8.2% (95% CI -18% to +1.4%); RR 0.79 (95% CI 0.59 to 1.05); p=0.09). There was no significant difference in clinical recovery (69.1% vs 60.8%; absolute risk difference 8.2% (95% CI -1.5% to +18.0%), RR 1.14 (95% CI 0.98 to 1.32)), intensive care unit admission (7.7% vs 11.0%, absolute risk difference -3.3% (95% CI -9.3% to +2.6%)), and in hospital length of stay (11 (IQR 8-17) vs 11 (IQR 7-20) days, absolute risk difference -1.0% (95% CI -3.1% to +1.1%)). CONCLUSIONS: Among patients with COVID-19 pneumonia and mild hypoxaemia, the use of HFNO did not significantly reduce the likelihood of escalation of respiratory support. TRIAL REGISTRATION NUMBER: NCT04655638.

The PaCO2/FiO2 ratio as outcome predictor in SARS-COV-2 related pneumonia: a retrospective study.

BACKGROUND AND AIM: Respiratory failure in SARS-CoV-2 patients is characterized by the presence of hypoxemia and hypocapnia without relevant dyspnea. To date, the use of respiratory parameters other than PaO2/FiO2 ratio to stratify the risk of worsening of these patients has not been sufficiently studied.  Aim of this work was to evaluate whether the ratio between partial pressure levels of carbon dioxide (PaCO2) and the fraction of inspired oxygen (FiO2) measured at emergency department (ED) admission is predictive of the clinical course of patients suffering from SARS-CoV-2 pneumonia. METHODS: We retrospectively studied 236 patients with SARS-CoV-2 pneumonia evaluated at the ED of the Perugia Hospital. The end-points were: in-hospital mortality, need for invasive mechanical ventilation (IMV) and length of in-hospital stay (LOS). Clinical, blood gas and laboratory data were collected at ED admission. RESULTS: Of the 236 patients 157 were male, the mean age was 64 ± 16. Thirtythree patients (14%) needed IMV, 49 died (21%). In the univariate analysis, the PaCO2/FiO2 ratio was inversely associated with the need for IMV (p <0.001), mortality (p <0.001) and LOS (p = 0.005). At the multivariate analysis the PaCO2/FiO2 ratio was found to be predictive of the need for IMV, independently from age, gender, number of comorbidities, neutrophils, lymphocytes, glomerular filtrate, d-dimer, LDH and CRP. CONCLUSIONS: the PaCO2/FiO2 ratio is predictive of the risk of respiratory failure worsening in patients with SARS-CoV-2 pneumonia, independently from other several confounding factors.

Circulating Levels of Sclerostin Predict Glycemic Improvement after Sleeve Gastrectomy.

Among the different effects of bariatric surgery, here we focus on bone-derived inflammatory molecules, and in particular, sclerostin; an osteocyte product potentially associated with cardio-metabolic diseases. In 94 morbidly obese patients undergoing laparoscopic sleeve gastrectomy (SG), over-time changes in anthropometric and biochemical measures-including insulin resistance (IR) indexes-were correlated with serum sclerostin levels. Sclerostin was positively associated with anthropometric indexes of obesity, and inversely with IR, namely homeostatic model assessment for peripheral insulin sensitivity (HOMA2%S) (r = -0.218; p = 0.045). Sclerostin emerged as the only significant predictor of HOMA2-%S normalization, independently of demographic and anthropometric variables (OR 1.01 (95% CI 1.00-1.02); p = 0.024). We also identified two distinct patterns of serum sclerostin change: the higher/lower sclerostin levels at baseline, the greater their post-surgical reduction/increase (p < 0.001 for all subgroups). Among those two patterns, especially the post-surgery increase in serum sclerostin was associated with lean mass reduction, without any association with IR indexes. Although counterintuitive, this change was likely dependent on the post-surgical increase in bone turnover. In conclusion, baseline serum levels of sclerostin correlate with anthropometric measures of obesity and IR, and the ability to predict glycemic improvements after SG. Specifically, serum sclerostin was closely associated with peripheral insulin sensitivity (HOMA2-%S), thus supporting the role of skeletal muscle/bone interactions in metabolic diseases.

