Manuel F. Landecho

Is leptin involved in phagocytic NADPH oxidase overactivity in obesity? Potential clinical implications

Objectives Hyperleptinemia and oxidative stress play a major role in the development of cardiovascular diseases in obesity. This study aimed to investigate whether there is a relationship between plasma levels of leptin and phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and its potential relevance in the vascular remodeling in obese patients. Methods The study was performed in 164 obese and 94 normal-weight individuals (controls). NADPH oxidase activity was evaluated by luminescence in phagocytic cells. Levels of leptin were quantified by ELISA in plasma samples. Carotid intima–media thickness (cIMT) was measured by ultrasonography. In addition, we performed in-vitro experiments in human peripheral blood mononuclear cells and murine macrophages. Results Phagocytic NADPH oxidase activity and leptin levels were enhanced (P < 0.05) in obese patients compared with controls. NADPH oxidase activity positively correlated with leptin in obese patients. This association remained significant in a multivariate analysis. cIMT was higher (P < 0.05) in obese patients compared with controls. In addition, cIMT also correlated positively with leptin and NADPH oxidase activity in obese patients. In-vitro studies showed that leptin induced NADPH oxidase activation. Inhibition of the leptin-induced NADPH oxidase activity by wortmannin and bisindolyl maleimide suggested a direct involvement of the phosphatidylinositol 3-kinase and protein kinase C pathways, respectively. Finally, leptin-induced NADPH oxidase activation promoted macrophage proliferation. Conclusions These findings show that phagocytic NADPH oxidase activity is increased in obesity and is related to preclinical atherosclerosis in this condition. We also suggest that hyperleptinemia may contribute to phagocytic NADPH oxidase overactivity in obesity.

Performance of SAPS II and SAPS 3 in Intermediate Care

Objective The efficacy and reliability of prognostic scores has been described extensively for intensive care, but their role for predicting mortality in intermediate care patients is uncertain. To provide more information in this field, we have analyzed the performance of the Simplified Acute Physiology Score (SAPS) II and SAPS 3 in a single center intermediate care unit (ImCU). Materials and Methods Cohort study with prospectively collected data from all patients admitted to a single center ImCU in Pamplona, Spain, from April 2006 to April 2012. The SAPS II and SAPS 3 scores with respective predicted mortality rates were calculated according to standard coefficients. Discrimination was evaluated by calculating the area under receiver operating characteristic curve (AUROC) and calibration with the Hosmer-Lemeshow goodness of fit test. Standardized mortality ratios (SMR) with 95% confidence interval (95% CI) were calculated for each model. Results The study included 607 patients. The observed in-hospital mortality was 20.1% resulting in a SMR of 0.87 (95% CI 0.73-1.04) for SAPS II and 0.56 (95% CI 0.47-0.67) for SAPS 3. Both scores showed acceptable discrimination, with an AUROC of 0.76 (95% CI 0.71-0.80) for SAPS II and 0.75 (95% CI 0.71- 0.80) for SAPS 3. Calibration curves showed similar performance based on Hosmer-Lemeshow goodness of fit C-test: (X2=12.9, p=0.113) for SAPS II and (X2=4.07, p=0.851) for SAPS 3. Conclusions Although both scores overpredicted mortality, SAPS II showed better discrimination for patients admitted to ImCU in terms of SMR.

Relación entre las fases precoces de la enfermedad renal y el síndrome metabólico

INTRODUCTION AND OBJECTIVES Advanced kidney disease is a major health problem due to its association with high cardiovascular morbidity and mortality. Early recognition of advanced kidney disease is the mainstay to avoid its progression. Since metabolic syndrome and insulin resistance are risk factors for both cardiovascular and advanced kidney disease, we investigated the relationship of early kidney disease (EKD) with metabolic syndrome and insulin resistance, and their association with surrogate markers of arteriosclerosis. METHODS We studied 1498 subjects. Insulin resistance was defined as HOMA ≥3.7 mmol (μU)/L(2) and EKD as stages 1 and 2 of the NKF-KDOQI. Carotid intima-media thickness was used as a surrogate marker of arteriosclerosis. RESULTS The presence of one trait of metabolic syndrome was associated with an odds ratio (OR) for EKD of 2.3 (95% confidence interval [CI], 1.18-4.48) that increased to 6.72 (95% CI, 3.56-13.69) in subjects with the syndrome. All the traits of the syndrome except low level of high-density lipoproteins showed an increased OR for EKD. Increasing HOMA was also directly correlated with higher OR for EKD, being as high as 3.89 (95% CI, 1.99-7.59) for subjects in the fourth quartile. Subjects with the syndrome plus EKD showed an increased intima-media thickness compared with those without kidney disease. CONCLUSIONS Insulin resistance and all metabolic syndrome traits except low level of high-density lipoproteins were significantly associated with an increased OR for EKD. Both metabolic syndrome and EKD were independently and additively related to the presence of surrogate markers of arteriosclerosis.

