Varo-Cenarruzabeitia, M.N. (Miren Nerea)
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- Exploring the Association Between Emphysema Phenotypes and Low Bone Mineral Density in Smokers with and without COPD(2020) Seijo, L. (Luis); Campo, A. (Arantza); Colina, I. (Inmaculada); Calleja, M. (María); Bertó, J. (Juan); Torres, J.P. (Juan P.) de; Alcaide, A.B. (Ana Belén); Rodriguez-Fraile, M. (Macarena); González, J. (Jessica); Rivera-Ortega, P. (Pilar); Restituto, P. (Patricia); Perez-Warnisher, M.T. (María Teresa); Zulueta, J. (Javier); Varo-Cenarruzabeitia, M.N. (Miren Nerea)Rationale: Emphysema and osteoporosis are tobacco-related diseases. Many studies have shown that emphysema is a strong and independent predictor of low bone mineral density (BMD) in smokers; however, none of them explored its association with different emphysema subtypes. Objective: To explore the association between the different emphysema subtypes and the presence of low bone mineral density in a population of active or former smokers with and without chronic obstructive pulmonary disease (COPD). Methods: One hundred and fifty-three active and former smokers from a pulmonary clinic completed clinical questionnaires, pulmonary function tests, a low-dose chest computed tomography (LDCT) and a dual-energy absorptiometry (DXA) scans. Subjects were classified as having normal BMD or low BMD (osteopenia or osteoporosis). Emphysema was classified visually for its subtype and severity. Logistic regression analysis explored the relationship between the different emphysema subtypes and the presence of low BMD adjusting for other important factors. Results: Seventy-five percent of the patients had low BMD (78 had osteopenia and 37 had osteoporosis). Emphysema was more frequent (66.1 vs 26.3%, p=<0.001) and severe in those with low BMD. Multivariable analysis adjusting for other significant cofactors (age, sex, FEV1, and severity of emphysema) showed that BMI (OR=0.91, 95% CI: 0.76–0.92) and centrilobular emphysema (OR=26.19, 95% CI: 1.71 to 399.44) were associated with low BMD. Conclusion: Low BMD is highly prevalent in current and former smokers. BMI and centrilobular emphysema are strong and independent predictors of its presence, which suggests that they should be considered when evaluating smokers at risk for low BMD.
- Association of prenatal exposure to endocrine-disrupting chemicals with liver injury in children(2022) Papadopoulou, E. (Eleni); García, E. (Erika); Wright, J. (John); Haug, L.S. (Line Smastuen); Chatzi, L. (Leda); Vos, M.B. (Miriam B.); Roumeliotaki, T. (Theano); Conti, D.V. (David V.); Vafeiadi, M. (Marina); Maitre, L. (Léa); Heude, B. (Barbara); Gómez-Urquiza, J. (José); McEachan, R.R.C. (Rosemary R. C.); McConnell, R. (Rob); Casas, M. (Maribel); Fossati, S. (Serena); Grazuleviciene, R. (Regina); Valvi, D. (Damaskini); Basagana, X. (Xavier); Colicino, E. (Elena); Vrijheid, M. (Martine); Thomsen, C. (Cathrine); Berhane, K.T. (Kiros T.); Philippat, C. (Claire); Midya, V. (Vishal); Stratakis, N. (Nikos); Andrusaityte, S. (Sandra); Varo-Cenarruzabeitia, M.N. (Miren Nerea)IMPORTANCE Prenatal exposures to endocrine-disrupting chemicals (EDCs) may increase the risk for liver injury in children; however, human evidence is scarce, and previous studies have not considered potential EDC-mixture effects. Furthermore, the association