Chemerin predicts carotid intima-media thickening in severe obesity.

BACKGROUND AND AIMS: Chemerin is an adipokine with an emerging role in the crosstalk between adipose tissue and immune system. It is overexpressed in severe obesity, affects adipogenesis and glucose homeostasis and it correlates with early vascular damage. The aim of this study is to investigate the correlation between circulating levels of chemerin and early vascular damage in subjects with severe obesity, before and after laparoscopic sleeve gastrectomy (LSG). METHODS: Fifty-six obese subjects eligible for LSG were enrolled in the study. The following parameters were evaluated: body mass index (BMI), glycemia, insulinemia, glycated haemoglobin, lipid profile, plasma chemerin levels and carotid intima-media thickness (cIMT). Fifty-four subjects were evaluated 1 year after the intervention. RESULTS: Univariate analysis showed a direct and significant correlation between chemerin and waist circumference, insulin resistance, glycated haemoglobin and cIMT. Chemerin was a better predictor of intima-media thickening than waist circumference and glycated haemoglobin at the ROC curve analysis, with a cut-off value for chemerin of 140 ng/mL. The reduction of chemerin is independently associated with the reduction of cIMT and the improvement of insulin sensitivity after LSG. CONCLUSION: Chemerin is involved in the development and progression of early vascular damage and insulin resistance in subjects with severe obesity, and in their healing after bariatric surgery. Chemerin could also have a role in the assessment of cardiovascular risk in subjects with severe obesity.

Folate and Vitamin B12 in Morbid Obesity: The Influence of Folate on Anti-Atherogenic Lipid Profile.

Previous studies showed a high prevalence of micronutrient deficiencies in obese subjects, with low folate and vitamin B12 serum levels and intakes. Correlations between vitamins and lipids have been investigated both in animal and human studies. The aim of our study is to evaluate the influence of dietetic and serum levels of folate and vitamin B12 on lipid pattern in morbidly obese subjects. We also analysed the relationship between serum concentrations and dietary intake of these micronutrients, and compared the intakes to the Recommended Levels of Nutrients and Energy Intakes (LARN). In 122 morbidly obese patients, mean BMI 45 ± 7 kg/m2, we evaluated anthropometric parameters, hepatic, glyco/lipid profile, total folate and vitamin B12, blood pressure, and finally nutritional intakes in a subgroup of 68 patients using a food frequency questionnaire about the frequency of food consumption and daily water intake. These values were determined in obese patients before and one year after sleeve gastrectomy. Both before and after surgery, levels of vitamins and minerals remained in normal range compared to LARN. According to univariate analysis, at baseline folate showed a significantly positive correlation with high-density lipoprotein cholesterol (p = 0.028, ρ = 0.204), apolipoprotein A-I (p = 0.006, ρ = 0.268) and vitamin B12 (p = 0.040, ρ = 0.192), and a significantly negative correlation with triglycerides (p = 0.049, ρ = -0.184). Folate and vitamin B12 levels do not correlate with their nutritional intakes, which remain within recommended range after surgery. In conclusion the correlation between folate and anti-atherogenic lipid profile is confirmed also in a large group of morbid obese patients.

Increased plasmatic NETs by-products in patients in severe obesity.

