Valor pronóstico de la troponina de alta sensibilidad en la cardiopatía isquémica crónica

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Medicina. Fecha de lectura: 6-09-201

Migración y salud: diferencias en mortalidad perinatal

INTRODUCCIÓN Más de un billón de personas en el mundo migraron en 2018, 258 millones eran migrantes internacionales, el 48,4% fueron mujeres. España está entre los 10 países con mayor número de migrantes entre 1990 y 2017. Las tasas de mortalidad infantil y perinatal son marcadores del estado de salud poblacional, y clave en la evaluación de la calidad asistencial. La Comunitat Valenciana cuenta con un registro de mortalidad perinatal, con datos de muertes desde la semana 22 de gestación hasta los 28 días de vida. OBJETIVO Analizar la evolución de la mortalidad perinatal en mujeres migrantes y españolas residentes en la Comunitat Valenciana en 2006-2017, y sus causas prevenibles usando diversas clasificaciones según la nacionalidad de la madre. METODOLOGÍA Estudio observacional transversal, usando datos del Registro de Mortalidad Perinatal de la Comunitat Valenciana entre 2006-2017. Las mujeres que no poseían la nacionalidad española se consideraron migrantes. Se usaron 3 clasificaciones de acuerdo a la nacionalidad de la madre: agrupación geográfica, agrupación basada en el nivel de desarrollo y agrupación basada en la clasificación por ingresos del Banco Mundial. Se calcularon las tasas de mortalidad perinatal, fetal y neonatal. Se calcularon las tasas crudas de mortalidad (CR) y sus intervalos de confianza al 95% (IC95%), y las tasas de mortalidad ajustadas por edad (ASR) por el método directo y sus IC95% para todos los periodos del estudio. Se calcularon las tasas brutas de mortalidad fetal, neonatal y perinatal para las causas prevenibles de muerte, usándose el test exacto de Fisher para estimar la razón de tasas de mortalidad. RESULTADOS De los 579.903 nacimientos en la Comunitat Valenciana, se registraron 3.560 muertes perinatales: 2.281 en el periodo fetal y 1.279 en el periodo neonatal; 1.040 correspondían a mujeres migrantes (29,21%). Las mujeres migrantes presentaron tasas de mortalidad perinatal mayores en todos los cuatrienios respecto a las españolas. La mayor parte de las muertes en migrantes se registraron en mujeres de Europa oriental, Latinoamérica y norte de África. Las tasas más altas, hasta 3 veces mayores en las tasas crudas, se dieron en las mujeres que provenían de países menos desarrollados. Las tasas de mortalidad perinatal fueron inversamente proporcionales al nivel de ingresos del país de origen de la madre: las tasas de países con ingresos bajos fueron 2,63 veces mayores a las de las españolas. En el estudio de las causas prevenibles, el mayor número de muertes se asoció a la prematuridad-inmadurez tanto en migrantes como en españolas. La razones de tasas de mortalidad de todas las causas prevenibles fueron superiores para el grupo de migrantes. CONCLUSIONES 1.Las mujeres migrantes presentaron tasas de mortalidad perinatal mayores a las de las españolas, teniendo ambos grupos una tendencia a la baja. 2.Las clasificaciones usadas abren una línea de investigación en mortalidad perinatal más allá del origen geográfico

Important abnormalities of bone mineral metabolism are present in patients with coronary artery disease with a mild decrease of the estimated glomerular filtration rate