between prenatal EDC exposure and hepatocellular apoptosis in children has not been studied previously. OBJECTIVE To investigate associations of prenatal exposure to EDC mixtures with liver injury risk and hepatocellular apoptosis in childhood. DESIGN, SETTING, AND PARTICIPANTS This prospective cohort study used data collected from April 1, 2003, to February 26, 2016, from mother-child pairs from the Human Early-Life Exposome project, a collaborative network of 6 ongoing, population-based prospective birth cohort studies from 6 European countries (France, Greece, Lithuania, Norway, Spain, and the UK). Data were analyzed from April 1, 2021, to January 31, 2022. EXPOSURES Three organochlorine pesticides, 5 polychlorinated biphenyls, 2 polybrominated diphenyl ethers (PBDEs), 3 phenols, 4 parabens, 10 phthalates, 4 organophosphate pesticides, 5 perfluoroalkyl substances, and 9 metals. MAIN OUTCOMES AND MEASURES Child serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), and CK-18 were measured at 6 to 11 years of age. Risk for liver injury was defined as having ALT, AST, and/or GGT levels above the 90th percentile. Associations of liver injury or cytokeratin 18 (CK-18) levels with each chemical group among the 45 EDCs measured in maternal blood or urine samples collected in pregnancy were estimated using 2 complimentary exposure-mixture methods: bayesian weighted quantile sum (BWQS) and bayesian kernel machine regression. RESULTS The study included 1108 mothers (mean [SD] age at birth, 31.0 [4.7] years) and their singleton children (mean [SD] age at liver assessment, 8.2 [1.6] years; 598 [54.0%] boys). Results of the BWQS method indicated increased odds of liver injury per exposure-mixture quartile increase for organochlorine pesticides (odds ratio [OR], 1.44 [95% credible interval (CrI), 1.21-1.71]), PBDEs (OR, 1.57 [95% CrI, 1.34-1.84]), perfluoroalkyl substances (OR, 1.73 [95% CrI, 1.45-2.09]), and metals (OR, 2.21 [95% CrI, 1.65-3.02]). Decreased odds of liver injury were associated with high-molecular-weight phthalates (OR, 0.74 [95% CrI, 0.60-0.91]) and phenols (OR, 0.66 [95% CrI, 0.54-0.78]). Higher CK-18 levels were associated with a 1-quartile increase in polychlorinated biphenyls (beta, 5.84 [95% CrI, 1.69-10.08] IU/L) and PBDEs (beta, 6.46 [95% CrI, 3.09-9.92] IU/L). Bayesian kernel machine regression showed associations in a similar direction as BWQS for all EDCs and a nonlinear association between phenols and CK-18 levels. CONCLUSIONS AND RELEVANCE With a combination of 2 state-of-the-art exposure-mixture approaches, consistent evidence suggests that prenatal exposures to EDCs are associated with higher risk for liver injury and CK-18 levels and constitute a potential risk factor for pediatric nonalcoholic fatty liver disease.
- Biochemical Diagnosis of Hypertensive Myocardial Fibrosis(Elsevier, 2000) Querejeta, R. (Ramón); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Laviades, C. (Concepción); Varo-Cenarruzabeitia, M.N. (Miren Nerea)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.
- Neurohormonas y citocinas en la insuficiencia cardíaca. Correlación con la reserva de flujo coronario(Elsevier España, 2005) Macias, A. (Alfonso); Coma-Canella, I. (Isabel); Sanchez-Ibarrola, A. (Alfonso); Varo-Cenarruzabeitia, M.N. (Miren Nerea)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.
