Adiponectin diminishes platelet aggregation and sCD40L release. Potential role in the metabolic syndrome

The proinflammatory and proatherogenic mediator, soluble CD40 ligand (CD40L), is increased in the metabolic syndrome (MS) and released from platelets. We hypothesized that adiponectin modulates platelet function, and we sought to evaluate the association of adiponectin and sCD40L levels with platelet aggregation in MS and the effects of adiponectin on platelet aggregation and activation. Platelet aggregation and circulating adiponectin, sCD40L and P-selectin were determined in 30 controls and 30 patients with MS. Also, in vitro studies were performed in platelet-rich plasma from nine healthy volunteers. Adiponectin receptors were demonstrated by Western blotting and flow cytometry. ADP and epinephrine platelet aggregation was measured after preincubation with adiponectin. sCD40L and P-selectin secretion was measured in the supernatants by ELISA. Patients with MS had higher sCD40L and P-selectin than controls (5.96 +/- 0.50 vs. 4.28 +/- 0.41 ng/ml, P < 0.05, and 151 +/- 8 vs. 122 +/- 9 ng/ml, P < 0.05). By contrast, adiponectin was lower in patients with MS than in controls (5.25 +/- 0.30 vs. 7.35 +/- 0.34 microg/ml, P < 0.001). Higher platelet aggregation was found in MS. Adiponectin inversely correlated with P-selectin (R = -0.35, P = 0.009), sCD40L (r = -0.24, P = 0.05) and epinephrine and collagen induced aggregation (r = -0.80, P = 0.005; r = -0.70, P = 0.011). Platelets express the receptors for adiponectin. Platelet aggregatory response to epinephrine and ADP significantly decreased following preincubation with adiponectin (96 +/- 4 vs. 23 +/- 3%, P < 0.001, and 102 +/- 9 vs. 85 +/- 9%, P = 0.004). Adiponectin prevented platelet sCD40L release (1.63 +/- 0.15 vs. 2.04 +/- 0.20 ng/ml, P < 0.001). Enhanced platelet aggregation and activation markers are found in MS associated with low adiponectin concentrations. Novel evidence is provided demonstrating that adiponectin has antithrombotic properties, since it inhibits platelet aggregation and platelet activation

Loss of myocardial LIF receptor in experimental heart failure reduces cardiotrophin-1 cytoprotection. A role for neurohumoral agonists?

OBJECTIVES: Cardiomyocyte loss is involved in the transition from compensatory left ventricular hypertrophy (LVH) to heart failure (HF). Our aim was to investigate the status of the leukaemia inhibitory factor receptor (LIFR)/gp130 survival pathway and its cytoprotective activity in intact cardiac tissue and in cardiomyocytes obtained from adult spontaneously hypertensive rats (SHR) with LVH (non-failing SHR) and from aged SHR with overt HF (failing SHR). METHODS: Cardiac morphometry was assayed by planimetry in an image analysis system. mRNA and protein expression were quantified by real time RT-PCR and Western blotting. Receptors were localized by immunocytochemistry. Trypan blue staining, TUNEL, and MTT cell viability assays were employed to study the cytoprotective activity of cardiotrophin-1 (CT-1) in isolated caridomyocytes. RESULTS: Compared to non-failing SHR, failing SHR exhibited enhanced myocardial cell death (p<0.01) demonstrated by the increase in Bax/Bcl-2 ratio, caspase-3 activation and poly (ADP-ribose) polymerase (PARP) fragmentation. Failing SHR had a 7-fold diminished expression (p<0.01) of LIFR, no changes in gp130, and 1.6-fold increased myocardial expression (p<0.01) of CT-1. In cardiomyocytes isolated from non-failing SHR, recombinant CT-1 inhibited apoptotic and non-apoptotic cell death induced by angiotensin II or hydrogen peroxide. LIFR protein was entirely absent in cardiomyocytes isolated from failing SHR, which were resistant to the cytoprotective effects of CT-1. Finally, stimulation of non-failing SHR cardiomyocytes with angiotensin II, aldosterone, norepinephrine or endothelin-1 significantly decreased (p<0.01) LIFR expression. CONCLUSIONS: These data suggest that loss of CT-1-dependent survival mechanisms may contribute to the increase of cell death associated with HF in SHR. Neurohumoral activation may contribute to this alteration via suppression of LIFR

Neurohormonas y citocinas en la insuficiencia cardíaca. Correlación con la reserva de flujo coronario

Introduction and objectives. In heart failure, the coronary flow reserve (CFR) measured by positron-emission tomography (PET) is reduced. As neurohormone and cytokine levels are also altered in patients with the condition, our aim was to determine whether there is a correlation between CFR and neurohormone and cytokine levels. Patients and method. The study included 40 patients with heart failure but without ischemic heart disease. Myocardial blood flow was measured by PET using nitrogen- 13 ammonia at baseline and during ATP infusion. The CFR was calculated for each patient. In addition, levels of the following were determined: norepinephrine, endothelin- 1, angiotensin-II, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), tumor necrosis factor-alpha, interleukin (IL)-1β, soluble IL-2 receptor, and IL-6. Results. All neurohormone levels were elevated above reference values. The levels of all cytokines, except IL-1β, were also elevated. There was a significant negative correlation between CFR and the levels of several neurohormones: ANP (r=–0.476), BNP (r=–0.442), and IL-6 (r=–0.509). Conclusions. In heart failure, the decrease in CFR is correlated with increases in the levels of certain neurohormones (i.e., ANP and BNP) and cytokines (i.e., IL-6), with vasodilatory effect. These increases are probably are related to compensatory mechanisms that are unable to correct for the endothelial dysfunction present in these patients

