Myocardial Protection during Fetal Bypass: Role of Calcium Cycling

描述（由申请人提供）：在美国，每100个出生的孩子中就有1个患有先天性心脏病。尽管最近取得了进展，但心脏畸形仍然占所有出生缺陷相关死亡率的三分之一。某些复杂的疾病在子宫内或出生后不久具有显著的相关死亡率和发病率。此外，由于先前在子宫内发生的损伤，由于心脏内血流模式的改变，这些缺陷的产后修复可能更加复杂。越来越多的有力证据表明，胎儿心脏干预可能会改变其中一些婴儿的不良预后。然而，将胎儿心脏直视手术转变为成功的临床现实的目标尚未实现。下一步，也是执行心脏内手术的必要部分，是在胎儿心内直视手术中安全保护胎儿心肌的能力。这需要了解胎儿心肌对旁路和缺血/再灌注损伤的反应。据我们所知，之前没有研究专门观察过胎儿心肌对搭桥手术或其他心脏手术的细胞反应。通过保护胎儿心肌来减轻或预防心肌功能障碍是胎儿心脏手术最终临床翻译的核心。我们的长期目标是成功地将胎儿心脏手术应用于临床。作为实现这一目标的另一步，该项目的目的是确定胎儿旁路手术后可能导致心肌功能障碍的潜在机制。该建议的中心假设是细胞内钙循环和收缩蛋白的破坏与胎儿心脏搭桥相关的心功能障碍有关，改良的心脏截瘫可以改善搭桥和心脏骤停后的心肌功能。值得注意的是，所获得的知识也将直接应用于越来越多需要心脏手术干预的早产儿的临床护理。我们使用由辛辛那提儿童医院心外科研究小组开发的新型妊娠中期绵羊胎儿心脏搭桥和骤停模型来验证这一假设，其具体目的如下：1)确定钙循环机制在胎儿心脏搭桥后心肌功能障碍发病机制中的作用；2)比较纤颤性和温血性心脏骤停作为胎儿心肌保护策略的疗效。预计在纤颤骤停时，钙循环将被保留。然后可以为临床环境确定最具心脏保护作用的方法。总之，胎儿心脏手术的翻译依赖于手术过程中足够的心肌保护。本提案利用我们研究小组的独特资格来评估胎儿搭桥和心脏骤停后的心肌损伤和检查保留心脏功能的方法。

DESCRIPTION (provided by applicant): In the United States, 1 in every 100 children born is affected by congenital heart disease. Despite recent advancements, heart malformations still account for one-third of all birth defect-related mortalities. Certain complex conditions have significant associated mortality and morbidity either in utero or shortly after birth. Furthermore, the postnatal repair of these defects can be more complex because of previous injury that occurs in the womb, due to altered intra-cardiac blood flow patterns. There is increasingly strong evidence that fetal cardiac interventions might alter the poor prognosis of some of these babies. However, the goal of turning fetal open-heart surgery into successful clinical reality has yet to be realized. The next step, and a requisite part of performing intra-cardiac procedures, is the ability to safely protect the fetal myocardium during fetal open-heart surgery. This requires an understanding of the response of the fetal myocardium to bypass and ischemia/reperfusion injury. To the best we can discern, no prior study has specifically looked at the cellular responses of fetal myocardium to bypass or other components of cardiac surgery. Alleviation or prevention of myocardial dysfunction by protecting the fetal myocardium is central in the ultimate clinical translation of fetal cardiac surgery. Our long-term goal is to successfully translate fetal heart surgery into the clinical setting. As another step towards that goal, the purpose of this project is to determine the potential mechanisms that can lead to myocardial dysfunction following fetal bypass. The central hypothesis of this proposal is that disruption of intracellular calcium cycling and contractile proteins contribute to cardiac dysfunction associated with fetal cardiac bypass and that modified cardioplegia can improve myocardial function after bypass and cardiac arrest. Of note, the knowledge gained would also directly apply to the clinical care of the increasing numbers of premature babies that require cardiac surgical interventions. We use a novel mid-gestation sheep model of fetal cardiac bypass and arrest that was developed by the Cardiothoracic Surgery research group at Cincinnati Children's Hospital to test the hypothesis with the following specific aims: 1) To determine the role of calcium cycling mechanisms underlying the pathogenesis of myocardial dysfunction following fetal cardiac bypass and 2) To compare the efficacy of fibrillatory versus warm blood cardioplegic arrest as a fetal myocardial protection strategy. It is expected that calcium cycling will be preserved in fibrillatory arrest. The most cardio-protective method can then be identified for clinical settings. In summary, the translation of fetal cardiac surgery is dependent upon sufficient myocardial protection during surgery. This proposal utilizes the unique qualifications of our research group to assess myocardial damage and to examine methods to preserve heart function after fetal bypass and cardiac arrest. PUBLIC HEALTH RELEVANCE: Many babies are born with heart malformations that are so complex or life threatening that these babies would benefit from corrective open-heart surgery in the womb. The ability to perform fetal open-heart surgery depends on providing myocardial protection during the required cardiac bypass support. This proposal examines the mechanisms underlying myocardial dysfunction with fetal bypass, thus leading to cardio- protective techniques necessary to successfully complete these procedures in human babies.