- Serum carboxy-terminal propeptide of procollagen type I is a marker of myocardial fibrosis in hypertensive heart disease(American Heart Association, 2000) Martinez-Ubago, J.L. (José L.); Gutierrez-Stampa, M. (M.); Querejeta, R. (Ramón); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Etayo, J.C. (Juan Carlos); Pardo-Mindan, F.J. (Francisco Javier); Larman, M. (Mariano); Gil, M.J. (María José); Monreal, J.I. (José Ignacio); Emparanza, J.I. (J. I.); Artiñano, E. (E.); Varo-Cenarruzabeitia, M.N. (Miren Nerea)BACKGROUND: This study was designed to investigate whether the serum concentration of the carboxy-terminal propeptide of procollagen type I (PIP), a marker of collagen type I synthesis, is related to myocardial fibrosis in hypertensive patients. METHODS AND RESULTS: The study was performed in 26 patients with essential hypertension in which ischemic cardiomyopathy was excluded after a complete medical workup. Right septal endomyocardial biopsies were performed in hypertensive patients to quantify collagen content. Collagen volume fraction (CVF) was determined on picrosirius red-stained sections with an automated image analysis system. The serum concentration of PIP was measured by specific radioimmunoassay. Compared with normotensives, both serum PIP and CVF were increased (P<0.001) in hypertensives. A direct correlation was found between CVF and serum PIP (r=0.471, P<0.02) in all hypertensives. Histological analysis revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 18 with nonsevere fibrosis. Serum PIP was higher (P<0.05) in patients with severe fibrosis than in patients with nonsevere fibrosis. Using receiver operating characteristic curves, we observed that a cutoff of 127 microg/L for PIP provided 78% specificity and 75% sensitivity for predicting severe fibrosis with a relative risk of 4.80 (95% CI, 1.19 to 19.30). CONCLUSIONS: These results show a strong correlation between myocardial collagen content and the serum concentration of PIP in essential hypertension. Although preliminary, these findings suggest that the determination of PIP may be an easy and reliable method for the screening and diagnosis of severe myocardial fibrosis associated with arterial hypertension.
- Biochemical Assessment of Myocardial Fibrosis in Hypertensive Heart Disease(American Heart Association, 2001) Querejeta, R. (Ramón); Lopez-Salazar, M.B. (María Begoña); Diez-Martinez, J. (Javier); Gonzalez, A. (Arantxa); Laviades, C. (Concepción); Varo-Cenarruzabeitia, M.N. (Miren Nerea)Fibrous tissue accumulation is an integral feature of the adverse structural remodeling of cardiac tissue seen with hypertensive heart disease. Given the importance of fibrous tissue in leading to myocardial dysfunction and failure, noninvasive monitoring of myocardial fibrosis by use of serological markers of collagen turnover could prove a clinically useful tool, particularly given the potential for cardioprotective and cardioreparative pharmacological strategies. An emerging experimental and clinical experience holds promise for the use of radioimmunoassays of various serological markers of fibrillar collagen type I and type III turnover in arterial hypertension. More specifically, the measurement of serum concentrations of procollagen type I C-terminal propeptide (a peptide that is cleaved from procollagen type I during the synthesis of fibril-forming collagen type I) may provide indirect diagnostic information on both the extent of myocardial fibrosis and the ability of antihypertensive treatment to diminish collagen type I synthesis and reduce myocardial fibrosis. This approach represents an exciting and innovative strategy, and available data set the stage for larger trials, in which noninvasive measures of fibrosis in hypertensive heart disease could prove useful.
- Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis(BioMed Central, 2011) Paramo, J.A. (José Antonio); Ferrer-Agüero, J.M. (José M.); Llimiñana, M.C. (María C.); Borreguero-Leon, J.M. (Juan María); Pastor, E. (Enrique); Lorente, L. (Leonardo); Orbe, J. (Josune); Rodriguez, J.A. (José Antonio); Blanquer, J. (José); Jimenez, A. (Alejandro); Ferreres, J. (José); Belmonte, F. (Felipe); Sole-Violan, J. (Jordi); Gomez-Melini, E. (Eduardo); Díaz, C. (César); Martin, M.M. (María M.); Labarta, L. (Lorenzo); Varo-Cenarruzabeitia, M.N. (Miren Nerea)INTRODUCTION: CD40 Ligand (CD40L) and its soluble counterpart (sCD40L) are proteins that exhibit prothrombotic and proinflammatory properties on binding to their cell surface receptor CD40. The results of small clinical studies suggest that sCD40L levels could play a role in sepsis; however, there are no data on the association between sCD40L levels and mortality of septic patients. Thus, the aim of this study was to determine whether circulating sCD40L levels could be a marker of adverse outcome in a large cohort of patients with severe sepsis. METHODS: This was a multicenter, observational and prospective study carried out in six Spanish intensive care units. Serum levels of sCD40L, tumour necrosis factor-alpha and interleukin-10, and plasma levels of tissue factor were measured in 186 patients with severe sepsis at the time of diagnosis. Serum sCD40L was also measured in 50 age- and sex-matched controls. Survival at 30 days was used as the endpoint. RESULTS: Circulating sCD40L levels were significantly higher in septic patients than in controls (P = 0.01), and in non-survivors (n = 62) compared to survivors (n = 124) (P = 0.04). However, the levels of CD40L were not different regarding sepsis severity. Logistic regression analysis showed that sCD40L levels >3.5 ng/mL were associated with higher mortality at 30 days (odds ratio = 2.89; 95% confidence interval = 1.37 to 6.07; P = 0.005). The area under the curve of sCD40L levels >3.5 ng/mL as predictor of mortality at 30 days was 0.58 (95% CI = 0.51 to 0.65; P = 0.03). CONCLUSIONS: In conclusion, circulating sCD40L levels are increased in septic patients and are independently associated with mortality in these patients; thus, its modulation could represent an attractive therapeutic target.
