Loss of GIPR in LEPR cells impairs glucose control by GIP and GIP:GLP-1 co-agonism without affecting body weight and food intake in mice.

OBJECTIVE: The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). METHODS: Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. RESULTS: Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the ß-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. CONCLUSIONS: GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism.

High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

The obesity-linked human lncRNA AATBC stimulates mitochondrial function in adipocytes.

Adipocytes are critical regulators of metabolism and energy balance. While white adipocyte dysfunction is a hallmark of obesity-associated disorders, thermogenic adipocytes are linked to cardiometabolic health. As adipocytes dynamically adapt to environmental cues by functionally switching between white and thermogenic phenotypes, a molecular understanding of this plasticity could help improving metabolism. Here, we show that the lncRNA Apoptosis associated transcript in bladder cancer (AATBC) is a human-specific regulator of adipocyte plasticity. Comparing transcriptional profiles of human adipose tissues and cultured adipocytes we discovered that AATBC was enriched in thermogenic conditions. Using primary and immortalized human adipocytes we found that AATBC enhanced the thermogenic phenotype, which was linked to increased respiration and a more fragmented mitochondrial network. Expression of AATBC in adipose tissue of mice led to lower plasma leptin levels. Interestingly, this association was also present in human subjects, as AATBC in adipose tissue was inversely correlated with plasma leptin levels, BMI, and other measures of metabolic health. In conclusion, AATBC is a novel obesity-linked regulator of adipocyte plasticity and mitochondrial function in humans.

Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1.

Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.

The dietary sweetener sucralose is a negative modulator of T cell-mediated responses.

Artificial sweeteners are used as calorie-free sugar substitutes in many food products and their consumption has increased substantially over the past years1. Although generally regarded as safe, some concerns have been raised about the long-term safety of the consumption of certain sweeteners2-5. In this study, we show that the intake of high doses of sucralose in mice results in immunomodulatory effects by limiting T cell proliferation and T cell differentiation. Mechanistically, sucralose affects the membrane order of T cells, accompanied by a reduced efficiency of T cell receptor signalling and intracellular calcium mobilization. Mice given sucralose show decreased CD8+ T cell antigen-specific responses in subcutaneous cancer models and bacterial infection models, and reduced T cell function in models of T cell-mediated autoimmunity. Overall, these findings suggest that a high intake of sucralose can dampen T cell-mediated responses, an effect that could be used in therapy to mitigate T cell-dependent autoimmune disorders.

Relationship of the T-wave Tpeak-Tend interval with conduction system disorders in arterial hypertension / Relación del intervalo Tpico-Tfinal de la onda T con trastornos del sistema de conducción en hipertensión arterial

Abstract Purpose: The Tpeak-Tend interval of the T wave has emerged as a new electrocardiographic marker of increased transmural dispersion of ventricular repolarization. We aimed to determine the presence of cardiac conduction system disorders in patients with systemic arterial hypertension (SAH) who have altered Tpeak-Tend interval of the T wave. Methods: The 67 patients with SAH were divided into two groups. Those with prolonged (≥ 77 ms) Tpeak-Tend intervals, 21 (31%) patients were in the study group. Those with normal (< 77 ms) Tpeak-Tend intervals, 46 (69%) patients were in the control group. Alteration of ventricular repolarization manifested as a prolongation of the Tpeak-Tend interval was detected by computerized electrocardiographic analysis tools. Results: The median value of QRS complex duration was significantly wider in the study group as compared to the control group (110 ± 12 ms vs. 94 ± 8 ms p < 0.001). There was a significantly greater incidence of left anterior hemiblock in the study group (14% vs. 0% p < 0.04). The median value of the QTc interval was significantly greater in the study group (440 ± 26 vs. 422 ± 15 p < 0.01). There was a significantly greater incidence of patients with prolonged QTc interval in the study group (33% vs. 11% p < 0.02). The median value of the Tpeak-Tend interval was significantly greater in the study group (84 ± 5 ms vs. 65 ± 4 ms p < 0.001), as well as, the Tpeak-Tend/QTc ratio in the study group (0.19 ± 0.1 vs. 0.16 ± 0.1 p < 0.001). Conclusion: There is a significantly greater ventricular repolarization disorders and abnormalities of the cardiac conduction system in SAH patients who possess altered Tpeak-Tend interval of the T wave.

