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Rachel Padget's Dissertation Defense (3/11/2022): Arrhythmogenic Mechanisms of Acute Cardiac Infection

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Rachel Padget

Dissertation Defense: Arrhythmogenic Mechanisms of Acute Cardiac Infection

Rachel Padget

Graduate Student, Virginia Tech Translational Biology, Medicine, and Health
Graduate Research Assistant, Smyth Lab, Fralin Biomedical Research Institute at VTC
March 11, 2022 at 1:00 p.m.

About this Dissertation

Cardiovascular disease is the leading cause of death in the United States, with 42% of sudden cardiac death in young adults caused by myocarditis. Viruses represent the main cause of myocarditis, with adenovirus being a leading pathogen. However, it is not well understood how adenoviruses cause sudden cardiac arrerst, due to the species-specific nature of this virus family. Myocarditis is defined by two phases, acute and chronic. The acute phase involves viral-mediated remodeling of the subcellular structures of the myocardium, which is thought to contribute to the arrhythmias of sudden cardiac death. The chronic phase is immune response-mediated, where the host immune system causes damage that can cause gross structural remodeling of the heart and result in sudden cardiac arrest or heart failure. Electrical impulses of the heart are propagated by cardiomyocytes, with their gap junctions, ion channels, and intracellular junctions, which create the healthy heartbeat. Cx43, the primary gap junction protein in the myocardium, not only propagates the electrical signal, but also anti-viral molecules. Targeting gap junctions would be advantageous to a virus to reduce anti-viral responses in neighboring cells, and Padget and the Smyth Lab have previously demonstrated human adenoviruses do indeed target gap junction function in epithelial cells. Such reduced cellular communication however, would also dangerously alter cardiac conduction. Using a cardiotropic adenovirus, MAdV-3, Padget and the research team find that viral genomes are significantly enriched in the heart causing a decrease of gap junction and ion channel mRNA in infected hearts, however, protein levels were unchanged. Phosphorylation of Cx43 at serine 368, known to reduce gap junction opening probability, was also increased in infected hearts. Ex vivo optical mapping illustrated decreased conduction velocity in the intact infected heart and patch clamping of isolated cardiomyocytes revealed prolonged action potential duration, along with decreased potassium current density during infection. Coupling this mouse work with human induced pluripotent stem cell-derived cardiomyocytes, Padget found that human adenovirus type-5 infection also increased pCx43-Ser368 and perturbation of intercellular coupling, just as she and mentor James Smyth, Ph.D., observed with in vivo MAdV-3 infection. Allowing adenovirus infection to progress longer in vivo, a chronic infection develops and we find remodeling of the myocardium and immune cell infiltration into the tissue. Together, these data demonstrate the complexity of cardiac infection from viral-infection induced subcellular alterations in electrophysiology to immune-mediated cardiomyopathy development of cardiac adenoviral infection. Padget's data describe virally-induced mechanisms of arrhythmogenesis, which could lead to the development of new diagnostic tools and therapies, to help protect patients from arrhythmia and/or development of cardiomyopathies following infection.

More About the Candidate and Project

Education

Virginia Tech Translational Biology, Medicine, and Health, Ph.D. Candidate

Missouri State University, M.S., Biology

University of Central Missouri, B.S., Biochemistry

Training

Graduate Research Assistant, Smyth Lab and Center for Vascular and Heart Research

 

Mentor

James Smyth, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC

Committee Members

  • Shihoko Kojima, Ph.D., Associate Professor, Department of Biological Sciences, College of Science, Virginia Tech
  • Steven Poelzing, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC and Co-Director, Translational Biology, Medicine, and Health Graduate Program, Virginia Tech
  • Stefanie Robel, Ph.D., Associate Professor, Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham

Honors

  • National Institutes of Health National Heart Lung and Blood Institute F31 Fellow
  • Virginia Tech Graduate and Professional Student Senate Fall Travel Fund Award, December 2021
  • Local chapter nominee, P.E.O. Scholar Awards, October 2020
  • Runner up, Outstanding Graduate Student Leader of the Year, Student Engagement and Campus Life at Virginia Tech, April 2020
  • First Place, Breakout Session Oral Presentation, Virginia Tech Biological Sciences Research Day, February 2020
  • Outstanding abstract author, Virginia Tech Translational Biology, Medicine, and Health Open House Research Symposium, October 2019
  • Second Place, Biomedical Innovation Pitch Competition, Virginia Tech Carilion Research Institute, November 2017