The final publication is avilable at: Journal of Bone and Mineral Metabolism 30.9 (2015): 1-34Chronic kidney disease (CKD)–mineral and bone disorder (MBD) is characterized by increased circulating levels of parathormone (PTH) and fibroblast growth factor 23 (FGF23), bone disease, and vascular calcification, and is associated with adverse outcomes. We studied the prevalence of mineral metabolism disorders, and the potential relationship between decreased estimated glomerular filtration rate (eGFR) and CKD-MBD in coronary artery disease patients in a cross-sectional study of 704 outpatients 7.5 ± 3.0 months after an acute coronary syndrome. The mean eGFR (CKD Epidemiology Collaboration formula) was 75.8 ± 19.1 ml/min/1.73 m2. Our patients showed lower calcidiol plasma levels than a healthy cohort from the same geographical area. In the case of men, this finding was present despite similar creatinine levels in both groups and older age of the healthy subjects. Most patients (75.6 %) had an eGFR below 90 ml/min/1.73 m2 (eGFR categories G2–G5), with 55.3 % of patients exhibiting values of 60–89 ml/min/1.73 m2 (G2). PTH (r = −0.3329, p < 0.0001) and FGF23 (r = −0.3641, p < 0.0001) levels inversely correlated with eGFR, whereas calcidiol levels and serum phosphate levels did not. Overall, PTH levels were above normal in 34.9 % of patients. This proportion increased from 19.4 % in G1 category patients, to 33.7 % in G2 category patients and 56.6 % in G3–G5 category patients (p < 0.001). In multivariate analysis, eGFR and calcidiol levels were the main independent determinants of serum PTH. The mean FGF23 levels were 69.9 (54.6–96.2) relative units (RU)/ml, and 33.2 % of patients had FGF23 levels above 85.5 RU/ml (18.4 % in G1 category patients, 30.0 % in G2 category patients, and 59.2 % in G3–G5 category patients; p < 0.001). In multivariate analysis, eGFR was the main predictor of FGF23 levels. Increased phosphate levels were present in 0.7 % of the whole sample: 0 % in G1 category patients, 0.3 % in G2 category patients, and 2.8 % in G3–G5 category patients (p = 0.011). Almost 90 % of patients had calcidiol insufficiency without significant differences among the different degrees of eGFR. In conclusion, in patients with coronary artery disease there is a large prevalence of increased FGF23 and PTH levels. These findings have an independent relationship with decreased eGFR, and are evident at an eGFR of 60–89 ml/min/1.73 m2. Then, mild decreases in eGFR must be taken in consideration by the clinician because they are associated with progressive abnormalities of mineral metabolismFondo de Investigaciones Sanitarias (PI10/00072, PI14/00386, PIE13/00051, PI05/0451, PI05/1497, PI05/52475, PI05/1043, PS09/01405, PI14/1567) y FRIAT, Spanish Society of Cardiology, Spanish Heart Foundation, Spanish Society of Arteriosclerosis, REDINREN (RD012/0021), Biobank grants from Instituto de Salud Carlos III FEDER, RD09/0076/00101 (FJD Biobank) and Abbvie Laboratories. PN I+D+I 2008-2011 and ISCIII co-financed by FEDER, CIBERDEM and e-PREDIC

N-terminal pro-brain natriuretic peptide is associated with a future diagnosis of cancer in patients with coronary artery disease