Neutrophil extracellular traps (NETs) are DNAs products involved in immune process. Obesity through a low-grade chronic inflammation determines neutrophil activation, but it is still unclear its role in NETs formation. Here we analyzed the NETs levels in healthy and morbid obese, their association with anthropometric and glyco-metabolic parameters and their changes after bariatric surgery. For this study, we enrolled 73 patients with morbid obesity (BMI ≥40 kg/m2 or ≥35 kg/m2 + comorbidity) eligible to sleeve gastrectomy. In parallel, 55 healthy subjects and 21 patients with severe coronary artery disease were studied as controls. We evaluated anthropometric parameters, peripheral blood pressure, biochemical and serum analysis at the enrollment and at twelve months after surgery. Plasmatic levels of MPO-DNA complexes were assessed by ELISA. NETs levels were higher in obese than in control group (p < 0.001) and correlated with the main anthropometric variable (BMI, waist, hip), glyco-metabolic variables and systolic blood pressure. NETs trend after intervention was uneven. The reduction of NETs correlated with the entity of reduction of BMI (ρ = 0.416, p < 0.05), visceral fat area (ρ = 0.351, p < 0.05), and glycemia (ρ = 0.495, p < 0.001). In medical history of patients in whom NETs increased, we observed a higher number of thromboembolic events. Our observations indicate that severe obesity is associated with increased generation of NETs, which in turn could influence the patients' systemic inflammatory state. Weight loss and in particular, loss of adipose tissue after bariatric surgery does not in itself correct NET's dysregulated production. Finally, patients in whom NETs accumulation persists after surgery are probably those at the highest risk of cardiovascular events.

Serum Bile Acid Levels Before and After Sleeve Gastrectomy and Their Correlation with Obesity-Related Comorbidities.

BACKGROUND AND AIMS: The rising prevalence of morbid obesity is increasing the demand for bariatric surgery. The benefits observed after bariatric surgery seems to be not fully explained by surgery-induced weight loss or traditional cardiovascular risk factors regression or improvement. Some evidences suggest that bile acid (BA) levels change after bariatric surgery, thus suggesting that BA concentrations could influence some of the metabolic improvement induced by bariatric surgery. In this report, we have characterized circulating BA patterns and compared them to metabolic and vascular parameters before and after sleeve gastrectomy (SG). PATIENTS AND METHODS: Seventy-nine subjects (27 males, 52 females, aged 45 ± 12 years, mean BMI 45 ± 7 kg/m2) SG candidates were included in the study. Before and about 12 months after SG, all subjects underwent a clinical examination, blood tests (including lipid profile, plasma glucose and insulin, both used for calculating HOMA-IR, and glycated hemoglobin), ultrasound visceral fat area estimation, ultrasound flow-mediated dilation evaluation, and determination of plasma BA concentrations. RESULTS: Before SG, both primary and secondary BA levels were higher in insulin-resistant obese subjects than in non-insulin resistant obese, and BA were positively associated with the markers of insulin-resistance. After SG, total (conjugated and unconjugated) cholic acids significantly decreased (p 0.007), and total lithocholic acids significantly increased (p 0.017). SG-induced total cholic and chenodeoxycholic acid changes were directly associated with surgery-induced glycemia (p 0.011 and 0.033 respectively) and HOMA-IR (p 0.016 and 0.012 respectively) changes. CONCLUSIONS: Serum BA are associated with glucose metabolism and particularly with markers of insulin-resistance. SG modifies circulating BA pool size and composition. SG-induced BA changes are associated with insulin-resistance amelioration. In conclusion, an interplay between glucose metabolism and circulating BA exists but further studies are needed.

Morbid obesity and hypertension: The role of perirenal fat.

Accumulation of fat in renal sinus and hilum is associated with hypertension development. We evaluated the relationship between perirenal fat and hypertension in a population of morbidly obese patients and the potential variations after sleeve-gastrectomy. Two hundred and eighty-four morbidly obese patients were included in the study, and 126 underwent sleeve-gastrectomy. At baseline and 10-12 months after surgery, we evaluated anthropometric parameters, blood pressure, glycometabolic, and lipidic assessment, and performed an ultrasonographic evaluation of visceral fat area and perirenal fat thickness. The perirenal fat thickness in hypertensive obese was higher than in nonhypertensive (13.6 ± 4.8 vs 11.6 ± 4.1, P = 0.001). It showed a significant direct correlation with age, waist circumference, BMI, systolic blood pressure (SBP), insulinemia, HOMA-IR, glycated hemoglobin, and creatinine. The independent predictors (R2  = 0.129) of SBP were perirenal fat thickness (ß = 0.160, P = 0.022) and age (ß = 0.175, P = 0.011). After surgery, perirenal fat thickness significantly decreased (from 13 ± 4 to 9 ± 4 mm, P <0.001). In the 89 hypertensive obese patients who underwent sleeve-gastrectomy, we observed a significant decrease in antihypertensive medications needed. Sixteen patients suspended therapy. The perirenal fat thickness in obese patients could be a valuable tool to define the risk of developing hypertension, providing the clinician with an additional parameter to define those who need a more aggressive treatment and could benefit most from bariatric surgery.