Resumen Objetivo: El intervalo Tpico-Tfinal de la onda T es un marcador electrocardiográfico de la dispersión transmural aumentada de la repolarización ventricular. Investigamos la presencia de trastornos del sistema de conducción cardíaca en pacientes con hipertensión arterial sistémica (HA) que poseen alterado el intervalo Tpico-Tfinal de la onda T. Métodos: Los 67 pacientes con HA fueron divididos en dos grupos. Aquellos con intervalos de Tpico-Tfinal prolongados (≥ 77 ms), 21 (31%) pacientes (grupo de estudio). Aquellos con intervalos normales (< 77 ms) Tpico-Tfinal, 46 (69%) pacientes (grupo control). Los intervalos Tpico-Tfinal fueron medidos por herramientas de análisis electrocardiográfico computarizado. Resultados: El valor mediano de la duración del complejo QRS fue significativamente más amplio en el grupo de estudio (110 ± 12 ms vs. 94 ± 8 ms p < 0.001). Hubo una incidencia significativamente mayor de hemibloqueo anterior izquierdo en el grupo de estudio (14% vs. 0% p < 0.04). El valor mediano del intervalo QTc fue significativamente mayor en el grupo de estudio (440 ± 26 vs. 422 ± 15 p < 0.01). Hubo una incidencia significativamente mayor de pacientes con intervalo QTc prolongado en el grupo de estudio (33% vs. 11% p < 0.02). El valor mediano del intervalo Tpico-Tfinal fue significativamente mayor en el grupo de estudio (84 ± 5 ms vs. 65 ± 4 ms p < 0.001), así como el cociente Tpico-Tfinal/QTc (0.19 ± 0.1 vs. 0.16 ± 0.1 p < 0.001). Conclusión: Existe una alteración de la repolarización ventricular significativamente mayor y anomalías del sistema de conducción cardíaca en pacientes con HA que poseen alteración del intervalo Tpico-Tfinal de la onda T.

Validation of Mct8/Oatp1c1 dKO mice as a model organism for the Allan-Herndon-Dudley Syndrome.

OBJECTIVE: The Allan-Herndon-Dudley syndrome (AHDS) is a severe disease caused by dysfunctional central thyroid hormone transport due to functional loss of the monocarboxylate transporter 8 (MCT8). In this study, we assessed whether mice with concomitant deletion of the thyroid hormone transporters Mct8 and the organic anion transporting polypeptide (Oatp1c1) represent a valid preclinical model organism for the AHDS. METHODS: We generated and metabolically characterized a new CRISPR/Cas9 generated Mct8/Oatp1c1 double-knockout (dKO) mouse line for the clinical features observed in patients with AHDS. RESULTS: We show that Mct8/Oatp1c1 dKO mice mimic key hallmarks of the AHDS, including decreased life expectancy, central hypothyroidism, peripheral hyperthyroidism, impaired neuronal myelination, impaired motor abilities and enhanced peripheral thyroid hormone action in the liver, adipose tissue, skeletal muscle and bone. CONCLUSIONS: We conclude that Mct8/Oatp1c1 dKO mice are a valuable model organism for the preclinical evaluation of drugs designed to treat the AHDS.

Insulin regulates neurovascular coupling through astrocytes.

Mice with insulin receptor (IR)-deficient astrocytes (GFAP-IR knockout [KO] mice) show blunted responses to insulin and reduced brain glucose uptake, whereas IR-deficient astrocytes show disturbed mitochondrial responses to glucose. While exploring the functional impact of disturbed mitochondrial function in astrocytes, we observed that GFAP-IR KO mice show uncoupling of brain blood flow with glucose uptake. Since IR-deficient astrocytes show higher levels of reactive oxidant species (ROS), this leads to stimulation of hypoxia-inducible factor-1α and, consequently, of the vascular endothelial growth factor angiogenic pathway. Indeed, GFAP-IR KO mice show disturbed brain vascularity and blood flow that is normalized by treatment with the antioxidant N-acetylcysteine (NAC). NAC ameliorated high ROS levels, normalized angiogenic signaling and mitochondrial function in IR-deficient astrocytes, and normalized neurovascular coupling in GFAP-IR KO mice. Our results indicate that by modulating glucose uptake and angiogenesis, insulin receptors in astrocytes participate in neurovascular coupling.

Synaptotagmin-13 Is a Neuroendocrine Marker in Brain, Intestine and Pancreas.

