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Dino A Giussani PhD

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Professor of Developmental Cardiovascular Physiology and Medicine
Tel: +44 (0)1223 333894, Fax: +44 (0)1223 333840, E-mail: dag26@cam.ac.uk

Prospective PhD students: I will be pleased to consider applications from prospective PhD students. Please contact me by e-mail in the first instance.

Prenatal origins of heart disease

Heart disease is the greatest killer in the UK today, imposing a substantial burden on the nation’s health and wealth. The concept that traditional risk factors, such as smoking and obesity increase the risk of heart disease is familiar to all of us. However, it does little to explain why some individuals develop the disease and others do not. Hence, in addition to the genetic basis of cardiovascular disease, another concept has now become established – one of developmental programming. This states that a component of both the cardiovascular health we enjoy and the risk of heart disease in adult life can be predetermined before birth, not only by our genes but also by their interaction with the quality of our prenatal development. In pregnancy complicated with adverse intrauterine conditions, physiological adaptations are enforced in the unborn child and placenta, which can reduce the rate of fetal growth and alter the development of key organs and systems, such as the heart and circulation. Whilst they are necessary to maintain viable pregnancy and sustain life before birth, these adaptations come at a cost, claiming many biological trade-offs. Overwhelming evidence in humans in more than a dozen countries worldwide now links development under sub-optimal intrauterine conditions with increased rates of heart disease and its major risk factors – hypertension, atherosclerosis and diabetes. This suggests that independent of lifestyle and genetic risk factors a developmental origin of increased susceptibility to heart disease has now been discovered, providing science a unique and exciting opportunity to bring preventive medicine back into the womb.

One of the most common adverse conditions in complicated pregnancy is a reduction in oxygen delivery to the developing young. The fetal defence to a short-term episode of hypoxia includes the redistribution of blood flow away from peripheral circulations towards essential vascular beds, such as those perfusing the brain. This brain-sparing effect is conserved across all species studied from the reptilian and avian embryo to the mammalian fetus, including the sheep, non-human and human primate. Should the duration of the hypoxic challenge become prolonged, the initial homeostatic cardiovascular defences persist. In response to chronic hypoxia, sustained redistribution of blood flow towards essential circulations ensures viable pregnancy, but the adaptation comes with a cost, triggering a number of biological tradeoffs. The best described unwanted side-effect of chronic hypoxic pregnancy is asymmetric fetal growth restriction. Chronic hypoxia during pregnancy also promotes an increase in cardiac afterload, imposing a strain on the developing fetal heart and major vessels, leading to ventricular and aortic wall thickening. Other studies have shown that prenatal hypoxia increases cardiac susceptibility to ischemia-reperfusion injury and that it promotes endothelial dysfunction in adult life. Thus, intrauterine hypoxia is not only a threat to fetal life, but is also provides a strong stimulus for a developmental origin of heart and vascular disease. However, the mechanism by which prenatal hypoxia programs cardiovascular dysfunction in adulthood has not been identifiedAn important component of fetal growth and development is determined by the quality of the intrauterine environment. In turn, the quality of the intrauterine environment is largely determined by the available nutrient and oxygen supply to the growing young. As such, the association between poor conditions in utero.

Past work
Our group has studied the physiology underlying the fetal adaptation to short- and long-term hypoxia for the last 20 years. We now know that the fetal cardiovascular defence to reductions in oxygenation is triggered by a carotid chemoreflex and that it is modified by endocrine agents and local factors, including nitric oxide and reactive oxygen species. We know that the cardiovascular defence matures with advancing gestational age in parallel with the pre-partum surge in fetal plasma cortisol. We know that the fetal cardiovascular defence close to term can be modified by the fetal experience earlier in gestation. Some of these experiences may be beneficial such as antenatal glucocorticoid therapy, which strengthen the fetal cardiovascular defence to hypoxia. Other fetal experiences may be detrimental, weakening the fetal cardiovascular defence, such as pre-exposure to compression of the umbilical cord. We know that high altitude pregnancy affects fetal growth and the fetal capacity to respond to hypoxia, and that generations of residence at high altitude in humans and animals modify the effects of high altitude hypoxia on fetal growth and the developing cardiovascular system.

