Discovery of an Experimental Model of Unicuspid Aortic Valve
Background The epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss‐of‐function mutation in epithelial growth factor receptor, which are EgfrVel/+ mice, would develop anomalous aorti...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2018-07-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.117.006908 |
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| author | Robert M. Weiss Yi Chu Robert M. Brooks Donald D. Lund Justine Cheng Kathy A. Zimmerman Melissa K. Kafa Phanicharan Sistla Hardik Doshi Jian Q. Shao Ramzi N. El Accaoui Catherine M. Otto Donald D. Heistad |
| author_facet | Robert M. Weiss Yi Chu Robert M. Brooks Donald D. Lund Justine Cheng Kathy A. Zimmerman Melissa K. Kafa Phanicharan Sistla Hardik Doshi Jian Q. Shao Ramzi N. El Accaoui Catherine M. Otto Donald D. Heistad |
| author_sort | Robert M. Weiss |
| collection | DOAJ |
| description | Background The epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss‐of‐function mutation in epithelial growth factor receptor, which are EgfrVel/+ mice, would develop anomalous aortic valves, valve dysfunction, and valvular cardiomyopathy. Methods and Results Aortic valves from EgfrVel/+ mice and control mice were examined by light microscopy at 2.5 to 4 months of age. Additional EgfrVel/+ and control mice underwent echocardiography at 2.5, 4.5, 8, and 12 months of age, followed by histologic examination. In young mice, microscopy revealed anatomic anomalies in 79% of EgfrVel/+ aortic valves, which resembled human unicuspid aortic valves. Anomalies were not observed in control mice. At 12 months of age, histologic architecture was grossly distorted in EgfrVel/+ aortic valves. Echocardiography detected moderate or severe aortic regurgitation, or aortic stenosis was present in 38% of EgfrVel/+ mice at 2.5 months of age (N=24) and in 74% by 8 months of age. Left ventricular enlargement, hypertrophy, and reversion to a fetal myocardial gene expression program occurred in EgfrVel/+ mice with aortic valve dysfunction, but not in EgfrVel/+ mice with near‐normal aortic valve function. Myocardial fibrosis was minimal or absent in all groups. Conclusions A new mouse model uniquely recapitulates salient functional, structural, and histologic features of human unicuspid aortic valve disease, which are phenotypically distinct from other forms of congenital aortic valve disease. The new model may be useful for elucidating mechanisms by which congenitally anomalous aortic valves become critically dysfunctional. |
| first_indexed | 2024-04-13T16:31:33Z |
| format | Article |
| id | doaj.art-9dcf4eb9be924473bef3e15f98df401f |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-13T16:31:33Z |
| publishDate | 2018-07-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-9dcf4eb9be924473bef3e15f98df401f2022-12-22T02:39:34ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802018-07-0171310.1161/JAHA.117.006908Discovery of an Experimental Model of Unicuspid Aortic ValveRobert M. Weiss0Yi Chu1Robert M. Brooks2Donald D. Lund3Justine Cheng4Kathy A. Zimmerman5Melissa K. Kafa6Phanicharan Sistla7Hardik Doshi8Jian Q. Shao9Ramzi N. El Accaoui10Catherine M. Otto11Donald D. Heistad12Division of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IAThe Central Microscopy Core Carver College of Medicine University of Iowa Iowa City IADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IADivision of Cardiology University of Washington School of Medicine Seattle WADivision of Cardiovascular Medicine Carver College of Medicine University of Iowa Iowa City IABackground The epithelial growth factor receptor family of tyrosine kinases modulates embryonic formation of semilunar valves. We hypothesized that mice heterozygous for a dominant loss‐of‐function mutation in epithelial growth factor receptor, which are EgfrVel/+ mice, would develop anomalous aortic valves, valve dysfunction, and valvular cardiomyopathy. Methods and Results Aortic valves from EgfrVel/+ mice and control mice were examined by light microscopy at 2.5 to 4 months of age. Additional EgfrVel/+ and control mice underwent echocardiography at 2.5, 4.5, 8, and 12 months of age, followed by histologic examination. In young mice, microscopy revealed anatomic anomalies in 79% of EgfrVel/+ aortic valves, which resembled human unicuspid aortic valves. Anomalies were not observed in control mice. At 12 months of age, histologic architecture was grossly distorted in EgfrVel/+ aortic valves. Echocardiography detected moderate or severe aortic regurgitation, or aortic stenosis was present in 38% of EgfrVel/+ mice at 2.5 months of age (N=24) and in 74% by 8 months of age. Left ventricular enlargement, hypertrophy, and reversion to a fetal myocardial gene expression program occurred in EgfrVel/+ mice with aortic valve dysfunction, but not in EgfrVel/+ mice with near‐normal aortic valve function. Myocardial fibrosis was minimal or absent in all groups. Conclusions A new mouse model uniquely recapitulates salient functional, structural, and histologic features of human unicuspid aortic valve disease, which are phenotypically distinct from other forms of congenital aortic valve disease. The new model may be useful for elucidating mechanisms by which congenitally anomalous aortic valves become critically dysfunctional.https://www.ahajournals.org/doi/10.1161/JAHA.117.006908aortic valveaortic valve regurgitationaortic valve stenosis |
| spellingShingle | Robert M. Weiss Yi Chu Robert M. Brooks Donald D. Lund Justine Cheng Kathy A. Zimmerman Melissa K. Kafa Phanicharan Sistla Hardik Doshi Jian Q. Shao Ramzi N. El Accaoui Catherine M. Otto Donald D. Heistad Discovery of an Experimental Model of Unicuspid Aortic Valve Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease aortic valve aortic valve regurgitation aortic valve stenosis |
| title | Discovery of an Experimental Model of Unicuspid Aortic Valve |
| title_full | Discovery of an Experimental Model of Unicuspid Aortic Valve |
| title_fullStr | Discovery of an Experimental Model of Unicuspid Aortic Valve |
| title_full_unstemmed | Discovery of an Experimental Model of Unicuspid Aortic Valve |
| title_short | Discovery of an Experimental Model of Unicuspid Aortic Valve |
| title_sort | discovery of an experimental model of unicuspid aortic valve |
| topic | aortic valve aortic valve regurgitation aortic valve stenosis |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.117.006908 |
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