Synaptotagmin-13 (Syt13) is an atypical member of the vesicle trafficking synaptotagmin protein family. The expression pattern and the biological function of this Ca2+-independent protein are not well resolved. Here, we have generated a novel Syt13-Venus fusion (Syt13-VF) fluorescence reporter allele to track and isolate tissues and cells expressing Syt13 protein. The reporter allele is regulated by endogenous cis-regulatory elements of Syt13 and the fusion protein follows an identical expression pattern of the endogenous Syt13 protein. The homozygous reporter mice are viable and fertile. We identify the expression of the Syt13-VF reporter in different regions of the brain with high expression in tyrosine hydroxylase (TH)-expressing and oxytocin-producing neuroendocrine cells. Moreover, Syt13-VF is highly restricted to all enteroendocrine cells in the adult intestine that can be traced in live imaging. Finally, Syt13-VF protein is expressed in the pancreatic endocrine lineage, allowing their specific isolation by flow sorting. These findings demonstrate high expression levels of Syt13 in the endocrine lineages in three major organs harboring these secretory cells. Collectively, the Syt13-VF reporter mouse line provides a unique and reliable tool to dissect the spatio-temporal expression pattern of Syt13 and enables isolation of Syt13-expressing cells that will aid in deciphering the molecular functions of this protein in the neuroendocrine system.

Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH.

Nonalcoholic steatohepatitis (NASH) is a manifestation of systemic metabolic disease related to obesity, and causes liver disease and cancer1,2. The accumulation of metabolites leads to cell stress and inflammation in the liver3, but mechanistic understandings of liver damage in NASH are incomplete. Here, using a preclinical mouse model that displays key features of human NASH (hereafter, NASH mice), we found an indispensable role for T cells in liver immunopathology. We detected the hepatic accumulation of CD8 T cells with phenotypes that combined tissue residency (CXCR6) with effector (granzyme) and exhaustion (PD1) characteristics. Liver CXCR6+ CD8 T cells were characterized by low activity of the FOXO1 transcription factor, and were abundant in NASH mice and in patients with NASH. Mechanistically, IL-15 induced FOXO1 downregulation and CXCR6 upregulation, which together rendered liver-resident CXCR6+ CD8 T cells susceptible to metabolic stimuli (including acetate and extracellular ATP) and collectively triggered auto-aggression. CXCR6+ CD8 T cells from the livers of NASH mice or of patients with NASH had similar transcriptional signatures, and showed auto-aggressive killing of cells in an MHC-class-I-independent fashion after signalling through P2X7 purinergic receptors. This killing by auto-aggressive CD8 T cells fundamentally differed from that by antigen-specific cells, which mechanistically distinguishes auto-aggressive and protective T cell immunity.

The glucose-dependent insulinotropic polypeptide (GIP) regulates body weight and food intake via CNS-GIPR signaling.

Uncertainty exists as to whether the glucose-dependent insulinotropic polypeptide receptor (GIPR) should be activated or inhibited for the treatment of obesity. Gipr was recently demonstrated in hypothalamic feeding centers, but the physiological relevance of CNS Gipr remains unknown. Here we show that HFD-fed CNS-Gipr KO mice and humanized (h)GIPR knockin mice with CNS-hGIPR deletion show decreased body weight and improved glucose metabolism. In DIO mice, acute central and peripheral administration of acyl-GIP increases cFos neuronal activity in hypothalamic feeding centers, and this coincides with decreased body weight and food intake and improved glucose handling. Chronic central and peripheral administration of acyl-GIP lowers body weight and food intake in wild-type mice, but shows blunted/absent efficacy in CNS-Gipr KO mice. Also, the superior metabolic effect of GLP-1/GIP co-agonism relative to GLP-1 is extinguished in CNS-Gipr KO mice. Our data hence establish a key role of CNS Gipr for control of energy metabolism.

Identification and characterization of distinct brown adipocyte subtypes in C57BL/6J mice.

