Pregnancy at high altitude

16 - 17 September 2024 09:00 - 17:00 Old Divinity School, Cambridge Free Watch online
Book event
Peruvian mother walking with child

Discussion meeting organised by Professor Graham J Burton FMedSci FRS, Professor Dino A Giussani, Professor Lorna Moore and Professor Andrew J Murray

Hypobaric hypoxia experienced at high altitude places additional stress on the mother and her fetus during pregnancy. We will explore contrasting physiological adaptations in different ethnic populations to this experiment-of-nature that help maintain fetal oxygen delivery, sustaining growth and long-term health. Insights generated will inform interventions to mitigate fetal hypoxia caused by complications of pregnancy at sea level.

Poster session

There will be posters displayed for the duration of the meeting. If you would like to present a poster, please submit your proposed title, abstract (up to 200 words), author list, and the name of the proposed presenter and institution to the Scientific Programmes team no later than Friday 31 May 2024.

Programme

The programme, including the speaker biographies and abstracts, will be available soon.

Attending the meeting

This event is free to attend and intended for researchers in the field. Please note that this meeting will be taking place in Cambridge and not at the Royal Society.

  • Both virtual and in-person attendance is available, but advance registration is essential. Registration will open soon.
  • Lunch is available on both days of the meeting and is optional. There are plenty of places to eat nearby if you would prefer to purchase food offsite.

Enquiries: contact the Scientific Programmes team

Image credit: iStock @hadynyah

Schedule

Chair

Graham J Burton

Graham J Burton, University of Cambridge, UK

09:00-09:05 Welcome by the Royal Society and lead organiser
09:05-09:30 Introduction and overview

Introduction and overview: Reproductive success, the driver of evolution, requires the coordinated responses of maternal, placental, and fetal physiology.

Pregnancy requires the coordinated functioning of maternal, placental, and fetal systems yet often one is studied in the absence or at least near exclusion of the others. Of the three, perhaps that least often studied is that of the mother who, clearly, is the one who is pregnant and in whom conception and hence some of the earliest physiological responses that are required. We speculate that the reasons for this oversight go back to ideas of homunculus as well as to the important, early pregnancy physiology studies conducted, of note, at high altitude by Joseph Barcroft, John S Haldane, and Donald Barron. These investigations, stimulated by the recognition that the obligatory fall in atmospheric pO2 made high altitude a natural laboratory for understanding the physiological responses required for defending oxygen and the other nutrient supply required for normal pregnancy outcomes, focused nearly exclusively on fetal and to a lesser extent placental systems. Such limitations are being filled, as the presentations to follow will show, but others remain to be filled by hopefully, you the conference attendees.

Professor Lorna G Moore, University of Colorado, Anschutz Medical Campus, USA

Professor Lorna G Moore, University of Colorado, Anschutz Medical Campus, USA

09:30-09:45 Discussion
09:45-10:15 Defining the risks of pregnancy at high altitude through meta-analysis of population-based studies

Globally, the likelihood of adverse perinatal outcomes, including low birth-weight, small-for-gestational age, spontaneous preterm birth and pregnancy loss, increases in high-altitude pregnancies. The aim of these studies was to quantify the risk across global settings and relationship with altitude via meta-regression.

59 studies were included in the analysis (n =1,604,770 pregnancies). Data were abstracted according to PRISMA guidelines, and were pooled using random-effects models. The risk of low birth weight (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.33-1.62, P < 0.001), small-for-gestational age (OR 1.88, CI 1.08-3.28, P = 0.026), and spontaneous preterm birth (OR 1.23, CI 1.04-1.47, P = 0.016) were all increased in high- versus low-altitude pregnancies. Birth weight decreases by 54.7 g (±13.0 g, P <0.0001) per 1000 m increase in altitude. Average gestational age at delivery was not significantly different.

Based on the risk of late pregnancy loss was increased in high altitude pregnancies. The likelihood of stillbirth was increased by 63% in pregnancies at high altitude compared with low altitude (odds ratio, 1.63 [1.12-2.35]; P <0.01). Using an observational cohort from Bolivia (n=5386), a strong effect of maternal ancestry on the risk of early miscarriage was shown; Andean women were 24% less likely to have ever experienced a miscarriage compared to European women (OR 0.76; CI:0.62-0.90, P <0.001).