http://www.cam.ac.uk/research/news/prenatal-origins-of-heart-disease
http://www.newscientist.com/article/mg17022901.100-head-in-the-clouds.html
http://news.bbc.co.uk/hi/spanish/science/newsid_1449000/1449386.stm
http://www.vetscite.org/publish/items/001307/index.html

Current research focus
The latest programmes of research in my laboratory focus on the contribution of prenatal hypoxia, oxidative stress and nitric oxide bio-availability to the developmental programming of cardiovascular disease. We have put forward two inter-related hypotheses: 1) that oxidative stress underlies the molecular basis via which prenatal hypoxia programmes cardiovascular disease and 2) that maternal antioxidant treatment will ameliorate this effect. If true, treatment with antioxidants of pregnancies complicated with reduced oxygen delivery to the fetus, such as during pre-eclampsia or placental insufficiency should diminish the hypoxia-induced origins of cardiovascular disease.

Our research is carried out using an integrative approach at the systems, isolated organ, cellular and molecular levels. The basic science is compared with epidemiological findings of human populations including those in developing countries and residing either at sea level and at high altitude in the South American Andes. Combined, therefore, our research programmes have components of basic, clinical, anthropological and translational science with direct relevance to human obstetric and cardiovascular medicine, veterinary medicine and the food and livestock commerce. The work not only offers insight to mechanism but it may also hasten translation to relatively simple clinical interventions to not only treat the mother, but also her progeny, thereby having a major clinical, economic and social impact on health. Our research has been recognised by the receipt of four international awards: The Royal Society’s Wolfson Research Merit Award, The Lister Institute for Preventive Medicine Prize, The Wim Schellekens Foundation Prize in the Netherlands and the inaugural Lang Pardy Italy Foundation award.

Current lab
Dr Emily J Camm, Post-Doctoral Research Associate
Dr Youguo G Niu, Post-Doctoral Research Associate
Dr Beth J Allison, Post-Doctoral Research Associate

Mr Andrew D Kane, PhD student
Miss Ciara Lusby, PhD student
Miss Kirsty L Brain, PhD student
Miss Nozomi Itani, PhD student
Dr Carlos E Salinas, PhD student

Miss Christine M Cross, technician
Mr Scott Gentle, technician
Mrs Sue Nicholls, technician
Mr Craig Forest, technician

Main collaborators
Prof Carlos E Blanco, Maastricht University
Prof Anibal J Llanos, Universidad de Chile
Prof Lucilla Poston, Kings College London
Prof Abigail L Fowden, University of Cambridge
Prof Graham J Burton, University of Cambridge
Dr Peter W Wooding, University of Cambridge
Dr Sue E Ozanne, University of Cambridge
Dr Jan B Derks, Utrecht Medical Centre
Prof Peter W Nathanielsz, University of Texas San Antonio
Prof Enrique Vargas, Instituto Boliviano de Biologia de Altura
Prof Mercedes Villena, Instituto Boliviano de Biologia de Altura
Prof Lorna G Moore, Wake Forest University

Former Post-Docs and PhD students
Dr Andrew J Fletcher, former PhD student
Dr Juanita K Jellyman, former PhD student
Dr Susan J O’Connor, former PhD student
Dr Avnesh S Thakor, former PhD student
Miss Alexandra Adler, former MPhil student
Dr Jeremy A Hansell, former PhD student
Dr David S Gardner, former Post-Doctoral Fellow
Dr Kate A Clarke, former Post-Doctoral Fellow
Dr Emilio A Herrera, former Post-Doctoral Fellow
Dr Hans G Richter, former Post-Doctoral Fellow

Sources of funding
Funding for our research amounts to £5.2 million to date from sources including The British Heart Foundation (Programme Grant), The Wellcome Trust, BBSRC, Tommy’s The Baby Charity UK, The Horserace Betting Levy Board, The Royal Society, The Isaac Newton Trust, The Jules Thorn Trust, the International Journal of Experimental Pathology and The Lister Institute for Preventive Medicine.

Publications (PubMed)

Gonville & Caius College
I am a fellow of Gonville & Caius College, where I am Director of Studies in Medicine and Tutor.

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