Pediatric Cardiac Surgery Lab

The Stanford Pediatric Cardiac Surgery Lab research program is focused on three aspects of surgery for congenital cardiac disease:

Development of surgical and technological approaches for cardiac surgery in the fetus.

These projects include the study of techniques to prevent fetal-placental dysfunction associated with fetal cardiac bypass and identifying specific conditions for protecting fetal myocardial function during open cardiac surgery. Cardiac bypass in the fetus is much more complex, because the placenta serves as the fetal “lung” and fetal-placental gas exchange is extraordinarily sensitive to perturbations in blood flow, blood pressure, or even umbilical cord stretch or cooling. Further, since the fetal heart has an immature calcium metabolism, conditions normally used to temporarily paralyze the heart for surgery are toxic to the fetal heart, and we are examining improved approaches to cadioplegia of the fetal heart.

Reduction of morbidity associated with pediatric cardiac surgery patients.

Currently, the major emphasis is on the development of approaches to the protection of the developing neonatal brain from cerebral injury during complex repairs requiring cardiopulmonary bypass in neonates.

Bioengineering of heart valves and vascular tissues for pediatric applications.

Tissue engineering is an emerging area of inquiry of the Lab that is initially focused on bioengineering of pediatric heart valves that can self-renew as well as grow with the child. This new area of emphasis of the Lab is supported in part by a recent endowment funding the Alex Vibber Fellowship.

Brain protection by regional low flow perfusion (RLFP) during deep hypothermic circulatory arrest (DHCA) is especially critical to pediatric patients, because their developing brains are particularly vulnerable to hypoxic damage. Such damage may occur during extended periods of circulatory arrest needed for repair of complex congenital cardiac lesions. We have recently begun to model the protective effects of RLFP during DHCA on neuronal and glial cell apoptosis in the piglet brain. These studies seek objective evidence of the beneficial effects of RLFP on brain apoptosis in a neonatal model. We are in the process of analyzing the data from a recent series of piglet studies that we expect will demonstrate the ability of RLFP to reduce cellular apoptosis in vulnerable brain regions. These studies have now been extended to the evaluation of neuronal damage via MRI.

We have implemented a program in heart valve tissue biology and bioengineering to meet the unique needs of pediatric patients. Since a child’s heart and great vessels are still growing rapidly, children soon outgrow the materials (cadaver-derived valves and vascular patch material) presently available for repairing congenital heart defects that require additional tissue. In addition, these non-growing tissues patches also do not self-renew and fail earlier in children than in adults. We are developing the technology to produce transplantable tissues that can grow with the children who need additional tissue to completely repair their heart. The efforts of the Lab are initially focused on bioengineering of pediatric heart valves. Experiments are underway to establish the conditions under which valves self-renew and grow, using a biomimetic culture system that replicates the biomechanical stimuli experienced by heart valves in vivo. This area of fundamental biology is critical to the goals of bioengineering custom-sized replacement tissues for children’s hearts.

Stanford's major programming emphasis on Regenerative Medicine brings together physicians, basic scientists, and engineers to tackle the immense issues of bioengineering, stem cell biology, and biotherapeutics. We believe that our research emphasis will prove fundamental and complementarily pivotal to the success of many approaches now underway worldwide to generate engineered tissues. We are collaborating with scientists in medical as well as engineering disciplines in a team approach to this project. These heart valve regenerative biology studies are largely underwritten by the Alex Vibber Endowment and also supported by the Oak Foundation.

We have developed unique large animal models - first in the sheep and presently in the baboon - and used them to develop techniques for fetal cardiac bypass and to study the pathophysiologic response to cardiac bypass. We believe that surgical correction of certain congenital heart defects in utero is feasible and provides the opportunity for significant reduction in morbidity by restoring normal blood flow patterns through the heart and great vessels. It has been shown that the bulk of the cardiac maldevelopment is secondary to the disturbed flow patterns that arise, for example, when the tricuspid valve fails to develop. During fetal life in the presence of tricuspid atresia, the failure of blood to flow into the right ventricle results in hypoplasia of the RV. If the normal flow pattern through the valve could be re-established early in gestation, the flow-dependent pathophysiology should be prevented. This is the rationale for fetal cardiac surgery.

To perform surgery on intracardiac structures or great vessels, it is necessary to put the fetus on extracorporeal circulation (i.e., cardiac bypass). Since the fetus is already on physiologic ‘bypass’ via the placenta, extracorporeal cardiac bypass in the fetus is much more complex than cardiopulmonary bypass after birth and presents many unique challenges. Through our ongoing studies, we have shown that cardiac bypass can be safely performed in fetuses as small as 450 grams without transfusion. We have also demonstrated that several critical variables - including anesthesia modality, fetal temperature changes, umbilical cord manipulation, uterine tone, and maternal blood pressure - interact in complex ways that frequently result in compromised utero-placental gas exchange following the return from bypass. These fetal surgical intervention studies are supported in part by the Oak Foundation.

Another area of post surgical morbidity we are addressing in our laboratory is the failing Fontan circulation. In a significant number (up to 40%) of patients undergoing single ventricle palliation to a Fontan circulation, this physiology ultimately fails. This can lead to signs of heart failure, liver failure, or protein losing enteropathy. All of these complications are associated with high mortality risks.

Mechanical support of left ventricular function is presently already in clinical use, but support of right ventricular function (or, as in a Fontan circulation, complete artificial replacement of the right ventricle) is less explored. We are currently testing the effectiveness of pump support as an approach to reversing Fontan failure in these patients.

Our fetal cardiac bypass studies focus on umbilical-placental circulatory changes. The heart is beating under the bypass conditions employed in those studies. However, to provide a clear surgical field for cardiac and great vessel repairs, the heart must be stopped and will therefore undergo a period of ischemia followed by reperfusion. Our studies focusing on cardioplegia of the fetal heart will extend our fetal cardiac surgery approaches into the area of protection from ischemic arrest. These studies focus on critically important variables that we believe will define fundamental differences in response to cardioplegia of the fetal myocardium and provide information fundamental to progress in our in vivo studies. These studies concern the specific needs for calcium ion concentration, oxygen concentration, and coronary perfusion pressure for cardioplegia of the fetal heart.

To provide safe surgery on the fetal heart, optimal conditions for protecting myocardium from cellular damage during periods of heart stoppage need to be determined. Several years ago, we began studies of methods for protecting the fetal heart using a fetal sheep model. We determined that the fetal heart tolerates fibrillation as a protective procedure and that reducing calcium ion concentration is better than using the concentration normally present in solutions used to stop the neonatal heart. However, neither of these neonatal cardioprotection conditions provides optimal protection of the fetal heart. Our goal is to determine the conditions that are best through further studies of fetal myocardial protection. At present, we are re-establishing the fetal heart model here at Stanford. These studies are done in vitro, but require a pregnant sheep as the source of the fetal heart.