Brown adipose tissue (BAT) plays an important role in the regulation of body weight and glucose homeostasis. Although increasing evidence supports white adipose tissue heterogeneity, little is known about heterogeneity within murine BAT. Recently, UCP1 high and low expressing brown adipocytes were identified, but a developmental origin of these subtypes has not been studied. To obtain more insights into brown preadipocyte heterogeneity, we use single-cell RNA sequencing of the BAT stromal vascular fraction of C57/BL6 mice and characterize brown preadipocyte and adipocyte clonal cell lines. Statistical analysis of gene expression profiles from brown preadipocyte and adipocyte clones identify markers distinguishing brown adipocyte subtypes. We confirm the presence of distinct brown adipocyte populations in vivo using the markers EIF5, TCF25, and BIN1. We also demonstrate that loss of Bin1 enhances UCP1 expression and mitochondrial respiration, suggesting that BIN1 marks dormant brown adipocytes. The existence of multiple brown adipocyte subtypes suggests distinct functional properties of BAT depending on its cellular composition, with potentially distinct functions in thermogenesis and the regulation of whole body energy homeostasis.

Asociación de la dilatación auricular izquierda con los trastornos del sistema de conducción en pacientes con hipertensión arterial sistémica / Association of left atrial dilatation with conduction system disorders in patients with systemic arterial hypertension

La dilatación de la aurícula izquierda (AI) se considera un predictor ecocardiográfico para la remodelación auricular y la fibrilación auricular. Por ende, hemos investigado la correlación existente entre la dilatación de la AI con las arritmias cardíacas y los trastornos del sistema de conducción en pacientes con hipertensión arterial (HTA). En este estudio observacional y prospectivo hemos investigado las variaciones electrocardiográficas, mediciones ecocardiográficas y Holter ECG de 24 hs en pacientes hipertensos y no hipertensos ambulatoria y hospitalizados que acuden a un hospital terciario entre marzo a septiembre del 2018. Se estudiaron 104 pacientes, 65 hipertensos conocidos y 39 no hipertensos como grupo control. El diámetro promedio de la AI fue significativamente mayor (p=0,03) en pacientes hipertensos que los no hipertensos (37±8 mm vs. 34±5 mm). Se encontró una asociación significativa entre hipertensión y la aurícula izquierda dilatada (>40 mm) (p= 0,026 OR: 3,25 IC95%: 1,01-11,02). La dilatación de la AI tuvo una especificidad de 73% y un valor predictivo negativo de 98% relacionado con la presencia de trastornos del sistema de conducción y arritmias cardiacas en pacientes con HTA. Se encontró asociación entre la hipertensión arterial y la dilatación de la aurícula izquierda. La dilatación de la aurícula izquierda tiene una elevada especificidad y un alto valor predictivo negativo en la detección de la presencia de prolongación del intervalo QT, ensanchamiento del complejo QRS, dispersión de la onda P, y trastornos del sistema de conducción y arritmias cardiacas en pacientes con hipertensión arterial(AU)

Dilation of the left atrium (LA) is considered an echocardiographic predictor for atrial remodeling and atrial fibrillation. Therefore, we have investigated the correlation between dilatation of the LA with cardiac arrhythmias and conduction system disorders in patients with systemic arterial hypertension. In this observational and prospective study we have investigated electrocardiographic variations, echocardiographic measurements and Holter ECG of 24 hours in hypertensive patients who attend a tertiary hospital from March 2018 to September 2018 as outpatients and inpatients. One hundred four patients were studied, 65 known to be hypertensive and 39 non-hypertensive subjects as control group. The diameter of the LA ​​had a mean value of 37±8 in hypertensive patients, while in non-hypertensive patients was 34±5 ​​(p = 0.03). A significant association was found between hypertension and increased diameter of the LA (p = 0.04 OR: 2.6 CI 0.88-7.7). Dilatation of the LA had a specificity of 73% and a negative predictive value of 98% related to the presence of conduction system disorders and cardiac arrhythmias in patients with hypertension. A significant relationship between arterial hypertension and dilatation of the left atrium was observed. The dilatation of the left atrium has a high specificity and a high negative predictive value in the detection of the presence of prolongation of the QT interval, widening of the QRS complex, dispersion of the P wave, and disorders of the conduction system and cardiac arrhythmias in patients with hypertension(AU)

Correlación entre la dispersión de la onda P con las arritmias cardíacas y los trastornos del sistema de conducción en pacientes con hipertensión arterial del Hospital de Clínicas, Asunción-Paraguay / Correlation among P wave dispersion and cardiac arrhythmias and alterations of the conduction system in patients with arterial hypertension from the Hospital de Clinicas, Asunción, Paraguay

