Epigenetic Programming of Cardiovascular Disease by Perinatal Hypoxia and Fetal Growth Restriction

Most of the worldwide deaths in patients with non-communicable diseases are due to cardiovascular and metabolic diseases, which are determined by a mix of environmental, genetic and epigenetic factors, and by their interactions. The aetiology of most cardiovascular diseases has been partially linked with in utero adverse conditions that may increase the risk of developing diseases later in life, known as Developmental Origins of Health and Disease (DOHaD). Perinatal hypoxia can program the fetal and postnatal developmental patterns, resulting in permanent modifications of cells, organs and systems function. In spite of the vast evidence obtained from human and animal studies linking development under adverse intrauterine conditions with increased cardiovascular risk, still few is known about the specific effects of intrauterine oxygen deficiency and the related pathogenic mechanisms. Currently, the most accepted processes that program cellular function are epigenetic mechanisms which determine gene expression in a cell-specific fashion. In this chapter we will review the current literature regarding the perinatal exposure to chronic hypoxia and Fetal Growth Restriction (FGR) in humans and animals and how this impinges the cardiovascular physiology through epigenetic, biochemical, morphologic and pathophysiologic modifications that translate into diseases blasting at postnatal life

Antioxidant treatment alters peripheral vascular dysfunction induced by postnatal glucocorticoid therapy in rats.

BACKGROUND: Postnatal glucocorticoid therapy in premature infants diminishes chronic lung disease, but it also increases the risk of hypertension in adulthood. Since glucocorticoid excess leads to overproduction of free radicals and endothelial dysfunction, this study tested the hypothesis that adverse effects on cardiovascular function of postnatal glucocorticoids are secondary to oxidative stress. Therefore, combined postnatal treatment of glucocorticoids with antioxidants may diminish unwanted effects. METHODOLOGY/PRINCIPAL FINDINGS: Male rat pups received a course of dexamethasone (Dex), or Dex with vitamins C and E (DexCE), on postnatal days 1-6 (P1-6). Controls received vehicle (Ctrl) or vehicle with vitamins (CtrlCE). At P21, femoral vascular reactivity was determined via wire myography. Dex, but not DexCE or CtrlCE, increased mortality relative to Ctrl (81.3 versus 96.9 versus 90.6 versus 100% survival, respectively; P<0.05). Constrictor responses to phenylephrine (PE) and thromboxane were enhanced in Dex relative to Ctrl (84.7+/-4.8 versus 67.5+/-5.7 and 132.7+/-4.9 versus 107.0+/-4.9% Kmax, respectively; P<0.05); effects that were diminished in DexCE (58.3+/-7.5 and 121.1+/-4.3% Kmax, respectively; P<0.05). Endothelium-dependent dilatation was depressed in Dex relative to Ctrl (115.3+/-11.9 versus 216.9+/-18.9, AUC; P<0.05); however, this effect was not restored in DexCE (68.3+/-8.3, AUC). Relative to Ctrl, CtrlCE alone diminished PE-induced constriction (43.4+/-3.7% Kmax) and the endothelium-dependent dilatation (74.7+/-8.7 AUC; P<0.05). CONCLUSIONS/SIGNIFICANCE: Treatment of newborn rats with dexamethasone has detrimental effects on survival and peripheral vasoconstrictor function. Coadministration of dexamethasone with antioxidant vitamins improves survival and partially restores vascular dysfunction. Antioxidant vitamins alone affect peripheral vascular function

Analysis of the geometrical influence of ring-opening samples on arterial circumferential residual stress reconstruction

This work consists of analyzing the impact of geometrical features (thickness and curvature) on the estimation of circumferential residual stresses in arteries. For this purpose, a specific sample of lamb abdominal artery is chosen for analysis and, through computational tools based on Python libraries, the stress-free geometry is captured after the ring opening test. Numerical simulations are then used to reconstruct the sample in order to estimate the circumferential residual stresses. Then, four stress-free geometry models are analyzed: an ideal geometry, i.e., constant curvature and thickness; a constant curvature and variable thickness geometry; a variable curvature and constant thickness geometry; and a variable curvature and thickness geometry. The numerical results show that models perform well from a geometric point of view, where the most different feature was the closed outer perimeter that differs about 14% from the closed real sample. As far as residual stress is concerned, differences up to 198% were found in more realistic models taking a constant curvature and thickness model as reference. Thus, the analysis of a realistic geometry with highly variable curvature and thickness can introduce, compared to an idealized geometry, significant differences in the estimation of residual stresses. This could indicate that the characterization of arterial residual stresses is not sufficient when considering only the opening angle and, therefore, it is also necessary to incorporate more geometrical variables

Melatonin modulates the fetal cardiovascular defense response to acute hypoxia.