Biochemical Diagnosis of Hypertensive Myocardial Fibrosis

A substantial increase in fibrillar collagen has been observed in the left cardiac ventricle of animals and humans with arterial hypertension. Hypertensive myocardial fibrosis is the result of both increased collagen types I and III due to the fact that its synthesis by fibroblasts and myofibroblasts is stimulated and its extracellular collagen degradation unchanged or decreased extracellular collagen degradation. Hemodynamic and non-hemodynamic factors may be involved in the disequilibrium between collagen synthesis and degradation that occurs in hypertension. As shown experimentally and clinically, an exaggerated rise in fibrilar collagen content promotes abnormalities of cardiac function, contributes to the decrease in coronary reserve and facilitates alterations in the electrical activity of the left ventricle. Although microscopic examination of cardiac biopsies is the most reliable method for documenting and measuring myocardial fibrosis, the development of non-invasive methods to indicate the presence of myocardial fibrosis in hypertensive patients would be useful. We have therefore applied a biochemical method based on the measurement of serum peptides derived from the tissue formation when synthesized and degradation of fibrillar collagens to monitor the turnover of these molecules in rats with spontaneous hypertension and patients with essential hypertension

Dimensiones de personalidad y calidad de vida relacionada con la salud en mujeres

Incluye: PDF de la presentación y video del seminario.El objetivo del estudio es analizar la asociación entre personalidad y calidad de vida relacionada con la salud (CVRS) en una muestra de mujeres españolas. Se quiere: explorar el papel de la edad como posible factor de confusión y el papel de la Family of Origin Socio Economic Status (FOSES) como posible modificador del efecto. Las conclusiones del estudio son: 1. Niveles altos de neuroticismo afectan negativamente los componentes físico y mental de la CVRS en mujeres españolas. 2. Extraversión alta está relacionada con mejores resultados en la CVRS mental en esta población. 3. Los niveles más altos de amabilidad se asocian con: Mujeres españolas con bajo nivel de FOSES: peores resultados de CVRS física pero mejores resultados de CVRS mental y mujeres con FOSES medio-alto: peor CVRS mental.N

The proinflammatory mediator CD40 ligand is increased in the metabolic syndrome and modulated by adiponectin

OBJECTIVES: We hypothesized that the CD40/CD40 ligand (CD40L) system is up-regulated in the metabolic syndrome (MS) and modulated by adiponectin (AN). The objectives were: 1) to compare plasma and monocyte CD40L in patients with MS and controls and its association with clinical and biochemical parameters, 2) to investigate platelets as a source of soluble CD40L (sCD40L), and 3) to analyze the effects of AN on CD40/CD40L. METHODS: Plasma sCD40L and AN were measured in 246 controls and 128 patients with MS by ELISA. Monocyte CD40/CD40L expression and platelet CD40L content and release were compared in patients with MS and controls. Monocytes and endothelial cells were cultured with AN and CD40/CD40L expression determined by real-time RT-PCR and Western blotting. RESULTS: Patients with MS had higher sCD40L and lower AN levels than controls (0.89 +/- 0.1 vs. 0.76 +/- 0.07 ng/ml and 10.10 +/- 0.65 vs. 12.99 +/- 0.80 microg /ml, P < 0.05). Monocyte CD40/CD40L expression was higher (P < 0.05) in patients than controls (CD40: 1.31 +/- 0.31 vs. 0.80 +/- 0.14 arbitrary units; CD40L: 1.24 +/- 0.85 vs. 0.43 +/- 0.14 pg/microg protein). No differences were observed on CD40L content between resting platelets from patients with MS and controls (7.7 +/- 3.5 vs. 7.2 +/- 2.2 pg/microg protein). Stimulated platelets from patients with the MS released more (P < 0.05) sCD40L than controls (582 +/- 141 vs. 334 +/- 60% change vs. nonstimulated platelets). AN reduced CD40L mRNA and protein expression in monocytes from MS patients and endothelial cells. CONCLUSIONS: The enhanced sCD40L and cellular CD40L expression in the MS suggests that CD40L is of pathophysiological relevance in MS. Also, a new antiinflammatory effect of AN is described through the modulation of the CD40/CD40L system

Correlation between serum content of the main COPs (cholesterol oxidation products) from autoxidation and cardiovascular risk factors