RESUMEN Introducción: La hipertensión arterial puede producir cambios auriculares que generan arritmias auriculares. La dispersión de la onda P (PWD) se considera un marcador electrocardiográfico no invasivo para la remodelación auricular y un predictor para el desarrollo de fibrilación auricular. Nuestro objetico es estudiar la correlación entre la dispersión de la onda P con las arritmias cardíacas y los trastornos del sistema de conducción en pacientes con hipertensión arterial (HTA). Metodología: Estudio observacional y prospectivo en el que estudiamos las variaciones electrocardiográficas, mediciones ecocardiográficas y Holter ECG de 24 hs en pacientes hipertensos que acuden a un hospital terciario desde marzo del 2018 a septiembre del 2018 en forma ambulatoria y a internados. Resultados: Se estudiaron 104 pacientes, 65 hipertensos conocidos y 39 no hipertensos como grupo control. El valor promedio de la dispersión de la onda P en hipertensos fue de 37±8 ms, y en el grupo control fue de 27±13 ms, P <0,001. Además se encontró una diferencia significativa entre estos dos grupos en la duración máxima de la onda P (p<0,05), y el diámetro de la aurícula izquierda (p<0,05). La PWD posee una especificidad de 72% y un valor predictivo negativo de 78% relacionado con la presencia de trastornos del sistema de conducción y arritmias cardiacas en pacientes con HTA. Además, la PWD posee una especificidad de 73% y un valor predictivo negativo de 83% relacionado con la presencia de ensanchamiento del complejo QRS. Conclusiones: Existe una mayor alteración significativa en la dispersión de la Onda P, la Onda P máxima, y la dilatación de la aurícula izquierda en HTA. También se observó una correlación significativa entre la dispersión de la onda P y el riesgo de desarrollar arritmias auriculares. La dispersión de la onda P tiene una elevada especificidad y un alto valor predictivo negativo en la detección de la presencia de prolongación del intervalo QT, ensanchamiento del complejo QRS, dilatación de la aurícula izquierda y trastornos del sistema de conducción y arritmias cardiacas en pacientes con hipertensión arterial. Palabras clave: Dispersión de la Onda P; Hipertensión arterial; Arritmias cardiacas.

Introduction:High blood pressure can produce atrial changes that generate atrial arrhythmias. P wave dispersion (PWD) is considered a noninvasive electrocardiographic marker for atrial remodeling and a predictor for the development of atrial fibrillation. Our objective is to study the correlation between the dispersion of the P wave with cardiac arrhythmias and conduction system disorders in patients with arterial hypertension (AHT). Methodology:Observational and prospective study in which we studied the electrocardiographic variations, echocardiographic measurements and Holter ECG of 24 hours in hypertensive patients who attend a tertiary hospital from March 2018 to September 2018 on an outpatient basis. Results:104 patients were studied, 65 known hypertensive patients and, 39 non-hypertensive as control group. The average value of the P wave dispersion in hypertensive patients was 37±8 ms, and in the control group it was 27±13 ms, P <0.001. In addition, a significant difference between these two groups was found in the maximum duration of the P wave (p <0.05), and the diameter of the left atrium (p <0.05). The PWD has a specificity of 72% and a negative predictive value of 78% related to the presence of disorders of the conduction system and cardiac arrhythmias in patients with hypertension. In addition, the PWD has a specificity of 73% and a negative predictive value of 83% related to the presence of the widening of the QRS complex. Conclusion:There is a greater significant alteration in the P Wave dispersion, the maximum P Wave, and the dilatation of the left atrium in AHT. A significant correlation was also observed between the dispersion of the P wave and the risk of developing atrial arrhythmias. The P wave dispersion has a high specificity and a high negative predictive value in the detection of the presence of QT interval prolongation, widening of the QRS complex, dilatation of the left atrium and disorders of the conduction system and cardiac arrhythmias in patients with arterial hypertension. Key words: P wave dispersion Arterial Hypertensión Cardiac arrhythmias

Asociación de la dilatación auricular izquierda con alteraciones hemodinámicas del ventrículo izquierdo en pacientes con Hipertensión Arterial del Hospital de Clínicas. Asunción, Paraguay / Association of left atrial dilatation with hemodynamic alterations of the left ventricle in patients with arterial hypertension of the Hospital de Clinicas. Asuncion, Paraguay

