Cardiomyocyte Chirality Defects in Congenital Heart Disease

Topic Area: Congenital Heart Disease

Area of Encouragement: Research to improve the understanding of the causes of congenital heart defects congenital heart disease (CHD) is defined as a structural abnormality in the heart present at birth. This can interfere with the normal function of the heart and in many cases is not compatible with life. It is the most common birth defect and affects about 1 million children and 1 million adults in the United States. It is also the most common cause of birth defect-related death, and in severe cases, many surgeries are required to fix defects. CHD is usually due to a failure of some part of heart development as a fetus, and in many cases can be linked to a genetic cause. The heart itself is divided into a left and right side, and failure to do so correctly leads to severe CHD. It is unclear why this happens, and in our proposal, we seek to make special stem cell lines known as induced pluripotent stem cells (iPSC) using both genetic data as well as directly from patients who have CHD due to this error. These cells have the capability to be directed into a number of tissue types, including heart cells. We will make these heart cells and compare their function to normal cells. We also have the capability of measuring the handedness of cells, which can be thought of as whether or not the cell is oriented to the left or the right. We will to measure this in our cell populations and determine whether cells derived from patients with this form of CHD have a defect in their left-right patterning. To do that, we will place these cells in a specialized system where we can measure whether they reproducibly orient themselves to the left or to the right. In this way, we will create an assay that could give us a readout of right and left at the cellular level, and we believe this is meaningful data in a disease process that is caused by an error in left and right specification as an embryo. This system will then be used to understand why certain genes, drugs, or even environmental exposures can lead to CHD during development. From these cells, we can also create engineered heart tissue and can explore how well the heart cells work both mechanically and electrically when they have problems with correctly oriented to the left or right. This would have an enormous amount of impact in our understanding of how certain CHDs form as well as clinically in terms of a mechanistic and functional understanding of the disease.