Dino Giussani

University of Cambridge | Cam · Department of Physiology, Development and Neuroscience

Chronic fetal hypoxia is one of the most common complications of pregnancy and can programme cardiac abnormalities in adult offspring including ventricular remodelling, diastolic dysfunction and sympathetic dominance. However, the underlying mechanisms at the level of the cardiomyocyte are unknown, preventing the identification of targets for thera...

Pregnancy complicated by maternal obesity contributes to an increased cardiovascular risk in offspring, which is increasingly concerning as the rates of obesity and cardiovascular disease are higher than ever before and still growing. There has been much research in humans and preclinical animal models to understand the impact of maternal obesity o...

Fetal growth restriction (FGR) is a common outcome in human suboptimal gestation and is related to prenatal origins of cardiovascular dysfunction in offspring. Despite this, therapy of human translational potential has not been identified. Using human umbilical and placental vessels and the chicken embryo model, we combined cellular, molecular, and...

Maternal mortality rates are at an all-time high across the world and are set to increase in subsequent years. Cardiovascular disease is the leading cause of death during pregnancy and postpartum, especially in the US. Therefore, understanding the physiological changes in the cardiovascular system during normal pregnancy is necessary to understand...

The specific biology of the male breast remains relatively unexplored in spite of the increasing global prevalence of male breast cancer. Delineation of the microenvironment of the male breast is restricted by the low availability of human samples and a lack of characterisation of appropriate animal models. Unlike the mouse, the male ovine gland pe...

High-altitude pregnancy increases the incidence of fetal growth restriction and reduces birth weight. This poses a significant clinical challenge as both are linked to adverse health outcomes, including raised infant mortality and the development of the metabolic syndrome in later life. While this reduction in birth weight is mostly understood to b...

Gestational hypoxia adversely affects uterine artery function, increasing complications. However, an effective therapy remains unidentified. Here, we show in rodent uterine arteries that hypoxic pregnancy promotes hypertrophic remodelling, increases constrictor reactivity via protein kinase C signalling, and triggers compensatory dilatation via nit...

Objective We investigated the potential involvement of miRNAs in the developmental programming of cardiovascular diseases (CVD) by maternal obesity. Methods Serum miRNAs were measured in individuals from the Helsinki Birth Cohort (with known maternal body mass index), and a mouse model was used to determine causative effects of maternal obesity du...

The specific biology of the male breast remains relatively unexplored in spite of the increasing global prevalence of male breast cancer. Delineation of the microenvironment of the male breast is restricted by the low availability of human samples and a lack of characterisation of appropriate animal models. Unlike the mouse, the male ovine gland pe...

Women with a history of preeclampsia (PE) have a greater risk of pulmonary arterial hypertension (PAH). In turn, pregnancy at high altitude is a risk factor for PE. However, whether women who develop PE during highland pregnancy are at risk of PAH before and after birth has not been investigated. We tested the hypothesis that during highland pregna...

Chronic fetal hypoxaemia is a common pregnancy complication that increases the risk of infants experiencing respiratory complications at birth. In turn, chronic fetal hypoxaemia promotes oxidative stress, and maternal antioxidant therapy in animal models of hypoxic pregnancy has proven to be protective with regards to fetal growth and cardiovascula...

Antenatal glucocorticoids accelerate fetal lung maturation and reduce mortality in preterm babies but can trigger adverse effects on the cardiovascular system. The mechanisms underlying off‐target effects of the synthetic glucocorticoids mostly used, Dexamethasone (Dex) and Betamethasone (Beta), are unknown. We investigated effects of Dex and Beta...

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...

Our understanding of fetal cardiovascular physiology has markedly increased in the last 50 years, with the introduction of suitable animal models. When studying the cardiovascular system before birth, the temporal profile of cardiovascular development between species is a highly important consideration for translation to the human clinical situatio...

The concept of the early life developmental origins of health and disease (DOHaD) in adults has stimulated a new approach to understanding disease trajectories, with major public health implications. Indeed, the principle of the 'lifecourse of disease' now influences health policies internationally. Environmental influences during pregnancy and ear...

Gestational hypoxia is a major contributor to fetal growth restriction (FGR) and perinatal morbidity and mortality and has been closely linked to the activation of the unfolded protein response (UPR) in the placenta. Recent studies on adverse pregnancy conditions show differential adaptive responses in pregnancies carrying male or female fetuses. H...