Introducción: La dilatación de la aurícula izquierda (AI) se considera un marcador ecocardiográfico para la remodelación auricular y la fibrilación auricular. Por ende, hemos investigado la correlación entre la dilatación de la AI con las alteraciones hemodinámicas del ventrículo izquierdo en pacientes con hipertensión arterial. Objetivo: Determinar la relación existente entre la hipertensión arterial y la dilatación auricular izquierda. Así mismo determinar las características epidemiológicas de la población en estudio y las diferencias ecocardiográficas entre pacientes hipertensos y pacientes sin HTA. Metodología: En este estudio observacional y prospectivo hemos investigado las variaciones electrocardiográficas, mediciones ecocardiográficas y Holter ECG de 24 hs en pacientes hipertensos que acuden a un hospital terciario desde marzo a septiembre del 2018 en forma ambulatoria y a internados en el Hospital de Clínicas. Resultados: Se estudiaron 104 pacientes, 65 hipertensos conocidos y 39 no hipertensos como grupo control. El diámetro de la AI tuvo una media de 37±8 en pacientes hipertensos, mientras que en pacientes no hipertensos la media fue de 34±5 (p=0,03). Se encontró una asociación significativa entre hipertensión y aumento del diámetro de la AI (p=0,04 OR: 2,6 IC 0,88­7,7). En los pacientes hipertensos se observó una asociación significativa entre la aurícula izquierda dilatada y la fracción de eyección disminuida (p= 0,01 OR: 4,66 IC: 1,28­16,98). Además, una asociación significativa entre la AI dilatada y el diámetro diastólico aumentado del ventrículo izquierdo (VI) (p= 0,0004 OR: 8,75 IC 2,18­35,01). Se observó una asociación significativa entre la presencia de una AI dilatada y el diámetro sistólico del VI aumentado en hipertensos (p= 0,006 OR: 5,74 IC 1,5­21,91). Conclusiones: Hubo una relación significativa entre la hipertensión arterial y la dilatación de la aurícula izquierda. Los pacientes hipertensos con una dilatación de la AI tuvieron un aumento significativo de los diámetros sistólicos y diastólicos del ventrículo izquierdo, así como una disminución significativa de la funcionalidad sistólica del ventrículo izquierdo. Por ende, los pacientes hipertensos que tienen una dilatación de la aurícula izquierda presentaron además alteraciones hemodinámicas asociadas del ventrículo izquierdo. Palabras clave: Dilatación de la aurícula izquierda; Hipertensión arterial; Fracción de eyección del VI. Diámetro sistólico y diastólico del VI.

Introduction: Dilation of the left atrium (LA) is considered an echocardiographic marker for atrial remodeling and atrial fibrillation. Therefore, we have investigated the correlation between dilatation of the IA with hemodynamic alterations of the left ventricle in patients with arterial hypertension. Objetive: Determine the relationship between arterial hypertension and left atrial dilatation. The same epidemiological characteristics of the study population and the echocardiographic differences between hypertensive patients and patients without HTN. Methodology: In this observational and prospective study we have investigated electrocardiographic variations, echocardiographic measurements and Holter ECG of 24 hours in hypertensive patients who attend a tertiary hospital from March 2018 to September 2018 as outpatients and inpatients. Results: 104 patients were studied, 65 known hypertensive patients and, 39 non-hypertensive as control group. The diameter of the AI had a mean of 37 ± 8 in hypertensive patients, while in non-hypertensive patients the mean was 34 ± 5 (p = 0.03). A significant association was found between hypertension and increased diameter of the LA (p = 0.04 OR: 2.6 CI 0.88-7.7). In hypertensive patients, a significant association was observed between the dilated left atrium and the decreased ejection fraction (p = 0.01 OR: 4.66 CI: 1.28- 16.98). In addition, a significant association between dilated LA and the increased diastolic diameter of the LV (p = 0.0004 OR: 8.75 IC 2.18-35.01). A significant association was observed between the presence of dilated IA and the left ventricular systolic diameter increased in hypertensive patients (p = 0.006 OR: 5.74 CI 1.5-21.91). Conclusion: There was a significant relationship between arterial hypertension and dilatation of the left atrium. Hypertensive patients with dilatation of the IA had a significant increase in systolic and diastolic diameters of the left ventricle, as well as a significant decrease in systolic functionality of the left ventricle. Therefore, hypertensive patients who have dilation of the left atrium also had associated hemodynamic alterations of the left ventricle. Key words: Dilation of the left atrium; Arterial hypertension; LV ejection fraction. Systolic and diastolicdiameter of the LV.

