Endocarditis infecciosa por microorganismos de la flora oral: cambios epidemiológicos, clínicos y pronósticos en los últimos 30 años

Justificación y objetivos La endocarditis infecciosa (EI) es una enfermedad no demasiado frecuente, pero muy grave, con tasas de mortalidad durante su fase activa que llegan hasta el 40-50%, dependiendo de los casos y de los subtipos de la enfermedad1-3 . La mayoría de las series más actuales reportan una mortalidad global del 20-30%, a pesar de los avances experimentados en sus métodos de diagnóstico y de su tratamiento antibiótico y quirúrgico2-6 . Clásicamente, la patogenia de la EI exigía la existencia de tres requisitos: a) cardiopatía predisponente, habitualmente una lesión valvular o cortocircuito intracardíaco que produjera un daño endotelial en el endocardio, con producción de un trombo plaquetario (endocarditis trombótica no bacteriana); b) fuente de bateriemia, como la causada por manipulaciones orodentales, que ocasionaba un paso de microorganismos desde la boca al torrente sanguíneo; y c) colonización del trombo plaquetario estéril endocárdico por la bateriemia7 . El trombo infectado crecía en forma de vegetación, y esta podía dañar a las estructuras cardíacas o producir embolias sépticas. Para evitar esta enfermedad se preconizaba la profilaxis antibiótica durante las manipulaciones orales y dentales en los sujetos con riesgo de EI8,9 . Sin embargo, en los últimos años se ha producido un notable cambio en la patogenia y epidemiología de la endocarditis infecciosa, debido sobre todo a la casi desaparición de EI en adictos a drogas, el envejecimiento de la población (con el consiguiente aumento de comorbilidades y enfermedades debilitantes con inmunodepresión), y al gran incremento de procedimientos diagnósticos y terapéuticos invasivos como fuente de bacteriemia (EI relacionados con procedimientos sanitarios, EI nosocomiales y nosohusiales)10-12. De hecho, recientes series indican que más de la mitad de los casos de EI afectan a pacientes sin cardiopatías predisponentes y que las clásicas fuentes de bacteriemia (dentales y otras) pueden haber perdido su importancia10,11. Esto cuestiona también la utilidad de la profilaxis antibiótica de EI, como se ha recogido en las actuales guías de práctica clínica sobre EI1,13-15 . Por todo ello, parece de interés evaluar los cambios producidos en nuestro medio en las últimas décadas en el campo de la EI. Aunque se ha desarrollado una notable investigación sobre las EI nosocomiales sin cardiopatía predisponente o las EI sobre prótesis valvulares, no existen apenas datos sobre la relevancia actual de las EI ocasionadas por los microorganismos de la flora oral, ni sobre los cambios experimentados por ellas en los últimos años. El conocimiento de su epidemiología, características clínicas, manejo y pronóstico actuales nos ayudarán al mejor tratamiento de estos pacientes, y también a adecuar las normas sobre profilaxis de endocarditis. Los objetivos de este trabajo son: a) Objetivo principal: comparar las características diferenciales (epidemiológicas, clínicas y pronósticas) de las EI por microorganismos de la flora oral con las de las EI causadas por otros microorganismos, tanto en el periodo global 1987-2016 como en tres subperiodos de 10 años (1987-1996, 1997-2006, y 2007-2017). b) Objetivos secundarios: b1) Analizar la relación entre la existencia previa de manipulaciones o procedimientos orodentales y el desarrollo de EI. b2) Analizar las conductas de los distintos profesionales sanitarios involucrados (cardiólogos, dentistas, médicos de atención primaria) ante las recomendaciones de profilaxis de EI. b3) Analizar la frecuencia relativa de cada tipo de EI en el periodo de 30 años estudiado y su evolución en el tiempo. Conclusiones 1. Los microorganismos de la flora oral producen aproximadamente un 20% del total de endocarditis infecciosa en pacientes no adictos a drogas por vía parenteral en nuestro medio, sobre todo en los subtipos de endocarditis nativas y protésicas tardías, siendo muy raros en las endocarditis protésicas precoces. Streptococcus viridans es el microrganismo predominante, produciendo el 95% de los casos. 2. Los microorganismos de la flora oral son significativamente menos frecuentes como agentes causales de endocarditis infecciosa sin cardiopatía subyacente (la mitad que en aquellos con cardiopatía predisponente). Como la incidencia de estas endocarditis sin cardiopatía subyacente ha aumentado significativamente en nuestro medio, la proporción de endocarditis por microorganismos de la flora oral se ha reducido en los períodos más recientes. 3. Las endocarditis causadas por microorganismos de la flora oral tienen un diferente perfil epidemiológico y clínico que aquellas producidas por otros microorganismos, con una menor relación con la atención sanitaria, más antecedentes de manipulaciones dentales, mayor prevalencia de cardiopatía subyacente (sobre todo de etiología reumática y congénita), menor proporción de endocarditis protésicas precoces, menor localización extramitral y extraórtica, y menor incidencia de complicaciones severas (sobre todo de persistencia de la sepsis). 4. El pronóstico de los pacientes con endocarditis por microorganismos de la flora oral es significativamente mejor que el de las causadas por otros microorganismos, con una mortalidad precoz menor de la mitad y una mortalidad total a largo plazo también inferior. Sin embargo, precisan cirugía en la fase activa con la misma frecuencia que las del resto de endocarditis. 5. Aunque no se observaron cambios en las características epidemiológicas ni clínicas de las endocarditis por microorganismos a lo largo del período de estudio de tres décadas, su mortalidad se redujo de forma significativa, siendo de solo el 10% en la última década, en contraste con el aumento de mortalidad observado en las endocarditis por otros microorganismos. Esto podría estar en relación con el aumento de las indicaciones de cirugía electiva y la reducción de las indicaciones urgentes. 6. Aunque el antecedente de visita al dentista con realización de procedimientos dentales en los 6 meses previos fue significativamente más frecuente en las endocarditis por microorganismos de la flora oral, en las tres cuartas partes de estas endocarditis no existió dicho antecedente, debiendo estar estos casos relacionados con bacteriemias “espontáneas” desde la cavidad oral (procedimientos diarios, enfermedad periodontal…). 7. Existe una gran variabilidad en el seguimiento de las recomendaciones sobre la profilaxis antibiótica de la endocarditis infecciosa entre los profesionales sanitarios más implicados en este procedimiento, lo que puede reflejar en parte la confusión generada por los cambios experimentados en dichas recomendaciones por parte de las guías de práctica clínica en la última década. 8. En general, se observa una tendencia a la sobreprescripción de profilaxis antibiótica en situaciones no recomendadas en la actualidad por las guías de práctica clínica (pacientes de moderado, bajo o nulo riesgo de desarrollar endocarditis tras procedimientos dentales), siendo los odontólogos los que mejor conocen los procedimientos de riesgo. La conducta de los odontólogos ante las recomendaciones de profilaxis de endocarditis ha sido homogénea y similar en las dos provincias estudiadas