Developmental hypoxia has profound and persistent effects on the vertebrate cardiovascular system, but the nature, magnitude and long-term outcome of the hypoxic consequences are species-specific. Here we aim to identify common and novel cardiovascular responses among vertebrates that encounter developmental hypoxia, and we discuss the possible med...

Background: Antenatal corticosteroids (ACS) are recommended in threatened preterm labour to improve short term neonatal outcome. Preclinical animal studies suggest detrimental effects of ACS exposure on offspring cardiac development; their effects in humans are unknown. Objectives: To systematically review the human clinical literature to determ...

Insufficient oxygen supply (hypoxia) during fetal development leads to cardiac remodelling and a predisposition to cardiovascular disease in later life. Previous work has shown hypoxia causes oxidative stress in the fetal heart and alters the activity and expression of mitochondrial proteins in a sex‐dependent manner. However, the functional effect...

The prevalence of maternal obesity is increasing at an alarming rate, and is providing a major challenge for obstetric practice. Adverse effects on maternal and fetal health are mediated by complex interactions between metabolic, inflammatory, and oxidative stress signaling in the placenta. Endoplasmic reticulum (ER) stress and activation of the un...

Background Antenatal corticosteroids (ACS) are recommended in threatened preterm labour to improve short term neonatal outcome. Preclinical animal studies suggest detrimental effects of ACS exposure on offspring cardiac development; their effects in humans are unknown. Objectives To systematically review the human clinical literature to determine t...

Background: Preeclampsia continues to be a prevalent pregnancy complication and underlying mechanisms remain controversial. A common feature of preeclampsia is utero-placenta hypoxia. In contrast to the impact of hypoxia on the placenta and fetus, comparatively little is known about the maternal physiology. Methods: We adopted an integrative app...

Introduction: Metformin is the first-line pharmacological treatment for gestational diabetes in many countries. Although effective at improving maternal glycaemia, metformin readily crosses the placenta and could directly affect the fetus. Indeed, metformin exposure in utero increases postnatal adiposity. However, other long-term effects on offspr...

Background: Preeclampsia and fetal growth restriction increase cardiopulmonary disease risk for affected offspring and occur more frequently at high-altitude (≥2500 m). Retrospective studies indicate that birth to a preeclampsia woman at high altitude increases the risk of pulmonary hypertension (PH) in later life. This prospective study asked whe...

The mechanosensitive cation channel Piezo1 is implicated in eNOS activation and endothelial-dependent relaxation (Wang et al. J Clin Invest. 126: 4527, 2016). The vasculature in the fetus and the placenta is tightly regulated by local cues, such as endothelial-derived factors in response to changes in blood flow and shear stress. However, little is...

Background The vascular endothelium has important endocrine and paracrine roles, particularly in the regulation of vascular tone and immune function, and it has been implicated in the pathophysiology of a range of cardiovascular and inflammatory conditions. This study uses a series of transgenic murine models to explore for the first time the role...

Work in preclinical animal models has established that pregnancy complicated by chronic fetal hypoxia and oxidative stress programmes cardiovascular dysfunction in adult offspring. Translating this to the human condition comes with challenges, including the early diagnosis of affected individuals to improve clinical outcomes. We hypothesize that co...

Heart disease remains one of the greatest killers. In addition to genetics and traditional lifestyle risk factors, we now understand that adverse conditions during pregnancy can also increase susceptibility to cardiovascular disease in the offspring. Therefore, the mechanisms by which this occurs and possible preventative therapies are of significa...

Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into...

Objective To understand the relationship between birth weight and altitude to improve health outcomes in high‐altitude populations, to systematically assess the impact of altitude on the likelihood of low birth weight (LBW), small for gestational age (SGA), and spontaneous preterm birth (sPTB), and to estimate the magnitude of reduced birth weight...

Commentary on “Systemic Acidemia Impairs Cardiac Function in Critically Ill Patients" by Rodrigez-Villar et al. (EClinical Medicine, 2021) Physiology can inform and help transform clinical practice. In turn, clinical practice demands physiological mechanisms to determine intervention and treatment. And so the spiral of fresh scientific discovery an...