With a growing population residing at high altitude worldwide, it is essential to clearly define the associated risk of adverse pregnancy outcomes for women in different settings.

Professor Catherine Aiken, University of Cambridge, UK

Professor Catherine Aiken, University of Cambridge, UK

10:15-10:30 Discussion
10:30-11:00 Break
11:00-11:30 Genetic adaptations in high-altitude populations

Advancements in genetic research have greatly enhanced our understanding of how humans adapt to high-altitude environments. This progress is primarily due to the development of high-throughput genotyping and powerful genome-wide tests that identify positive selection that has occurred throughout hundreds of generations in humans. Researchers have pinpointed specific genetic markers, including those within the hypoxia-inducible factor (HIF) pathway, that are crucial for adaptation to low oxygen levels in both humans and other highland species. For instance, EPAS1/HIF2A, a key player in the HIF pathway, is linked to haemoglobin concentration in individuals of Tibetan ancestry living at high altitude. Through our recent investigations, we established a connection between a particular adaptive variant of EPAS1 and similar, relatively lower haematocrit levels in a separate high-altitude group in the Andes. This variant is present at a moderate frequency in Andeans and nearly absent in other human populations and vertebrate species. Using advanced gene-editing techniques, we have observed changes in gene expression related to low oxygen levels in human cells with this putatively adaptive variant and provide further functional support from metabolomic analyses. While a relatively low haemoglobin concentration/haematocrit is observed in many Tibetan and some Andean highlanders, the underlying genetic mechanisms likely differ due to distinct non-coding and coding variants identified, respectively, in each group. Our recent studies provide further evidence for genomic signatures of high-altitude adaptation relevant to lowland individuals with implications for understanding hypoxia responses in health and disease.

Tatum S Simonson, University of California San Diego School of Medicine, USA

Tatum S Simonson, University of California San Diego School of Medicine, USA

11:30-11:45 Discussion
11:45-12:15 Genomic selection signals in Andean highlanders reveal adaptive placental metabolic phenotypes that are disrupted in preeclampsia

Background

Exposure to high altitude during pregnancy alters placental metabolism and increases the incidence of placental pathologies associated with fetal growth restriction (FGR), including preeclampsia. High-altitude ancestry protects against altitude-associated FGR, indicating hypoxia tolerance that is genetic in nature. Yet not all babies are protected and preeclampisa occurs in some Andean highlanders. Here, links are presented between genomic selection signals and placental metabolic phenotypes in Andean highlanders as well as phenotypic differences in preeclampisa vs control.

Methods

The study cohort included 79 Andeans (18-45y; 39 preeclamptic, 40 normotensive) living in La Paz, Bolivia (3600 - 4100m) delivered by unlabored C-section. Genotyping was performed using a 1.8 million SNP Multiethnic Genotyping Array. Mitochondrial oxidative metabolism was examined in cryopreserved villous placental samples using the Oxygraph-2K. Abundance of fatty acid derivatives acyl carnitines was examined using ultra-high-pressure liquid chromatography-mass spectrometry.

Results

A maternal haplotype within PTPRD associated with lower placental mitochondrial respiratory capacity. Mitochondrial oxidative capacity associated with fetal oxygen delivery in normotensive but not preeclamptic placenta and was also suppressed in term preeclamptic pregnancy. A fetal haplotype within 200kb of CPT2 associated with increased abundance of placental short chain acyl carnitines. In preeclamptic pregnancy, the abundance of placental  medium and long chain carnitines was increased in preeclampsia vs. control.

Conclusions

These findings reveal novel associations between putatively adaptive gene regions and phenotypes linked to placental metabolic function in highland Andeans. They also demonstrate maladaptive metabolic mechanisms in the context of preeclampsia, including dysregulation of placental oxygen consumption and disruption of fatty acid oxidation.