Experimental studies in animal models supporting protective effects on the fetus of melatonin in adverse pregnancy have prompted clinical trials in human pregnancy complicated by fetal growth restriction. However, the effects of melatonin on the fetal defense to acute hypoxia, such as that which may occur during labor, remain unknown. This translational study tested the hypothesis, in vivo, that melatonin modulates the fetal cardiometabolic defense responses to acute hypoxia in chronically instrumented late gestation fetal sheep via alterations in fetal nitric oxide (NO) bioavailability. Under anesthesia, 6 fetal sheep at 0.85 gestation were instrumented with vascular catheters and a Transonic flow probe around a femoral artery. Five days later, fetuses were exposed to acute hypoxia with or without melatonin treatment. Fetal blood was taken to determine blood gas and metabolic status and plasma catecholamine concentrations. Hypoxia during melatonin treatment was repeated during in vivo NO blockade with the NO clamp. This technique permits blockade of de novo synthesis of NO while compensating for the tonic production of the gas, thereby maintaining basal cardiovascular function. Melatonin suppressed the redistribution of blood flow away from peripheral circulations and the glycemic and plasma catecholamine responses to acute hypoxia. These are important components of the fetal brain sparing response to acute hypoxia. The effects of melatonin involved NO-dependent mechanisms as the responses were reverted by fetal treatment with the NO clamp. Melatonin modulates the in vivo fetal cardiometabolic responses to acute hypoxia by increasing NO bioavailability.This work was supported by the ‘International Journal of Experimental Pathology’. Dino A. Giussani is Professor of Cardiovascular Physiology & Medicine at the Department of Physiology Development & Neuroscience at the University of Cambridge, Professorial Fellow and Director of Studies in Medicine at Gonville & Caius College, a Lister Institute Fellow, and a Royal Society Wolfson Research Merit Award Holder. He is supported by the British Heart Foundation, the Biotechnology and Biological Sciences Research Council, and the Isaac Newton Trust.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1111/jpi.1224

The placental pursuit for an adequate oxidant balance between the mother and the fetus

The placenta is the exchange organ that regulates metabolic processes between the mother and her developing fetus. The adequate function of this organ is clearly vital for a physiologic gestational process and a healthy baby as final outcome. The umbilico-placental vasculature has the capacity to respond to variations in the materno-fetal milieu. Depending on the intensity and the extensity of the insult, these responses may be immediate-, mediate-, and long-lasting, deriving in potential morphostructural and functional changes later in life. These adjustments usually compensate the initial insults, but occasionally may switch to long-lasting remodeling and dysfunctional processes, arising maladaptation. One of the most challenging conditions in modern perinatology is hypoxia and oxidative stress during development, both disorders occurring in high-altitude and in low-altitude placental insufficiency. Hypoxia and oxidative stress may induce endothelial dysfunction and thus, reduction

Induction of controlled hypoxic pregnancy in large mammalian species.

Progress in the study of pregnancy complicated by chronic hypoxia in large mammals has been held back by the inability to measure long-term significant reductions in fetal oxygenation at values similar to those measured in human pregnancy complicated by fetal growth restriction. Here, we introduce a technique for physiological research able to maintain chronically instrumented maternal and fetal sheep for prolonged periods of gestation under significant and controlled isolated chronic hypoxia beyond levels that can be achieved by habitable high altitude. This model of chronic hypoxia permits measurement of materno-fetal blood gases as the challenge is actually occurring. Chronic hypoxia of this magnitude and duration using this model recapitulates the significant asymmetric growth restriction, the pronounced cardiomyopathy, and the loss of endothelial function measured in offspring of high-risk pregnancy in humans, opening a new window of therapeutic research.This work was supported by The British Heart Foundation and The Royal Society. DG is Professor of Cardiovascular Physiology & Medicine at the Department of Physiology Development & Neuroscience at the University of Cambridge, Professorial Fellow and Director of Studies in Medicine at Gonville & Caius College, a Lister Institute Fellow and a Royal Society Wolfson Research Merit Award Holder.This is the final version of the article. It was first available from the American Physiological Society via http://dx.doi.org/10.14814/phy2.1261