Sleeve Gastrectomy Efficacy on Metabolic and Cardiovascular Dysfunction With a Focus on the Role of Comorbidities.

We evaluated the effects of sleeve gastrectomy (SG) on metabolic/cardiovascular parameters according to weight loss, visceral fat area (VFA), and homeostasis model assessment (HOMA)-insulin resistance index; we also assessed the influence of SG on comorbidities (diabetes/hypertension). At baseline and 10 to 12 months after SG, we assessed anthropometric and biochemical parameters, bioimpedentiometry, ultrasonographic VFA, liver steatosis, flow-mediated dilation, and echocardiography in 110 patients with obesity. We found that 23 (21%) patients had diabetes. Diabetic patients who normalized their glycated hemoglobin A1C (HbA1C) level experienced greater total weight loss (TWL), and the probability of normalizing HbA1C levels directly correlated with TWL. Diabetic patients experienced a greater improvement in systolic blood pressure, VFA, and high-density lipoprotein cholesterol than nondiabetics, while patients with hypertension experienced a greater improvement in VFA, triglycerides, HOMA, and HbA1C than nonhypertensive patients. The most important determinant of glucose control in diabetic patients was weight loss. Patients with diabetes and hypertension experienced a greater improvement in vascular and metabolic status after SG.

Plasma cholesterol homeostasis, HDL remodeling and function during the acute phase reaction.

Acute phase reaction (APR) is a systemic inflammation triggered by several conditions associated with lipid profile alterations. We evaluated whether APR also associates with changes in cholesterol synthesis and absorption, HDL structure, composition, and cholesterol efflux capacity (CEC). We analyzed 59 subjects with APR related to infections, oncologic causes, or autoimmune diseases and 39 controls. We detected no difference in markers of cholesterol synthesis and absorption. Conversely, a significant reduction of LpA-I- and LpAI:AII-containing HDL (-28% and -44.8%, respectively) and of medium-sized HDL (-10.5%) occurred in APR. Total HDL CEC was impaired in APR subjects (-18%). Evaluating specific CEC pathways, we found significant reductions in CEC by aqueous diffusion and by the transporters scavenger receptor B-I and ABCG1 (-25.5, -41.1 and -30.4%, respectively). ABCA1-mediated CEC was not affected. Analyses adjusted for age and gender provided similar results. In addition, correcting for HDL-cholesterol (HDL-C) levels, the differences in aqueous diffusion total and ABCG1-CEC remained significant. APR subjects displayed higher levels of HDL serum amyloid A (+20-folds; P = 0.003). In conclusion, APR does not associate with cholesterol synthesis and absorption changes but with alterations of HDL composition and a marked impairment of HDL CEC, partly independent of HDL-C serum level reduction.

Modulation of natriuretic peptide receptors in human adipose tissue: molecular mechanisms behind the "natriuretic handicap" in morbidly obese patients.