Dr Katie O’Brien, University of Colorado Anschutz, USA

Dr Katie O’Brien, University of Colorado Anschutz, USA

12:15-12:30 Discussion

Chair

Professor Abigail Fowden

Professor Abigail Fowden, University of Cambridge, UK

13:30-14:00 Maternal cardiovascular adaptations to pregnancy
14:00-14:15 Discussion
14:15-14:45 The uteroplacental circulation at high altitude

The maternal cardiovascular system undergoes widespread adaptations during pregnancy that collectively increase uteroplacental blood flow, a process critical for maintaining sufficient fetal oxygen and nutrient supply. Insufficient hemodynamic adaptation to pregnancy is linked to fetal growth restriction and preeclampsia, each a major contributor to maternal and offspring morbidity and mortality across the lifespan. Chronic exposure to the environmental hypoxia of high altitudes ( 2500 m) impairs maternal vascular adaptation to pregnancy, restricting expansion of uterine artery diameter, limiting redistribution of cardiac output to favor the uteroplacental circulation, and blunting the pregnancy-associated fall in blood pressure. Dampened relaxation of uteroplacental resistance vessels has also been identified as an important determinant of restricted uteroplacental blood flow at high altitudes. The increased incidence of fetal growth restriction observed at high altitudes has been attributed to diminished uterine blood flow; however, the lower uterine blood flow alone cannot be solely responsible for reduced fetal growth because uterine oxygen supply exceeds the sum of placental and fetal oxygen consumption. This suggests the involvement of metabolic factors. Integrated genomic, transcriptomic, and physiological studies point to a key role for the adenosine monophosphate kinase signaling pathway, which is hypothesized to serve as a nexus between uteroplacental perfusion and metabolism under conditions of chronic hypoxia, regulating fetal growth through dual roles as a potent vasodilator and regulator of cellular energy homeostasis. Ongoing studies aiming to fill critical knowledge gaps by establishing how uteroplacental oxygenation, perfusion and metabolism interact to regulate fetal growth will also be discussed.

Colleen G Julian, University of Colorado, USA

Colleen G Julian, University of Colorado, USA

14:45-15:00 Discussion
15:00-15:30 Break
15:30-16:00 AMPK function in uterine vasculature and placenta at high altitude

The chronic hypoxia of residence at high altitude (HA, >2500m) reduces uterine artery (UtA) blood flow, contributing to an increased frequency of fetal growth restriction (FGR). FGR pregnancies at low altitudes (LA, <1700m) have reduced UtA blood flow, partially due to impaired myometrial artery (MyoA) vasodilation. Studies in Andeans, who are protected from HA-associated reductions in fetal growth, detected an association between genetic variants predicted to activate the AMP-activated protein kinase (AMPK) pathway and increased birth weight. Our wire myography studies have shown that AMPK-dependent vasodilator responses are augmented in MyoA from women at HA with uncomplicated pregnancies compared to LA and reduced in FGR pregnancies regardless of altitude. We also observed an increase in the phosphorylation levels of AMPK, as an indicator of augmented activation, and the expression of downstream targets in placentas from uncomplicated pregnancies at HA and LA compared to sea-level residents. These findings suggest a role for AMPK in vasodilating MyoA at HA and in the impaired vasodilation of MyoA in FGR pregnancies. Furthermore, placental AMPK seems to play a role in adapting placental function in uncomplicated HA pregnancy. Future studies will aim to elucidate the mechanisms underlying the altitude-dependent activation of AMPK in uncomplicated pregnancies and its reduction in FGR.

