Humanized <i>Dsp</i> ACM Mouse Model Displays Stress-Induced Cardiac Electrical and Structural Phenotypes
Tyler L. Stevens,
Heather R. Manring,
Michael J. Wallace,
Aaron Argall,
Trevor Dew,
Peter Papaioannou,
Steve Antwi-Boasiako,
Xianyao Xu,
Stuart G. Campbell,
Fadi G. Akar,
Maegen A. Borzok,
Thomas J. Hund,
Peter J. Mohler,
Sara N. Koenig,
Mona El Refaey
Affiliations
Tyler L. Stevens
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Heather R. Manring
Comprehensive Cancer Center, The Ohio State University College of Medicine and Wexner Medical Center, Columbus, OH 43210, USA
Michael J. Wallace
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Aaron Argall
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Trevor Dew
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Peter Papaioannou
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Steve Antwi-Boasiako
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Xianyao Xu
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Stuart G. Campbell
Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
Fadi G. Akar
Department of Biomedical Engineering, Yale University, New Haven, CT 06520, USA
Maegen A. Borzok
Biochemistry, Chemistry, Engineering, and Physics Department, Commonwealth University of Pennsylvania, Mansfield, PA 16933, USA
Thomas J. Hund
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Peter J. Mohler
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Sara N. Koenig
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Mona El Refaey
Frick Center for Heart Failure and Arrhythmia Research, The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
Arrhythmogenic cardiomyopathy (ACM) is an inherited disorder characterized by fibro-fatty infiltration with an increased propensity for ventricular arrhythmias and sudden death. Genetic variants in desmosomal genes are associated with ACM. Incomplete penetrance is a common feature in ACM families, complicating the understanding of how external stressors contribute towards disease development. To analyze the dual role of genetics and external stressors on ACM progression, we developed one of the first mouse models of ACM that recapitulates a human variant by introducing the murine equivalent of the human R451G variant into endogenous desmoplakin (DspR451G/+). Mice homozygous for this variant displayed embryonic lethality. While DspR451G/+ mice were viable with reduced expression of DSP, no presentable arrhythmogenic or structural phenotypes were identified at baseline. However, increased afterload resulted in reduced cardiac performance, increased chamber dilation, and accelerated progression to heart failure. In addition, following catecholaminergic challenge, DspR451G/+ mice displayed frequent and prolonged arrhythmic events. Finally, aberrant localization of connexin-43 was noted in the DspR451G/+ mice at baseline, becoming more apparent following cardiac stress via pressure overload. In summary, cardiovascular stress is a key trigger for unmasking both electrical and structural phenotypes in one of the first humanized ACM mouse models.