Mechanisms involved in reduced cardiac contractility as a consequence of growth restriction during fetal development

在过去的40年里，心肌的功能发展一直是研究的焦点。尽管我们目前了解心肌细胞兴奋如何导致收缩的变化，一个被广泛称为兴奋-收缩（E-C）耦合的过程，一个用于研究人类胎儿发育平行细胞的主要模型，羊，尚未在此背景下进行检查。因此，目前尚不清楚E-C偶联是如何从胎儿进化到成人的。了解正常的生理是必要的，随后了解病理状态，如子宫间生长限制（IUGR）。在澳大利亚，IUGR导致低出生体重婴儿的发生率为7%。IUGR是由产妇营养不良、产妇吸烟吸毒和胎盘功能不全引起的。它与围产期死亡率、呼吸系统问题、小岛屿发展中国家和发病率的增加有关。流行病学研究表明，低出生体重婴儿在成年后患心血管疾病（包括心力衰竭）的风险也会增加。迄今为止，关于胎儿生长受限对心肌正常发育和功能的影响的信息很少。了解IUGR对心肌发育的影响将有助于阐明连接这两个暂时不同事件的潜在生理机制。这种机制的理解将有助于改善那些成年后因IUGR而有心血管疾病风险的个体的临床管理。它也可能允许早期干预策略，可以改善心血管功能。因此，我们建议检查E-C偶联的正常发育变化，以便我们了解胎盘功能不全导致IUGR如何损害正常心肌发育。这将导致细胞水平的功能受损，最终表现为心脏在以后的生活中对损伤的易感性增加。

Functional development of the heart muscle has been a focus of intense research over the last 40 years. Despite our current understanding of the changes in how excitation of the cardiomyocyte leads to contraction, a process broadly termed excitation-contrcation (E-C) coupling, a major model used to study paralells of human fetal development, the sheep, has not been examined in this context. As such, it remains unclear how E-C coupling evolves from the fetus to the adult. Understanding normal physiology is imperative to subsequetly understand pathological states, such as interuterine growth restriction (IUGR). In Australia, the incidence of IUGR leading to low birth weight babies is 7%. IUGR is caused by maternal undernutrition, maternal smoking-drug use and placental insufficiency. It is associated with an increase in perinatal mortality, respiratory problems, SIDS and morbidity. Epidemiological studies show that low birth weight babies are also at an increased risk of cardiovascular disease, including heart failure, in adult life. To date, there is little information on the impact of fetal growth restriction on the normal development and function of the heart muscle. Understanding the impact of IUGR on heart muscle development will allow the elucidation of the underlying physiological mechanisms linking these two temporally distinct events. This mechanistic understanding will allow improved clinical management of those individuals at risk of cardiovascular disease in adult life arising from IUGR. It may also allow for early intervention strategies that can improve cardiovascular function. Therefore, we propose to examine both the normal developmental changes to E-C coupling so that we can understand how placental insufficiency leading to IUGR impairs normal heart muscle development. This will result in impaired function at a cellular level, which will ultimately manifest as an increased susceptibility of the heart to injury in later life.