The B-type natriuretic peptide (BNP) hormone plays a crucial role in the regulation of cardiovascular and energy homeostasis. Obesity is associated with low circulating levels of BNP, a condition known as "natriuretic handicap." Recent evidences suggest an altered expression of BNP receptors-both the signaling natriuretic peptide receptors (NPR)-A and the clearance NPR-C receptor-in adipose tissue (AT) as one of the putative causes of natriuretic handicap. The current study aims at clarifying the molecular mechanisms behind the natriuretic handicap, focusing on NPR modulation in the AT of obese and control subjects. The study enrolled 34 obese and 20 control subjects undergoing bariatric or abdominal surgery, respectively. The main clinical and biochemical parameters, including circulating BNP, were assessed. In visceral (VAT) and subcutaneous AT (SAT) samples, collected during surgery, the adipocytes and stromal vascular fraction (SVF) expression of NPR-A and NPR-C and the SVF secretion of interleukin 6 (IL-6) were determined. Both VAT and SAT from obese patients expressed a lower NPR-A/NPR-C ratio in adipocytes and the SVF secreted a higher level of IL-6, compared with the controls. Moreover, NPR-A/NPR-C ratio expressed by VAT and SAT adipocytes negatively correlated with body mass index, insulin, the Homeostasis Model Assessment of Insulin resistance, and IL-6 secreted by SVF, and the expression of the clearance receptor NPR-C, in both the VAT and SAT adipocytes, showed a negative correlation with circulating BNP. Overall, insulin resistance/hyperinsulinemia and AT inflammation (ie, high level of IL-6) are the major determinants of the lower NPR-A/NPR-C ratio in adipocytes, thus contributing to the natriuretic handicap in obese subjects.

Determinants of low levels of brain natriuretic peptide in morbid obesity.

BACKGROUND & AIMS: morbid obesity is associated with cardiovascular comorbidity. A noteworthy feature of this relationship could regard low levels of brain natriuretic peptide (BNP). The study investigates the relationship between BNP and obesity-related markers in a morbid obese population, along with echocardiographic and vascular parameters. METHODS: in 154 morbid obese patients we evaluated anthropometric parameters, glycometabolic/lipid profile, bioimpedentiometry, echocardiography, visceral fat area and flow-mediated dilation (FMD) by ultrasonography. RESULTS: we divided population in two groups on the basis of median BMI levels; patients with higher BMI had significantly lower BNP (p = .008), FMD (p = .014) and HDL-C (p = .001) and showed a more impaired heart function. A similar trend emerged subdividing patients on the basis of median visceral fat area. BNP showed a significant inverse correlation with BMI (p < .001), left ventricular mass (p = .026) and inter-ventricular septum thickness (p = .007) and a significant positive correlation with FMD (p = .008), HDL-C (p = .022), and ejection fraction (p = .013). BMI and triglycerides were independent predictors of BNP levels. CONCLUSIONS: patients with higher BMI show lower BNP levels associated with greater total body fat amount. The correlation of BNP with endothelium-dependent vasodilation and cardiac impairment could represent another link between obesity and cardiovascular damage.

Non-alcoholic fatty liver disease fibrosis score and preclinical vascular damage in morbidly obese patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is strongly related with enhanced morbidity and mortality from cardiovascular disease. In obese patients with both NAFLD and features of the metabolic syndrome, the cardiovascular risk is further increased. AIM: The aim of this study is to investigate the relationship between severity of liver fibrosis evaluated by NAFLD fibrosis score (NAFLD-FS), Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), other obesity-related markers and preclinical atherosclerosis in morbidly obese patients with previously diagnosed NAFLD. METHODS: Laboratory parameters, visceral fat area (VFA), flow-mediated dilatation (FMD), intima-media thickness (IMT), HOMA-IR and NAFLD-FS were determined in 196 morbidly obese patients. RESULTS: Patients with higher NAFLD-FS or HOMA-IR show higher left max-IMT and lower FMD (p<0.001). VFA and NAFLD-FS, but not HOMA-IR, were independent predictors of reduced FMD (respectively ß -0.268, p=0.001 and ß -0.165, p=0.039, p of the model<0.001) and increased left max-IMT (respectively ß 0.165, p=0.031 and ß 0.301, p<0.001, p of the model<0.001). CONCLUSIONS: In morbidly obese patients, NAFLD-FS correlates with markers of early vascular damage. NAFLD-FS, easier to obtain than VFA, seems to be a better score than HOMA-IR to categorize such subjects who are potentially at risk of future cardiovascular events.

Facing Morbid Obesity: How to Approach It.

