Abstract 19764: Cardiac Disease Modeling of Familial Left Ventricular Noncompaction Cardiomyopathy Using Induced Pluripotent Stem Cells

Abstract

Left ventricular noncompaction cardiomyopathy (LVNC) is thought to arise from developmental arrest of the normal compaction of ventricular heart muscle, sometime between weeks 4-8 of gestation. In normal heart development, a network of muscle bands (trabeculations) compact fully, resulting in a dense muscle and a smooth inner surface. Failure of trabecular compaction results in a muscle wall consisting of a spongy myocardium with a meshwork of trabeculations that can lead to thin dilated heart muscle and impaired muscle function. Although several disease-causing genes have been implicated in LVNC, the genetic cause remains unknown in more than 50% of patients. We hypothesize that LVNC arises from developmental arrest of the embryonic ventricular myocardial compaction process and that LVNC patients will have expression profiles reflective of this. We have identified a family with LVNC affecting 4 individuals. Through whole exome sequencing we identified a mutation in a cardiac developmental gene that was associated with the LVNC phenotype and was fully penetrant in this family. Using dermal fibroblasts from members of this family, we generated induced pluripotent stem (iPS) cells from affected and unaffected family members to identify transcriptome and functional consequences in cardiomyocytes harboring the genetic mutation. We will present our results from this genetic and cellular approach to LVNC, which allows study of the physiologic consequences of genetic mutations in relevant human cells.