Doctor Ramón A Lorca, University of Colorado Anschutz Medical Campus, USA

Doctor Ramón A Lorca, University of Colorado Anschutz Medical Campus, USA

16:00-16:15 Discussion
16:15-16:45 Mitochondrial responses to hypoxia in healthy and pathological placentas at high altitude

Ascent to high altitude is accompanied by physiological responses that, to an extent, mitigate the challenge of hypobaric hypoxia, maintaining arterial oxygen content and convective oxygen delivery. Nevertheless, arterial oxygen tension remains low and tissue hypoxia persists, posing a challenge for metabolic and redox homeostasis, as well as function. At high altitude, a suppression of placental respiratory capacity and switch to glycolytic ATP production occurs downstream of hypoxia-inducible factor (HIF) stabilization. This may play an adaptive role to protect oxygen tension in the fetal circulation, albeit at the cost of greater placental glucose utilization. As such, this can result in compromised cellular energetics and is associated with lower birth weight. Studies in human populations of highland ancestry have revealed physiological traits, underpinned by genetic variants, that have undergone selection, and which allow people to live, work, and reproduce at high altitude. Notably, placental metabolic adaptations form a vital component of an integrated response that supports healthy pregnancies in highlander populations at altitude. Moreover, in the case of preeclampsia, both at sea level and in high-altitude populations, mitochondrial abnormalities are associated with the redox stress of ischemia/reperfusion, and may play a role in the pathology. Indeed, maternal and fetal genetic signals associated with outcomes implicate a vital role for mitochondria and substrate metabolism in the relative protection against preeclampsia in highlander populations. Placental metabolic responses to tissue hypoxia therefore have important implications for pregnancies both at high altitude and more generally, being associated with outcomes in healthy pregnancies and in those with common complications.

Professor Andrew Murray, University of Cambridge, UK

Professor Andrew Murray, University of Cambridge, UK

16:45-17:00 Discussion
17:00-17:30 Nutrient shuttles and crosstalk between the fetal liver and placenta

The liver is both a privileged and vulnerable site of metabolism in the fetus because it is directly exposed to nutrients, oxygen, and signals incoming from the placenta via the umbilical venous blood. During placental insufficiency-induced fetal growth restriction (FGR), the fetal liver responds to this incoming milieu with early activation of hepatic glucose production and lower oxidative metabolism with increased lactate production, increased pyruvate output, and decreased glutamate output. Moreover, there are 3 reciprocal shuttles between the fetal liver and placenta whereby, under normal conditions, the fetal liver takes up lactate, glutamine, and glycine from the placenta, and releases pyruvate, glutamate, and serine back to the placenta. However, during FGR there is increased placental utilisation of pyruvate from the fetus, without higher maternal glucose utilisation, and lower fetoplacental amino acid shuttling. Here, we will present an integrative view to explain how fetal hepatic metabolic adaptive responses to hypoxia during FGR compared to normal pregnancy conditions may provide benefits to both the placenta to sustain oxidative metabolism and extrahepatic fetal tissues to defend their rates of oxidative metabolism and growth. This highlights the importance of bidirectional nutrient shuttles and communication between the placenta and fetus.

Doctor Stephanie Wesolowski, University of Colorado, USA

Doctor Stephanie Wesolowski, University of Colorado, USA

17:30-17:45 Discussion
09:00-09:30 Fetal growth at high altitude

The compelling evidence linking small size at birth with later cardiovascular disease has renewed and amplified scientific and clinical interests into the determinants of fetal growth. High altitude pregnancy has long been known to increase the incidence of fetal growth restriction and reduced birth weight. This poses a significant clinical challenge as both are linked to adverse health outcomes, including raised infant mortality and the development of cardiometabolic disorders in later life. While this reduction in birth weight is mostly understood to be driven by the hypobaric hypoxia of high altitude, the causative mechanism is unclear. Moreover, it is now recognised that highland ancestry confers protection against this reduction in birth weight, but again underlying mechanisms are unclear. The work will discuss a cohort of ca. 25,000 birth records from Bolivia of men and women of European and Andean ancestry who are currently adults and compare findings with the effect of high-altitude incubation of chicken embryos developing in eggs laid by hens of varying high altitude residence ancestry. We will present recent findings showing that embryonic development at high altitude promotes cardiac oxidative and inflammatory stress and activates cellular, endoplasmic reticulum and mitochondrial markers of the unfolded protein response, and that highland ancestry confers protection.

