Abstract 15719: Deletion of Desmoplakin, a Gene Responsible for Arrhythmogenic Cardiomyopathy, Specifically in Cardiac CSPG4pos Cells Leads to Cardiac Arrhythmias and Premature Death
Introduction: Arrhythmogenic cardiomyopathy (AC) is an inherited myocardial disease, manifesting with cardiac arrhythmias, sudden cardiac death, and heart failure. AC is commonly caused by mutations in genes encoding desmosome proteins, which are primarily expressed in cardiac myocytes and epithelial cells. Dsp encoding desmoplakin is a major cause of AC and a subgroup of AC, referred to as cardiocutaneous syndrome. In the heart, hitherto, cardiac myocytes are the only cell type known to express desmosome proteins. Thus, AC is considered primarily a disease of myocytes.
Hypothesis: Heart, a cellularly heterogeneous organ, contains cells of epithelial origin that express desmosome proteins and contribute to the pathogenesis of AC
Methods: Dsp gene was conditionally deleted in the CSPG4pos cells. Cardiac function was assessed by echocardiography, cardiac rhythm by monitoring and electrophysiology studies, and gene expression by molecular biology techniques.
Results: DSP is expressed, in addition to cardiac myocytes, in a subset of cardiac cells of epithelial origin identified by the expression of chondroitin sulfate proteoglycan 4 (CSPG4). CSPG4pos cells comprised < 10% of the non-cardiac myocyte cells in the heart. Inducible post-natal (P20) deletion of Dsp specifically in the CSPG4pos cells led to a near total mortality by 6 months of age, despite a normal myocardial histology and cardiac function. Electrocardiographic monitoring showed intermittent atrioventricular blocks and atrial fibrillation. Electrophysiologial studies showed inducible ventricular tachycardia and atrial fibrillation. Cspg4-Cre:DspF/F mice also exhibit growth retardation, severe skin keratosis and progressive baldness, resembling cardiocutaneous syndrome.
Conclusions: DSP is also expressed in a subset of cardiac cells of epithelial origin expressing the CSPG4 protein. Deletion of Dsp in the CSPG4pos cells induces a phenotype resembling cardiocutaneous syndrome in man, including cardiac arrhythmias, keratosis, and premature death. The findings extend the cellular spectrum of AC, which is considered a disease of cardiac myocytes, to include non-cardiac myocyte cells in the hearts. <!--EndFragment-->
Author Disclosures: J. Karmouch: None. C. Miyake: None. R. Lombardi: None. X. Wehrens: None. J.T. Willerson: None. A.J. Marian: None.
- © 2016 by American Heart Association, Inc.