Obesity is a major public health problem, with a prevalence of 10% to 20% in Western Europe. Morbid obesity, characterized by body mass index >40 kg/m(2), showed an increased prevalence in the last 30 years. Obesity is associated with reduced economic and social opportunities, reduced quality of life, and is a determinant of several "intermediate risk factors," leading to an increased mortality and a loss in life expectancy. The rising prevalence of morbid obesity increased the demand for bariatric surgery, also called "metabolic surgery": after these interventions, there is a decrease in metabolic comorbidities, cardiovascular (CV) risk, and total mortality. In this review, we update the evaluation of morbid obese patients from the physical examination to the metabolic, CV and respiratory assessments in order to correctly stratify the CV risk and provide the best treatment. To obtain these achievements, multidisciplinary work has to be carried out with a team involving several experts with different skills.

Frequency of Left Ventricular Hypertrophy in Non-Valvular Atrial Fibrillation.

Left ventricular hypertrophy (LVH) is significantly related to adverse clinical outcomes in patients at high risk of cardiovascular events. In patients with atrial fibrillation (AF), data on LVH, that is, prevalence and determinants, are inconsistent mainly because of different definitions and heterogeneity of study populations. We determined echocardiographic-based LVH prevalence and clinical factors independently associated with its development in a prospective cohort of patients with non-valvular (NV) AF. From the "Atrial Fibrillation Registry for Ankle-brachial Index Prevalence Assessment: Collaborative Italian Study" (ARAPACIS) population, 1,184 patients with NVAF (mean age 72 ± 11 years; 56% men) with complete data to define LVH were selected. ARAPACIS is a multicenter, observational, prospective, longitudinal on-going study designed to estimate prevalence of peripheral artery disease in patients with NVAF. We found a high prevalence of LVH (52%) in patients with NVAF. Compared to those without LVH, patients with AF with LVH were older and had a higher prevalence of hypertension, diabetes, and previous myocardial infarction (MI). A higher prevalence of ankle-brachial index ≤0.90 was seen in patients with LVH (22 vs 17%, p = 0.0392). Patients with LVH were at significantly higher thromboembolic risk, with CHA2DS2-VASc ≥2 seen in 93% of LVH and in 73% of patients without LVH (p <0.05). Women with LVH had a higher prevalence of concentric hypertrophy than men (46% vs 29%, p = 0.0003). Logistic regression analysis demonstrated that female gender (odds ratio [OR] 2.80, p <0.0001), age (OR 1.03 per year, p <0.001), hypertension (OR 2.30, p <0.001), diabetes (OR 1.62, p = 0.004), and previous MI (OR 1.96, p = 0.001) were independently associated with LVH. In conclusion, patients with NVAF have a high prevalence of LVH, which is related to female gender, older age, hypertension, and previous MI. These patients are at high thromboembolic risk and deserve a holistic approach to cardiovascular prevention.

Insulin resistance and not BMI is the major determinant of early vascular impairment in patients with morbid obesity.

AIM: Several factors contribute to the development of atherogenesis in patients with obesity. The aim of our study was to evaluate the different roles of insulin resistance, strictly correlated to visceral adiposity, and the body mass index (BMI), an estimate of overall adiposity, on early vascular impairment in patients with morbid obesity. METHODS: We enrolled 65 morbidly obese subjects (BMI 44.6 ± 7 kg/m(2)) who were free of previous cardiovascular events and 28 nonobese subjects (control group) in a cross-sectional study. The presence of glycemia and insulinemia, the levels of lipids and liver parameter and the ultrasonographic assessment of the flow-mediated dilatation (FMD), carotid intima-media thickness (IMT) and visceral fat area (VFA) were evaluated in all subjects. RESULTS: In the obese patients with a median HOMA value of ≥ 3.5, the FMD was significantly lower (p < .05) and the left carotid maximum-IMT was significantly higher (p < .05) than those observed in the group with lower HOMA values. No vascular differences were found between the two groups that were subdivided according to the BMI median value. Both the left max-IMT and FMD exhibited a significant correlation with HOMA-IR ("ρ" .292, p=0.02 , "ρ"-.292, p=0.02 respectively) but not with BMI. According to a multivariate analysis, the VFA was an independent predictor of a reduced FMD (ß - .541, p.002; p of the model .002), while age (ß .611 p < .0001) and HOMA-IR (ß .399 p < .001) were independent predictors of the left max-IMT (p of the model .002). CONCLUSIONS: The HOMA-IR, which is strictly related to visceral fat and is an index of metabolic impairment, and not BMI, which reflects of global adiposity, can be used to identify early vascular impairment in patients with morbid obesity.