Results of a retrospective observational study of intermediate care staffed by hospitalists: Impact on mortality, co‐management, and teaching

BACKGROUND Hospitalized patients are complex and institutions have to face the high cost of critical care and the limited resources of the ward. Intermediate care appears as an attractive strategy to provide rational care according to patient needs. It is an interesting scenario to expand co-management and teaching. STUDY DESIGN Retrospective observational study. SETTING Intermediate care unit (ImCU) of a single academic hospital. PATIENTS AND METHODS 456 patients admitted from April 2006 to April 2010 were included in the study. Demographics, admission physiologic parameters and in-hospital mortality were recorded. We used the Simplified Acute Physiology Score II (SAPS II) as prognostic score system. Co-management with medical and surgical teams, and the number of training residents were evaluated. RESULTS In-hospital mortality was 20.6%, whereas the expected mortality was 23.2% based on SAPS II score. The correlation between SAPS II predicted and observed death rates was accurate and statistically significant (Rho = 1.0, p < 0.001). Co-management was performed with several medical and surgical teams, with an increase in perioperative comanagement of 22.7% (p = 0.014). The number of training residents in ImCU increased from 4.3% to 30.4% (p = 0.002) CONCLUSIONS An ImCU led by hospitalists showed encouraging results regarding patient survival and SAPS II is an useful tool for prognostic evaluation in this population. Intermediate care serves as an expansion of role for hospitalists; and clinicians, trainees and patients may benefit from co-management and teaching opportunities at this unique level of care.

Insulin resistance determines phagocytic nicotinamide adenine dinucleotide phosphate oxidase overactivation in metabolic syndrome patients.

Objective Metabolic syndrome (MetS) is associated with insulin resistance and increases the cardiovascular risk. Oxidative stress constitutes a potential mechanism that links insulin resistance and cardiovascular disease. The aim of this study was to analyze the relationship of NADPH oxidase activation with insulin resistance, and the effect of this interaction on the cardiovascular risk in MetS patients. Methods NADPH oxidase-dependent superoxide production and expression was evaluated by luminescence and western blot, respectively, in peripheral blood mononuclear cells obtained from 125 patients with MetS. Insulin resistance was defined by the homeostasis model assessment index. Matrix metalloproteinase-9 was quantified by enzyme-linked immunosorbent assay in plasma samples. To ascertain the mechanisms involved in vivo, we performed in-vitro experiments in cultured macrophages. Results Fifty-six percent of patients with MetS showed insulin resistance. Plasma matrix metalloproteinase-9 levels were higher (P < 0.05) in insulin-resistant patients than in patients with insulin sensitivity. NADPH oxidase-dependent superoxide production was augmented (P < 0.05) in insulin-resistant patients with respect to insulin-sensitive patients. The interaction between insulin resistance and abnormally high NADPH oxidase-mediated superoxide production was associated with the highest matrix metalloproteinase-9 values. Increased NADPH oxidase-dependent superoxide production was significantly associated with higher NADPH oxidase p22phox expression in insulin-resistant than in insulin-sensitive patients. Interestingly, insulin upregulated p22phox in peripheral blood mononuclear cells and in murine macrophages. Conclusion Insulin resistance is associated with phagocytic NADPH oxidase activation. This association results in the highest cardiovascular risk in MetS patients.

Increased IL-32 Levels in Obesity Promote Adipose Tissue Inflammation and Extracellular Matrix Remodeling. Effect of Weight Loss.

Interleukin (IL)-32 is a recently described cytokine involved in the regulation of inflammation. We aimed to explore whether IL-32 could function as an inflammatory and angiogenic factor in human obesity and obesity-associated type 2 diabetes. Samples obtained from 90 subjects were used in the study. Obese patients exhibited higher expression levels of IL-32 in visceral adipose tissue (AT) as well as in subcutaneous AT and peripheral blood mononuclear cells. IL32 was mainly expressed by stromovascular fraction cells, and its expression was significantly enhanced by inflammatory stimuli and hypoxia, whereas no changes were found after the incubation with anti-inflammatory cytokines. The addition of exogenous IL-32 induced the expression of inflammation and extracellular matrix–related genes in human adipocyte cultures, and IL32-silenced adipocytes showed a downregulation of inflammatory genes. Furthermore, adipocyte-conditioned media obtained from obese patients increased IL32 gene expression in human monocyte cultures, whereas the adipocyte-conditioned media from lean volunteers had no effect on IL32 mRNA levels. These findings provide evidence, for the first time, about the inflammatory and remodeling properties of IL-32 in AT, implicating this cytokine in obesity-associated comorbidities.

