Long-lasting cardiovascular responses to gestation at high altitude: lessons from a sheep model.

Adaptations of maternal and fetal cardiovascular physiology may be most important when there are unfavourable environmental conditions during pregnancy, such as hypoxia when living at high altitudes. Chronic hypobaric hypoxia during intrauterine development may permanently modify fetal organ function, conditioning an increased risk for cardiovascular adult diseases. This review summarizes our 20 years of work on a sheep model assessing the impact of high-altitude hypoxia on the offspring's cardiovascular development and function at fetal, neonatal and adult stages.

The perinatal llama immersed in the thin oxygen of the Andean Altiplano.

The llama fetus shows specific adaptations to the challenge of low oxygen levels in the Andean Altiplano. Lowland fetal mammals like sheep respond to hypoxia with a brain-sparing effect, which increases cerebral blood flow at the expense of peripheral vasoconstriction. Fetal peripheral vasoconstriction is triggered by a carotid chemoreflex and maintained by constrictor hormones like catecholamines and neuropeptide Y, as well as local vascular responses.

The role of agitated saline contrast echocardiography in the evaluation of pulmonary hypertension.

The diagnostic approach to pulmonary hypertension using cardiac imaging, particularly echocardiography, provides a practical, accessible, and highly valuable tool. It helps establish the initial diagnostic probability, offers prognostic information, and supports aetiological assessment. The agitated saline contrast test, also referred to as bubble contrast echocardiography, can aid not only in confirming the diagnosis but also in characterising the condition and identifying various underlying causes of pulmonary hypertension.

Redox Imbalance Is Associated with Neuronal Apoptosis in the Cortex of Neonates Gestated Under Chronic Hypoxia.

Gestational chronic hypoxia impacts prenatal development, leading to fetal growth restriction (FGR), defined as the fetus's failure to reach its genetic growth potential. Postnatal hypoxia in the cerebral tissue can induce a redox imbalance and mitochondrial dysfunction, consequently increasing neuronal death. However, these data cannot necessarily be extrapolated to prenatal hypoxia.

Melatonin Improves Quality of Life, Oxidative Stress, and Cardiovascular Function in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) Group 1 from the World Health Organization (WHO) is a rare, severe chronic, and progressive condition. Patients with PAH have increased oxidative stress (OS) and diminished antioxidant capacity. Melatonin is a potent antioxidant hormone with reported benefits in PAH animal models.

Assessment of the passive viscoelastic response of aortic tissue from guinea pigs subjected to hypobaric hypoxia.

Aims: The long-term effect of high altitude hypoxia (HAH) exposure is a relevant problem in cardiovascular biomechanics, that has not yet been fully assessed. Regarding this, the study examined the passive viscoelastic response of the descending thoracic aorta of individuals exposed to HAH.

Main Methods: Through a guinea-pig animal model, subjected to either normoxic-normobaric or HAH conditions (groups N and H, respectively), biaxial tensile and uniaxial stress relaxation tests were performed on artery samples.

Biomechanical and histomorphometric characterization of the melatonin treatment effect in the carotid artery subjected to hypobaric hypoxia.

This study aims to assess the efficacy of melatonin in mitigating the adverse effects of hypobaric hypoxia on the cardiovascular system of neonatal lambs (30 days old). Two groups were considered for this purpose: (i) Melatonin-treated group (N = 5) and (ii) Control group (N = 6) without treatment. All subjects were exposed to hypobaric hypoxia during gestation and perinatal periods, with melatonin administered after birth.

Characterization of mechanical damage and viscoelasticity on aortas from guinea pigs subjected to hypoxia.

To reliably assess the rupture risk of the aorta, along with the hazardousness of cardiovascular diseases and other extreme conditions or the effect of possible treatments, it is necessary to understand the influence of damage mechanisms along with the frequency and rate of mechanical loads. In particular, hypobaric hypoxia, an oxygen deficiency in the organism due to its low atmospheric partial pressure, is reported to alter the mechanical properties of blood vessels. In this work, we characterized the passive mechanical response of the aorta, seeking to capture the influence of hypoxia on their elastic, damage, and viscoelastic properties under ex-vivo conditions.

Effect of melatonin on passive, ex-vivo biomechanical behavior of lamb esophagus.

One of the purposes of tissue engineering is to offer therapeutic alternatives to treat various esophagus-related diseases. To develop viable esophageal replacements that are both mechanically and biologically compatible and to assess the impact of pharmacological treatments on esophageal tissue at the macro- and micro-structural levels, it is crucial to understand the biomechanical properties of the esophagus. In this study, we analyzed esophageal tissue samples from nine newborn lambs.

Antenatal Vitamin C differentially affects lung development in normally grown and growth restricted sheep.

Background: Chronic hypoxemia is a common cause of fetal growth restriction and can have significant effects on the developing fetal lung. Maternal antioxidant treatment in hypoxic pregnancy protects against offspring cardiovascular dysfunction. The effects of antenatal antioxidants on lung development in the chronically hypoxic growth restricted fetus is unknown.

Gestational hypoxia elicits long-term cardiovascular dysfunction in female guinea pigs.

Background: Gestational hypoxia (GH) has been implicated in the developmental programming of cardiovascular diseases (CVDs) in the offspring, with most studies focusing on males, conversely, the effects on female cardiovascular health remain understudied. We aimed to investigate the impact of GH on the cardiovascular system of female guinea pig offspring from the early postnatal period to adulthood.

Methods: Pregnant guinea pigs were subjected to normoxic or hypoxic conditions from gestational day 30 until delivery (∼70 days).

