Neary, MT; (2015) The role of oxygen in the postnatal maturation and adaptation of the cardiovascular system. Doctoral thesis , UCL (University College London).

Abstract

Background: The heart undergoes major changes at birth: shifting preference from glycolysis to fatty acid oxidation, rapid development of the electrical conduction system and closure of the ductus arteriosus. The ultimate physiological trigger(s) causing the transitions are not known and I hypothesised that the postpartum increase in oxygen availability plays an important role. A changing oxygen environment also occurs ex utero, and I investigated the role of oxygen in the successful genetic adaptation of yaks and cattle to high altitude, and the genetic adaptations that correlate to athletic success at high altitude in humans. Results: I documented the changes in gene expression, cardiac electrical conduction, mitochondrial maturation and ductus arteriosus closure around birth in a mouse model. In all instances, maturation from fetal to adult phenotypes became evident within hours after birth. Changing oxygen conditions in the neonatal mice had no effect on ductus arteriosus closure but affected metabolic gene expression, mitochondrial morphology and maturation of the cardiac conduction system. I found that amongst elite long-distance runners the ACE ‘insertion’ allele and UCP3 T polymorphism were associated with a faster time in the Leadville high altitude ultra-marathon. My study in highland-dwelling cattle in Wyoming uncovered the first polymorphism (rs29016420 myosin heavy chain 15, T allele) associated with a reduction in hypoxia-induced pulmonary hypertension in cattle. I found positive selection of this polymorphism in yaks. Conclusions: Oxygen plays an important and variable role in postnatal maturation of the cardiovascular system. I discuss my findings as they may relate to the aetiology of Sudden Infant Death Syndrome and heart failure. I have also shown the important role of oxygen in genetic adaptation to a ‘fetal-like’ environment such as high altitude. Genetic studies in high altitude runners revealed significant associations with alleles involved in metabolism and the renin-angiotensin system and has prompted further study of this population for novel polymorphisms associated with high altitude adaptation. I also evaluated the first gene correlated with success at high altitude in cattle and the closely related yak.

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