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

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

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.

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

Assessment of in vivo fetal growth and placental vascular function in a novel intrauterine growth restriction model of progressive uterine artery occlusion in guinea pigs

Intra-uterine growth restriction (IUGR) is associated with short and long-term metabolic and cardiovascular alterations. Mice and rats have been extensively used to study the effects of IUGR, but there are notable differences in fetal and placental physiology relative to those of humans that argue for alternative animal models. This study proposes that gradual occlusion of uterine arteries from mid-gestation in pregnant guinea pigs produces a novel model to better assess human IUGR. Fetal biometry and in vivo placental vascular function were followed by sonography and Doppler of control pregnant guinea pigs and sows submitted to surgical placement of ameroid constrictors in both uterine arteries (IUGR) at mid-gestation (35 days). The ameroid constrictors induced a reduction in the fetal abdominal circumference growth rate (0.205 cm day-1) compared to control (0.241 cm day-1, P \u3c 0.001) without affecting biparietal diameter growth. Umbilical artery pulsatility and resistance indexes at 10 and 20 days after surgery were significantly higher in IUGR animals than controls (P \u3c 0.01). These effects were associated with a decrease in the relative luminal area of placental chorionic arteries (21.3 ± 2.2% vs. 33.2 ± 2.7%, P \u3c 0.01) in IUGR sows at near term. Uterine artery intervention reduced fetal (∼30%), placental (∼20%) and liver (∼50%) weights (P \u3c 0.05), with an increased brain to liver ratio (P \u3c 0.001) relative to the control group. These data demonstrate that the ameroid constrictor implantations in uterine arteries in pregnant guinea pigs lead to placental vascular dysfunction and altered fetal growth that induces asymmetric IUGR

Assessment of in vivo fetal growth and placental vascular function in a novel intrauterine growth restriction model of progressive uterine artery occlusion in guinea pigs

Intra-uterine growth restriction (IUGR) is associated with short and long-term metabolic and cardiovascular alterations. Mice and rats have been extensively used to study the effects of IUGR, but there are notable differences in fetal and placental physiology relative to those of humans that argue for alternative animal models. This study proposes that gradual occlusion of uterine arteries from mid-gestation in pregnant guinea pigs produces a novel model to better assess human IUGR. Fetal biometry and in vivo placental vascular function were followed by sonography and Doppler of control pregnant guinea pigs and sows submitted to surgical placement of ameroid constrictors in both uterine arteries (IUGR) at mid-gestation (35 days). The ameroid constrictors induced a reduction in the fetal abdominal circumference growth rate (0.205 cm day-1) compared to control (0.241 cm day-1, P \u3c 0.001) without affecting biparietal diameter growth. Umbilical artery pulsatility and resistance indexes at 10 and 20 days after surgery were significantly higher in IUGR animals than controls (P \u3c 0.01). These effects were associated with a decrease in the relative luminal area of placental chorionic arteries (21.3 ± 2.2% vs. 33.2 ± 2.7%, P \u3c 0.01) in IUGR sows at near term. Uterine artery intervention reduced fetal (∼30%), placental (∼20%) and liver (∼50%) weights (P \u3c 0.05), with an increased brain to liver ratio (P \u3c 0.001) relative to the control group. These data demonstrate that the ameroid constrictor implantations in uterine arteries in pregnant guinea pigs lead to placental vascular dysfunction and altered fetal growth that induces asymmetric IUGR