Caracterización del daño mecánico de la aorta en condición de hipoxia

Para evaluar de manera fidedigna el riesgo de ruptura de la aorta – junto a los índices de peligrosidad de enfermedades cardiovasculares u otras condiciones extremas y los efectos de posibles tratamientos – se requiere conocer los mecanismos de daño que conducen a ésta. En este trabajo, se caracteriza el daño mecánico del tejido aórtico en condición de hipoxia, analizando numéricamente su respuesta al ser sujeto a un estado de presurización similar al inducido por un ensayo de acopado hidráulico. El comportamiento mecánico de la pared aórtica, se describe mediante un modelo de material hiperelástico con dos direcciones de isotropía transversal y un modelo de daño isótropo; ambos calibrados experimentalmente, a partir de resultados de ensayos de tracción uniaxial previamente reportados, realizados a muestras de aorta torácica de corderos expuestos a hipoxia hipobárica crónica. Se estudia un grupo tratado con melatonina, en contraste a un grupo control. Una vez calibrado el modelo constitutivo, se evalúa su desempeño en la simulación numérica del ensayo de acopado hidráulico, en la cual se analiza la respuesta cuasi-estática de una estructura – en forma de cuarto de disco, fijada en el perímetro curvo – solicitada fuera de su plano por una presión o fuerza por unidad de superficie, permanentemente normal al área de carga. Los datos experimentales y los resultados de las simulaciones numéricas indican, que un tratamiento con melatonina reduce rigidez de la aorta. Adicionalmente, las presiones asociadas al inicio del daño entregadas por la simulación del ensayo son compatibles con una condición de hipertensión arterial.Palabras clave: hiperelasticidad, daño mecánico isótropo, pared aórtica, ensayo acopado hidráulico, hipoxia.

Effect of Etidronate and Ibandronate on Cytosolic Ca2+ in HT29 and Parasite Cell Line from Echinococcus Granulosus sensu lato

Background: The bisphosphonates are synthetic analogs of pyrophosphate in which two phosphates are connected through carbon instead of oxygen. They are approved compounds for the treatment of hypercalcemia, bone diseases and they have been proposed to treat infectious diseases. Bisphosphonates’ main mechanisms of action are on calcium metabolism, inhibition of protein prenylation and on ATP synthesis. In a previous work, the antiparasitic activity of bisphosphonates on a cell line from Echinococcus granulosus, sensu lato protoscoleces, 30 µM etidronate and ibandronate have antiproliferative activity after 72 h of incubation, decreasing intracellular ATP and only etidronate increased intracellular total calcium concentration. Objective: This work studied the effect of etidronate and ibandronate on cytoplasmic ionic calcium concentration in parasitic cell line and in HT29, cell line from human colon adenocarcinoma. Methods: Ionic calcium was measured by spectrofluorometric, labeling cells with Fluo-4AM. Cells were suspended in Na+ or K+ rich buffer and two calcium salts were used Cl- or Gluc- , anion permeable and impermeable, respectively. Results: Remarkable differences between cell lines were shown with the effect of bisphosphonates on intracellular ionic calcium concentration in hyperpolarized cells and these differences were smoothed on depolarized cells, in spite of the similar cellular response to calcium salts in absence of bisphosphonates. Conclusion: The bisphosphonates, mainly etidronate, decreased intracellular ionic calcium on parasitic cells explaining other aspects of their antiproliferative effect. Results suggested that other mechanism, such as Cl- and Na+ interchange are differentially affected by bisphosphonates, depending on cell line originFil: Ferrulli, Mariana. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; ArgentinaFil: Pérez Rojo, Fernando Gabriel. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; ArgentinaFil: Granada Herrera, Lilian Andrea. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; ArgentinaFil: Maglioco, Andrea Florencia. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Roldán, Emilio A. J.. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; ArgentinaFil: Fuchs, Alicia Graciela. Universidad Abierta Interamericana. Secretaría de Investigación. Centro de Altos Estudios En Ciencias Humanas y de la Salud - Sede Buenos Aires; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud "Dr. C. G. Malbrán". Instituto Nacional de Parasitología "Dr. Mario Fatala Chaben"; Argentin

Fracturas peritrocantéricas tratadas con el clavo proximal de fémur: Técnica y resultados