Design and Performance of a New Severity Score for Intermediate Care

Background Application of illness-severity scores in Intermediate Care Units (ImCU) shows conflicting results. The aim of the study is to design a severity-of-illness score for patients admitted to an ImCU. Methods We performed a retrospective observational study in a single academic medical centre in Pamplona, Spain. Demographics, past medical history, reasons for admission, physiological parameters at admission and during the first 24 hours of ImCU stay, laboratory variables and survival to hospital discharge were recorded. Logistic regression analysis was performed to identify variables for mortality prediction. Results A total of 743 patients were included. The final multivariable model (derivation cohort = 554 patients) contained only 9 variables obtained at admission to the ImCU: previous length of stay 7 days (6 points), health-care related infection (11), metastatic cancer (9), immunosuppressive therapy (6), Glasgow comma scale 12 (10), need of non-invasive ventilation (14), platelets 50000/mcL (9), urea 0.6 g/L (10) and bilirubin 4 mg/dL (9). The ImCU severity score (ImCUSS) is generated by summing the individual point values, and the formula for determining the expected in-hospital mortality risk is: eImCUSS points*0.099 – 4,111 / (1 + eImCUSS points*0.099 – 4,111). The model showed adequate calibration and discrimination. Performance of ImCUSS (validation cohort = 189 patients) was comparable to that of SAPS II and 3. Hosmer-Lemeshow goodness-of-fit C test was χ2 8.078 (p=0.326) and the area under receiver operating curve 0.802. Conclusions ImCUSS, specially designed for intermediate care, is based on easy to obtain variables at admission to ImCU. Additionally, it shows a notable performance in terms of calibration and mortality discrimination.

Association of Phagocytic NADPH Oxidase Activity With Hypertensive Heart Disease: A Role for Cardiotrophin-1?

Left ventricular hypertrophy (LVH) is an independent marker of mortality in hypertension. Although the mechanisms contributing to LVH are complex, inflammation and oxidative stress may favor its development. We analyzed the association of the phagocytic NADPH oxidase–mediated superoxide anion release and LVH in patients with essential hypertension and the role of cardiotrophin-1 (CT-1) and interleukin-6 (IL-6), cytokines implicated in cardiac growth. Blood pressure, echocardiography data, and serum CT-1 and IL-6 levels were obtained in 140 subjects: 18 normotensives without LVH, 42 hypertensives without LVH, and 80 hypertensives with LVH. The NADPH oxidase–dependent superoxide production was assessed by chemiluminescence in peripheral blood mononuclear cells. Peripheral blood mononuclear cells were stimulated with CT-1 in vitro. Superoxide anion production by peripheral blood mononuclear cells associated with LVH and correlated with the left ventricular mass index. Serum CT-1 and IL-6 levels, which associated with the left ventricular mass index, correlated with superoxide production. Serum CT-1 and IL-6 levels were correlated. CT-1 stimulated NADPH oxidase superoxide production in peripheral blood mononuclear cells, which resulted in an increased release of IL-6. Our results show that superoxide anion production by the phagocytic NADPH oxidase associates with hypertensive heart disease, being significantly enhanced in hypertensive patients with LVH. This may be attributable to the activation of the NADPH oxidase by CT-1 and the subsequent release of IL-6. The phagocytic NADPH oxidase may be a therapeutic target in hypertensive heart disease.

Increased phagocytic NADPH oxidase activity associates with coronary artery calcification in asymptomatic men

Abstract Vascular calcification is a common feature in atherosclerosis and associates with cardiovascular events. Oxidative stress may be involved in the pathogenesis of vascular calcification. Previous studies have shown that the phagocytic NADPH oxidase is associated with atherosclerosis. The objective of the present study was to investigate the association between phagocytic NADPH oxidase-mediated superoxide production and coronary artery calcium (CAC). NADPH oxidase-mediated superoxide production was determined by chemiluminescence and CAC by computed tomography in 159 asymptomatic men free of overt clinical atherosclerosis. Multivariate linear regression analyses were used to assess the relationship between CAC and NADPH oxidase-mediated superoxide production. Compared with individuals in the lowest score of CAC (= 0 Agatston units), those in the upper score (>400 Agatston units) showed higher superoxide production (p < 0.05). In correlation analysis, superoxide production positively (p < 0.01) correlated with CAC, which in multivariate analysis remained significant after adjusting for age, HDL-cholesterol, triglycerides, body mass index, smoking, arterial hypertension and diabetes mellitus. In conclusion, in a population of men without clinically overt atherosclerotic disease, increased NADPH oxidase-mediated superoxide production associated with enhanced CAC. Albeit descriptive, these findings suggest a potential involvement of phagocytic NADPH oxidase-mediated oxidative stress in CAC.

Metabolic Surgery Enters the T2DM Treatment Algorithm

A Joint Statement endorsed by 45 international organizations, clinicians, and researchers indicating when to recommend or consider metabolic surgery in type 2 diabetes mellitus (T2DM) treatment has been recently published. These new guidelines, resulting from the Second Diabetes Surgery Summit (DSS-II), represent the most radical change in T2DM management of the past few decades.