Niveles sanguíneos de digoxina en pacientes con fibrilación auricular y su relación con alteraciones de la repolarización y arritmias ventriculares. Hospital de Clínicas. FCM-UNA, Paraguay / Plasma levels of digoxin in patients with atrial fibrillation and its relation to alterations of repolarization and ventricular arrhythmias. Hospital de Clínicas, FCM-UNA, Paraguay

Introducción: La fibrilación auricular es la arritmia sostenida más común en el campo de la medicina interna, con prevalencia de 1% y riesgo de vida 25% aproximadamente, después de los 40 años. Estudios previos para examinar la seguridad de la digoxina en pacientes con fibrilación auricular, presentan como limitación, la falta de determinaciones de la concentración sérica de este fármaco, necesarias para definir una posible relación entre dosis y respuesta. Metodología: Estudio prospectivo, descriptivo, de corte transversal con componente analítico,se analizó el valor de la digoxina en sangre, los tipos de arritmias cardiacas concomitantes con la fibrilación auricular, factores de riesgo, dosis diaria de digoxina recibida, en pacientesambulatorios de la División de Medicina Cardiovascular-Hospital de Clínicas, de julio a octubre de 2018. Resultados: De 48 pacientes, 5 (10%) tenían una digoxinemia mayor a 1,2ng/ml, y 43 (90%) pacientes tenían una digoxinemia menor a 1,2ng/ml.Del total de pacientes, 18 (38%) pacientes recibían una dosis diaria de 0,25 mg y 30 (62%) pacientes una dosis diaria menor a 0,25 mg.El trastorno del sistema de conducción más frecuente encontrado fue la alteración de la repolarización (20%), la presencia de ondas Q (9%), las alteraciones de la repolarización con extrasístoles ventriculares y la presencia de ondas T negativas (7%), la presencia de bloqueo completo de rama derecha y hemibloqueo anterior izquierdo (5%).Se encontró una asociación significativa entre la dosis de digoxina y la digoxinemia en rango normal (p=0,03); también se halló una asociación significativa entre la digoxinemia alta y alteraciones de la repolarización(p=0,0005). Se halló asociación entre la digoxinemia alta y la presencia de aurícula izquierda dilatada (p=0,001 OR: 0,8 IC 0,6 - 1,03). Conclusión: La mayoría de los pacientes presentaron digoxinemia en rango de seguridad es decir menor a 1,2 ng. La mayoría de los pacientes recibían una dosis menor a 0,25 mg. Existe asociación significativa entre la dosis de digoxina y la digoxinemia sérica. También encontramos asociación significativa entre la digoxinemia alta y las alteraciones de la repolarización y la presencia de aurícula izquierda dilatada. Palabras clave: Fibrilación auricular; Arritmias ventriculares; Dilatación auricular izquierda

Introduction: Atrial fibrillation is the most common sustained arrhythmia in the field of internal medicine, with prevalence of 1% and risk of life 25% approximately, after 40 years. Previous studies to examine the safety of digoxin in patients with atrial fibrillation have as limitation, the lack of determinations of the serum concentration of this drug, necessary to define a possible relationship between dose and response. Methodology: Prospective, descriptive, cross-sectional study with analytical component, the value of digoxin in blood was analyzed the types of cardiac arrhythmias concomitant with atrial fibrillation, risk factors, daily dose of digoxin received, in ambulatory patients from the Division of Cardiovascular Medicine-Hospital de Clínicas, from July to October 2018. Results: Of 48 patients, 5 (10%) had a digoxinemia greater than 1.2 ng / ml, and 43 (90%) patients had digoxinemia less than 1.2 ng / ml. Of the total patients, 18 (38%) patients received a daily dose of 0.25 mg and 30 (62%) patients a daily dose of less than 0.25 mg. The most frequent conduction system disorder found was the alteration of repolarization (20%), the presence of Q waves (9%), the alterations of repolarization with ventricular premature beats and the presence of negative T waves (7%), the presence of complete blockage of the right bundle branch and left anterior hemiblock (5%). A significant association was found between the dose of digoxin and digoxinaemia in the normal range (p = 0.03); A significant association was also found between high digoxinemia and alterations in repolarization (p = 0.0005). An association was found between high digoxinemia and the presence of a dilated left atrium (p = 0.001 OR: 0.8 CI 0.6 - 1.03). Conclusion: The majority of patients presented digoxinemia in a safety range, that is, less than 1.2 ng. The majority of patients received a dose of less than 0.25 mg. There is a significant association between digoxin dose and serum digoxinemia. We also found a significant association between high digoxinemia and alterations in repolarization and the presence of a dilated left atrium. Keywords: Atrial fibrillation; Ventricular arrhythmias; Left atrial dilatation.

