The effect of moderate preterm birth on an immature cardiovascular system
thesisposted on 03.03.2017 by Nguyen, Vivian Bich
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Preterm birth (<37 weeks completed weeks of gestation) affects 9 - 12% of all live births; with the majority being moderately preterm birth (32 - 36 weeks gestation). It is the leading cause of neonatal mortality and morbidity and males have been reported to be at greater risk than females. In this thesis, I have examined the effect of moderate preterm birth, using an ovine model, on the structure of the heart and cardiomyocyte growth, and on the structure and composition of the large conduit arteries (thoracic aorta and left carotid artery). Pregnant ewes were induced to deliver vaginally using epostane (50 mg in 2 ml ethanol) at 0.9 of term (132 ± 1 days of gestation) or at term (147 ± 1 days of gestation). Clinically relevant doses of Betamethasone (11.4 mg) were also administered 24 hours and 48 hours before birth to ewes delivering preterm. Offspring were euthanised 2 days after birth or at 14.5 months of age. During the study period, preterm sheep were significantly lighter and smaller compared to term controls, with survival rates 75% for both preterm male and preterm female lambs after the first 2 weeks of life. At 12 months of age, body composition was not different between preterm and term sheep. By 14 months of age, preterm female sheep had caught up in body weight to terms; however preterm males were still lighter than term males. At this time, no detectable differences in arterial pressure and heart rate were observed between preterm and term sheep. In the immediate period after birth, preterm hearts were lighter and smaller compared to terms; however, relative to body weight, only right ventricular (RV) chamber volume remained smaller and left ventricle (LV) and RV walls were thicker. Total number of cardiomyocytes within the LV plus septum (LV+S) was not significantly different between preterm and term lambs; however relative to body weight, preterm lambs exhibited significantly more cardiomyocytes. Preterm lambs also had a significantly higher proportion of mononucleated cardiomyocytes in the LV+S but significantly lower proportion of binucleated cardiomyocytes compared to term lambs; indicative of an immature heart. In adulthood, preterm sheep had smaller RV and LV wall volumes, but when adjusted to body weight, there were no longer any differences. Interestingly, there was sexual dimorphism in the long-term effects on the LV+S; preterm male sheep exhibited significantly reduced wall volume, wall thickness and cardiomyocyte number compared to term male sheep, whereas no differences were observed between preterm and term females. In the immediate period after birth, there was no evidence of arterial injury in the thoracic aorta or left carotid artery. At this time, preterm lambs had narrower lumen areas in both blood vessels and thinner walls were observed in the left carotid artery. When adjusted for body weight, lumen area and wall thickness actually increased in the aorta of preterm lambs compared to term controls. Collagen deposition within the aortic wall was significantly reduced in preterm male lambs compared to terms. In adulthood, the number of elastin layers and elastin content was significantly reduced, whereas smooth muscle content increased in the left carotid artery of preterm sheep compared to term sheep. Interestingly, there was sexual dimorphism observed in the effects of preterm birth on aortic structure, such that preterm male sheep exhibited significant reductions in lumen size, medial area, intima-media thickness and layers of elastin compared to term male sheep, however no differences were observed in females. In my studies, moderate preterm birth after antenatal corticosteroid exposure has resulted in significant alterations in cardiovascular structure, predominantly in males. Even though, these differences are likely attributed to the smaller body size of the preterm male sheep, the reduced complement of cardiomyocytes in the LV+S and thinner walls with fewer layers of elastin in the aorta are likely to render the adult preterm male cardiovascular system particularly vulnerable to secondary postnatal insults and increase the risk of adverse cardiovascular consequences in later life. In conclusion, this thesis provides valuable insight into the effects of moderate preterm birth on the cardiovascular system in the immediate period after birth and in early adulthood. Overall, this study is clinically important given the large proportion of individuals born moderately preterm. The findings highlight the cardiovascular vulnerability of those born moderately preterm, particularly in males, and these adverse effects are expected to be greater with increasing severity of prematurity.