Objective Several papers have reported elevated plasma levels of natriuretic peptides in patients with a previous diagnosis of cancer. We have explored whether N-terminal pro-brain natriuretic peptide (NT-proBNP) plasma levels predict a future diagnosis of cancer in patients with coronary artery disease (CAD). Methods We studied 699 patients with CAD free of cancer. At baseline, NT-proBNP, galectin-3, monocyte chemoattractant protein-1, soluble tumor necrosis factor-like weak inducer of apoptosis, high-sensitivity C-reactive protein, and high-sensitivity cardiac troponin I plasma levels were assessed. The primary outcome was new cancer diagnosis. The secondary outcome was cancer diagnosis, heart failure requiring hospitalization, or death. Results After 2.15±0.98 years of follow-up, 24 patients developed cancer. They were older (68.5 [61.5, 75.8] vs 60.0 [52.0, 72.0] years; p=0.011), had higher NT-proBNP (302.0 [134.8, 919.8] vs 165.5 [87.4, 407.5] pg/ml; p=0.040) and high-sensitivity C-reactive protein (3.27 [1.33, 5.94] vs 1.92 [0.83, 4.00] mg/L; p=0.030), and lower triglyceride (92.5 [70.5, 132.8] vs 112.0 [82.0, 157.0] mg/dl; p=0.044) plasma levels than those without cancer. NT-proBNP (Hazard Ratio [HR]=1.030; 95% Confidence Interval [CI]=1.008-1.053; p=0.007) and triglyceride levels (HR=0.987; 95%CI=0.975-0.998; p=0.024) were independent predictors of a new cancer diagnosis (multivariate Cox regression analysis). When patients in whom the suspicion of cancer appeared in the first one-hundred days after blood extraction were excluded, NT-proBNP was the only predictor of cancer (HR=1.061; 95% CI=1.034-1.088; p<0.001). NT-proBNP was an independent predictor of cancer, heart failure, or death (HR=1.038; 95%CI=1.023-1.052; p<0.001) along with age, and use of insulin and acenocumarol. Conclusions NT-proBNP is an independent predictor of malignancies in patients with CAD. New studies in large populations are needed to confirm these findingsThis work was supported by grants from Fondo de Investigaciones Sanitarias (PI05/0451, PI05/1497,PI05/2475, PI05/1043, PS09/01405, PI10/ 00072, and PI10/0234, PI14/1567, Programa de Estabilización to LBC); Spanish Society of Cardiology and Spanish Heart Foundation; Spanish Society of Arteriosclerosis; RECAVA (RD06/0014/0035, www. recava.com); Fundación Lilly; and Instituto de Salud Carlos III FEDER (FJD biobank: RD09/0076/00101)

Monocyte chemoattractant protein-1 Is an independent predictor of coronary artery ectasia in patients with acute coronary syndrome

Our purpose was to assess a possible association of inflammatory, lipid and mineral metabolism biomarkers with coronary artery ectasia (CAE) and to determine a possible association of this with acute atherotrombotic events (AAT).We studied 270 patients who underwent coronary angiography during an acute coronary syndrome 6 months before. Plasma levels of several biomarkers were assessed, and patients were followed during a median of 5.35 (3.88–6.65) years. Two interventional cardiologists reviewed the coronary angiograms, diagnosing CAE according to previously published criteria in 23 patients (8.5%). Multivariate binary logistic regression analysis was used to search for independent predictors of CAE. Multivariate analysis revealed that, aside from gender and a diagnosis of dyslipidemia, only monocyte chemoattractant protein-1 (MCP-1) (OR = 2.25, 95%CI = (1.35–3.76) for each increase of 100 pg/mL, p = 0.001) was independent predictor of CAE, whereas mineral metabolism markers or proprotein convertase subtilisin/kexin type 9 were not. Moreover, CAE was a strong predictor of AAT during follow-up after adjustment for other clinically relevant variables (HR = 2.67, 95%CI = (1.22–5.82), p = 0.013). This is the first report showing that MCP-1 is an independent predictor of CAE, suggesting that CAE and coronary artery disease may share pathogenic mechanisms. Furthermore, CAE was associated with an increased incidence of AATThis work was supported by grants from the following: Fondo de Investigaciones Sanitarias (PI05/0451, PI05/1497, PI05/52475, PI05/1043, PS09/01405, and PI10/00072, PI14/01567, PI17/01615): http://www.isciii.es/ISCIII/ es/contenidos/fd-investigacion/fd-financiacion/convocatorias-ayudas-accion-estrategica-salud.shtml; Spanish Society of Cardiology; Spanish Heart Foundation. http://www.secardiologia.es/; Spanish Society of Arteriosclerosis.www.searteriosclerosis.org; CiberCV. http://www.cibercv.es/; RECAVA (RD06/0014/0035); www.recava.com; Fundación Lilly. https://www.lilly.es/nuestra-compania/fundacion-lilly-folder; Instituto de Salud Carlos III FEDER (FJD biobank: RD09/0076/00101); http://www.isciii.es/; and AbbVie Laboratories. http://www.abbvie.es/