A silent mutation of Niemann-Pick C1-like 1 and apolipoprotein E4 modulate cholesterol absorption in primary hyperlipidemias.

OBJECTIVE: To investigate the influence of the silent mutation c.816C > G (L272) of Niemann-Pick C1-like 1 (NPC1L1) and of apolipoprotein (APO) E alleles on cholesterol absorption markers, sitosterol and campesterol, in 87 patients with primary hyperlipidemias. METHODS: In all subjects genotyped for silent polymorphism in NPC1L1 gene c.816C > G (L272L) and for APO E polymorphism, campesterol and sitosterol were measured by gas chromatography coupled to mass spectrometry. RESULTS: Thirty-eight patients carrying the G allele of NPC1L1 showed significantly greater concentrations (log values) of campesterol (1.86 ± 0.3 vs 1.61 ± 0.3 10(2) µmol/mmol cholesterol, p < .001) and sitosterol (2.03 ± 0.2 vs 1.94 ± 0.2 10(2) µmol/mmol cholesterol, P = .05). Patients with at least one E4 allele showed values of sitosterol greater than those carrying E3E3 or E3E2 (2.05 ± 0.2 10(2) µmol/mmol cholesterol vs 1.95 ± 0.2 10(2) µmol/mmol cholesterol, P = .004). The presence of the G allele (ß = .379, P < 0.001) and high-density lipoprotein cholesterol (ß = .242, P = .019) was an independent predictor of campesterol values (R of the model = 0.473, P < .001). The E4 allele (ß = .293, P = .005) and high-density lipoprotein cholesterol (ß = .311, P = .003) were independent predictors of sitosterol values (R 0.416, P of the model <.001). CONCLUSIONS: In patients with hyperlipidemias, G allele of NPC1L1 and APO E4 could account for some of the inter-individual variability in cholesterol absorption.

Cholesterol metabolism differs after statin therapy according to the type of hyperlipemia.

AIM: Non-cholesterol sterols reflect cholesterol metabolism. Statins reduce cholesterol synthesis usually with a rise in cholesterol absorption. Common hyperlipemias have shown different patterns of cholesterol metabolism. We evaluated whether cholesterol absorption and synthesis may differ after statin therapy in primary hyperlipemias. MAIN METHODS: We determined lipid profile, apoprotein B and serum sterols (lathosterol, sitosterol, campesterol by gas chromatography/mass spectrometry) before and after statins in 80 untreated hyperlipemic patients, 40 with polygenic hypercholesterolemia (PH) and 40 with familial combined hyperlipemia (FCH). KEY FINDINGS: At baseline in FCH lathosterol was significantly higher while campesterol and sitosterol were significantly lower than in PH. After statins, the reduction in LDL-C did not significantly differ between the two groups; in PH there was a significant decrease of lathosterol from 96.1 to 52.6 102 µmol/mmol cholesterol (p=0.0001) with no significant modifications in campesterol and sitosterol; on the opposite, in FCH lathosterol decreased from 117 to 43 102 µmol/mmol cholesterol (p=0.0001) and campesterol and sitosterol significantly increased from 38 to 48 102 µmol/mmol cholesterol (p=0.0001), and from 75 to 86 102 µmol/mmol cholesterol, (p=0.022), respectively. After statin therapy only in FCH Δ-LDL-C showed a significant inverse correlation with Δ-sitosterol and with Δ-campesterol. SIGNIFICANCE: Primary hyperlipemias show different patterns of response to statins: in PH LDL reduction appears completely "synthesis inhibition" dependent, while in FCH LDL decrease appears to be synthesis dependent, partially limited by absorption increase. Studying cholesterol metabolism before and after hypolipemic therapy might be useful in identifying the best tailored treatment.