Professor Dino A Giussani, University of Cambridge, UK

Professor Dino A Giussani, University of Cambridge, UK

09:30-09:45 Discussion
09:45-10:15 Placental uptake and consumption of glucose and oxygen- a human model

The principal fetal energy source is glucose provided by placental transfer of maternal glucose. Fetal overgrowth is a major clinical challenge in obstetrics and is closely linked to maternal obesity and gestational diabetes mellitus. A clinical conundrum is that the fetus is more prone to overgrowth in diabetic pregnancies even when maternal glucose levels are well controlled. Placental transport and handling of glucose is therefore a crucial process for fetal development and growth. However, based on our findings, the placenta’s own glucose consumption exhibits considerable variation. To study placental glucose metabolism, we have developed the 4 vessel sampling method. Mass of glucose taken up by the uteroplacental unit and the fetus was obtained by measuring arterio-venous glucose differences combined with Doppler assessment of uterine and umbilical blood flow. Blood samples were obtained from maternal radial artery, uterine vein and umbilical artery and vein at scheduled caesarean delivery. The uteroplacental glucose consumption constituted the difference between uteroplacental and fetal glucose uptake. Oxygen gradients were obtained by comparing oxygen concentrations in artery and vein on both sides of the placenta. We will present recent findings describing glucose metabolism in the placental and fetal compartments including support for aerobic glycolysis in the placenta and a possible fetal-maternal lactate ketone trade.

Dr Trond M Michelsen, University of Oslo, Norway

Dr Trond M Michelsen, University of Oslo, Norway

10:15-10:30 Discussion
10:30-11:00 Break
11:00-23:30 Fetal physiology in high-altitude species (online talk)

In the Andean Altiplano, where the air thins and oxygen becomes scarce, the fetal llama navigates a delicate balance. Adapted to the high-altitude environment, it faces not only the challenge of low fetal arterial oxygen levels shared by all species but also an additional layer of maternal hypoxia, by the Altiplano’s low oxygen. This dual hypoxic burden, a hypoxia within another hypoxia, demands remarkable adaptations. When acute hypoxia strikes, the fetal llama responds with precision. The marked peripheral vasoconstriction, orchestrated by alpha-adrenergic mechanisms, may participate in the preconditioning of the llama several organs. Elevated plasma catecholamines and NPY further fine-tune this mechanism. Endothelial factors, including nitric oxide (NO) and endothelin-1, modulate local blood flows, maintaining equilibrium. Unlike lowland species, the fetal llama’s cerebral response to hypoxia is unique. It downshifts cerebral metabolism, reducing oxygen consumption, Na-K-ATPase activity, and temperature. Remarkably, this adjustment occurs without cerebral damage. In the realm of pulmonary circulation, the neonatal llama defies expectations. No pulmonary hypertension afflicts this high-altitude old dweller. Their enhanced HO-CO pathway outpaces neonatal sheep at the same elevation. The NO pathway, too, plays a pivotal role during acute hypoxia. Lower asymmetric dimethylarginine (ADMA) plasma concentrations and reduced arginase II activity in lung parenchyma enhance NO availability in the llama neonate. Pulmonary vessels dilate, ensuring optimal oxygen exchange. In contrast, newborn sheep rely mainly on their eNOS-NO system, falling short in preventing pulmonary artery hypertension. With poise, the llama fetus and neonate thrive in the rarefied oxygen trail of the Andean Altiplano.

Professor Anibal J Llanos, Faculty of Medine University of Chile, Chile

Professor Anibal J Llanos, Faculty of Medine University of Chile, Chile

11:30-11:45 Discussion
11:45-00:15 Gestation at high altitude and programming of maternal, fetal and newborn vascular function