Differential profile in inflammatory and mineral metabolism biomarkers in patients with ischemic heart disease without classical coronary risk factors

AbstractBackgroundPatients with coronary heart disease (CHD) without classical cardiovascular risk factors (CRFs) are uncommon, and their profile has not been thoroughly studied. In CHD patients, we have assessed the differences in several biomarkers between those with and without CRF.MethodsWe studied 704 patients with CHD, analyzing plasma levels of biomarkers related to inflammation, thrombosis, renal damage, and heart failure: high-sensitivity C-reactive protein (hs-CRP), monocyte chemoattractant protein-1 (MCP-1), galectin-3, N-terminal fragment of brain natriuretic peptide (NT-pro-BNP), calcidiol (vitamin D metabolite), fibroblast growth factor-23 (FGF-23), parathormone, and phosphate.ResultsTwenty patients (2.8%) exhibited no CRFs. Clinical variables were well balanced in both groups, with the logical exceptions of no use of antidiabetic drugs, lower triglyceride and glucose, and higher high-density lipoprotein cholesterol in no-CRF patients.No-CRF patients showed lower hs-CRP (2.574±3.120 vs. 4.554±9.786mg/L; p=0.018), MCP-1 (114.75±36.29 vs. 143.56±65.37pg/ml; p=0.003), and FGF-23 (79.28±40.22 vs. 105.17±156.61RU/ml; p=0.024), and higher calcidiol (23.66±9.12 vs. 19.49±8.18ng/ml; p=0.025) levels. At follow-up, 10.0% vs. 11.0% patients experienced acute ischemic event, heart failure, or death in the non-CRF and CRF groups, respectively (p=0.815, log-rank test). The limited number of non-CRF patients may have influenced this finding. A Cox regression analysis in the whole population showed that high calcidiol, and low MCP-1 and FGF-23 plasma levels are associated with a better prognosis.ConclusionsCHD patients without CRFs show a favorable biomarker profile in terms of inflammation and mineral metabolism. Further studies are needed to investigate whether this difference translates into a better prognosis

Inhibition of VEGF Expression in Cancer Cells and Endothelial Cell Differentiation by Synthetic Stilbene Derivatives

We here report the synthesis of several stilbene derivatives. They show a measurable inhibitory effect on angiogenesis, some of them to a higher degree than resveratrol. Test methods included cell proliferation and tube formation assays using bovine aorta endothelial cells. In addition, it has been confirmed through the reverse transcriptase/polymerase chain reaction experiment that these stilbene derivatives downregulate the expression of the gene related to the production of the angiogenesis factor VEGF in cancer cells

Synthesis and Biological Evaluation of Small Molecules as Potential Anticancer Multitarget Agents

Twenty-six triazole-based derivatives were designed for targeting both PD-L1 (programmed death receptor ligand 1) and VEGFR-2 (vascular endothelial growth factor receptor 2). These compounds were synthetized and biologically evaluated as multitarget inhibitors of VEGFR-2, PD-L1 and c-Myc proteins. The antiproliferative activity of these molecules on several tumor cell lines (HT-29, A-549, and MCF-7) and on the non-tumor cell line HEK-293 was determined. The effects on the abovementioned biological targets were evaluated for some selected compounds. Compound 23, bearing a p-chlorophenyl group, showed better results than sorafenib in regard to the downregulation of VEGFR-2 and a similar effect to BMS-8 on both PD-L1 and c-Myc proteins. The antiangiogenic and antivascular activities of chloro derivatives were also established by endothelial microtube formation assay on Matrigel®

Impacto de los niveles plasmáticos de pro-péptido natriurético tipo B aminoterminal, proteína quimiotáctica de monocitos-1 y galectina 3 en la capacidad predictiva de eventos de la escala clínica LIPID en la enfermedad coronaria estable