Usefulness of the 2MACE Score to Predicts Adverse Cardiovascular Events in Patients With Atrial Fibrillation

[Abstract] We investigated the incidence of nonembolic adverse events in 2 cohorts of patients with atrial fibrillation (AF) and validated the 2MACE score ([metabolic syndrome, age ≥75] [doubled]; [myocardial infarction or revascularization, congestive heart failure {HF}, and stroke, transient ischemic attack or thromboembolism]) as predictor of major adverse cardiovascular events (MACEs). We recruited 2,630 patients with AF from 2 different cohorts (Murcia AF and FANTASIIA). The 2MACE score was calculated, and during a median of 7.2 years (Murcia AF cohort) and 1.01 years (FANTASIIA) of follow-up, we recorded all nonembolic adverse events and MACEs (composite of nonfatal myocardial infarction or revascularization and cardiovascular death). Receiver operating characteristic curves comparison, reclassification and discriminatory analyses, and decision curve analyses were performed to compare predictive ability and clinical usefulness of the 2MACE score against CHA2DS2-VASc. During follow-up, there were 65 MACEs in the Murcia cohort and 60 in the FANTASIIA cohort. Events rates were higher in the high-risk category (score ≥3) (1.94%/year vs 0.81%/year in the Murcia cohort; 6.01%/year vs 1.71%/year, in FANTASIIA, both p <0.001). The predictive performance of 2MACE according to the receiver operating characteristic curve was significantly higher than that of CHA2DS2-VASc (0.662 vs 0.618, p = 0.008 in the Murcia cohort; 0.656 vs 0.565, p = 0.003 in FANTASIIA). Decision curve analyses demonstrated improved clinical usefulness of the 2MACE compared with the CHA2DS2-VASc score. In conclusion, in “real-world” patients with AF, the 2MACE score is a good predictor of MACEs. A score ≥3 should be used to categorize patients at “high risk,” in identifying patients at risk of MACE.Instituto de Salud Carlos III; PI13/00513Instituto de Salud Carlos III; P14/00253Fundación Séneca; 19245/PI/14Instituto Murciano de Investigación Biosanitaria; IMIB16/AP/01/0

Association of body mass index with clinical outcomes in patients with atrial fibrillation: a report from the FANTASIIA Registry

