Abstract 13889: Endothelin-1 Has a Pivotal Role in Contraction Variability in Hypertrophic Cardiomyopathy-Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Introduction. Despite the accumulating genetic and molecular research into hypertrophic cardiomyopathy (HCM), it remains unclear how this condition develops and worsens pathologically and clinically in terms of the genetic-environmental interactions. Establishing a human disease model for HCM would help us to clarify these disease mechanisms; however cardiomyocytes from living patients are not easily obtained for basic research. Patient-specific induced pluripotent stem cells (iPSCs) thus hold much promise for deciphering HCM.
Hypothesis. Interactions between genetic backgrounds and environmental factors are involved in the disease progression of HCM.
Methods. We generated iPSCs from two patients with HCM and a healthy control subject, and cardiomyocytes were differentiated by embryoid body formation. To identify candidate disease-promoting environmental factors, the cardiomyocytes were stimulated by several cardiomyocyte hypertrophy-promoting factors. The HCM pathological phenotypes were examined based on morphological properties such as cell size and intracellular sarcolemmal structures in randomly chosen cardiac troponin-T-positive single cardiomyocytes. In addition, high-speed video imaging with motion vector prediction revealed physiological contractile dynamics in the iPSC-derived single cardiomyocytes.
Results. Control- and HCM-iPSC-derived cardiomyocytes were similar under the basal condition in pathological features and contractile dynamics. However, only the HCM-iPSC-derived cardiomyocytes showed pathological phenotypes such as cardiomyocyte hypertrophy and increased intracellular sarcolemmal disorganization in the presence of endothelin-1 (ET-1) induction, and the effect was dose dependent (10, 100, and 1000 nM). Physiological analyses also revealed that self-beating HCM-iPSC-derived single cardiomyocytes stimulated by ET-1 showed variable contractile directions. Finally, inhibiting the endothelin type A receptor rescued these deleterious effects.
Conclusions. Interactions between a patient’s genetic background and the environmental factor, ET-1, promote the HCM pathological phenotypes and contractile variability in iPSC-derived cardiomyocytes.
- © 2012 by American Heart Association, Inc.