Objective Exposure to high altitude (≥2500m) is associated with increased arterial blood pressure. During pregnancy, even mild elevation of maternal blood pressure is associated with reduced birth weight and increased prevalence of pregnancy complications. This paper aims to systematically assess the impact of altitude on maternal blood pressure at...

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long‐term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with mate...

Background In the fetus, the appropriate balance of prooxidants and antioxidants is essential to negate the detrimental effects of oxidative stress on lung maturation. Antioxidants improve respiratory function in postnatal life and adulthood. However, the outcomes and biological mechanisms of antioxidant action in the fetal lung are unknown. Metho...

Mitochondria‐derived oxidative stress during fetal development increases cardiovascular risk in adult offspring of pregnancies complicated by chronic fetal hypoxia. We investigated the efficacy of the mitochondria‐targeted antioxidant MitoQ in preventing cardiovascular dysfunction in adult rat offspring exposed to gestational hypoxia, integrating f...

The use of statins in complicated pregnancy is being considered, as they protect endothelial function in the mother and placenta. However, whether statins affect cardiovascular function in the fetus is completely unknown. Here, we have determined the effects of pravastatin and underlying mechanisms on the cardiovascular system of the hypoxic chicke...

The hypoxic fetus is at greater risk of cardiovascular demise during a challenge, but the reasons behind this are unknown. Clinically, progress has been hampered by the inability to study the human fetus non-invasively for long period of gestation. Using experimental animals, there has also been an inability to induce gestational hypoxia while reco...

High altitude pregnancy is associated with increased frequency of low birth weight infants and neonatal complications, the risks of which are higher in women of low‐altitude ancestry. Does ancestry also influence the risk of miscarriage (pregnancy loss <20 weeks) in high‐altitude pregnancy? To answer this, 5386 women from La Paz, Bolivia (3300‐4150...

Key points In mammals, pregnancy complications can trigger an embryonic or fetal origin of cardiac dysfunction. However, underlying mechanisms remain uncertain because the partial contributions of the challenge on the mother, placenta or offspring are difficult to disentangle. The avian embryo permits isolation of the direct effects of suboptimal c...

The prenatal origins of heart disease in offspring have been established. However, research in species with developmental milestones comparable to humans is lacking, preventing translation of this knowledge to clinical contexts. Using sheep and chickens, two species with similar cardiovascular developmental milestones to humans, we combined in vivo...

A cohort study of 6,500,000 human pregnancies showed an increased risk of adverse fetal outcomes following abdominal but not non-abdominal surgery under general anesthesia. This may be the consequence of uterine handling during abdominal surgery. However, there are no data on any effects on the cardiometabolic physiology of the fetus or mother in r...

Most mammals have a poor tolerance to hypoxia, and prolonged O 2 restriction can lead to organ injury, particularly during fetal and early postnatal life. Nevertheless, the llama (Lama Glama) has evolved efficient mechanisms to adapt to acute and chronic perinatal hypoxia. One striking adaptation is the marked peripheral vasoconstriction measured i...

In mammals, pregnancy complicated by chronic hypoxia can program hypertension in the adult offspring. However, mechanisms remain uncertain because the partial contributions of the challenge on the placenta, mother, and fetus are difficult to disentangle. Here, we used chronic hypoxia in the chicken embryo-an established model system that permits is...

Antenatal glucocorticoid therapy reduces mortality in the preterm infant, but evidence suggests off‐target adverse effects on the developing cardiovascular system. Whether deleterious effects are direct on the offspring or secondary to alterations in uteroplacental physiology is unclear. Here, we isolated direct effects of glucocorticoids using the...

Prenatal glucocorticoid overexposure has been shown to programme adult cardiovascular function in a range of species, but much less is known about the long-term effects of neonatal glucocorticoid overexposure. In horses, prenatal maturation of the hypothalamus–pituitary–adrenal axis and the normal prepartum surge in fetal cortisol occur late in ges...

Chronic fetal hypoxia and infection are examples of adverse conditions during complicated pregnancy, which impact cardiac myogenesis and increase the lifetime risk of heart disease. However, the effects that chronic hypoxic or inflammatory environments exert on cardiac pacemaker cells are poorly understood. Here, we review the current evidence and...

