Myocardial Protection during Fetal Bypass: Role of Calcium Cycling

胎儿搭桥期间的心肌保护：钙循环的作用

• 批准号: 8133412
• 负责人: Charles R Cole
• 金额: $ 5.3万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-07 至 2012-07-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8133412
• 关键词: Accounting; Affect; Biochemical; Birth; Blood; Blood flow; Bypass; Calcium; Calcium Signaling; Cardiac; Cardiac Output; Cardiac Surgery procedures; Cell Survival; Child; Clinical; Complex; Congenital Abnormality; Congenital Heart Defects; Contractile Proteins; Defect; Disease; Exposure to; Extracorporeal Circulation; Fellowship; Fetus; Functional disorder; Goals; Heart; Heart Arrest; Human; Imagery; Induced Heart Arrest; Injury; Intervention; Knowledge; Lead; Life; Medical; Methods; Modeling; Molecular; Morbidity - disease rate; Myocardial; Myocardial dysfunction; Myocardium; Neonatal; Operative Surgical Procedures; Outcome; Paralysed; Pathogenesis; Pattern; Pediatric Hospitals; Physicians; Potassium; Pregnancy; Premature Infant; Prevention; Procedures; Proteins; Regimen; Reperfusion Injury; Research; Role; Safety; Scientist; Sheep; Surgeon; Talents; Techniques; Testing; Translating; Translations; United States; Uterus; clinical application; clinical care; comparative efficacy; congenital heart disorder; experience; fetal; fetal cardiac surgery; heart function; improved; in utero; malformation; mortality; natural hypothermia; novel; outcome forecast; postnatal; protein function; public health relevance; repaired; research study; response

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.

描述（由申请人提供）：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，但心脏畸形仍然占所有出生缺陷相关死亡率的三分之一。某些复杂的病症在子宫内或出生后不久具有显著相关的死亡率和发病率。此外，这些缺陷的产后修复可能更加复杂，因为先前的损伤发生在子宫内，由于改变了心内血流模式。越来越多的证据表明，胎儿心脏干预可能会改变这些婴儿的不良预后。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旁路和缺血/再灌注损伤的反应。就我们所知，没有先前的研究专门研究胎儿心肌对旁路或心脏手术的其他组成部分的细胞反应。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转化的中心。 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。作为实现这一目标的另一步，本项目的目的是确定可能导致胎儿旁路术后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导致与胎儿心脏搭桥相关的心功能障碍，并且改良的心脏停搏液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外科手术干预的早产儿的临床护理。 我们使用了一种新的妊娠中期绵羊胎儿心脏搭桥和心脏骤停模型，该模型由辛辛那提儿童医院心胸外科研究小组开发，以测试具有以下特定目的的假设：1）确定钙循环机制在胎儿心脏搭桥术后心肌功能障碍发病机制中的作用; 2）目的比较灌注性与温血停搏液作为胎儿心肌保护策略的有效性。预期钙循环将在呼吸骤停中得以保留。然后，可以确定临床设置的最心脏保护方法。 总之，胎儿心脏手术的成功取决于手术过程中充分的心肌保护。这项建议利用我们研究小组的独特资格，以评估心肌损伤，并检查方法，以保持心脏功能后，胎儿旁路和心脏骤停。 公共卫生关系：许多婴儿出生时患有心脏畸形，这些畸形非常复杂或危及生命，这些婴儿将受益于子宫内的心脏直视手术。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。该提案研究了胎儿旁路术心肌功能障碍的潜在机制，从而导致成功完成人类婴儿这些程序所需的心脏保护技术。