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

在过去的40年里，心肌的功能发育一直是密集研究的焦点。尽管我们目前了解心肌细胞的兴奋如何导致收缩的变化，但广泛称为兴奋-收缩（E-C）偶联的过程，用于研究人类胎儿发育的细胞（绵羊）的主要模型，尚未在此背景下进行研究。因此，目前尚不清楚E-C耦合如何从胎儿发展到成人。了解正常的生理是必要的，以准确地了解病理状态，如宫内生长受限（IUGR）。在澳大利亚，IUGR导致低出生体重婴儿的发生率为7%。IUGR是由母亲营养不良、母亲吸烟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，出生体重低的婴儿在成年后患心血管疾病的风险也会增加，包括心力衰竭。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。了解胎儿宫内发育迟缓对心肌发育的影响将有助于阐明这两个时间上不同的事件之间的潜在生理机制。这种机制的理解将允许改善临床管理的人在成年生活中的心血管疾病的风险所产生的IUGR。它还可以允许早期干预策略，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，以便我们能够了解导致IUGR的胎盘功能不全如何损害正常的心肌发育。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.