Chronic fetal hypoxia and infection are examples of adverse conditions during complicated pregnancy, which impact cardiac myogenesis and increase the lifetime risk of heart disease. However, the effects that chronic hypoxic or inflammatory environments exert on cardiac pacemaker cells are poorly understood. Here, we review the current evidence and...

Key points We introduce a technique to test whether intrinsic fetal heart rate variability (iFHRV) exists and we show the utility of the technique by testing the hypothesis that iFHRV is affected by chronic fetal hypoxia, one of the most common adverse outcomes of human pregnancy complicated by fetal growth restriction. Using an established late ge...

In healthy pregnancy, glucose and oxygen availability are essential for fetal growth and well being. However, how substrate delivery and fetal uptake are affected in human pregnancy complicated by fetal growth restriction (FGR) is still unknown. Here, we show that the human FGR fetus has a strikingly reduced umbilical uptake of both oxygen and gluc...

In many species, the pattern of growth and physiological development in utero has an important role in determining not only neonatal viability but also adult phenotype and disease susceptibility. Changes in fetal development induced by a range of environmental factors including maternal nutrition, disease, placental insufficiency and social stresse...

The last decade has seen rapid advances in the understanding of the central role of glucocorticoids in preparing the fetus for life after birth. However, relative to other organ systems, maturation by glucocorticoids of the fetal cardiovascular system has been ignored. Here, we review the effects of glucocorticoids on fetal basal cardiovascular fun...

Purpose To investigate the effects of the antenatal administration of betamethasone on fetal Doppler and short term fetal heart rate variation (CTG-STV) in early growth restricted (FGR) fetuses. Materials and Methods Post hoc analysis of data derived from the TRUFFLE study, a prospective, multicenter, randomized management trial of severe early ons...

Table S1: Primer sequences and product length for reported genes

High-intensity focused ultrasound (HIFU) is a non-invasive method of selective placental vascular occlusion, providing a potential therapy for conditions such as twin-twin transfusion syndrome. In order to translate this technique into human studies, evidence of prolonged fetal recovery and maintenance of a healthy fetal physiology following exposu...

Complications of pregnancy remain key drivers of morbidity and mortality, affecting the health of both the mother and her offspring in the short and long term. There is lack of detailed understanding of the pathways involved in the pathology and pathogenesis of compromised pregnancy, as well as a shortfall of effective prognostic, diagnostic and tr...

Key points Exposure to chronic hypoxia during gestation influences long‐term health and development, including reproductive capacity, across generations. If the peri‐conceptual environment in the developing oviduct is affected by gestational hypoxia, then this could have implications for later fertility and the health of future generations. In the...

Chronic fetal hypoxia is a common complication observed in human pregnancy, impacting pregnancies across global contexts. Exposure to chronic intrauterine hypoxia has major short‐ and long‐term consequences for offspring health. However, the impact of chronic gestational hypoxia on female reproductive system development is unknown. We aimed to unde...

Ante- and postnatal glucocorticoid therapy reduces morbidity and mortality in the preterm infant, and it is therefore one of the best examples of the successful translation of basic experimental science into human clinical practice. However, accruing evidence derived from human clinical studies and from experimental studies in animal models raise s...

Scaling of the heart across development can reveal the degree to which variation in cardiac morphology depends on body mass. In this study, we assessed the scaling of heart mass, left and right ventricular masses, and ventricular mass ratio, as a function of eviscerated body mass across fetal and postnatal development in Horro sheep Ovis aries (~50...

Evidence derived from human clinical studies and experimental animal models shows a causal relationship between adverse pregnancy and increased cardiovascular disease in the adult offspring. However, translational studies isolating mechanisms to design intervention are lacking. Sheep and humans share similar precocial developmental milestones in ca...

Raw data. Complying with data policy, Excel spreadsheet files are provided with the underlying numerical data points for all graphs contained within the manuscript. (XLSX)

Placental measurements. Measurements at 138 dGA: A, total placentome weight; B, placentome distribution; and C, fetal:placentome weight ratio. Values are mean ± SEM. Groups are N (open symbols, n = 12), H (grey symbols, n = 8), HC (red symbols, n = 9), and NC (blue symbols, n = 9). There are no significant differences between groups. dGA, days of g...