Ryan King's Dissertation Defense (12/4/20): Effects of Perfusate Composition (Na+ and Ca2+) on Cardiac Electrical and Mechanical Function in the Isolated Langendorff-Perfused Heart
Dissertation Defense: Effects of Perfusate Composition (Na+ and Ca2+) on Cardiac Electrical and Mechanical Function in the Isolated Langendorff-Perfused Heart
Ryan King
Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Poelzing Lab, Fralin Biomedical Research Institute at VTC
Dec. 4, 2020 at 1:00 p.m.
About this Dissertation
In recent years, scientific rigor and reproducibility has garnered increased attention in both the scientific and public media. In several recent reports, the high attrition rate observed in clinical trials has been attributed to irreproducibility at the preclinical level. Preclinical cardiology is no exception to this rule. In King's systematic review of the ex vivo Langendorff-perfused heart, he found methods reporting to be sparse at best, specifically as it pertains to documenting the ex vivo perfusate compositions employed in the Langendorff heart. Previously, the Poelzing Lab, in which King conducts research, has demonstrated that variation in perfusate compositions can unmask disease states in genetically modified animals. In this dissertation, King exploits this concept with a therapeutic end-point in mind. The research shows that perfusate variation, specifically sodium and calcium elevations, can attenuate conduction slowing associated with severe hyperkalemia. Likewise, elevating sodium is capable of sustaining intrinsic rhythm where hearts would otherwise go asystolic. In doing so, elevated sodium prevents repolarization prolongation in these hearts. Together, these studies would suggest that elevating extracellular sodium, and calcium, should be considered as therapeutic targets in the context of conduction defects. However, when considering the heart’s primary role as a pump, King's research found that elevating sodium depresses cardiac mechanical function. This is both in a healthy and post-ischemic setting. In short, the dissertation shows that electrolyte variation may influence both cardiac electrophysiology and contraction; however, an improvement in one does not guarantee an improvement in both. Maintaining proper cardiac physiological function is a complex process that is tightly regulated by the ionic makeup of the extracellular environment and in order to improve insights from preclinical studies at the clinical level it is paramount that researchers properly document employed methodologies as they pertain to perfusate composition.
More About the Candidate and Project
Education
Virginia Tech Translational Biology, Medicine, and Health, Ph.D. Candidate
University of North Carolina - Chapel Hill, B.S., Biology
Training
Graduate Research Assistant, Poelzing Lab, Fralin Biomedical Research Institute at VTC
Mentor
Steven Poelzing, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC
Committee Members
- Robert Gourdie, Ph.D., Professor and Director, Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute
- Robert W. Grange, Ph.D., Associate Professor, Department of Human Nutrition, Foods, and Exercise, College of Agriculture and Life Sciences, Virginia Tech
- Sarah Henrickson Parker, Ph.D., Research Associate Professor, Fralin Biomedical Research Institute at VTC
Ex-officio Committee Members
- Michael Friedlander, Ph.D., Executive Director, Fralin Biomedical Research Institute at VTC, and Virginia Tech Vice President for Health Sciences and Technology
- Michelle Theus, Ph.D., Associate Professor, Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine
- Steven Poelzing, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC
Honors
- Michael J Quillen Leadership Award
- Ruth L. Kirschstein Predoctoral (F31) Fellowship
- Honorable Mention, National Science Foundation Graduate Research Fellows Program
Presentations
King DR, Entz II M, Blair G, Crandell I, Hanlon AL, Lin J, Hoeker GS, Poelzing S. Increased Extracellular Sodium and Calcium Modify the Extracellular Potassium and Cardiac Conduction Velocity Relationship in a Langendorff-Perfused Guinea Pig Heart. American Heart Association 2020 Scientific Sessions. (ePoster)
Wu X, Hoeker GS, King DR, Gourdie R, Weinberg SH, Poelzing S. Increased Extracellular Sodium and Intercellular Cleft Separation Synergistically Prolong Repolarization in the Long-QT Syndrome Type 3. American Heart Association 2020 Scientific Sessions. (ePoster)
Padget R, King DR, North MD, Tanenbaum MN, Calhoun PJ, Hoeker GS, Poelzing S, Smyth JW. Cardiotropic Adenovirus Increases Arrhythmia Susceptibility During Acute Infection. American Heart Association Basic Cardiovascular Sciences Scientific Sessions, July 2020. (Poster)
Publications
King DR, Padget RL, Perry J, Smyth JW, Brown DA, Poelzing S. The effect of modulating perfusate ionic composition on recovery of cardiac electrical and mechanical function following global ischemia. Scientific Reports, 2020. PMID: 33057157
George SA, Hoeker G, Calhoun PJ, Entz II M, Raisch TB, King DR, Kahn M, Baker C, Smyth JW, Nielsen MS, Poelzing S. Modulation electrophysiology during metabolic ischemia with perfusate sodium and calcium in guinea pigs. American Journal of Physiology– Heart and Circulatory Physiology. 2019;316(4):H849-H861. PMID: 30707595
Albatat M, King DR, Unger LA, Arevalo H, Wall S, Sundnes J, Bergsland J, Balasingham I. Electromechanical model to predict cardiac resynchronization therapy. 40th Annual International Conference of the IEEE EMBC. PMID: 30441569
Veeraraghavan R, Hoeker GS, Alvarez-Laviada A, Hoagland D, Wan X, King DR, Sanchez-Alonso J, Chen C, Jourdan J, Isom LL, Deschenes I, Smyth J, Gorelik J, Poelzing S, Gourdie RG. The adhesion function of the sodium channel beta subunit contributes to cardiac action potential propagation. eLife. 2018;7e37610. PMID: 30106376
Raisch TB, Yanoff MS, Larsen TR, Farooqui MA, King DR, Veeraraghavan R, Gourdie RG, Baker JW, Arnold WS, AlMahameed ST, Poelzing S. Intercalated Disk Extracellular Nanodomain Expanision in Patients with Atrial Fibrillation. Frontiers in Physiology. 2018;9:398. PMID: 29780324
Entz MW, King DR, Poelzing S. Design and validation of a tissue bath 3D printed with PLA for optically mapping suspended whole heart preparations. American Journal of Physiology – Heart and Circulatory Physiology. 2017;313(6):H1190-H1198. PMID: 28939646
King DR, Mehta ND, Gehi AK, Pursell I, Mounsey P, Kumar P, Bamimore A, Chung EH. Minimally Symptomatic Atrial Fibrillation Patients Derive Significant Symptom Relief Following Rate Control or Rhythm