El Clavo Proximal de Fémur (PFN: Proximal Femoral Nail) es un sistema de osteosíntesis desarrollado por la AO/ASIF para el tratamiento quirúrgico de las fracturas de la región trocantérea del fémur y que se basa en los principios del enclavado endomedular a cielo cerrado. Se presenta un estudio prospectivo sobre 175 fracturas de cadera tratadas con P.F.N. en nuestro servicio, con un seguimiento mínimo exigido de 1 año. El 74,3% de los casos correspondieron a mujeres y el resto a hombres. La edad media fue de 81,87 años. Las fracturas se han clasificado según la AO, siendo el subtipo más frecuentemente registrado el A2. Se realizaron controles clínicos y radiológicos a los 1, 3, 6 y 12 meses. El sistema ha permitido la movilización y la deambulación precoz en la mayoría de nuestros pacientes, al igual que la consolidación de las fracturas en un tiempo aceptable (12 semanas de media). Se analizan los resultados y las diversas complicaciones registradas, así como la capacidad de recuperación de la capacidad funcional previa. El PFN se revela como un buen sistema de osteosíntesis para las fracturas de la región trocantérea del fémur, permitiendo una carga precoz que favorece la consolidación ósea. La técnica quirúrgica no es compleja, la tasa de complicaciones técnicas registradas es aceptable y los resultados globales obtenidos son equiparables e incluso superiores, en determinados aspectos, a los obtenidos con otros sistemas de osteosíntesis disponibles en el mercado para el tratamiento de este tipo de fracturas.The PFN ("proximal femoral nail") is an osteosynthesis system developed by the AO/ASIF group for the surgical treatment of fractures of the trochanteric region of the femur, which is based on the principles of closed endomedullary nailing. A prospective study of 175 hip fractures treated with the PFN is presented, with a minimum follow-up of 1 year. 74,3% of the patients were female, the rest male. The average age was 81,87 years. Fractures were classified according to the AO system, the most common sub-type recorded being the A2. Clinical and radiographic evaluations were performed at 1, 3, 6 and 12 months. The system allowed early mobilisation and walking in the majority of our patients, along with fracture consolidation in an acceptable time period (12 weeks on average). The results and the various complications recorded are analysed. The ability to recover previous walking ability was also studied. The PFN emerges as a good system of osteosynthesis for fractures of the trochanteric region of the femur, allowing early weight-bearing which favours bone consolidation. The surgical technique is not complex, the number of complications recorded is acceptable and the overall results obtained are comparable and even superior to those obtained with other osteosynthesis systems available on the market for treatment of this type of fracture

Tratamiento quirúrgico de las fracturas supracondíleas de húmero en la infancia

Presentamos un estudio retrospectivo de 130 niños tratados quirúrgicamente por fractura supracondílea desplazada de húmero. Todos los pacientes tuvieron un seguimiento de al menos 12 meses. Utilizando la clasificación de Gartland, el 16% fueron tipo II (21/130) y el 84% (109/130) tipo III. En 6 casos hubo ausencia de pulso radial, que se recuperó en 4 casos tras la reducción y estabilización de la fractura. El 70% (91/130) fueron tratados con agujas de Kirschner cruzadas. Se estudiaron los resultados siguiendo los criterios de Flynn, siendo éstos satisfactorios en el 85% (111/130). Hubo 6 fallos de reducción cerrada en el quirófano que requirieron reducción abierta. La secuela más frecuente fue el cúbito varo, en 9 casos, y 3 niños tenían cúbito valgo, con escasa repercusión funcional. El nervio más comúnmente afectado, tras el tratamiento quirúrgico, fue el mediano (5 casos) y el cubital (5 casos), con neuroapraxia resuelta en 6 meses salvo en un caso.A retrospective review of 130 children treated surgically for displaced supracondylar humeral fractures was conducted. All patients had a minimum of 12 months follow-up. According to Gartland classification, 16% were type II (21/130) and 84% (111/130) type III. A lack of radial pulse was reported in 6 cases, with a total recovery after the reduction and stabilization of the fracture, except in 2 cases. 70% (91/130) were treated with crossed Kirschner wires. The results were studied following Flynn criteria, 85% (111/130) were considered satisfactory. There were 6 failed closed reductions in the operating room, that required open reduction. The most frequent permanent damage was cubitus varus in 9 cases, and 3 children had cubitus valgus, but with little functional impairment. During the surgery, the most commonly affected nerve was median (5 cases) and ulnar (5 cases), with neurapraxias mostly recovered in 6 months