Biomechanical effects of hemin and sildenafil treatments on the aortic wall of chronic-hypoxic lambs.

Gestation under chronic hypoxia causes pulmonary hypertension, cardiovascular remodeling, and increased aortic stiffness in the offspring. To mitigate the neonatal cardiovascular risk, pharmacological treatments (such as hemin and sildenafil) have been proposed to improve pulmonary vasodilation. However, little is known about the effects of these treatments on the aorta.

Obesogenic Diet in Mice Leads to Inflammation and Oxidative Stress in the Mother in Association with Sex-Specific Changes in Fetal Development, Inflammatory Markers and Placental Transcriptome.

Background: Obesity during pregnancy is related to adverse maternal and neonatal outcomes. Factors involved in these outcomes may include increased maternal insulin resistance, inflammation, oxidative stress, and nutrient mishandling. The placenta is the primary determinant of fetal outcomes, and its function can be impacted by maternal obesity.

[Paravalvular leak closure using devices: a useful resource].

We present the case of a patient with a paravalvular leak of mechanical prosthesis in aortic position. Due to a recent previous surgery, it was decided to perform a percutaneous repair to reduce perioperative risk, under an off-label indication using a device for ventricular septal defect closure, successful and without complications in the follow-up.

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.

Dietary Implications of Polyunsaturated Fatty Acids during Pregnancy and in Neonates.

Certain limitations exist for animals to modify fatty acid changes. Besides the role of arachidonic acid (AA), docosahexaenoic acid (DHA) and other 20-carbon long-chain polyunsaturated fatty acids (LCPUFAs) for the synthesis of inflammatory mediators as eicosanoids, different LCPUFAs have many other effects, including their abilities to regulate gene expression and downstream events. LCPUFAs are susceptible to autoxidation, which is prevented by the action of antioxidants in the form of enzymes like superoxide dismutases, catalases and peroxidases, as well as antioxidant compounds that protect against oxidation or repair the damage caused.

Chronic intermittent hypobaric hypoxia induces cardiovascular dysfunction in a high-altitude working shift model.

Aims: Chronic intermittent hypobaric hypoxia (CIHH) exposure due to shift work occurs mainly in 4 × 4 or 7 × 7 days shifts in mining, astronomy, and customs activities, among other institutions. However, the long-lasting effects of CIHH on cardiovascular structure and function are not well characterized. We aimed to investigate the effects of CIHH on the cardiac and vascular response of adult rats simulating high-altitude (4600 m) x low-altitude (760 m) working shifts.

Combined Statin and Glucocorticoid Therapy for the Safer Treatment of Preterm Birth.

Background: Prematurity is strongly associated with poor respiratory function in the neonate. Rescue therapies include treatment with glucocorticoids due to their anti-inflammatory and maturational effects on the developing lung. However, glucocorticoid treatment in the infant can increase the risk of long-term cardiovascular complications including hypertension, cardiac, and endothelial dysfunction.

Hyperelastic and damage properties of the hypoxic aorta treated with Cinaciguat.

Chronic hypoxia during gestation and postnatal period induces pulmonary hypertension, aorta stiffening and vascular remodeling. In this study, we hypothesized that a postnatal treatment with Cinaciguat, a guanylate cyclase activator, may improve the vascular function by enhancing NO-sGC pathways that induce vasodilation. To assess this, we collected aortas from six lambs gestated, born and raised at 3600 masl.

Relationship of ANGPTL6 With Neonatal Glucose Homeostasis and Fat Mass Is Disrupted in Gestational Diabetic Pregnancies.

Context: Angiopoietin-like protein 6 (ANGPTL6) is a hepatokine, which, in animal studies, improves insulin sensitivity and increases energy expenditure to counteract insulin resistance.

Objective: Evaluate in a human population, the role of serum ANGPTL6 in gestational diabetes mellitus (GDM) or its presence in fetal circulation.

Research Design And Methods: A total of 190 women (115 controls and 75 GDM) and their offspring were studied.

Cardioprotective Antioxidant and Anti-Inflammatory Mechanisms Induced by Intermittent Hypobaric Hypoxia.

More than 80 million people live and work (in a chronic or intermittent form) above 2500 masl, and 35 million live in the Andean Mountains. Furthermore, in Chile, it is estimated that 100,000 people work in high-altitude shifts, where stays in the lowlands are interspersed with working visits in the highlands. Acute exposure to high altitude has been shown to induce oxidative stress in healthy human lowlanders due to increased free radical formation and decreased antioxidant capacity.

Cinaciguat (BAY-582667) Modifies Cardiopulmonary and Systemic Circulation in Chronically Hypoxic and Pulmonary Hypertensive Neonatal Lambs in the Alto Andino.

Neonatal pulmonary hypertension (NPHT) is produced by sustained pulmonary vasoconstriction and increased vascular remodeling. Soluble guanylyl cyclase (sGC) participates in signaling pathways that induce vascular vasodilation and reduce vascular remodeling. However, when sGC is oxidized and/or loses its heme group, it does not respond to nitric oxide (NO), losing its vasodilating effects.

Melatonin treatment during chronic hypoxic gestation improves neonatal cerebrovascular function.

Background: Fetal chronic hypoxia is associated with blood flow redistribution and oxidative damage in the brain, leading to increased perinatal morbimortality. Melatonin reduces oxidative stress, improves vascular function, and has neuroprotective effects.

Objectives: This study aimed to determine the effects of an oral melatonin treatment to pregnant ewes at high-altitude, on the cerebrovascular function of their neonates.