Presentations

Oral: 

Padget RL, King DR, North MD, Zeitz MJ, Tanenbaum MN, Calhoun PJ, Hoeker GS, Poelzing S, Smyth JW. Cardiotropic adenovirus increases arrhythmia susceptibility during acute infection. Oral Presentation at American Society for Virology Annual Meeting, virtual event. July 21, 2021

Padget RL, King DR, North MD, Tanenbaum MN, Calhoun PJ, Hoeker GS, Poelzing S, Smyth JW. “Viral subversion of intercellular coupling; bridging the gap from mouse to human heart disease.” Oral presentation at International Gap Junction Conference 2021 Webinar series, A Coruña, Spain, virtual event. January 19, 2021

Padget RL, King DR, North MD, Tanenbaum MN, Calhoun PJ, Hoeker GS, Poelzing S, Smyth JW. “Viral subversion of intercellular coupling; bridging the gap from mouse to human heart disease.” Oral presentation at Science Xpression 2020, A Coruña, Spain, virtual event. October 7, 2020

Posters: 

Padget RL, King DR, North MD, Calhoun PJ, Hoeker GS, Poelzing S, Smyth JW. “Cardiotropic adenovirus increases arrhythmia susceptibility during acute infection.” Poster presented at American Heart Association Basic Cardiovascular Sciences Scientific Sessions, Chicago, Illinois, USA, virtual event. July 27, 2020

Padget RL, North M, King DR, Tanenbaum M, Calhoun P, Barrett S, Poelzing S, Smyth JW. “Employing a cardiotropic mouse adenovirus to model acute viral myocarditis and investigate mechanisms of arrhythmogenesis.” Poster presented at American Society for Cell Biology and European Molecular Biology Organization Annual Meeting, Washington D.C., USA. December 9, 2019

Publications

King DR, Padget RL, Perry JB, Hoeker G, Smyth JW, Brown DA, Poelzing S. Elevated perfusate [Na+] increases contractile dysfunction during ischemia and reperfusion. Scientific Reports. 2020 Oct 14; 10, 17289. DOI: 10.1038/s41598-020-74069-x

Calhoun PJ, Phan AV, Taylor JD, James CC, Padget RL, Zeitz MJ, Smyth JW. Adenovirus targets transcriptional and posttranslational mechanisms to limit gap junction function. The FASEB Journal. 2020 Jul;34(7):9694-9712. DOI: 10.1096/fj.202000667R

Padget RL, Mohite SS, Hoog TD, Justis BS, Green BE, Udan RS. Hemodynamic force is required for recruitment of vascular smooth muscle cells to blood vessels during mouse embryonic development. Mechanisms of Development. 2019 Apr;156:8-19. DOI: 10.1016/j.mod.2019.02.002

In Prep

Padget RL, Blair GA, North MD, King DR, Zeitz MJ, Tanenbaum MN, Hoeker GS, Swanger SA, Poelzing S, Smyth JW. Arrhythmogenic mechanisms of acute cardiac adenoviral infection. Research article.

Padget RL, North MN, Jan D, Smyth JW. The viral heart: From infection to heart failure. Review.

  • Communications Director, Big Lick of Science Podcast, 2020 – Current  (https://abiglickofscience.libsyn.com)
  • Meet a Scientist, Roanoke Welcoming Week Event, 2021, Roanoke, Virginia
  • Judge, NeuroSURF and Molecular Visualization SURF Summer Symposium, 2021, Roanoke, Virginia
  • Judge, Virginia State Science and Engineering Fair, 2020 – 2021, Roanoke, Virginia
  • Judge, Western Virginia Regional Science Fair, 2018 – 2021, Roanoke, Virginia
  • Judge, Roanoke Valley Governor’s School Project Forum, 2018 – 2021, Roanoke, Virginia      
  • Roanoke Graduate Student Association                                                              
    • Executive Chair, June 2019 – May 2020
    • Health and Student Services Chair, June 2018 – May 2019