Mecanismos compensatorios a nivel sistémico en pacientes con tronco arterial persistente / Systemic Compensatory Mechanisms in Patients with Persistent Truncus Arteriosus

Resumen Introducción: El tronco arterial persistente es una rara malformación cardíaca congénita que provoca diversas complicaciones en el sistema cardiovascular. Se caracteriza por la presencia de un tabique ventricular defectuoso, una única válvula troncal y un tronco arterial común entre la arteria pulmonar y aorta, conllevando a una mezcla entre la sangre arterial y venosa, debido a un cortocircuito cardíaco bidireccional predominante de izquierda a derecha que compromete el suministro de flujo sanguíneo, nutrientes y oxigenación sistémica. Las manifestaciones clínicas incluyen desaturación con cianosis, hipoxemia, taquicardia, taquipnea, alteraciones en la contractilidad cardíaca, pulsos distales anómalos, pérdida de peso, fatiga y hepatomegalia. Objetivo: El propósito de esta investigación es establecer hipótesis sobre los diversos mecanismos compensatorios que se activan a nivel sistémico para contrarrestar los efectos de esta malformación. Reflexión: Se sugiere que se producen respuestas biomoleculares similares en los sistemas cardiovascular, pulmonar y renal, reduciendo la producción de óxido nítrico y provocando respuestas vasoconstrictoras. A nivel hepático, se generan factores de crecimiento y se inician procesos de angiogénesis para aumentar la perfusión sanguínea. En el cerebro, se activan enzimas para incrementar el flujo sanguíneo y proporcionar oxígeno y nutrientes esenciales. Conclusión: A pesar de estos mecanismos compensatorios, no logran contrarrestar por completo las manifestaciones clínicas, conduciendo a una serie de problemas de salud, como hipertensión pulmonar, insuficiencia cardíaca, hepatomegalia, hipoperfusión de órganos y déficits neurológicos. Estos factores convergen para generar una compleja condición cardíaca que desencadena respuestas adaptativas en el cuerpo que terminan siendo una afección médica desafiante y potencialmente grave.

Abstract Introduction: Persistent truncus arteriosus is a rare congenital cardiac malformation that causes various complications in the cardiovascular system. It is characterized by the presence of a defective ventricular septum, a single truncal valve and a common truncus arteriosus between the pulmonary artery and aorta, leading to a mixture between arterial and venous blood, due to a predominantly left-to-right bidirectional cardiac shunt that compromises the supply of blood flow, nutrients, and systemic oxygenation. Clinical manifestations include desaturation with cyanosis, hypoxemia, tachycardia, tachypnea, alterations in cardiac contractility, abnormal distal pulses, weight loss, fatigue, and hepatomegaly. Aim: The purpose of this research is to establish hypotheses about the various compensatory mechanisms that are activated at a systemic level to counteract the effects of this malformation. Reflection: It is suggested that similar biomolecular responses occur in the cardiovascular, pulmonary, and renal systems, reducing nitric oxide production and causing vasoconstrictive responses. At the liver level, growth factors are generated and angiogenesis processes are initiated to increase blood perfusion. In the brain, enzymes are activated to increase blood flow and provide oxygen and essential nutrients. Conclusion: Despite these compensatory mechanisms, they fail to completely counteract the clinical manifestations, leading to a series of health problems such as pulmonary hypertension, heart failure, hepatomegaly, organ hypoperfusion, and neurological deficits. These factors converge to generate a complex cardiac condition that triggers adaptive responses in the body that end up being a challenging and potentially serious medical condition.

Endothelium-related biomarkers and cognitive decline in prevalent hemodialysis patients: A prospective cohort study.

INTRODUCTION: Cognitive decline is prevalent in maintenance hemodialysis patients. The blood-brain barrier has been implicated in cognitive decline. In this prospective cohort study, we investigated the associations between endothelium-related biomarkers and steeper cognitive decline in this population. METHODS: Cognitive function was assessed using the Portuguese-adapted Cambridge Cognitive Examination (CAMCOG) with items of the Mini-Mental State Examination (MMSE). Endothelium-related biomarkers included syndecan-1, ICAM-1, VCAM-1 and angiopoietin-2 (AGPT2). Patients were followed up for 4 years, and cognitive assessments were repeated. Multinomial regression analyses were performed to evaluate associations between biomarkers and cognitive decline. RESULTS: A total of 216 patients completed the test battery at baseline. After 4 years, 102 patients had follow-up data. There was a significant decrease in cognitive function according to the CAMCOG and MMSE scores: a change of -0.39 (95% CI -0.27 to -0.51) and -0.51 (95% CI -0.27 to -0.76) standard deviation (SD) of the baseline scores. Additionally, executive function but not memory significantly decreased. Syndecan-1 level was independently associated with steeper cognitive decline; each increase in the SD of the syndecan-1 level was associated with a decrease in the CAMCOG of 0.20 (95% CI 0.07-0.33) SD from baseline. Syndecan-1 was associated with a steeper decline in MMSE score (ß 0.54, 95% CI 0.28-0.81) and executive function (ß 0.17, 95% CI 0.02-0.32). Syndecan-1 predicted severe cognitive impairment with an area under the curve for receiver operating characteristic curves of 0.75 (95% CI 0.64-0.83). CONCLUSION: Our findings highlight the potential of syndecan-1, a biomarker of endothelium glycocalyx derangement, as a predictor of steeper cognitive decline in prevalent hemodialysis patients.

Safety of intraoperative autologous plasma incubation of corneal grafts for reducing endothelial cell loss: a pilot study.

Background/aims: Corneal endothelial cell loss contributes to transplant failure. Autologous plasma products (APP) activate salvaging pathways that can prevent oxidative stress perioperatively. This study aimed to evaluate the safety of intraoperative incubation of full-thickness corneal grafts in platelet-rich plasma (aPRP) and plasma rich in growth factors (PRGF-Endoret) in mitigating postoperative corneal endothelial cell loss (ECL). Methods: Pilot study including patients undergoing penetrating keratoplasty (PK) for various indications between June 2021 and December 2022. Patients were randomly assigned to receive either aPRP or PRGF-Endoret incubation, while those who declined intervention served as the control group. Demographic and clinical data were collected, including preoperative and postoperative endothelial cell count, intraocular pressure, pachymetry, and adverse reactions. Results: Thirty individuals who underwent PK completed follow-up: eight from the aPRP group, 10 from the PRGF-Endoret group, and 12 from the control group. No adverse events related to APP treatment were recorded. In the first and third postoperative months, the APP group had significantly lower ECL percentages (37% vs. 25%, p = 0.02, and 44% vs. 33%, p = 0.02, respectively); this trend was maintained in the sixth month. When stratified, the PRGF-Endoret group showed significant differences in ECL reduction compared to controls at both time points (p = 0.03 and p = 0.05, respectively). The aPRP group showed a similar statistically significant outcome exclusively on the third postoperative month (p = 0.04). APP tended to reduce corneal edema faster than controls. Hexagonality was significantly better in the APP groups in the first and third months, particularly in the PRGF-Endoret group (p < 0.005). Conclusion: Preoperative incubation with APP is safe and promotes better endothelial cell quality and quantity in the early postoperative period following PK. These findings suggest a potential clinical benefit in enhancing graft outcomes and warrant further investigation.

Evaluating the impact of short-term nitrate-rich dietary supplementation on endothelial function in COPD: A randomized crossover study.

AIM: This study aimed to investigate the acute effects of dietary nitrate ingestion through l-arginine supplementation or dehydrated beet consumption on endothelial function in chronic obstructive pulmonary disease (COPD) patients. The secondary outcome was to analyze arterial stiffness, plasma nitrate, and nitrate/protein concentration. METHODS: In this randomized crossover study, subjects with COPD underwent three series of supplementation: (1) l-arginine, (2) dehydrated beetroot, and (3) a placebo that appeared like the other supplements. Each intervention lasted 14 days, with a 7-day washout period between series. Participants underwent endothelial function assessment using flow-mediated dilatation (FMD), and plasma nitrate levels were measured at the end of each supplementation series. RESULTS: Seventeen subjects (twelve male) completed the study protocol. Only five subjects presented endothelial dysfunction (RHI ≤0.51) at baseline. The mean baseline characteristics included age 66.5 ± 9.4 years, BMI 27.5 ± 4.5 kg/m2, FEV1, 0.79 (0.67-1.06) L. There were no differences (p > 0.05) between the groups or from pre-to post-interventions for RHI and arterial stiffness index (AIx) values, as well as parameters of endothelium-dependent vasodilation, such as blood flow velocity (BFV), shear stress, shear rate, FMD (mm), and FMD%. There was also no differences (p > 0.05) between the groups or from pre-to post-interventions plasma nitrate levels. CONCLUSIONS: Acute dietary supplementation with nitrates, at the doses provided, did not show a significant improvement in endothelial function assessed by FMD, EndoPAT, or plasma nitrate levels in COPD. These findings suggest that a higher dose or prolonged supplementation might be required to achieve a therapeutic effect.

Microcirculation, endothelium and glycocalyx changes associated with the use of milrinone in children with septic shock.

Background: The goal of fluid resuscitation and the use of inotropes in septic shock has traditionally focused on improving blood pressure and cardiac output, without considering the microcirculatory changes. Reaching macrocirculatory goals but with persistent microcirculatory abnormalities (hemodynamic incoherence) in septic shock has been associated with greater organ dysfunction and mortality. The objective of this study was to evaluate the microcirculation (flow and capillary density) and endothelial glycocalyx changes associated with the use of milrinone in children with septic shock, as well as their relationship with clinical variables and organ dysfunction. Methods: A prospective cohort study from February 2022 to January 2023 at a university hospital (Fundación Cardioinfantil-Instituto de Cardiología). Sublingual video microscopy was used to evaluate capillary density, microvascular flow rates and perfused boundary region (PBR-inverse parameter of glycocalyx thickness-abnormal if >2.0 microns). The primary outcome was the association between microcirculation and endothelial glycocalyx changes related to the use of milrinone. Results: A total of 140 children with a median age of two years [interquartile range (IQR) 0.58-12.1] were included. About 57.9% (81/140) of the patients received milrinone infusions. Twenty-four hours after receiving milrinone, the patients maintained functional capillary density (P<0.01) and capillary recruitment capacity (P=0.04) with no changes in capillary blood volume versus those who did not receive milrinone. Children under two years old who received milrinone had better 4-6-micron capillary density than older children [odds ratio (OR) 0.33; 95% confidence interval (95% CI): 0.12-0.89; P=0.02] and less endothelial glycocalyx degradation [adjusted OR (aOR) 0.34 95% CI: 0.11-0.99; P=0.04]. These changes persisted despite elevated ferritin (aOR 0.41; 95% CI: 0.18-0.93; P=0.03). Prolonged capillary refill and elevated lactate were correlated with microcirculation changes in both groups. The patients who died had the highest PBR levels (P=0.04). Conclusions: Children with septic shock who receive milrinone infusions have microcirculation changes compared with those who do not receive them. The group that received milrinone was found to maintain functional capillary density and capillary recruitment capacity and have less endothelial glycocalyx degradation 24 hours after administration. These changes were present despite the inflammatory response and were more significant in those under two years of age.

Infrared thermography for normal endothelial function screening.

BACKGROUND: Endothelial dysfunction (ED) suspicion will allow to prevent accelerated atherosclerosis and premature death. OBJECTIVE: To establish the usefulness of thermography for endothelial function screening in adults with cardiovascular risk factors. MATERIAL AND METHODS: Cross-sectional, analytical diagnostic test. A brachial arterial diameter (BAD) increase < 11% at one-minute post-ischemia meant probable ED and was confirmed if BAD was ≥ 11% post-sublingual nitroglycerin. Thermographic photographs of the palmar region were obtained at one minute. Descriptive statistics, ROC curve, Mann-Whitney's U-test, chi-square test, or Fisher's exact test were used. RESULTS: Thirty-eight subjects with a median age of 50 years, and with 624 thermographic measurements were included. Nine had ED (flow-mediated vasodilation [FMV]: 2.5%). The best cutoff point for normal endothelial function in subjects with cardiovascular risk factors was ≥ 36 °C at one minute of ischemia, with 85% sensitivity, 70% specificity, positive and negative predictive values of 78 and 77%, area under the curve of 0.796, LR+ 2.82, LR- 0.22. CONCLUSION: An infrared thermography-measured temperature in the palmar region greater than or equal to 36 °C after one minute of ischemia is practical, non-invasive, and inexpensive for normal endothelial function screening in adults with cardiovascular risk factors.

ANTECEDENTES: La sospecha de disfunción endotelial (DE) permitirá prevenir la aterosclerosis acelerada y la muerte prematura. OBJETIVO: Establecer la utilidad de la termografía en el cribado de la función endotelial en adultos con factores de riesgo cardiovascular. MATERIAL Y MÉTODOS: Estudio transversal analítico de prueba diagnóstica. El incremento del diámetro de la arteria braquial < 11 % a un minuto posisquemia significó probable DE, confirmada si el diámetro fue ≥ 11 % posnitroglicerina sublingual. Se obtuvieron fotografías termográficas al minuto de la región palmar. Se aplicó estadística descriptiva, curva ROC, pruebas U de Mann-Whitney, chi cuadrada o exacta de Fisher. RESULTADOS: Se incluyeron 38 sujetos, mediana de edad de 50 años, con 624 mediciones termográficas; nueve presentaron DE (vasodilatación mediada por flujo de 2.5 %). El mejor punto de corte para la función endotelial normal en sujetos con factores de riesgo cardiovascular fue ≥ 36 °C al minuto de isquemia, con sensibilidad de 85%, especificidad de 70%, valores predictivos positivo y negativo de 78 y 77%, área bajo la curva de 0.796, razón de verisimilitud positiva de 2.82 y razón de verisimilitud negativa de 0.22. CONCLUSIÓN: La medición de la temperatura en la región palmar mediante termografía infrarroja ≥ 36 °C tras un minuto de isquemia es práctica, no invasiva y económica para el cribado de la función endotelial normal en adultos con factores de riesgo cardiovascular.

Genes Differentially Expressed Across Major Arteries Are Enriched in Endothelial Dysfunction-Related Gene Sets: Implications for Relative Inter-artery Atherosclerosis Risk.

Atherosclerosis differs across major arteries. Although the biological basis is not fully understood, limited evidence of genetic differences has been documented. This study, therefore, was aimed to identify differentially expressed genes between clinically relevant major arteries and investigate their enrichment in endothelial dysfunction-related gene sets. A bioinformatic analysis of publicly available gene-level read counts for coronary, aortic, and tibial arteries was performed. Differential gene expression was conducted with DeSeq2 at a false discovery rate of 0.05. Differentially expressed genes were then subjected to over-representation analysis and active-subnetwork-oriented enrichment analysis, both at a false discovery rate of 0.005. Enriched terms common to both analyses were categorized for each contrast into immunity/inflammation-, membrane biology-, lipid metabolism-, and coagulation-related terms, and the top differentially expressed genes validated against Swiss Institute of Bioinformatics' Bgee database. There was mostly upregulation of differentially expressed genes for the coronary/tibial and aorta/tibial contrasts, but milder changes for the coronary/aorta contrast. Transcriptomic differences between coronary or aortic versus tibial samples largely involved immunity/inflammation-, membrane biology-, lipid metabolism-, and coagulation-related genes, suggesting potential to modulate endothelial dysfunction and atherosclerosis. These results imply atheroprone coronary and aortic environments compared with tibial artery tissue, which may explain observed relative inter-artery atherosclerosis risk.

Maternal pregnancy hypertension impairs nitric oxide formation and results in increased arterial blood pressure in first-generation offspring female rats.

OBJECTIVES: Maternal endothelial dysfunction in pregnancy hypertension is related to impairment of nitric oxide (NO) formation. However, NO levels and hemodynamic repercussions on the female offspring remain unclear. Therefore, this study hypothesized that maternal pregnancy hypertension reduces circulating NO metabolites and increases arterial blood pressure in first-generation offspring female rats. STUDY DESIGN: Descendant female rats were distributed in four groups as follows: virgin offspring of normotensive (VN) and hypertensive (VH) mothers and pregnant offspring of normotensive (PN) and hypertensive (PH) mothers. Hemodynamic and biochemical analyses were performed. MAIN OUTCOME MEASURES: The systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR), and body weight were measured. NO metabolites in plasma, NO formation in human umbilical vein endothelial cells (HUVECs) incubated with plasma, and endothelial NO synthase (eNOS) expression in aortas were determined. RESULTS: Increased SBP, DBP, and reduced HR were found on the 60 days of life in the VH group, whereas the PH group showed increased SBP and HR on pregnancy day 7. All groups showed no differences in body weight gain and eNOS expression. Plasma levels of NO metabolites were increased in the PN compared to the other groups. Increases in the NO formation were greater in HUVECs incubated with plasma from VN and PN groups compared to the VH and PH groups. CONCLUSIONS: Female virgin and pregnant first-generation offspring rats from hypertensive pregnant mothers may have negative cardiovascular repercussions featured by increases in SBP, and possibly impaired NO formation is involved.

Understanding Local Reactions Induced by Bothrops jararaca Venom: The Role of Inflammatory Mediators in Leukocyte-Endothelium Interactions.

In recent years, extensive research has delved into the pathophysiology of local reactions triggered by Bothrops snake venoms. Even though antivenom works well at reducing death and systemic effects, it is still not very effective in treating local reactions because it cannot counteract damage that has already been triggered. This limitation might be attributed to certain molecules that amplify the venom-induced innate response. While evidence suggests endogenous mediators at the venom site play a role in this envenomation, in Brazil, the concurrent use of anti-inflammatory agents or other drugs alongside antivenom remains uncommon. This study evaluated the pharmacological mediation of alterations in leukocyte-endothelium interactions following the experimental envenomation of mice with Bothrops jararaca venom, the main culprit of snake-related accidents in Southeast Brazil. We treated envenomed mice with inhibitors of different pharmacological pathways and observed the cremaster muscle microcirculation with intravital microscopy. We found that eicosanoids related to cyclooxygenase pathways and nitric oxide significantly contributed to B. jararaca venom-induced alterations in leukocyte-endothelium interactions. Conversely, lipoxygenase-mediated eicosanoids, histamine, and serotonin had minimal participation. Notably, dexamethasone and antivenom treatment diminished B. jararaca venom-induced alterations in leukocyte-endothelium interactions. The limited efficacy of the antivenom in managing Bothrops venom-induced local reactions emphasizes the critical need for supplementary treatments to enhance therapeutic outcomes.

Intravital Microscopy Evidence That Methylene Blue Should Be a Vasopressor-Sparing Agent in Sepsis Vasoplegia.

Microvasculature failure is expected in sepsis and at higher amine concentrations. Therefore, special attention focused individually on microcirculation is needed. Here, we present that methylene blue can prevent leukocytes from adhering to the endothelium in a rat model of lipopolysaccharide-induced endotoxemia. As hypothesis evidence, an intravital microscopy image is presented.

Determination of progressive endothelial cell loss after posterior chamber phakic intraocular lens implantation.

Comments about endothelial cell loss after posterior chamber phakic intraocular lens are provided, with a particular emphasis on the importance of determining progressive postoperative cell density reduction, excluding that related to surgical trauma.

Nrf2 pre-recruitment at Enhancer 2 is a hallmark of H2 O2 -induced epigenetic transcriptional memory in the HMOX1 gene in human umbilical artery endothelial cells.

Maternal obesity (MO) is a significant cause of increased cardiometabolic risk in offspring, who present endothelial dysfunction at birth. Alterations in physiologic and cellular redox status are strongly associated with altered gene regulation in arterial endothelium. However, specific mechanisms by which the pro-oxidant fetal environment in MO could modulate the vascular gene expression and function during the offspring's postnatal life are elusive. We tested if oxidative stress could reprogram the antioxidant-coding gene's response to a pro-oxidant challenge through an epigenetic transcriptional memory (ETM) mechanism. A pro-oxidant double-hit protocol was applied to human umbilical artery endothelial cells (HUAECs) and EA.hy 926 endothelial cell lines. The ETM acquisition in the HMOX1 gene was analyzed by RT-qPCR. HMOX1 mRNA decay was evaluated by Actinomycin-D treatment and RT-qPCR. To assess the chromatin accessibility and the enrichment of NRF2, RNAP2, and phosphorylation at serin-5 of RNAP2, at HMOX1 gene regulatory regions, were used DNase HS-qPCR and ChIP-qPCR assays, respectively. The CpG methylation pattern at the HMOX1 core promoter was analyzed by DNA bisulfite conversion and Sanger sequencing. Data were analyzed using two-way ANOVA, and p < 0.05 was statistically significant. Using a pro-oxidant double-hit protocol, we found that the Heme Oxygenase gene (HMOX1) presents an ETM response associated with changes in the chromatin structure at the promoter and gene regulatory regions. The ETM response was characterized by a paused-RNA Polymerase 2 and NRF2 enrichment at the transcription start site and Enhancer 2 of the HMOX1 gene, respectively. Changes in DNA methylation pattern at the HMOX1 promoter were not a hallmark of this oxidative stress-induced ETM. These data suggest that a pro-oxidant milieu could trigger an ETM at the vascular level, indicating a potential epigenetic mechanism involved in the increased cardiovascular risk in the offspring of women with obesity.

Human Coronary Artery Endothelial Cell Response to Porphyromonas gingivalis W83 in a Collagen Three-Dimensional Culture Model.

P. gingivalis has been reported to be an endothelial cell inflammatory response inducer that can lead to endothelial dysfunction processes related to atherosclerosis; however, these studies have been carried out in vitro in cell culture models on two-dimensional (2D) plastic surfaces that do not simulate the natural environment where pathology develops. This work aimed to evaluate the pro-inflammatory response of human coronary artery endothelial cells (HCAECs) to P. gingivalis in a 3D cell culture model compared with a 2D cell culture. HCAECs were cultured for 7 days on type I collagen matrices in both cultures and were stimulated at an MOI of 1 or 100 with live P. gingivalis W83 for 24 h. The expression of the genes COX-2, eNOS, and vWF and the levels of the pro-inflammatory cytokines thromboxane A2 (TXA-2) and prostaglandin I2 (PGI2) were evaluated. P. gingivalis W83 in the 2D cell culture increased IL-8 levels at MOI 100 and decreased MCP-1 levels at both MOI 100 and MOI 1. In contrast, the 3D cell culture induced an increased gene expression of COX-2 at both MOIs and reduced MCP-1 levels at MOI 100, whereas the gene expression of eNOS, vWF, and IL-8 and the levels of TXA2 and PGI2 showed no significant changes. These data suggest that in the collagen 3D culture model, P. gingivalis W83 induces a weak endothelial inflammatory response.

Endothelium-related biomarkers enhanced prediction of kidney support therapy in critically ill patients with non-oliguric acute kidney injury.

Acute kidney injury (AKI) is a common condition in hospitalized patients who often requires kidney support therapy (KST). However, predicting the need for KST in critically ill patients remains challenging. This study aimed to analyze endothelium-related biomarkers as predictors of KST need in critically ill patients with stage 2 AKI. A prospective observational study was conducted on 127 adult ICU patients with stage 2 AKI by serum creatinine only. Endothelium-related biomarkers, including vascular cell adhesion protein-1 (VCAM-1), angiopoietin (AGPT) 1 and 2, and syndecan-1, were measured. Clinical parameters and outcomes were recorded. Logistic regression models, receiver operating characteristic (ROC) curves, continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were used for analysis. Among the patients, 22 (17.2%) required KST within 72 h. AGPT2 and syndecan-1 levels were significantly greater in patients who progressed to the KST. Multivariate analysis revealed that AGPT2 and syndecan-1 were independently associated with the need for KST. The area under the ROC curve (AUC-ROC) for AGPT2 and syndecan-1 performed better than did the constructed clinical model in predicting KST. The combination of AGPT2 and syndecan-1 improved the discrimination capacity of predicting KST beyond that of the clinical model alone. Additionally, this combination improved the classification accuracy of the NRI and IDI. AGPT2 and syndecan-1 demonstrated predictive value for the need for KST in critically ill patients with stage 2 AKI. The combination of AGPT2 and syndecan-1 alone enhanced the predictive capacity of predicting KST beyond clinical variables alone. These findings may contribute to the early identification of patients who will benefit from KST and aid in the management of AKI in critically ill patients.

Adjuvant-induced arthritis promotes vascular hyporesponsiveness to phenylephrine through a nitric oxide-related mechanism

Arthritis has important cardiovascular repercussions. Phenylephrine-induced vasoconstriction is impaired in rat aortas in the early phase of the adjuvant-induced arthritis (AIA), around the 15th day post-induction. Therefore, the present study aimed to verify the effects of AIA on hyporesponsiveness to phenylephrine in rat aortas. AIA was induced by intradermal injection of Mycobacterium tuberculosis (3.8 mg/dL) in the right hind paw of male Wistar rats (n=27). Functional experiments in isolated aortas were carried out 15 days after AIA induction. Morphometric and stereological analyses of the aortas were also performed 36 days after the induction of AIA. AIA did not promote structural modifications in the aortas at any of the time points studied. AIA reduced phenylephrine-induced contraction in endothelium-intact aortas, but not in endothelium-denuded aortas. However, AIA did not change KCl-induced contraction in either endothelium-intact or denuded aortas. L-NAME (non-selective NOS inhibitor), 1400W (selective iNOS inhibitor), and ODQ (guanylyl cyclase inhibitor) reversed AIA-induced hyporesponsiveness to phenylephrine in intact aortas. 7-NI (selective nNOS inhibitor) increased the contraction induced by phenylephrine in aortas from AIA rats. In summary, the hyporesponsiveness to phenylephrine induced by AIA was endothelium-dependent and mediated by iNOS-derived NO through activation of the NO-guanylyl cyclase pathway.

Termografía infrarroja en la detección de la función endotelial normal / Infrared thermography for normal endothelial function screening

Resumen Antecedentes: La sospecha de disfunción endotelial (DE) permitirá prevenir la aterosclerosis acelerada y la muerte prematura. Objetivo: Establecer la utilidad de la termografía en el cribado de la función endotelial en adultos con factores de riesgo cardiovascular. Material y métodos: Estudio transversal analítico de prueba diagnóstica. El incremento del diámetro de la arteria braquial < 11 % a un minuto posisquemia significó probable DE, confirmada si el diámetro fue ≥ 11 % posnitroglicerina sublingual. Se obtuvieron fotografías termográficas al minuto de la región palmar. Se aplicó estadística descriptiva, curva ROC, pruebas U de Mann-Whitney, chi cuadrada o exacta de Fisher. Resultados: Se incluyeron 38 sujetos, mediana de edad de 50 años, con 624 mediciones termográficas; nueve presentaron DE (vasodilatación mediada por flujo de 2.5 %). El mejor punto de corte para la función endotelial normal en sujetos con factores de riesgo cardiovascular fue ≥ 36 °C al minuto de isquemia, con sensibilidad de 85%, especificidad de 70%, valores predictivos positivo y negativo de 78 y 77%, área bajo la curva de 0.796, razón de verisimilitud positiva de 2.82 y razón de verisimilitud negativa de 0.22. Conclusión: La medición de la temperatura en la región palmar mediante termografía infrarroja ≥ 36 °C tras un minuto de isquemia es práctica, no invasiva y económica para el cribado de la función endotelial normal en adultos con factores de riesgo cardiovascular.

Abstract Background: Endothelial dysfunction (ED) suspicion will allow to prevent accelerated atherosclerosis and premature death. Objective: To establish the usefulness of thermography for endothelial function screening in adults with cardiovascular risk factors. Material and methods: Cross-sectional, analytical diagnostic test. A brachial arterial diameter (BAD) increase <11 % at one-minute post-ischemia meant probable ED and was confirmed if BAD was ≥ 11 % post-sublingual nitroglycerin. Thermographic photographs of the palmar region were obtained at one minute. Descriptive statistics, ROC curve, Mann-Whitney’s U-test, chi-square test, or Fisher’s exact test were used. Results: Thirty-eight subjects with a median age of 50 years, and with 624 thermographic measurements were included. Nine had ED (flow-mediated vasodilation (FMV): 2.5 %. The best cutoff point for normal endothelial function in subjects with cardiovascular risk factors was ≥ 36 °C at one minute of ischemia, with 85 % sensitivity, 70 % specificity, positive and negative predictive values of 78 and 77 %, area under the curve of 0.796, LR+ 2.82, LR- 0.22. Conclusions: An infrared thermography-measured temperature in the palmar region greater than or equal to 36 °C after one minute of ischemia is practical, non-invasive, and inexpensive for normal endothelial function screening in adults with cardiovascular risk factors.

Calcium signaling in endothelial and vascular smooth muscle cells: sex differences and the influence of estrogens and androgens.

Calcium signaling in vascular endothelial cells (ECs) and smooth muscle cells (VSMCs) is essential for the regulation of vascular tone. However, the changes to intracellular Ca2+ concentrations are often influenced by sex differences. Furthermore, a large body of evidence shows that sex hormone imbalance leads to dysregulation of Ca2+ signaling and this is a key factor in the pathogenesis of cardiovascular diseases. In this review, the effects of estrogens and androgens on vascular calcium-handling proteins are discussed, with emphasis on the associated genomic or nongenomic molecular mechanisms. The experimental models from which data were collected were also considered. The review highlights 1) in female ECs, transient receptor potential vanilloid 4 (TRPV4) and mitochondrial Ca2+ uniporter (MCU) enhance Ca2+-dependent nitric oxide (NO) generation. In males, only transient receptor potential canonical 3 (TRPC3) plays a fundamental role in this effect. 2) Female VSMCs have lower cytosolic Ca2+ levels than males due to differences in the activity and expression of stromal interaction molecule 1 (STIM1), calcium release-activated calcium modulator 1 (Orai1), calcium voltage-gated channel subunit-α1C (CaV1.2), Na+-K+-2Cl- symporter (NKCC1), and the Na+/K+-ATPase. 3) When compared with androgens, the influence of estrogens on Ca2+ homeostasis, vascular tone, and incidence of vascular disease is better documented. 4) Many studies use supraphysiological concentrations of sex hormones, which may limit the physiological relevance of outcomes. 5) Sex-dependent differences in Ca2+ signaling mean both sexes ought to be included in experimental design.

Testosterone modulates vasodilation in mesenteric arteries of hypertensive rats.

AIMS: To evaluate the effects of testosterone on endothelium-dependent vasodilation and oxidative stress in mesenteric resistance arteries. MAIN METHODS: Spontaneously hypertensive rats (SHR), aged 8 to 10 weeks, were divided into four groups: intact (SHAM), intact treated with testosterone (TTO; 3 mg/kg/day) via subcutaneous route (s.c.), intact treated with testosterone and anastrozole [aromatase enzyme inhibitor (TTO + ANA; 0.1 mg/kg/day, s.c.)] and intact treated with testosterone and finasteride [5 α-reductase enzyme inhibitor (TTO + FIN; 5 mg/kg/day, s.c.)] for four weeks. Concentration-response curves to acetylcholine (ACh, 0.1 nmol/L - 10 µmol/L) were obtained in mesenteric resistance arteries previously contracted with phenylephrine (PE, 3 µmol/L), before and after the use of selective inhibitors. Reactive oxygen species (ROS) levels were assessed in the vessels and the endothelium analyzed by scanning electron microscopy. KEY FINDINGS: TTO group showed a lower participation of nitric oxide (NO), increased oxidative stress, and participation of prostanoids and endothelium-dependent hyperpolarization (EDH), possibly to maintain the vasodilator response. Lower participation of NO and prostanoids, combined to an increased participation of EDH, were observed in the TTO + ANA group, in addition to higher levels of ROS and altered endothelial morphology. The vasodilation to ACh was impaired in TTO + FIN, along increased participation of NO, reduction of prostanoids, and greater EDH-dependent vasodilation. SIGNIFICANCE: Testosterone contributes to endothelial vasodilation by enhancing EDH through an increased participation of epoxyeicosatrienoic acids. While the decrease in NO appears to involve the participation of dihydrotestosterone, 17 ß-estradiol seems to stimulate the action of the NO pathway and prostanoids.

