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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Meadows, Tawanna
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Cincinnati Children's Hospital Medical Center
United States
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Cole, Charles R; Eghtesady, Pirooz (2016) The myocardial and coronary histopathology and pathogenesis of hypoplastic left heart syndrome. Cardiol Young 26:19-29
Cole, Charles R; Yutzey, Katherine E; Brar, Anoop K et al. (2014) Congenital heart disease linked to maternal autoimmunity against cardiac myosin. J Immunol 192:4074-82