[Abstract] Background. Obesity and atrial fibrillation (AF) frequently coexist and independently increase mortality. We sought to assess the association between obesity and adverse events in patients receiving oral anticoagulants for AF. Methods and Results. Consecutive AF outpatients receiving anticoagulant agents (both vitamin K antagonists and direct oral anticoagulants) were recruited into the FANTASIIA (Atrial fibrillation: influence of the level and type of anticoagulation on the incidence of ischemic and hemorrhagic stroke) registry. This observational, multicenter, and prospective registry of AF patients analyzes the quality of anticoagulation, incidence of events, and differences between oral anticoagulant therapies. We analyzed baseline patient characteristics according to body mass index, normal: <25 kg/m2, overweight: 25–30 kg/m2, and obese: ≥30 kg/m2), assessing all‐cause mortality, stroke, major bleeding and major adverse cardiovascular events (a composite of ischemic stroke, myocardial infarction, and total mortality) at 3 years’ follow‐up. In this secondary prespecified substudy, the association of weight on prognosis was evaluated. We recruited 1956 patients (56% men, mean age 73.8±9.4 years): 358 (18.3%) had normal body mass index, 871 (44.5%) were overweight, and 727 (37.2%) were obese. Obese patients were younger (P<0.01) and had more comorbidities. Mean time in the therapeutic range was similar across body mass index categories (P=0.42). After a median follow‐up of 1070 days, 255 patients died (13%), 45 had a stroke (2.3%), 146 a major bleeding episode (7.5%) and 168 a major adverse cardiovascular event (8.6%). Event rates were similar between groups for total mortality (P=0.29), stroke (P=0.90), major bleeding (P=0.31), and major adverse cardiovascular events (P=0.24). On multivariate Cox analysis, body mass index was not independently associated with all‐cause mortality, cardiovascular mortality, stroke, major bleeding, or major adverse cardiovascular events. Conclusions. In this prospective cohort of patients anticoagulated for AF, obesity was highly prevalent and was associated with more comorbidities, but not with poor prognosis

Association of Body Mass Index With Clinical Outcomes in Patients With Atrial Fibrillation: A Report From the FANTASIIA Registry

Background Obesity and atrial fibrillation (AF) frequently coexist and independently increase mortality. We sought to assess the association between obesity and adverse events in patients receiving oral anticoagulants for AF. Methods and Results Consecutive AF outpatients receiving anticoagulant agents (both vitamin K antagonists and direct oral anticoagulants) were recruited into the FANTASIIA (Atrial fibrillation: influence of the level and type of anticoagulation on the incidence of ischemic and hemorrhagic stroke) registry. This observational, multicenter, and prospective registry of AF patients analyzes the quality of anticoagulation, incidence of events, and differences between oral anticoagulant therapies. We analyzed baseline patient characteristics according to body mass index, normal: <25 kg/m2, overweight: 25-30 kg/m2, and obese: ≥30 kg/m2), assessing all‐cause mortality, stroke, major bleeding and major adverse cardiovascular events (a composite of ischemic stroke, myocardial infarction, and total mortality) at 3 years' follow‐up. In this secondary prespecified substudy, the association of weight on prognosis was evaluated. We recruited 1956 patients (56% men, mean age 73.8±9.4 years): 358 (18.3%) had normal body mass index, 871 (44.5%) were overweight, and 727 (37.2%) were obese. Obese patients were younger (P<0.01) and had more comorbidities. Mean time in the therapeutic range was similar across body mass index categories (P=0.42). After a median follow‐up of 1070 days, 255 patients died (13%), 45 had a stroke (2.3%), 146 a major bleeding episode (7.5%) and 168 a major adverse cardiovascular event (8.6%). Event rates were similar between groups for total mortality (P=0.29), stroke (P=0.90), major bleeding (P=0.31), and major adverse cardiovascular events (P=0.24). On multivariate Cox analysis, body mass index was not independently associated with all‐cause mortality, cardiovascular mortality, stroke, major bleeding, or major adverse cardiovascular events. Conclusions In this prospective cohort of patients anticoagulated for AF, obesity was highly prevalent and was associated with more comorbidities, but not with poor prognosis

Nanoinformatics: developing new computing applications for nanomedicine

Nanoinformatics has recently emerged to address the need of computing applications at the nano level. In this regard, the authors have participated in various initiatives to identify its concepts, foundations and challenges. While nanomaterials open up the possibility for developing new devices in many industrial and scientific areas, they also offer breakthrough perspectives for the prevention, diagnosis and treatment of diseases. In this paper, we analyze the different aspects of nanoinformatics and suggest five research topics to help catalyze new research and development in the area, particularly focused on nanomedicine. We also encompass the use of informatics to further the biological and clinical applications of basic research in nanoscience and nanotechnology, and the related concept of an extended ?nanotype? to coalesce information related to nanoparticles. We suggest how nanoinformatics could accelerate developments in nanomedicine, similarly to what happened with the Human Genome and other -omics projects, on issues like exchanging modeling and simulation methods and tools, linking toxicity information to clinical and personal databases or developing new approaches for scientific ontologies, among many others

Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib

The most frequent BCR-ABL1-p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine-kinase inhibitor (TKI) used to treat CML. Some studies suggest that BCR-ABL1 transcript types confer different responses to IM. The objective of this study was to correlate the expression of e14a2 or e13a2 to clinical characteristics, cumulative cytogenetic and molecular responses to IM, acquisition of deep molecular response (DMR) and its duration (sDMR), progression rate (CIP), overall survival (OS), and treatment-free remission (TFR) rate. We studied 202 CML patients, 76 expressing the e13a2 and 126 the e14a2, and correlated the differential transcript expression with the above-mentioned parameters. There were no differences in the cumulative incidence of cytogenetic responses nor in the acquisition of DMR and sDMR between the two groups, but the e14a2 transcript had a positive impact on molecular response during the first 6 months, whereas the e13a2 was associated with improved long-term OS. No correlation was observed between the transcript type and TFR rate

E14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response

e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript

Restoring cellular magnesium balance through Cyclin M4 protects against acetaminophen-induced liver damage

Acetaminophen overdose is one of the leading causes of acute liver failure and liver transplantation in the Western world. Magnesium is essential in several cellular processess. The Cyclin M family is involved in magnesium transport across cell membranes. Herein, we identify that among all magnesium transporters, only Cyclin M4 expression is upregulated in the liver of patients with acetaminophen overdose, with disturbances in magnesium serum levels. In the liver, acetaminophen interferes with the mitochondrial magnesium reservoir via Cyclin M4, affecting ATP production and reactive oxygen species generation, further boosting endoplasmic reticulum stress. Importantly, Cyclin M4 mutant T495I, which impairs magnesium flux, shows no effect. Finally, an accumulation of Cyclin M4 in endoplasmic reticulum is shown under hepatoxicity. Based on our studies in mice, silencing hepatic Cyclin M4 within the window of 6 to 24 h following acetaminophen overdose ingestion may represent a therapeutic target for acetaminophen overdose induced liver injury.Acknowledgements: This work was supported by Ministerio de Ciencia, Innovación y Universidades MICINN: PID2020-117116RB-I00 integrado en el Plan Estatal de Investigación Cientifica y Técnica y Innovación, cofinanciado con Fondos FEDER (to MLM-C), Ministerio de Ciencia e Innovación CONSOLIDER-INGENIO 2010 Program Grant CSD2008-00005 (to LAMC); Spanish Ministry of Economy and Competitiveness Grant BFU2013-47531-R, BFU2016-77408-R, PID2019-109055RB-100 (to L.A.M.-C.) (MINECO/FEDER, UE); Asociación Española contra el Cáncer (MLM-C, TC-D), Fundación Científica de la Asociación Española Contra el Cáncer (AECC Scientific Foundation) Rare Tumor Calls 2017 (to M.L.M.-C.), La Caixa Foundation Program (to M.L.M.-C.), Fundacion BBVA UMBRELLA project (to M.L.M.-C.), Ayuda RYC2020-029316-I financiada por MICIN/AEI/10.13039/501100011033 (to TC-D), Plataforma de Investigación Clínica-SCReN (PT17 0017 0020) (to M.I.-L.), programa retos RTC2019-007125-1 (to M.L.M.-C, J.S.), Proyectos Investigacion en Salud DTS20/00138 (to M.L.M.-C., J.S), ERA-Net E-Rare EJP RD Joint Translational Call for Rare Diseases FIGHT-CNNM2 (EJPRD19-040) and from Instituto Carlos III, Spain (REF G95229142) (to L.A.M.-C.), US National Institutes of Health under grant CA217817 (to D.B.), Ciberehd_ISCIII_MINECO is funded by the Instituto de Salud Carlos III. We thankMINECO for the Severo Ochoa Excellence Accreditation to CIC bioGUNE (SEV-2016-0644) and PhD fellowship fromMINECO (REF BES-2017-080435) awarded to I.G.-R. The collection and storage of patients tissues was supported by the Newcastle Biomedicine Biobank and the European Community’s Seventh Framework Programme (FP7/2001–2013) and Cancer Research UK awards Cancer Research UK grants C18342/A23390; C9380/A18084 and C9380/A26813. Finally, we would like to acknowledge Begoña Rodríguez Iruretagoyena for the technical support provided

miR-873-5p targets mitochondrialGNMT-Complex II interface contributing tonon-alcoholic fatty liver disease

Objective:Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolicpathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation andfibrosis.The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, isdownregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression.Methods:miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Differentin vitroandin vivoNAFLD murinemodels were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy.Results:We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria.In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondrial functionality in a preclinicalmurine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating withhepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation andfibrosis byenhancing fatty acidb-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment.Conclusion:GNMT participates in the regulation of metabolic pathways and mitochondrial functionality through the regulation of Complex II activityin the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment