Covid-19 - endothelial axis and coronary artery bypass graft patency: a target for therapeutic intervention?

Abstract It has been reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces endothelial inflammation, therefore facilitating the progression of endothelial and vascular dysfunction in coronavirus disease 2019 (COVID-19) patients. Coronary artery bypass grafting (CABG) involves mainly the use of the saphenous vein (SV) and internal mammary artery as graft material in the stenosed coronary arteries. Unfortunately, graft patency of the SV is low due to endothelial dysfunction and inflammation. We propose that SARS-CoV-2 might cause vascular inflammation, endothelial dysfunction, and thrombosis in coronary artery bypass graft vessels by binding angiotensin-converting enzyme 2 receptor. Therefore, in this Special Article, we consider the potential influence of COVID-19 on the patency rates of coronary artery bypass graft vessels, mainly with reference to the SV. Moreover, we discuss the technique of SV graft harvesting and the therapeutic potential of focusing on endothelial dysfunction, vascular inflammation, and thrombosis for protecting coronary artery bypass grafts in COVID-19 infected CABG patients.

A hiperemia reativa correlaciona-se com presença de sepse e degradação de glicocálix na unidade de terapia intensiva: um estudo de coorte prospectiva / Reactive hyperemia correlates with the presence of sepsis and glycocalyx degradation in the intensive care unit: a prospective cohort study

RESUMO Objetivo: Investigar se a hiperemia reativa correlaciona-se com marcadores de disfunção endotelial e pode ser utilizada para identificar sepse na doença crítica. Métodos: Trata-se de estudo prospectivo em uma coorte de pacientes críticos. A disfunção endotelial foi avaliada quando da admissão, por meio da quantificação de hiperemia por tonometria arterial periférica e níveis plasmáticos de endotelina 1, E-selectina solúvel, endocana e sindecano 1. Os pacientes sépticos foram comparados com pacientes sem evidência de infecção. Resultados: Cinquenta e oito pacientes sépticos foram comparados com 28 controle. O logaritmo natural da tonometria arterial periférica teve correlação negativa com comorbidades cardiovasculares, severidade da doença e níveis plasmáticos de E-selectina solúvel (p = 0,024) e sindecano 1 (p < 0,001). O logaritmo natural da tonometria arterial periférica foi mais baixo nos pacientes sépticos quando comparado com os de pacientes controle (0,53 ± 0,48 versus 0,69 ± 0,42, respectivamente) e, quando ajustado à idade, o modelo multivariado predisse que cada 0,1 de diminuição em unidades de logaritmo natural da tonometria arterial periférica levou a aumento de 14,6% na probabilidade de infecção. Conclusão: A hiperemia reativa avaliada por tonometria arterial periférica tem estreita relação com E-selectina solúvel e sindecano 1, o que sugere associação entre ativação endotelial, degradação de glicocálix e reatividade vascular. A hiperemia reativa por tonometria arterial periférica parece estar comprometida em pacientes críticos, especialmente os com sepse.

Abstract Objective: To investigate whether reactive hyperemia measured by peripheral arterial tonometry correlates with markers of endothelial dysfunction and may be used to identify sepsis in critical illness. Methods: A prospective study was performed using a cohort of critically ill patients. Endothelial dysfunction was assessed on admission by quantifying reactive hyperemia-peripheral arterial tonometry and plasma levels of endothelin-1, soluble E-selectin, endocan and syndecan-1. Septic patients were compared to patients without evidence of infection. Results: Fifty-eight septic patients were compared to 28 controls. The natural logarithm of reactive hyperemia-peripheral arterial tonometry was negatively correlated with cardiovascular comorbidities, disease severity and plasma levels of soluble E-selectin (p = 0.024) and syndecan-1 (p < 0.001). The natural logarithm of reactive hyperemia-peripheral arterial tonometry was lower in septic patients than in controls (0.53 ± 0.48 versus 0.69 ± 0.42, respectively). When adjusted for age, the multivariable model predicted that each 0.1-unit decrease in natural logarithm of reactive hyperemia-peripheral arterial tonometry increased the odds for infection by 14.6%. m. Conclusion: Reactive hyperemia-peripheral arterial tonometry is closely related to soluble E-selectin and syndecan-1, suggesting an association between endothelial activation, glycocalyx degradation and vascular reactivity. Reactive hyperemia-peripheral arterial tonometry appears to be compromised in critically ill patients, especially those with sepsis.

Disfunción endotelial en una etapa precoz del diagnóstico de hipertensión arterial / Endothelial dysfunction in hypertension early stage

Introducción: La hipertensión arterial tiene una asociación compleja con la disfunción endotelial, una alteración fenotípica del endotelio vascular que precede al desarrollo de eventos cardiovasculares adversos y presagia un riesgo cardiovascular futuro. Objetivo: Determinar la presencia de disfunción endotelial en pacientes hipertensos precozmente diagnosticados. Métodos: Se realizó un estudio analítico de corte transversal entre marzo 2017 y marzo 2019, con los datos de los pacientes que acudieron al examen médico de control de Salud del Hospital Militar Central Dr. Luis Díaz Soto. El grupo A (GA) estuvo conformado por pacientes hipertensos de reciente diagnóstico (hasta un año) sin lesión en órganos diana; mientras el Grupo B (GB) fueron sujetos sin hipertensión arterial. Previo consentimiento informado, se recogieron variables demográficas, clínicas, y se realizaron determinaciones de laboratorio y prueba de vasodilatación por flujo. Resultados: La prevalencia de disfunción endotelial en el grupo A fue de 39,0 por ciento(p=0,021). Predominaron los hombres (55,0 por ciento) y la edad media 41,7 ± 8,6 años sin diferencias significativas. El 73,0 por ciento de los hipertensos eran sobrepeso u obesos. El colesterol total elevado (60,0 por ciento) y la microalbuminuria (69,0 por ciento) fueron las variables que aportaron mayor riesgo de disfunción endotelial en los pacientes hipertensos. Conclusiones: Se comprobó una elevada prevalencia de disfunción endotelial en los pacientes hipertensos de reciente diagnóstico, la cual se asoció a factores de riesgo ateroscleróticos: colesterol total elevado y microalbuminuria(AU)

Introduction: The arterial hypertension has a complex association with the endothelial dysfunction, and phenotypic alteration of the vascular endothelia that precedes the development of cardiovascular adverse events and it foreshadows future risk cardiovascular. Objective: To determine the presence of endothelial dysfunction in precociously diagnosed hypertensive patients. Methods: A transversal analytic study was conducted from March 2017 to March 2019, using data of the patients who attended to the military physical medical control at Dr. Luis Díaz Soto Military Hospital. Group A (GA) was formed by hypertensive patients recently diagnosed (up to a year) with no lesion in target organs; whereas Group B (GB) gathered the subjects with no hypertension. After establishing the informed consent, demographic, clinical variables were collected, and laboratory determinations and flow vasodilatation tests were performed. Results: Endothelial dysfunction prevalence in Group A was 39, 0 percent (p=0, 021). Men (55, 0 percent) and the mean age 41, 7 ± 8, 6 years prevailed with no significant differences. 73, 0 percent of the hypertensive subjects was overweight or obese. The total high cholesterol (60, 0 percent) and the micro albuminuria (69, 0 percent) were the variables that contributed to the higher risk of endothelial dysfunction in hypertensive patients. Conclusions: High prevalence of endothelial dysfunction was proven in recently diagnosed hypertensive patients. This endothelial dysfunction was associated to atherosclerosis risk factors as total high cholesterol and microalbuminuria(AU)

Possible mechanisms involved in the effect of the subchronic administration of rosuvastatin on endothelial function in rats with metabolic syndrome

Metabolic syndrome is a multifaceted condition associated with a greater risk of various disorders (e.g., diabetes and heart disease). In a rat model of metabolic syndrome, an acute in vitro application of rosuvastatin causes relaxation of aortic rings. Since the outcome of a subchronic rosuvastatin treatment is unknown, the present study explored its effect on acetylcholine-induced vasorelaxation of aortic rings from rats with metabolic syndrome. Animals were submitted to a 16-week treatment, including a standard diet, a cafeteria-style diet (CAF-diet), or a CAF-diet with daily rosuvastatin treatment (10 mg/kg). After confirming the development of metabolic syndrome in rats, aortic segments were extracted from these animals (those treated with rosuvastatin and untreated) and the acetylcholine-induced relaxant effect on the corresponding rings was evaluated. Concentration-response curves were constructed for this effect in the presence/absence of L-NAME, ODQ, KT 5823, 4-aminopyridine (4-AP), tetraethylammonium (TEA), apamin plus charybdotoxin, glibenclamide, indomethacin, clotrimazole, and cycloheximide pretreatment. Compared to rings from control rats, acetylcholine-induced vasorelaxation decreased in rings from animals with metabolic syndrome, and was maintained at a normal level in animals with metabolic syndrome plus rosuvastatin treatment. The effect of rosuvastatin was inhibited by L-NAME, ODQ, KT 5823, TEA, apamin plus charybdotoxin, but unaffected by 4-AP, glibenclamide, indomethacin, clotrimazole, or cycloheximide. In conclusion, the subchronic administration of rosuvastatin to rats with metabolic syndrome improved the acetylcholine-induced relaxant response, involving stimulation of the NO/cGMP/PKG/Ca2+-activated K+ channel pathway.

Physical fitness and activity, metabolic profile, adipokines and endothelial function in children / Aptidão e atividade física, perfil metabólico, adipocinas e função endotelial em crianças

Abstract Objectives: The prevalence of obesity is increasing. The aim of this study was to investigate if there is endothelial dysfunction in children with normal or excess weight, and whether the metabolic profile, adipokines, and endothelial dysfunction would be more strongly associated with physical fitness or with physical activity levels. Method: Cross-sectional study involving children aged 5-12 years. The evaluation included venous occlusion plethysmography, serum levels of adiponectin, leptin and insulin, lipid profile, physical activity score (PAQ-C questionnaire), and physical fitness evaluation (Yo-Yo test). Results: A total of 62 children participated in this study. Based on the body mass index, 27 were eutrophic, 10 overweight and 25 obese. Triglycerides, LDL cholesterol, HOMA-IR, and leptin were higher in the obese and excess-weight groups compared to the eutrophic group (p < 0.01). HDL cholesterol and adiponectin levels were higher in the eutrophic group compared to the obese and excess-weight groups (p < 0.01). Flow-mediated vasodilation after hyperemia was higher in the eutrophic group in comparison to obese and excess-weight subjects (p < 0.05). There was no difference in the physical activity levels among groups measured by PAQ-C. The Yo-Yo test was significantly associated with HDL cholesterol (rho = −0.41; p = 0.01), and this association remained after adjusting for body mass index z-score (rho = 0.28; p = 0.03). Conclusion: This study showed that endothelial dysfunction is already present in obese children, suggesting a predisposition to atherosclerotic disease. Moreover, HDL cholesterol levels were correlated with physical fitness, regardless of body mass index.

Resumo: Objetivos: A prevalência da obesidade está aumentando. O objetivo deste estudo foi investigar se há disfunção endotelial nas crianças com peso normal ou excesso de peso e se o perfil metabólico, as adipocinas e a disfunção endotelial seriam mais fortemente associados à aptidão física ou aos níveis de atividade física. Método: Estudo transversal que envolve crianças de 5-12 anos. A avaliação incluiu pletismografia de oclusão venosa, níveis séricos de adiponectina, leptina, insulina e lipidograma, escore de atividade física (questionário PAQ-C) e avaliação da aptidão física (teste Yo-yo). Resultados: Um total de 62 crianças participou deste estudo. Com base no índice de massa corporal, 27 eram eutróficos, 10 estavam acima do peso e 25 estavam obesos. Os níveis de triglicerídeos, colesterol LDL, HOMA-RI e leptina estavam mais elevados nas crianças obesas e com excesso de peso que o grupo de eutróficos (p < 0,01). Os níveis de colesterol HDL e adiponectina estavam mais elevados no grupo de eutróficos em comparação ao grupo de obesos e com excesso de peso (p < 0,01). A vasodilatação mediada pelo fluxo após hiperemia foi maior no grupo de eutróficos em comparação aos indivíduos obesos e com excesso de peso (p < 0,05). Não houve nenhuma diferença nos níveis de atividade física entre os grupos medidos pelo PAQ-C. O teste de ida e volta foi significativamente associado ao colesterol HDL (ró = −0,41; p = 0,01) e essa associação continuou após ajustar o escore z do índice de massa corporal (ró = 0,28; p = 0,03). Conclusão: Este estudo mostrou que a disfunção endotelial já está presente nas crianças obesas, sugeriu uma predisposição à doença aterosclerótica. Além disso, os níveis de colesterol HDL foram correlacionados à aptidão física, independentemente do índice de massa corporal.

Efecto de la terapia de resincronización ventricular en los parámetros de disfunción endotelial y función sistólica izquierda en pacientes con insuficiencia cardíaca crónica y bloqueo completo de rama izquierda / Endothelial dysfunction, left ventricular function, and chronic heart failure with complete left bundle branch block: effect of resynchronization therapy

Resumen: Introducción: La insuficiencia cardíaca crónica (ICC) es una condición compleja asociada a inflamación sistémica y a disfunción endotelial (DE) cuya patogénesis no es bien comprendida. Objetivo: Evaluar una posible relación entre marcadores de DE periférica con la respuesta a terapia de resincronización ventricular (TRV). Método: 20 pacientes con ICC, QRS ≥120ms y fracción de eyección ventricular izquierda (FEVI) ≤35% se estudiaron pre y 6 meses post-TRV con: Minnesota Living with Heart Failure Questionnaire (MLHFQ); test de marcha (TM-6min); Ecocardiografía-2D y SPECT de perfusión gatillado en reposo; proteína C-reactiva ultra sensible (us-PCR); péptido natriurético cerebral (pro-BNP); células endoteliales circulantes (CEC); moléculas de adhesión soluble vascular (sVCAM) e intercelular (sICAM); interleukina-6 (IL-6) y Factor von Willebrand (FvW). Se clasificaron como respondedores o no a TRV según criterios preestablecidos. Resultados: Promedios basales: pro-BNP 5.290pg/ml; us-PCR 1,7ug/mL; MLHFQ 72; TM-6min 391 metros. Las CEC y sICAM estaban sobre límites normales. Post-TRV, el 50% fue respondedor: 11/20 mejoraron ≥1 clase NYHA y ≥10% del TM-6min; ML-HFQ disminuyó (p<0.0001); FEVI mejoró (p=0.003); volumen final sistólico disminuyó (p=0.008) y también pro-BNP (p=0.03). En los respondedores, las CEC disminuyeron, persistiendo elevadas, sobre lo normal. Existieron correlaciones entre cambios de pro-BNP con TM-6min y entre us-PCR con MLHFQ y FvW (p≤0.004 en todas). Conclusiones: En ICC existe evidencia de significativa DE, expresada por sICAM y CEC, biomarcador periférico sensible. Estas disminuyeron 6 meses post-TRV, persistiendo sobre el límite normal. Otros parámetros funcionales e inflamatorios se correlacionaron en el grupo total, sin diferencias entre grupos respondedores y no respondedores.

Abstract: Introduction: Chronic heart failure (CHF) is a complex condition associated with systemic inflammation and endothelial dysfunction (ED) whose pathogenesis is not well understood. Objective: to evaluate a possible relationship between peripheral ED markers and response to cardiac resynchronization therapy (CRT). Method: 20 patients with CHF, QRS ≥120ms and left ventricular ejection fraction (LVEF) ≤35% were studied before and 6 months post-CRT. Minnesota Living with Heart Failure Questionnaire (MLHFQ); walking test (6min-WT); 2D-echocardiography and gated perfusion SPECT at rest; ultra-sensitive C-reactive protein (us-CRP); brain natriuretic peptide (pro-BNP); circulating endothelial cells (CEC); vascular soluble adhesion (sVCAM) and intercellular adhesion molecules (sICAM); interleukin-6 (IL-6) and von Willebrand Factor (vWF) were measured in all subjects. They were classified as responders or not to CRT, according to pre-established criteria. Results: Basal means: pro-BNP 5,290 pg / ml; us-CRP 1.7 ug/mL; MLHFQ 72; 6min-WT 391 meters. The CEC and IL-6 were above normal limits. Post-CRT, 50% were responders: 11/20 improved ≥1 NYHA class and ≥10% increase in 6min-WT; MLHFQ decreased (p <0.0001); LVEF improved (p = 0.003); final systolic volume decreased (p = 0.008) and also pro-BNP (p= 0.03). In responders CEC decreased, persisting over normal limits. There were correlations between changes of pro-BNP with TM-6min and between us-PCR with MLHFQ and vWF (p≤0.004 in all). Conclusions: In CHF there is evidence of significant ED, expressed by sICAM and CEC, a sensitive peripheral biomarker that decreased 6 months post-CRT although persisting above normal limits. Other functional and inflammatory parameters were correlated in the total group, without differences between responders and non-responders.

Endothelial Dysfunction and Inflammation Precedes Elevations in Blood Pressure Induced by a High-Fat Diet / Disfunção Endotelial e Inflamação Precedem a Elevação da Pressão Arterial Induzida por Dieta Hiperlipídica

Abstract Background: Obesity leads to a chronic inflammatory state, endothelial dysfunction and hypertension. Objective: To establish the time-course of events regarding inflammatory markers, endothelial dysfunction, systolic blood pressure (SBP) in obesity in only one experimental model. Methods: We fed male Wistar rats (eight-week age) with a standard diet (Control - CT, n = 35), or palatable high-fat diet (HFD, n = 35) for 24 weeks. Every six weeks, 7 animals from each group were randomly selected for euthanasia. SBP and serum levels of interleukin-6, tumor necrosis factor-α, C-reactive protein, adiponectin and nitric oxide were determined. Endothelial and vascular smooth muscle functions were determined in dissected aorta and lipid peroxidation was measured. Statistical significance was set at p < 0.05. Results: Levels of pro-inflammatory cytokines began to increase after six weeks of a high-fat diet, while those of the anti-inflammatory cytokine adiponectin decreased. Interestingly, the endothelial function and serum nitric oxide began to decrease after six weeks in HFD group. The SBP and lipid peroxidation began to increase at 12 weeks in HFD group. In addition, we showed that total visceral fat mass was negatively correlated with endothelial function and positively correlated with SBP. Conclusion: Our results show the time-course of deleterious effects and their correlation with obesity.

Resumo Fundamento: A obesidade leva a um estado de inflamação crônica, disfunção endotelial e hipertensão. Objetivo: Estabelecer a sequência de eventos relacionados a marcadores inflamatórios, disfunção endotelial e pressão arterial sistólica (PAS) na obesidade em um modelo experimental. Métodos: Ratos Wistar machos (8 semanas de idade) receberam dieta padrão (Controle - CT, n = 35) ou uma dieta palatável hiperlipídica (DHL, n = 35) por 24 semanas. A cada seis semanas, 7 animais de cada grupo foram aleatoriamente selecionados para eutanásia. Foram determinados a PAS, e níveis séricos de interleucina-6, fator de necrose tumoral-a, proteína C reativa, adiponectina e óxido nítrico. As funções do músculo liso endotelial e vascular foram determinadas na aorta dissecada, e medida a peroxidação lipídica. A significância estatística foi estabelecida em p < 0,05. Resultados: os níveis das citocinas pró-inflamatórias começaram a aumentar após seis semanas de dieta hiperlipídica, enquanto os níveis da citocina anti-inflamatória adiponectina diminuíram. Um resultado interessante foi a redução da função endotelial e do óxido nítrico após seis semanas no grupo DHL. Além disso, mostramos que a massa de tecido adiposo visceral total esteve negativamente correlacionada com função endotelial e positivamente correlacionada com a PAS. Conclusão: Nossos resultados demonstram a progressão temporal dos efeitos deletérios e sua correlação com a obesidade.

Penile microvascular endothelial function in hypertensive patients: effects of acute type 5 phosphodiesterase inhibition

The primary aim of this study was to evaluate penile endothelial microvascular function in patients with primary arterial hypertension and age-matched normotensive subjects using laser speckle contrast imaging (LSCI). Additionally, we analyzed the acute penile microvascular effects induced by oral phosphodiesterase type 5 inhibitor (sildenafil; SIL) administration. Endothelium-dependent microvascular reactivity was evaluated in the penises and forearms of hypertensive patients (aged 58.8±6.6 years, n=34) and age-matched healthy volunteers (n=33) at rest and 60 min following oral SIL (100 mg) administration. LSCI was coupled with cutaneous acetylcholine (ACh) iontophoresis using increasing anodal currents. Basal penile cutaneous vascular conductance (CVC) values were not significantly different between control subjects and hypertensive individuals. Penile CVC values increased significantly after SIL administration in control (P<0.0001) and hypertensive (P<0.0001) subjects. Peak CVC values were not different between the two groups during penile ACh iontophoresis before SIL administration (P=0.2052). Peak CVC values were higher in control subjects than in hypertensive subjects after SIL administration (P=0.0427). Penile endothelium-dependent microvascular function is, to some extent, preserved in patients presenting with primary arterial hypertension under effective anti-hypertensive treatment. LSCI may be a valuable non-invasive tool for the evaluation of penile vascular responses to phosphodiesterase type 5 inhibitor.

Association between syndecan-1 and renal function in adolescents with excess weight: evidence of subclinical kidney disease and endothelial dysfunction

Excess weight (overweight and obesity) is associated with kidney and cardiovascular disease. The aim of this study was to investigate the association between syndecan-1 and renal function among adolescents with excess weight. A total of 56 students from a public school at Fortaleza, CE, Brazil, were investigated. The adolescents were submitted to anthropometric evaluation, including weight, height, blood pressure and body mass index. Blood and urine samples were collected for the determination of serum lipids (total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglycerides), and the endothelial injury biomarker syndecan-1. Participants' mean age was 16±1 years (range 14-19 years), and 68% were females. Overweight was observed in 4 cases (7.1%) and obesity in 7 (12.5%). Changes in serum lipid levels were more frequent in the overweight group. A positive correlation between syndecan-1 and serum creatinine (r=0.5, P=0.001) and triglycerides (r=0.37, P=0.004), and a negative correlation with glomerular filtration rate (r=-0.33, P=0.02) were found. These findings suggest that adolescents with excess weight present incipient changes at the cellular level that make them more vulnerable to the development of kidney and cardiovascular diseases.

Impaired flow-mediated dilation response and carotid intima-media thickness in patients with type 1 diabetes mellitus with a mean disease duration of 4 1 years

ABSTRACT Objective This study aimed at assessing the endothelial function in patients with Type 1 diabetes (T1DM) using flow-mediated dilation (FMD) response and carotid artery intima-media thickness (CIMT). Materials and methods This study enrolled 32 T1DM patients (mean disease duration 4.1 years) and 28 age-matched controls (CTL Group). Endothelial function and CIMT were assessed with high-resolution ultrasound using standardized offline measurements. Results FMD was significantly lower in patients in the T1DM Group (8.9 ± 3.2%) compared with those in the CTL Group (13.3 ± 4.3%; P-value < 0.0001). Similarly, CIMT differed significantly between T1DM patients (0.525 ± 0.03 mm) and controls (0.508 ± 0.03 mm; P-value = 0.041). Even though, the values are within the normal range for age. Conclusions Patients with T1DM have impaired endothelial function characterized by reduced FMD when compared to controls. However, vascular remodeling as seen by increases in CIMT was not found in this study.

Association of Inflammation and Endothelial Dysfunction with Coronary Microvascular Resistance in Patients with Cardiac Syndrome X / Associação de Inflamação e Disfunção Endotelial com Resistência Microvascular Coronariana em Pacientes com Síndrome Cardíaca X

Abstract Background: Although a proportion of CSX patients have impaired brachial artery flow-mediated dilatation (FMD) in response to hyperemia, suggesting that endothelial dysfunction in these patients may be systemic and not just confined to the coronary circulation; the underlying mechanisms triggering endothelial dysfunction in these patients are still incompletely understood. Objectives: To assess the association of the index of Microcirculatory Resistance (IMR) with endothelial dysfunction and inflammation in patients with CSX. Methods: We studied 20 CSX patients and 20 age and gender-matched control subjects. Thermodilution-derived coronary flow reserve (CFR) and IMR were measured using a pressure-temperature sensor-tipped guidewire. Brachial artery FMD was measured using high-resolution, two-dimensional ultrasound images obtained with a Doppler ultrasound device (HDI-ATL 5000, USA) with a 5 MHz to 12 MHz linear-array transducer. Results: Compared with in control subjects, CFR was significantly lower (2.42 ± 0.78 vs. 3.59 ± 0.79, p < 0.001); IMR was higher (32.2 ± 8.0 vs. 19.5 ± 5.5, p < 0.001); the concentration of hs-CRP and FMD was higher (4.75 ± 1.62 vs. 2.75 ± 1.50; 5.24 ± 2.41 vs. 8.57 ± 2.46, p < 0.001) in CSX patients. The Duke treadmill score (DTS) was correlated positively to CFR and FMD (0.489 and 0.661, p < 0.001), it was negative to IMR and hsCRP (-0.761 and -0.087, p < 0.001) in CSX patients. Conclusions: The main finding in this study is that the DTS measured in patients with CSX was associated to hsCRP and FMD. Moreover, the independent effects of exercise tolerance can significantly impair FMD and hsCRP in CSX patients; especially it is particularly important to whom where FMD was associated negatively with IMR.

Resumo Fundamentos: Embora uma proporção de pacientes com SCX tenha dilatação mediada por fluxo da artéria braquial (DMF) prejudicada em resposta à hiperemia, sugerindo que a disfunção endotelial nestes pacientes pode ser sistémica e não limitar-se à circulação coronariana, os mecanismos subjacentes que desencadeiam a disfunção endotelial nestes pacientes ainda não são completamente compreendidos. Objetivos: Avaliar a associação do índice de resistência microcirculatória (IMR) com a disfunção endotelial e a inflamação em pacientes com SCX. Métodos: Estudaram-se 20 pacientes com SCX e 20 sujeitos de controle emparelhados em idade e género. A reserva de fluxo coronariano derivada da termodiluição (RFC) e a IMR forma medidas usando um fio guia com ponta de sensor de temperatura e pressão. A DMF da artéria braquial foi medida utilizando imagens ultrassónicas bidimensionais de alta resolução obtidas com um aparelho de ultrassom Doppler (HDI-ATL 5000, EE.UU.) com transdutor linear de 5 MHz a 12 MHz. Resultados: Em comparação com os sujeitos de controle, a RFC foi significativamente menor (2,42 ± 0,78 vs 3,59 ± 0,79, p < 0,001); o IMR foi maior (32,2 ± 8,0 frente a 19,5 ± 5,5, p < 0,001); a concentração de PCR-as e DMF foi maior (4,75 ± 1,62 frente a 2,75 ± 1,50, 5,24 ± 2,41 diante de 8,57 ± 2,46, p < 0,001) em pacientes com SCX. A escore de Duke (ED) se correlacionou positivamente com RFC e DMF (0,489 e 0,661, p < 0,001), foi negativa para IMR e PCR-as (-0,761 e -0,087, p < 0,001) em pacientes com SCX. Conclusões: O principal achado neste estudo é que o ED medido em pacientes com SCX esteve associado a PCR-as e DMF. Por outra parte, os efeitos independentes da tolerância ao exercício podem piorar significativamente a DMF e a PCR-as em pacientes com SCX especialmente, é particularmente importante que a DMF se associou negativamente com a RIM.

Endothelial dysfunction in children with type 1 diabetes mellitus

ABSTRACT Objective The purpose of this study was to verify the presence of endothelial dysfunction and initial structural atherosclerotic changes in children with Type 1 diabetes mellitus (T1DM). Subjects and methods The study population comprised 31 diabetic children aged 6 to 12 years, divided into two subgroups according to the duration of the T1DM diagnosis: subgroup 1, with less than 5 years elapsed since diagnosis, and subgroup 2, with more than 5 years elapsed since diagnosis. The control group comprised 58 age-matched healthy children. Ultrasonographic techniques were used to measure the flow-mediated dilatation (FMD) of the brachial artery and the intima-media thickness (IMT) of the carotid arteries. Results Children with T1DM with longer disease duration showed significantly decreased mean values of FMD compared with those in the control group. No significant differences between the groups were found in relation to IMT. The FMD percentage presented a moderate negative correlation with glycated hemoglobin (HbA1c) and fasting glucose levels. Conclusion Our findings suggest that endothelial dysfunction may be already present in children with 5 years or more elapsed since diagnosis, even in the absence of atherosclerotic structural changes. The decreased vasodilation response correlated with hyperglycemia.

Visceral adiposity index and triglyceride/high-density lipoprotein cholesterol ratio in hypogonadism

ABSTRACT Background Cardiometabolic risk is high in patients with hypogonadism. Visceral adiposity index (VAI) and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio are the practical markers of atherosclerosis and insulin resistance and independent predictors of cardiaovascular risk. To date, no study has evaluated VAI levels and TG/HDL-C ratio in hypogonadism. Subjects and methods A total of 112 patients with congenital hypogonadotrophic hypogonadism (CHH) (mean age, 21.7 ± 2.06 years) and 124 healthy subjects (mean age, 21.5 ± 1.27 years) were enrolled. The demographic parameters, VAI, TG/HDL-C ratio, asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (hs-CRP), and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured for all participants. Results The patients had higher total cholesterol (p = 0.04), waist circumference, triglycerides, insulin, and HOMA-IR levels (p = 0.001 for all) than the healthy subjects. VAI and ADMA and TG/HDL-C levels were also higher in patients than in healthy subjects (p < 0.001 for all). VAI was weakly correlated with ADMA (r = 0.27, p = 0.015), HOMA-IR (r = 0.22, p = 0.006), hs-CRP (r = 0.19, p = 0.04), and total testosterone (r = −0.21, p = 0.009) levels, whereas TG/HDL-C ratio was weakly correlated weakly with ADMA (r = 0.30, p = 0.003), HOMA-IR (r = 0.22, p = 0.006), and total testosterone (r = −0.16, p = 0.03) levels. Neither VAI nor TG/HDL-C ratio determined ADMA, HOMA-IR, and hs-CRP levels. Conclusions The results of this study demonstrate that patients with hypogonadism have elevated VAI and TG/HDL-C ratio. These values are significantly correlated with the surrogate markers of endothelial dysfunction, inflammation, and insulin resistance. However, the predictive roles of VAI and TG/HDL-C ratio are not significant. Prospective follow-up studies are warranted to clarify the role of VAI and TG/HDL-C ratio in predicting cardiometabolic risk in patients with hypogonadism.

Aerobic Swim Training Restores Aortic Endothelial Function by Decreasing Superoxide Levels in Spontaneously Hypertensive Rats

OBJECTIVE: We aimed to determine whether aerobic training decreases superoxide levels, increases nitric oxide levels, and improves endothelium-dependent vasodilation in the aortas of spontaneously hypertensive rats. METHODS: Spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were distributed into 2 groups: sedentary (SHRsd and WKYsd, n=10 each) and swimming-trained (SHRtr, n=10 and WKYtr, n=10, respectively). The trained group participated in training sessions 5 days/week for 1 h/day with an additional work load of 4% of the animal’s body weight. After a 10-week sedentary or aerobic training period, the rats were euthanized. The thoracic aortas were removed to evaluate the vasodilator response to acetylcholine (10-10 to 10-4 M) with or without preincubation with L-NG-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10-4 M) in vitro. The aortic tissue was also used to assess the levels of the endothelial nitric oxide synthase and nicotinamide adenine dinucleotide oxidase subunit isoforms 1 and 4 proteins, as well as the superoxide and nitrite contents. Blood pressure was measured using a computerized tail-cuff system. RESULTS: Aerobic training significantly increased the acetylcholine-induced maximum vasodilation observed in the SHRtr group compared with the SHRsd group (85.9±4.3 vs. 71.6±5.2%). Additionally, in the SHRtr group, superoxide levels were significantly decreased, nitric oxide bioavailability was improved, and the levels of the nicotinamide adenine dinucleotide oxidase subunit isoform 4 protein were decreased compared to the SHRsd group. Moreover, after training, the blood pressure of the SHRtr group decreased compared to the SHRsd group. Exercise training had no effect on the blood pressure of the WKYtr group. CONCLUSIONS: In SHR, aerobic swim training decreased vascular superoxide generation by nicotinamide adenine dinucleotide oxidase subunit isoform 4 and increased nitric oxide bioavailability, thereby improving endothelial function.

A Single Resistance Exercise Session Improves Aortic Endothelial Function in Hypertensive Rats / Uma Única Sessão de Exercício Resistido Melhora a Função Endotelial Aórtica em Ratos Hipertensos

Abstract Background: Physical exercise is an important tool for the improvement of endothelial function. Objective: To assess the effects of acute dynamic resistance exercise on the endothelial function of spontaneously hypertensive rats (SHR). Methods: Ten minutes after exercise, the aorta was removed to evaluate the expression of endothelial nitric oxide synthase (eNOS), phosphorylated endothelial nitric oxide synthase (p-eNOS1177) and inducible nitric oxide synthase (iNOS) and to generate concentration-response curves to acetylcholine (ACh) and to phenylephrine (PHE). The PHE protocol was also performed with damaged endothelium and before and after NG-nitro-L-arginine methyl ester (L-NAME) and indomethacin administration. The maximal response (Emax) and the sensitivity (EC50) to these drugs were evaluated. Results: ACh-induced relaxation increased in the aortic rings of exercised (Ex) rats (Emax= -80 ± 4.6%, p < 0.05) when compared to those of controls (Ct) (Emax = -50 ± 6.8%). The Emax to PHE was decreased following exercise conditions (95 ± 7.9%, p < 0.05) when compared to control conditions (120 ± 4.2%). This response was abolished after L-NAME administration or endothelial damage. In the presence of indomethacin, the aortic rings' reactivity to PHE was decreased in both groups (EC50= Ex -5.9 ± 0.14 vs. Ct -6.6 ± 0.33 log µM, p < 0.05 / Emax = Ex 9.5 ± 2.9 vs. Ct 17 ± 6.2%, p < 0.05). Exercise did not alter the expression of eNOS and iNOS, but increased the level of p-eNOS. Conclusion: A single resistance exercise session improves endothelial function in hypertensive rats. This response seems to be mediated by increased NO production through eNOS activation.

Resumo Fundamento: O exercício físico é uma importante ferramenta para o aprimoramento da função endotelial. Objetivo: Avaliar os efeitos do exercício dinâmico resistido agudo na função endotelial de ratos espontaneamente hipertensos (SHR). Métodos: Após 10 minutos de exercício, a aorta foi removida para avaliação da expressão de óxido nítrico sintase endotelial (eNOS), óxido nítrico sintase endotelial fosforilada (p-eNOS1177) e óxido nítrico sintase endotelial induzível (iNOS), e para a construção de curvas concentração-resposta de acetilcolina (ACT) e fenilefrina (FEN). O protocolo FEN foi também realizado com lesão endotelial e antes e depois da administração de N-nitro-L-arginina metil éster (L-NAME) e indometacina. A resposta máxima (Emax) e a sensibilidade (EC50) a esses fármacos foram avaliadas. Resultados: Houve aumento do relaxamento induzido por ACT nos anéis aórticos dos ratos exercitados (Ex) (Emax = -80 ± 4,6%; p < 0,05) quando comparado àquele dos controles (Ct) (Emax = -50 ± 6,8%). A Emax à FEN diminuiu após exercício (95 ± 7,9%; p < 0,05) quando comparada àquela dos controles (120 ± 4,2%). Tal resposta foi abolida após administração de L-NAME ou lesão endotelial. Na presença de indometacina, a reatividade dos anéis aórticos à FEN diminuiu nos dois grupos (EC50= Ex -5,9 ± 0,14 vs. Ct -6,6 ± 0,33 log µM; p < 0,05/ Emax = Ex 9,5 ± 2,9 vs. Ct 17 ± 6,2%; p < 0,05). O exercício não alterou a expressão de eNOS e de iNOS, mas aumentou o nível de p-eNOS. Conclusão: Uma única sessão de exercício resistido melhora a função endotelial em ratos hipertensos. Essa resposta parece ser mediada por elevação da produção de NO através de ativação de eNOS.

Swimming training prevents coronary endothelial dysfunction in ovariectomized spontaneously hypertensive rats

Estrogen deficiency and hypertension are considered major risk factors for the development of coronary heart disease. On the other hand, exercise training is considered an effective form to prevent and treat cardiovascular diseases. However, the effects of swimming training (SW) on coronary vascular reactivity in female ovariectomized hypertensive rats are not known. We aimed to evaluate the effects of SW on endothelium-dependent coronary vasodilation in ovariectomized hypertensive rats. Three-month old spontaneously hypertensive rats (SHR, n=50) were divided into four groups: sham (SH), sham plus swimming training (SSW), ovariectomized (OVX), and ovariectomized plus swimming training (OSW). The SW protocol (5 times/week, 60 min/day) was conducted for 8 weeks. The vasodilatory response was measured in isolated hearts in the absence and presence of a nitric oxide synthase inhibitor (L-NAME, 100 µM). Cardiac oxidative stress was evaluated in situ by dihydroethidium fluorescence, while the expression of antioxidant enzymes (SOD-2 and catalase) and their activities were assessed by western blotting and spectrophotometry, respectively. Vasodilation in SHR was significantly reduced by OVX, even in the presence of L-NAME, in conjunction with an increased oxidative stress. These effects were prevented by SW, and were associated with a decrease in oxidative stress. Superoxide dismutase 2 (SOD-2) and catalase expression increased only in the OSW group. However, no significant difference was found in the activity of these enzymes. In conclusion, SW prevented the endothelial dysfunction in the coronary bed of ovariectomized SHR associated with an increase in the expression of antioxidant enzymes, and therefore may prevent coronary heart disease in hypertensive postmenopausal women.

Omentina: papel en la resistencia a la insulina, inflamación y protección cardiovascular / Omentin: Role in insulin resistance, inflammation and cardiovascular protection

La omentina es una nueva adipocina a la que se le ha atribuido la capacidad de regular actividades metabólicas (sensibilidad a la insulina) y antiinflamatorias, ofreciendo protección cardiovascular en la obesidad y diabetes mellitus tipo 2. Por lo anterior, es importante conocer los mecanismos a través de los cuales confiere protección cardiovascular, con el objetivo de considerar la omentina como blanco o agente terapéutico en este escenario.

The omentin is an adipokine, which role is due to the capacity of regulate metabolic (insulin sensitivity) and anti-inflammatory activities, thus conferring vascular protection during obesity and diabetes mellitus type 2. By this, it is important to know the mechanisms by which omentin confers cardiovascular protection, with the purpose of establish omentin a possible therapeutic target or molecule on this scenario.