Congenital heart disease research

Congenital heart defects are the most common birth defect. In order to provide the best treatment possible, we need to better understand what causes the heart to develop abnormally and improve early detection.

The lab of Michael E. Mitchell, MD, and Aoy Tomita-Mitchell, PhD

Genetic and molecular etiology of congenital heart disease

Our laboratory is interested in studying underlying genetic risk factors of congenital heart disease and in understanding how these genetic alterations can impact pathways at the molecular level and lead to clinical variability. Ultimately, we hope to be able to use molecular biology and genetics to improve outcomes for patients with congenital heart disease. To reach this goal, our lab focuses on:

• Management of a congenital heart disease tissue and DNA bank, a repository of DNA and surgical discards from patients and family members
• Integration of genetic information with clinical variability and outcomes
• Utilizing stem cells in congenital heart disease — investigating potential in therapy and using induced pluripotent stem cell technology to investigate gene expression profiles

Development of genetic screening assays for congenital heart disease

There is a critical need to develop a more sensitive and cost-effective screening method to identify DiGeorge syndrome type 1 (DGS1), which is estimated to be the most prevalent inheritable genetic deletion syndrome, occurring in greater than 1 in 2,000 live births. The condition is associated with a wide range of complications, including congenital heart defects, velopharyngeal abnormalities, learning difficulties, endocrine abnormalities, renal anomalies and immune defects.

Unfortunately, most DGS1 patients go undiagnosed for years because of the condition's varied clinical symptoms and the fact that previous diagnostic tests missed at least 15 percent of all microdeletions in the DGS1 region (chromosome 22q11.2), which is the region associated with DGS1. As a result, only 25 percent of DiGeorge patients are diagnosed in infancy, with the median age of diagnosis for all other affected patients being 8 years of age. Early diagnosis and appropriate medical intervention can prevent and effectively treat many of the co-morbidities associated with this condition. We believe that detecting DGS1 early in life will allow for potentially life-saving medical interventions for the many disabilities associated with this disorder, such as congenital heart disease and severe immunodeficiency.

Development of a noninvasive diagnostic test for fetal genetic and chromosomal abnormalities

An increasing number of fetal medical conditions can be successfully managed during the neonatal period if an early diagnosis is made. Because of the inadequate sensitivity and specificity of currently available noninvasive tools, amniocentesis and chorionic villus sampling, which are both invasive procedures, remain the standard for the definitive detection of fetal genetic and chromosomal abnormalities. Both of these procedures carry health risk for the developing fetus. We are involved with developing a noninvasive approach using maternal plasma to identify fetal genetic variation associated with fetal conditions. We believe that early intervention, including immediate postnatal access to cardiac care, will improve neonatal mortality rates and long-term outcomes for Wisconsin's children.

Role of metakaryotic stem cells in vascular stenosis including transplant atherosclerosis, coronary artery disease and progressive pulmonary venous stenosis

Working with a team at the Massachusetts Institute of Technology, we have observed that metakaryotic stem cells are present and enriched in a variety of both normal and pathologic tissue in the developing heart and in conditions such as coronary atherosclerosis associated with chronic rejection of heart transplant patients as well as in progressive pulmonary venous stenosis.

Development of a highly sensitive and specific non-invasive test for monitoring transplant rejection by quantifying circulating donor specific cell-free DNA

We and others have established that donor organs release small quantities of fragmented cell-free DNA at basal levels into the circulation of recipients and that these levels increase during cellular injury from immune-mediated rejection. We are employing a novel targeted approach which is cost effective, scalable, sensitive and specific to evaluate this relationship. This NIH-funded research effort will conduct a large-scale prospective multicentered study at the Medical College of Wisconsin and Children's with MCW/CHW as the lead.