Hypoxia is one of the most common and severe stresses to an organism’s homeostatic mechanisms, and hypoxia during gestation has profound adverse effects on maternal health and developmental plasticity. Gestational hypoxia is associated with a high incidence of clinical complications including pre-eclampsia and intrauterine growth restriction (IUGR). Both human and animal studies have revealed a causative role of increased uterine vascular resistance and lowered uterine blood flow in pre-eclampsia and IUGR. Our research strategy takes advantage of a unique animal model of pregnant sheep acclimatised to high altitude (3801 m/12,470 ft) hypoxia. This model has been well-established and extensively studied by a one-of-a-kind team of investigators at Loma Linda University over the past 40 years, and it is a unique animal model to investigate cardiovascular and metabolic complications of pregnancy and developmental plasticity of cardiovascular disease associated with chronic hypoxia during gestation. We demonstrated that high altitude hypoxia suppressed pregnancy-induced uterine arterial adaptation and increased uterine vascular resistance and systemic blood pressure in pregnant sheep. In addition, we showed that gestational hypoxia at high altitude elevated pulmonary vascular resistance and increased pulmonary artery pressure and pressure response to acute hypoxia in newborn lambs. Furthermore, we revealed that fetal hypoxia impaired cerebral blood flow autoregulation in the neonate. Our study is a broadly based, multidisciplinary, integrated research programme and provides new insights into the understanding of pathophysiological mechanisms underlying pregnancy complications including pre-eclampsia and increased risk of pulmonary hypertension and intraventricular haemorrhage in newborns associated with gestational hypoxia.

Professor Lubo Zhang, Loma Linda University School of Medicine, USA

Professor Lubo Zhang, Loma Linda University School of Medicine, USA

12:15-12:30 Discussion

Chair

Professor Anna David

Professor Anna David, Elizabeth Garrett Anderson Institute for Women’s Health, University College London, UK

13:30-14:00 The hypoxic fetus as a patient

Fetal oxygen and glucose delivery and uptake are the main drivers of fetal growth. The placenta is the centre of physiological exchange of oxygen, nutrients and metabolic waste between mother and fetus. 

Many hypoxic FGR fetuses are the result of what is simplified as intrauterine «asphyxia». The factors governing the adequacy of placental function, particularly respiratory gas exchange, assume great importance in order to understand pathophysiological mechanisms of pregnancy pathologies. The possibility to measure umbilical uptake in human pregnancies has been developed in recent years by the potential to calculate umbilical blood flow through US measurements and then utilise the values of oxygenation from the umbilical artery and vein obtained at caesarean section. In normal fetuses, oxygen delivery is strikingly similar to that of other animal species, on a per kg basis. The human FGR fetus shows a strikingly reduced umbilical uptake of both oxygen and glucose. Specifically, there is significantly lower umbilical oxygen delivery and uptake, both as absolute values (delivery:–78%; uptake: –78%) and normalised (delivery:–50%; uptake: –48%) for fetal body weight. Umbilical glucose uptake is also significantly reduced (–72%) also when normalised for fetal body weight (–30%). The glucose/oxygen quotient is significantly increased (+100%) while glucose clearance is significantly decreased (71%) in FGR pregnancy.  The human fetus in FGR pregnancy triggers adaptive mechanisms to reduce its metabolic rate, matching the proportion of substrate consumption relative to oxygen delivery as a survival strategy during complicated pregnancy.

Professor Irene Cetin, University of Milan, Italy

Professor Irene Cetin, University of Milan, Italy

14:00-14:15 Discussion
14:15-14:45 Gestation at high altitude and programming of maternal, fetal and newborn vascular function

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 altitude. Chronic hypobaria during intrauterine development may permanently modify fetal organs function, conditioning an increased risk for cardiovascular adult diseases. This talk will showcase the latest work assessing the impact of high-altitude hypoxia on the offspring cardiovascular development. It will explore diverse approaches on two animal models (sheep and guinea pigs) to describe the involved mechanisms and mitigate the negative impacts of chronic hypoxia during gestation on the lifelong health of the offspring.

Professor Emilio A Herrera, Universidad de Chile, Chile

Professor Emilio A Herrera, Universidad de Chile, Chile

14:45-15:00 Discussion
15:00-15:30 Break
15:30-16:00 MitoQ therapy for programmed hypertension in adult offspring of hypoxic pregnancy

A fetal origin of heart disease in offspring of hypoxic pregnancy is well-established. However, research into preventative therapies, particularly in species with developmental milestones comparable to humans is limited, hindering clinical translation. Using sheep and chickens, which have similar cardiovascular development to humans, we combined in vivo experiments with in vitro studies at organ, cellular, mitochondrial, and molecular levels. In sheep, we assessed fetal and adult cardiovascular function using surgical techniques not feasible in humans, whilst chicken embryos helped isolate effects independent of maternal or placental effects.  We tested the hypothesis that maternal treatment with the mitochondria-targeted antioxidant MitoQ will protect against offspring cardiovascular dysfunction programmed by developmental hypoxia.

