Dino Giussani

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

MA, PhD, ScD, FRCOG

About

347
Publications
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Publications

Publications (347)
Article
Full-text available
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...
Article
Full-text available
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...
Preprint
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...
Article
Full-text available
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...
Article
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...
Article
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...
Conference Paper
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
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 weigh...
Article
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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...
Article
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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...
Article
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Preprint
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
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...
Article
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...
Article
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...
Article
Full-text available
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...
Data
Table S1: Primer sequences and product length for reported genes
Article
Full-text available
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...
Article
Full-text available
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...
Article
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...
Article
Full-text available
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...
Article
Full-text available
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...
Article
Full-text available
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...
Data
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)
Data
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...
Article
Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made sig...
Article
Full-text available
Integrating functional and molecular levels, we investigated the effects of maternal treatment with a xanthine oxidase inhibitor on the programming of cardiac dysfunction in adult offspring using an established rat model of hypoxic pregnancy. Female Wistar rats were divided into normoxic or hypoxic (13% O2) pregnancy±maternal allopurinol treatment...
Article
Full-text available
Pre-clinically, High Intensity Focused Ultrasound (HIFU) has been shown to safely and effectively occlude placental blood vessels in the acute setting, when applied through the uterus. However, further development of the technique to overcome the technical challenges of targeting and occluding blood vessels through intact skin remains essential to...
Article
Background and objectives: The mechanism underlying fetal-placental Doppler changes in pre-eclampsia and/or fetal growth restriction are unknown though both are associated with maternal cardiovascular dysfunction. We sought to investigate whether there was a relationship between maternal cardiac output and vascular resistance and feto-placental Do...
Article
Full-text available
The placenta responds to adverse environmental conditions by adapting its capacity for substrate transfer to maintain fetal growth and development. The effects of early-onset hypoxia on placental morphology and activation of the unfolded protein response (UPR) were determined using an established rat model in which fetal growth restriction is minim...
Article
Full-text available
It is now well accepted that exposure to adverse environmental conditions in utero can predispose a fetus to disease later in life. Using an avian model to study the programming of disease has a unique advantage as it allows isolation of the direct effects of adverse conditions on fetal physiology, without any confounding effects via the mother or...
Poster
Full-text available
What’s That Smell? First Evidence of Cardio-Protective Actions of Hydrogen Sulphide in the Developing Heart
Article
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Objective Obesity during pregnancy is associated with an elevated risk of cardiovascular disease in the offspring. With increased numbers of women entering pregnancy overweight or obese, there is a requirement for targeted interventions to reduce disease risk in future generations. Using an established murine model of maternal obesity during pregna...
Article
Full-text available
Aims: Obesity during pregnancy increases risk of cardiovascular disease (CVD) in the offspring and individuals exposed to over-nutrition during fetal life are likely to be exposed to a calorie-rich environment postnatally. Here, we established the consequences of combined exposure to a maternal and post-weaning obesogenic diet on offspring cardiac...
Article
Full-text available
AIMS Obesity during pregnancy increases risk of cardiovascular disease (CVD) in the offspring and individuals exposed to over-nutrition during fetal life are likely to be exposed to a calorie-rich environment postnatally. Here, we established the consequences of combined exposure to a maternal and post-weaning obesogenic diet on offspring cardiac s...
Article
Full-text available
Key points: Fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, and a decrease in FHRV is associated with fetal compromise. However, the mechanisms by which FHRV is reduced in the chronically hypoxic fetus have yet to be established. The sympathetic and parasympathetic influences on heart rate m...
Article
Although fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, the mechanisms by which it is reduced in the chronically hypoxic fetus have yet to be established. In particular, the physiological mechanism underlying the reduction of short term variation (STV) in fetal compromise remains unclear. In...