- Rol de sCD40L en la predicción de súper-respuesta a la terapia de resincronización cardiaca(2021) Rodriguez-Mañero, M. (Moisés); Barba, J. (Joaquín); Pujol, C. (C.); Garcia-Bolao, I. (Ignacio); Macías-Gallego, A. (A.); Torres-Santamaría, M.J. (María José); Castaño-Rodríguez, S. (S.); Varo-Cenarruzabeitia, M.N. (Miren Nerea)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.
- The angiotensin-converting enzyme insertion/deletion polymorphism is associated with phagocytic NADPH oxidase-dependent superoxide generation: potential implication in hypertension.(Portland Press, 2009) Moreno, M.U. (María Ujué); Beloqui, O. (Óscar); Robador, P.A. (Pablo A.); Bidegain, J. (J.); Fortuño, A. (Ana); Diez-Martinez, J. (Javier); San-Jose, G. (Gorka); Zalba, G. (Guillermo); Varo-Cenarruzabeitia, M.N. (Miren Nerea)The objective of the present study was to analyse the influence of the ACE (angiotensin-converting enzyme) gene I/D (insertion/deletion) polymorphism on NADPH oxidase-dependent O(2)(*-) (superoxide radical) production, and to investigate the clinical implication of this association in hypertensive subjects. A case-control study was performed in a random sample of the general population composed of 189 normotensive subjects and 223 hypertensive subjects. The ACE polymorphism was determined by PCR. NADPH oxidase-dependent O(2)(*-) production was quantified in phagocytic cells by chemiluminescence. MMP-9 (matrix metalloproteinase-9), a marker of atherosclerosis previously reported to be associated with NADPH oxidase overactivity, was quantified by ELISA in plasma samples. The distribution of genotypes was in Hardy-Weinberg equilibrium. The I/D polymorphism was not associated with hypertension. NADPH oxidase-dependent O(2)(*-) production was significantly higher in D/D (deletion/deletion) than in I/I (insertion/insertion) and I/D, both in normotensive and hypertensive subjects. Interestingly, plasma levels of angiotensin II were significantly higher in D/D than in I/I and I/D, both in normotensive and hypertensive subjects. Plasma levels of MMP-9 and systolic blood pressure values were significantly higher in D/D than in I/I and I/D hypertensive subjects, whereas no differences were found among genotypes in normotensive subjects. Interestingly, NADPH oxidase-dependent O(2)(*-) production positively associated with plasma MMP-9 levels in hypertensive subjects, which remained significant after adjustment for age and gender. In conclusion, in the present study we have reported for the first time an association of the D/D genotype of the ACE I/D polymorphism with phagocytic NADPH oxidase-mediated O(2)(*-) overproduction. Within the group of hypertensive patients, D/D cases also associated with increased blood pressure values and with enhanced plasma levels of MMP-9.
- Correlation between serum content of the main COPs (cholesterol oxidation products) from autoxidation and cardiovascular risk factors(Sociedad Española de Nutrición Parenteral y Enteral, 2011) Astiasarán, I. (Iciar); Ansorena-Artieda, D. (Diana); Menendez-Carreño, M. (María); Mugueta, C. (Carmen); Restituto, P. (Patricia); Varo-Cenarruzabeitia, M.N. (Miren Nerea)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.