Our findings show that hypoxia induces mitochondria-derived oxidative stress during cardiovascular development, programming endothelial dysfunction and hypertension in adult offspring. Maternal treatment with MitoQ during hypoxic pregnancy protects against this cardiovascular risk by enhancing nitric oxide signalling.  Our data suggest viable mitochondria-targeted intervention to protect offspring against cardiovascular dysfunction in pregnancies affected by chronic hypoxia, such as during pregnancy at high altitude or sea level pregnancy with placental insufficiency.

Dr Kim Botting, University College London, UK

Dr Kim Botting, University College London, UK

16:00-16:15 Discussion
16:15-16:45 Programming of ventricular arrhythmia susceptibility by fetal hypoxia

Ventricular arrhythmias are a major cause of sudden cardiac death. Genetics, lifestyle choices and environmental factors undoubtedly contribute to the origin and penetrance of ventricular arrhythmic disorders. However, to our knowledge, no studies have considered the role of the intrauterine environment during pregnancy. Importantly, recent evidence from the Galli and Giusssani laboratories suggests that lack of oxygen during fetal development (fetal hypoxia) can remodel the heart and cause abnormal ventricular myocyte calcium cycling in adulthood, which could promote arrhythmia. Therefore, we investigated whether hypoxic pregnancy increases arrhythmic susceptibility in adult rat progeny. Time-mated Wistar rats were assigned to Normoxia (21% oxygen) or Hypoxia (13% oxygen) between GD6-20. Optical mapping was performed on Langendorff perfused hearts to assess arrhythmia susceptibility and to simultaneously measure intracellular calcium and membrane potential. The data shows that hearts from hypoxic pregnancies are more susceptible to arrhythmia, with some individuals becoming arrhythmic in the absence of any stress. This was associated with calcium transient abnormalities and an increased duration of the ventricular action potential. qRT-PCR revealed the expression of key genes involved in excitation-contraction coupling were significantly altered within hypoxic hearts. Taken together, these data suggest some ventricular arrhythmias may have a developmental origin, which provides an exciting opportunity to prevent these conditions with maternal therapeutics.

Doctor Gina Galli, University of Manchester, UK

Doctor Gina Galli, University of Manchester, UK

16:45-17:00 Discussion
17:00-17:30 Fetal growth at high altitude: what can study of a pregnant population from Leh, Ladakh tell us?

Human Fetal Growth is a complex process influenced by both the in-utero environment and genetic factors. Hypoxia, specifically HIF oxygen sensing pathways, have been implicated and genetic adaptation is a recognised feature influencing growth. 

High altitude environments provide an ideal natural experiment to study the impact of a low oxygen environment, on pregnancy outcomes. Leh, Ladakh, in the Jammu and Kashmir region of India, lies between the Karakoram and Himalayan Mountain ranges. Genetic selection of the Ladakhi population is relatively poorly studied. The Sonam Norboo Memorial (SNM) Hospital in Leh [situated at 3,540m above sea level], provides maternity care for Ladakh, has an institutional birth rate of >90% making it a unique site to study a pregnant population at high altitude. 

Over the last 10 years a collaborative research group of clinical academics from University College London, All India Institute of Medical Science Hospital, New Delhi and SNM Hospital have been studying pregnancies in Leh. Findings, that will be presented here, support both physical and genetic adaptation in babies born to pregnant women who generationally have long residence at high altitude. Interestingly, the Ladakh population was found to be less homogenous genetically than initially thought. There were clear trends seen in babies born of heavier birth weights, towards enrichment of genes implicated, particularly in height, body mass and skeletal development.

Dr Sara Hillman, University College London, UK

Dr Sara Hillman, University College London, UK

17:30-17:45 Discussion