p53 in AgRP neurons is required for protection against diet-induced obesity via JNK1.

p53 is a well-known tumor suppressor that has emerged as an important player in energy balance. However, its metabolic role in the hypothalamus remains unknown. Herein, we show that mice lacking p53 in agouti-related peptide (AgRP), but not proopiomelanocortin (POMC) or steroidogenic factor-1 (SF1) neurons, are more prone to develop diet-induced obesity and show reduced brown adipose tissue (BAT) thermogenic activity. AgRP-specific ablation of p53 resulted in increased hypothalamic c-Jun N-terminal kinase (JNK) activity before the mice developed obesity, and central inhibition of JNK reversed the obese phenotype of these mice. The overexpression of p53 in the ARC or specifically in AgRP neurons of obese mice decreased body weight and stimulated BAT thermogenesis, resulting in body weight loss. Finally, p53 in AgRP neurons regulates the ghrelin-induced food intake and body weight. Overall, our findings provide evidence that p53 in AgRP neurons is required for normal adaptations against diet-induced obesity.

Manejo terapéutico y diagnóstico en equipo multidisciplinario y resultados obtenidos en gestantes con cardiopatía orgánica / Diagnostic and therapeutic management and clinical outcome by a multidisciplinary team in pregnant women with heart disease

Las enfermedades cardiovasculares afectan aproximadamente al 2% de las mujeres embarazadas, por lo que suponen un aumento del riesgo tanto para la madre como para el feto. El embarazo y el parto producen cambios fisiológicos sustanciales que requieren de una adecuada adaptación del sistema cardiovascular. Estos cambios fisiológicos que son muy bien tolerados en las gestantes sin cardiopatía, exponen a la mujer con enfermedad cardiovascular a eventos clínicos significativos. Este es un trabajo descriptivo, retrospectivo, de casos consecutivos de pacientes que acudieron a la División de Medicina Cardiovascular, del Hospital de Clínicas en un período comprendido entre Agosto de 2013 a Junio de 2014. Incluye a 5 pacientes embarazas y portadoras de cardiopatías conocidas o desconocidas. La edad promedio fue de 27 años, rango etario de 17 a 36 años. La edad gestacional al momento de la consulta fue de 34 semanas por fecha de última menstruación, menor edad gestacional 30 semanas y mayor edad gestacional 38 semanas. El síntoma principal de consulta fue la disnea (100%), edema de miembros inferiores en 3 pacientes (60%), y palpitaciones en 2 pacientes (40%). El manejo diagnóstico y terapéutico conjunto con un seguimiento detallado y adecuado por un equipo multidisciplinario de cardiólogos, clínicos, ginecólogos, anestesiólogos y cirujanos cardiovasculares facilitan una buena evolución clínica y un desenlace exitoso del embarazo y parto de la gestante con la cardiopatía orgánica. Como resultado de este manejo multidisciplinario todos los recién nacidos tuvieron buena evolución durante su permanencia en la unidad de cuidados intensivos sin inconvenientes(AU)

Heart diseases affect approximately 2% of pregnant women increasing the risk of the mother and the child. The pregnancy and the delivery produce substantial physiological changes requiring an adequate adaptation of the cardiovascular system. These changes, which are well tolerated by pregnant women without heart disease, expose the pregnant women with heart disease to significant clinical events. This is a descriptive, retrospective study of consecutive cases in the Division of Cardiovascular Medicine of the Hospital de Clínicas between August 2013 and June 2014. It includes five pregnant women with known or unknown heart disease at the time of consultation. The average age was 27 years old (17 to 36 years old). The average gestational age was 34 weeks (30 to 38 weeks). The main symptom at consultation was dyspnea (100%), edema of inferior limbs (60%), and palpitations (40%). The joint diagnostic and therapeutic management with a detailed and adequate follow-up by a multidisciplinary team of cardiologists, physicians, gynecologists, anesthesiologists, and cardiac surgeons facilitated a good clinical outcome and a successful completion of the pregnancy and delivery of the pregnant women with heart disease. As a result of the work of this multidisciplinary team, all the newborns had good evolution during their stay at the intensive care unit without any difficulties(AU)