Eghtesady Lab

Exploring the causes of congenital heart disease

The Eghtesady Lab seeks to eradicate congenital heart disease through a better understanding of the mechanisms involved in its pathogenesis.

The causes of congenital heart disease (CHG) are likely multiple and often genetic in nature. For many, though, the etiology remains unknown. Our hypothesis is that perinatal infection during cardiac morphogenesis induces CHD. We are conducting studies to test this hypothesis—both by analysis of specimens from woman with pregnancies affected by CHD, as well as by studying offspring in animal models exposed to infections in early gestation.

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Principal investigator

Current research

Mechanisms in the pathogenesis of congenital heart disease

Under the guidance and supervision of Dr. Eghtesady and Dr. Garand, our laboratory conducts basic and clinical research to explore the causes of congenital heart disease. We test hypotheses by analyzing specimens from women with pregnancies affected by CHD and pediatric patient samples, as well as by studying offspring in animal models exposed to infections in early gestation. To drive discoveries, we used advanced experimental and analytical tools such as phage immunoprecipitation coupled with next generation sequencing technology.

Prevalence of human Pegivirus in subjects with SARS-CoV-2 infection

Investigating Enterovirus and the stool microbiome in pregnant women with and without diabetes

Enterovirus has been a major interest of the lab due to its significance in congenital heart disease. Diabetes and pregnancy are common major factors that affect the microbiome, especially considering that Type I and II diabetes are known to increase the severity of infections. In order to deeply understand the interplay between Enterovirus and the microbiome, we must understand how common factors affect its presence and role in the microbiome.

Dry-lab work for this project initially involved searching for public data repositories and exploring cloud computing for analysis. Now, we are using R and Python to write a bioinformatics pipeline for analysis of microarray data. On the wet-lab side, we perform extraction, purification, and quantification with bio specimens such as human whole blood, plasma, white blood cells, stool, and nucleic acid. We also use RT-qPCR, gel electrophoresis, viral culture, and more for this project.

Perinatal viral infection on development of heart defects in animal models

Our long-term goal is to understand the burden and mechanism(s) of virally induced CHD. We and others have data to support a role of “cardiotropic” viruses (i.e., viruses that have specific receptors in the fetal heart) in causing heart defects, by interfering with normal development during the critical window of the first trimester. These studies have shown infection with type B coxsackievirus (CVB) in early gestation induces heart defects in mice. To determine mechanisms in mediation of heart defects by CVB our studies include examination of the proliferation of CVB and signal transduction pathways.

The coxsackievirus-adenovirus (CAR) receptor plays a critical role in embryonic heart development, supporting our hypothesis that viral infections can be detrimental to normal cardiac formation. Using Cre-lox technology to achieve tissue-specific deletion of the CAR gene, we are examining heart development in mice.

Clinical research

For the past 20+ years, our group has been interested in improving outcomes of surgical interventions in infants and children with CHD, as well as extracorporeal circulatory support devices and pediatric thoracic organ transplantation.

Cardiac surgery

Implementation of quality-improvement measures has been a long-term focus for our group. To this end, we developed a prioritization scheme to target efforts in pediatric cardiac surgical procedures, as well as protocols for surgical pre-brief communication, which have been adopted by the American Heart Association. Additionally, our group has aimed to improve surgical outcomes using patient-specific 3D-printed models of complex CHD, such as tetralogy of Fallot with pulmonary atresia and major aortopulmonary collateral arteries, facilitating preoperative planning. Another primary focus of our clinical research has been single-ventricle CHD. Using data from a 10-year period in the United States, we found an association between seasonality and hypoplastic left heart syndrome. We have also analyzed the effect of preoperative factors, including age, weight, and ascending aorta size, on surgical outcomes at different stages of surgical palliation for these children.

More recently, we contributed to the 2020 STAT Update, aimed at assessing the risk of mortality in congenital heart surgery, and proposed a guide to facilitate clinical decision-making for patients with Trisomy 13 and 18 undergoing cardiac surgery. Moreover, we are currently participating in one of the largest multi-center trials, the STRESS trial, ever conducted in children with CHD to evaluate the safety and efficacy of perioperative steroids in infants undergoing cardiac surgery.

Mechanical and circulatory support

One of our areas of interest in clinical research is the use of mechanical circulatory support devices as a bridge to recovery or transplant in children. In particular, our institution pioneered the use of paracorporeal lung assist devices (PLAD) as a bridge to pediatric lung transplant, as well as ventricular assist devices (VAD) in children with single-ventricle CHD. We have also participated in various multi-center analyses of mechanical circulatory support outcomes and assessed multi-center results of extracorporeal membrane oxygenation (ECMO) and VAD support in children with end-stage cardiopulmonary failure.

Heart and lung transplantation

As one of the most experienced pediatric heart and lung transplant centers in the world, St. Louis Children’s Hospital provides an excellent environment for conducting research in these procedures.

In the realm of heart transplantation, our research has focused on various outcomes, including primary graft dysfunction and neurologic complications. We have analyzed heart transplantation in select populations, including children with Duchenne muscular dystrophy, single ventricle CHD, failed Fontan palliation, and chromosomal anomalies.

In terms of lung transplantation our research has focused on many areas, including the effect of different intraoperative circulatory support strategies, waitlist times, and outcomes in select populations, i.e., infants and children with alveolar capillary dysplasia and surfactant protein deficiency. Similarly, our center recently published a comparison of an alternative approach to pulmonary hypertension, the Potts shunt, versus lung transplant in children, and participated in a working group created by the International Society for Heart and Lung Transplantation to develop a universal definition and grading system for adult and pediatric airway complications following lung transplant.

Translational research

We currently have two lines of investigation into potential immune mechanisms in the pathogenesis of CHD. These include the potential role of Human Leukocyte Antigen in CHD, where we found a potential association between HLA-A*30 and CHD in patients transplanted due to CHD in the United Network for Organ Sharing (UNOS) database. Based on our murine model suggesting an association between gestational infection with coxsackievirus type B (CVB) and CHD, we conducted a prospective study examining CVB antibodies in pregnant women carrying babies with CHD. Results from our study found a potential link between maternal CVB infection and congenital pulmonary atresia.

Our team

Faculty investigators

Staff

Chelsea Mannie, BSN, BS

Research Nurse Coordinator

Chelsea Mannie oversees a number of research projects focusing on congenital heart defects in children. She joined the lab in 2022.

Students

• Pranav Kirti
• Ching Ching Zhang

News and updates

Lab alumni