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

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

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

The Influence of Individual, Social and Physical Environment Factors on Physical Activity in the Adult Population in Andalusia, Spain

A person’s physical and social environment is considered as an influencing factor in terms of rates of engagement in physical activity. This study analyses the influence of socio-demographic, physical and social environmental factors on physical activity reported in the adult population in Andalusia. This is a cross-sectional study using data collected in the Andalusia Health Survey in 1999 and 2003. In addition to the influence of the individual’s characteristics, if there are no green spaces in the neighbourhood it is less likely that men and women will take exercise (OR = 1.26; 95% CI = 1.13, 1.41). Likewise, a higher local illiteracy rate also has a negative influence on exercise habits in men (OR = 1.39; 95% CI = 1.21, 1.59) and in women (OR = 1.22; 95% CI = 1.07, 1.40). Physical activity is influenced by individuals’ characteristics as well as by their social and physical environment, the most disadvantaged groups are less likely to engage in physical activity

Rol de sCD40L en la predicción de súper-respuesta a la terapia de resincronización cardiaca

Background. The aim of this paper is to analyze the role of the biomarkers Interleukin 6, Tumoral Necrosis Factor α, sCD40L, high sensitive Troponin T, high sensitive C-Reactive Protein and Galectin-3 in predicting super response (SR) to Cardiac Resynchronization Therapy (CRT), as they have not been studied in this field before. Methods. Clinical, electrocardiographic and echocardiographic data was obtained preimplant and after one year. SR was defined as reduction in LVESV ≥ 30% at one year follow-up. Blood samples were extracted preimplant. Multivariate logistic regression and ROC curves were performed. Results. 50 patients were included, 23 (46%) were SR. Characteristics related to SR were: female (35 vs. 11%, p=0.04), suffering from less ischemic cardiomyopathy (13 vs. 63%, p<0.0001) and lateral (0 vs. 18%, p=0.03), inferior (4 vs. 33%, p=0.01) and posterior infarction (0 vs. 22%, p=0.01); absence of mitral regurgitation (47% vs. 22%, p=0.04), wider QRS width (157.7±22.9 vs. 140.8±19.2ms, p=0.01), higher concentrations of sCD40L (6.9±5.1 vs. 4.4±3.3 ng/mL, p=0.02), and left ventricular lead more frequent in lateral medial position (69 vs. 26%, p=0.002). QRS width, lateral medial position of the lead and absence of mitral regurgitation were independent predictors of SR. sCD40L showed a moderate direct correlation with SR (r=0.39, p=0.02) and with the reduction of LVESV (r=0.44, p=0.02). Conclusion. sCD40L correlates significantly with SR to CRT. QRS width, absence of mitral regurgitation and lateral medial position of the lead are independent predictors of SR in this cohort.Fundamento. Analizar los biomarcadores Interleuquina 6, factor de necrosis tumoral α, sCD40L, troponina T hipersensible, proteína C-reactiva hipersensible y galectina-3 en la predicción de súper-respuesta (SR) a la terapia de resincronización cardiaca (TRC), ya que no han sido valorados con anterioridad. Material y métodos. Se recopilaron datos clínicos, electrocardiográficos y ecocardiográficos preimplante y al año. Se definió SR como disminución del VTSVI ≥ 30% al año de seguimiento. Las muestras sanguíneas fueron extraídas preimplante. Se realizó regresión logística multivariante y curvas ROC. Resultados. Se incluyeron 50 pacientes, 23 (46%) fueron SR.Las características relacionadas con la SR fueron: ser mujer (35 vs. 11%, p=0,04), sufrir menos cardiopatía isquémica (13 vs. 63%, p<0,0001) e infarto lateral (0 vs. 18%, p=0,03), inferior (4 vs. 33%, p=0,01) y posterior (0 vs. 22%, p=0,01); ausencia de insuficiencia mitral (47% vs. 22%, p=0,04), mayor anchura del QRS (157,7±22,9 vs. 140,8±19,2 ms, p=0,01), mayor concentración de sCD40L (6,9±5,1 vs. 4,4±3,3 ng/mL, p=0,02), y electrodo ventricular izquierdo más frecuentemente en posición lateral media (69 vs. 26%, p=0,002). El QRS, la posición lateral media del electrodo y la ausencia de insuficiencia mitral fueron predictores independientes de SR. sCD40L mostró una correlación moderada directa con SR (r=0,39, p=0,02) y con la disminución del VTSVI (r=0,44, p=0,02). Conclusiones. sCD40L se correlaciona significativamente con SR a la TRC. El QRS, la ausencia de insuficiencia mitral y la posición lateral media del electrodo son predictores independientes de SR en esta cohorte

Trabecular bone score in active or former smokers with and without COPD

Background Smoking is a recognized risk factor for osteoporosis. Trabecular bone score (TBS) is a novel texture parameter to evaluate bone microarchitecture. TBS and their main determinants are unknown in active and former smokers. Objective To assess TBS in a population of active or former smokers with and without Chronic Obstructive Pulmonary Disease (COPD) and to determine its predictive factors. Methods Active and former smokers from a pulmonary clinic were invited to participate. Clinical features were recorded and bone turnover markers (BTMs) measured. Lung function, low dose chest Computed Tomography scans (LDCT), dual energy absorptiometry (DXA) scans were performed and TBS measured. Logistic regression analysis explored the relationship between measured parameters and TBS. Results One hundred and forty five patients were included in the analysis, 97 (67.8%) with COPD. TBS was lower in COPD patients (median 1.323; IQR: 0.13 vs 1.48; IQR: 0.16, p = 0.003). Regression analysis showed that a higher body mass index (BMI), younger age, less number of exacerbations and a higher forced expiratory volume-one second (FEV1%) was associated with better TBS (β = 0.005, 95% CI:0.000–0.011, p = 0.032; β = -0.003, 95% CI:-0.007(-)-0.000, p = 0.008; β = -0.019, 95% CI:-0.034(-)-0.004, p = 0.015; β = 0.001, 95% CI:0.000–0.002, p = 0.012 respectively). The same factors with similar results were found in COPD patients. Conclusions A significant proportion of active and former smokers with and without COPD have an affected TBS. BMI, age, number of exacerbations and the degree of airway obstruction predicts TBS values in smokers with and without COPD. This important information should be considered when evaluating smokers at risk of osteoporosis