The association between prolonged capillary refill time and microcirculation changes in children with sepsis.

BACKGROUNDS: In children with sepsis, circulatory shock and multi-organ failure remain major contributors to mortality. Prolonged capillary refill time (PCRT) is a clinical tool associated with disease severity and tissue hypoperfusion. Microcirculation assessment with videomicroscopy represents a promising candidate for assessing and improving hemodynamic management strategies in children with sepsis. Particularly when there is loss of coherence between the macro and microcirculation (hemodynamic incoherence). We sought to evaluate the association between PCRT and microcirculation changes in sepsis. METHODS: This was a prospective cohort study in children hospitalized with sepsis. Microcirculation was measured using sublingual video microscopy (capillary density and flow and perfused boundary region [PBR]-a parameter inversely proportional to vascular endothelial glycocalyx thickness), phalangeal tissue perfusion, and endothelial activation and glycocalyx injury biomarkers. The primary outcome was the association between PCRT and microcirculation changes. RESULTS: A total of 132 children with sepsis were included, with a median age of two years (IQR 0.6-12.2). PCRT was associated with increased glycocalyx degradation (PBR 2.21 vs. 2.08 microns; aOR 2.65, 95% CI 1.09-6.34; p = 0.02) and fewer 4-6 micron capillaries recruited (p = 0.03), with no changes in the percentage of capillary blood volume (p = 0.13). Patients with hemodynamic incoherence had more PBR abnormalities (78.4% vs. 60.8%; aOR 2.58, 95% CI 1.06-6.29; p = 0.03) and the persistence of these abnormalities after six hours was associated with higher mortality (16.5% vs. 6.1%; p < 0.01). Children with an elevated arterio-venous CO2 difference (DCO2) had an abnormal PBR (aOR 1.13, 95% CI 1.01-1.26; p = 0.03) and a lower density of small capillaries (p < 0.05). Prolonged capillary refill time predicted an abnormal PBR (AUROC 0.81, 95% CI 0.64-0.98; p = 0.03) and relative percentage of blood in the capillaries (AUROC 0.82, 95% CI 0.58-1.00; p = 0.03) on admission. A normal CRT at 24 h predicted a shorter hospital stay (aOR 0.96, 95% CI 0.94-0.99; p < 0.05). CONCLUSIONS: We found an association between PCRT and microcirculation changes in children with sepsis. These patients had fewer small capillaries recruited and more endothelial glycocalyx degradation. This leads to nonperfused capillaries, affecting oxygen delivery to the tissues. These disorders were associated with hemodynamic incoherence and worse clinical outcomes when the CRT continued to be abnormal 24 h after admission.

Evaluation of the common pauraque (Nyctidromus albicollis) cornea using light and scanning electron microscopy.

The common pauraque Nyctidromus albicollis (Gmelin, 1789) is a widespread avian species; however due to its nocturnal habits and reclusive behaviour, little is known about their vision and ecology. Most avian species are visually dependent with advanced visual systems providing high spatial resolution, on the species needs. Each ocular structure has a specific role in contributing towards high visual function, and the cornea is the first refractive structure in the visual process. However, the common pauraque cornea had not been described until the present data. Therefore, this study aims to describe the morphology and morphometry of the common pauraque cornea by means of light and scanning electron microscopy to evaluate the cross-sectional anatomy as well as the ultrastructure of the endothelial cells. Histological similarities with the cornea of other birds have been observed, but the thickness of the common pauraque cornea is much smaller than the other described corneas. A better understanding of the common pauraque cornea can help us better explain the physiology of vision and the visual requirements of this species. In turn, this will help us better understand how this species successfully interacts with its environment, and will improve our knowledge on how to interpret pathological changes in their cornea in a clinical setting.