BACKGROUND/AIMS: Risk factors for cardiovascular disease (CVD) have been proven to be associated with an increased oxidative stress. Several studies have considered cholesterol oxidation products (COPs) as specific in vivo markers of oxidative stress. The aim of this study was to investigate the association between the levels of COPs derived from autoxidation processes and established cardiovascular risk factors, comparing the levels of serum COPs in subjects with or without showing values out of the reference ranges. METHODS: It was a cross-sectional study in which 88 subjects were recruited and individual and total COPs from autoxidation origin was analyzed in serum by GC-MS. The simultaneous correlation of COPs with different CVD risk factors have been analyzed. RESULTS AND DISCUSSION: A great variability of total COPs concentrations were found. Subjects presented total COPs values from 0.091 to 2.052 μg/mL. Total COPs were significantly higher (p < 0.05) in patients with hypertriglycerolemia, hypertension, diabetes and overweight/ obesity status compared to those subjects who did not present those CVD risk factors. Moreover, 7α and 7β hydroxycholesterol and 7-ketocholesterol were significantly higher (p < 0.05) in patients with hypertension and diabetes. No significant differences in total COPs were found between patients with and without hypercholesterolemia. CONCLUSIONS: The obtained results showed that the analyzed COPs correlate well with at least 4 out of 6 risk factors of development of CVD

Gender Differences in Plasma Biomarker Levels in a Cohort of COPD Patients: A Pilot Study

Little is known about gender differences in plasma biomarker levels in patients with chronic obstructive pulmonary disease (COPD). HYPOTHESIS: There are differences in serum biomarker levels between women and men with COPD. OBJECTIVE: Explore gender differences in plasma biomarker levels in patients with COPD and smokers without COPD. METHODS: We measured plasma levels of IL-6, IL-8, IL-16, MCP-1, MMP-9, PARC and VEGF in 80 smokers without COPD (40 males, 40 females) and 152 stable COPD patients (76 males, 76 females) with similar airflow obstruction. We determined anthropometrics, smoking history, lung function, exercise tolerance, body composition, BODE index, co-morbidities and quality of life. We then explored associations between plasma biomarkers levels and the clinical characteristics of the patients and also with the clinical and physiological variables known to predict outcome in COPD. RESULTS: The plasma biomarkers level explored were similar in men and women without COPD. In contrast, in patients with COPD the median value in pg/mL of IL-6 (6.26 vs 8.0, p = 0.03), IL-16 (390 vs 321, p = 0.009) and VEGF (50 vs 87, p = 0.02) differed between women and men. Adjusted for smoking history, gender was independently associated with IL-16, PARC and VEGF levels. There were also gender differences in the associations between IL-6, IL-16 and VEGF and physiologic variables that predict outcomes. CONCLUSIONS: In stable COPD patients with similar airflow obstruction, there are gender differences in plasma biomarker levels and in the association between biomarker levels and important clinical or physiological variables. Further studies should confirm our findings

Inflammatory and Repair Serum Biomarker Pattern. Association to Clinical Outcomes in COPD

Background: The relationship between serum biomarkers and clinical expressions of COPD is limited. We planned to further describe this association using markers of inflammation and injury and repair. Methods: We studied lung function, comorbidities, exercise tolerance, BODE index, and quality of life in 253 COPD patients and recorded mortality over three years. Serum levels of Interleukins 6,8 and16, tumor necrosis factor alpha (TNF α) [inflammatory panel], vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) [injury and repair panel] and pulmonary and activation-regulated chemokine (PARC/CCL-18) and monocyte chemotactic protein 1 (MCP-1/CCL2) [chemoattractant panel] were measured. We related the pattern of the biomarker levels to minimal clinically important differences (MCID) using a novel visualization method [ObServed Clinical Association Results (OSCAR) plot]. Results: Levels of the inflammatory markers IL-6, TNF α were higher and those of injury and repair lower (p < 0.01) with more advanced disease (GOLD 1 vs. 4). Using the OSCAR plot, we found that patients in the highest quartile of inflammatory and lowest quartile of injury and repair biomarkers level were more clinically compromised and had higher mortality (p < 0.05). Conclusions: In COPD, serum biomarkers of inflammation and repair are distinctly associated with important clinical parameters and survival

Biochemical biomarkers for multiple sclerosis

Introduction: Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system. Although there is currently no definite cure for MS, new therapies have recently been developed based on a continuous search for new biomarkers. Development: MS diagnosis relies on the integration of clinical, imaging and laboratory findings as there is still no single pathognomonic clinical feature or diagnostic laboratory biomarker. The most commonly laboratory test used is the presence of immunoglobulin G oligoclonal bands (OCB) in cerebrospinal fluid of MS patients. This test is now included in the 2017 McDonald criteria as a biomarker of dissemination in time. Nevertheless, there are other biomarkers currently in use such as kappa free light chain, which has shown higher sensitivity and specificity for MS diagnosis than OCB. In addition, other potential laboratory tests involved in neuronal damage, demyelination and/or inflammation could be used for detecting MS. Conclusions: CSF and serum biomarkers have been reviewed for their use in MS diagnosis and prognosis to stablish an accurate and prompt MS diagnosis, crucial to implement an adequate treatment and to optimize clinical outcomes over time