Myocardial Protection during Fetal Bypass: Role of Calcium Cycling

描述(申请人提供)：在美国，每100名出生的儿童中就有1名患有先天性心脏病。尽管最近取得了进展，心脏畸形仍占所有出生缺陷相关死亡的三分之一。某些复杂的疾病与子宫内或出生后不久的死亡率和发病率显著相关。此外，这些缺陷的出生后修复可能更加复杂，因为以前在子宫中发生的损伤，由于心脏内血流模式的改变。越来越有力的证据表明，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化为成功的临床现实的目标尚未实现。下一步，也是进行心脏内手术的必要部分，是在胎儿心脏直视手术期间安全保护胎儿心肌的能力。这需要了解胎儿心肌对转流和缺血/再灌注损伤的反应。据我们所知，之前还没有专门研究过心脏手术中胎儿心肌对搭桥手术或其他部分的细胞反应。通过保护胎儿心肌减轻或预防心肌功能障碍是胎儿心脏手术最终临床应用的核心。我们的长期目标是成功地将胎儿心脏手术转化为临床环境。作为迈向这一目标的另一步，该项目的目的是确定胎儿搭桥术后可能导致心肌功能障碍的潜在机制。这一建议的中心假设是，细胞内钙循环和收缩蛋白的破坏导致了胎儿心脏转流相关的心功能障碍，改良的停搏液可以改善转流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对越来越多需要心脏手术干预的早产儿的临床护理。我们使用辛辛那提儿童医院心胸外科研究组开发的一种新的孕中期胎儿心脏转流和停搏模型来检验这一假说，具体目的如下：1)确定钙循环机制在胎儿心脏转流后心肌功能障碍发病机制中的作用；2)比较纤颤停搏和温血停搏作为胎儿心肌保护策略的有效性。预计钙循环将被保存在纤颤停滞状态。然后，可以确定最适合临床环境的心脏保护方法。综上所述，胎儿心脏手术的转归有赖于术中充分的心肌保护。这项建议利用我们研究小组的独特资格来评估心肌损伤，并研究在胎儿搭桥和心脏骤停后保护心脏功能的方法。 与公共卫生相关：许多婴儿出生时心脏畸形非常复杂或危及生命，这些婴儿将受益于子宫内的纠正性心内直视手术。进行胎儿心脏直视手术的能力取决于在所需的心脏搭桥支持期间提供心肌保护。这项建议研究了胎儿搭桥导致心肌功能障碍的机制，从而导致在人类婴儿身上成功完成这些程序所需的心脏保护技术。

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.