This is the peer reviewed version of the following article: Clínica e Investigación en Arterioesclerosis 27.2 (2015) which has been published in final form at http://dx.doi.org/10.1016/j.arteri.2014.06.003Introducción: No existe ninguna herramienta validada para la estratificación de riesgo de lospacientes con enfermedad coronaria estable (ECE). Se ha visto que los niveles plasmáticos dela proteína quimioatractante de monocitos-1 (MCP-1), galectina-3 y pro-péptido natriuréticotipo B aminoterminal (NT-proBNP) tienen valor pronóstico en esta población. Objetivo: Analizar la utilidad pronóstica de la escala clínica de riesgo del estudio Long-TermIntervention with Pravastatin in Ischemic Disease (LIPID) y la mejora de su capacidad predictivaal combinarla con los niveles plasmáticos de MCP-1, galectina-3 y NT-proBNP en pacientes conECE.Métodos y resultados:Se analizaron 706 pacientes con ECE y antecedentes de síndrome coro-nario agudo (SCA). Se realizó un seguimietno de 2,2 ± 0,99 a˜nos. El objetivo primario era laaparición de un evento isquémico (cualquier SCA, infarto cerebral o accidente isquémico tran-sitorio), insuficiencia cardiaca o muerte.La escala clínica de riesgo predijo significativamente el desarrollo del objetivo primario, conun área bajo la curva receiver operating characteristic (ROC) de 0,642 (0,579-0,705); p 21,5 mostró una sensibilidad del 74% y una especificidad del 61% para el desarrollodel objetivo primario (p < 0,001; test de log-rank).Conclusión: Los niveles plasmáticos de MCP-1, galectina-3 y NT-proBNP mejoran la capacidadde la escala clínica LIPID para predecir el pronóstico de los pacientes con ECEIntroduction: At present, there is no tool validated by scientific societies for risk stratificationof patients with stable coronary artery disease (SCAD). It has been shown that plasma levelsof monocyte chemoattractant protein-1 (MCP-1), galectin-3 and pro-B-type natriuretic peptideamino-terminal (NT-proBNP) have prognostic value in this population.Objetive: To analyze the prognostic value of a clinical risk scale published in Long-term Inter-vention with Pravastatin in Ischemic Disease (LIPID) study and determining its predictivecapacity when combined with plasma levels of MCP-1, galectin-3 and NT-proBNP in patientswith SCAD.Methods and results: A total of 706 patients with SCAD and a history of acute coronary syndrome(ACS) were analyzed over a follow up period of 2.2 ± 0.99 years. The primary endpoint was theoccurrence of an ischemic event (any SCA, stroke or transient ischemic attack), heart failure,or death.A clinical risk scale derived from the LIPID study significantly predicted the development ofthe primary endpoint, with an area under the ROC curve (Receiver Operating Characteristic) of0.642 (0.579 to 0.705); P < 0.001. A composite score was developed by adding the scores of theLIPID and scale decile levels of MCP -1, galectin -3 and NT-proBNP. The predictive value improvedwith an area under the curve of 0.744 (0.684 to 0.805); P < 0.001 (P = 0.022 for comparison). Ascore greater than 21.5 had a sensitivity of 74% and a specificity of 61% for the development ofthe primary endpoint (P < 0.001, log -rank test).Conclusion: Plasma levels of MCP-1, galectin -3 and NT-proBNP improve the ability of the LIPIDclinical scale to predict the prognosis of patients with SCADFinanciación Sociedad Española de Arteriosclerosis, FIS (PI: 05/451,05/1497, 05/2475, 05/1043, 09/01405, 10/0234, Programa Estabilización a LBC), Sociedad Española de Cardiología,Fundación Española del Corazón, Ministerio de Ciencia e Innovación (SAF 2010/21852), Comunidad de Madrid (sGEN/0247/2006), Becas de Biobancos del Instituto Car-los III FEDER, RD09/0076/00101 (Biobanco FJD