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Dissertation Defense: The Role of the Perinexus in Long QT Syndrome Type 3

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Xiaobo Wu

Dissertation Defense: The Role of the Perinexus in Long QT Syndrome Type 3

Xiaobo Wu

Graduate Student, Translational Biology, Medicine, and Health
Graduate Research Assistant, Poelzing Lab, Fralin Biomedical Research Institute at VTC
Dec. 1, 2022, at 10:00 a.m.,  R3012, 2 Riverside Circle

About this Dissertation

Cardiovascular disease remains the leading cause of death around the world, and over 40% of those deaths are attributable to sudden cardiac death by ventricular arrhythmias. It has been demonstrated that sudden cardiac death is associated with prolonged QT interval measured by an electrocardiogram. The etiology of prolonged QT interval has been extensively described in a group of cardiac diseases known as the Long QT Syndromes (LQTS). As an exemplar of LQTS, Long QT Syndrome Type 3 (LQT3), which is caused by a gain-of- function of cardiac voltage-gated sodium channel (Nav1.5), has a high risk of sudden cardiac death relative to other types of LQTS. This gain of function leads to disruption of Nav1.5 inactivation, which increases the late sodium current (INaL) to prolong action potential duration (APD, equivalent to QT interval). However, LQT3 patients can have normal QT intervals, which hasn’t been clinically interpreted. Dr. Poelzing’s lab recently found in a drug-induced LQT3 guinea pig heart model that this concealed LQT3 phenotype may be caused by narrow perinexi, which are intercalated-disc nano-meter spaces that densely express Nav1.5. The putative mechanism states that narrowing the perinexus decreases the amount of local sodium ions in the perinexus, and Nav1.5 activation rapidly depletes perinexal sodium ions to decrease INaL and thereby shorten APD. In other words, widening the perinexus increases the amount of sodium ions to increase INaL and prolong APD. Logically and technically, the increase in the perinexal sodium ion availability can also be achieved by elevating sodium concentration without widening the perinexus. Poelzing's lab found that elevating extracellular sodium concentration alone prolonged APD and together with perinexal expansion synergistically exacerbated APD relative to the individual effects of high sodium or perinexal widening alone in drug-induced LQT3 guinea pig hearts, which suggests that managing sodium intake and preventing intercellular edema could benefit LQT3 patients. Furthermore, they also found that the perinexus narrows with aging to conceal the LQT3 phenotype, and importantly, widening the perinexus in aged LQT3 hearts increases the susceptibility to arrhythmias, which suggests that the increased incidence of sudden cardiac death in aged LQT3 patients may be associated with perinexal expansion. Furthermore, to rule out the off-targets of the drug that is commonly used to induce LQT3 phenotype in guinea pig hearts, the team further investigated the individual and combined effects of high sodium and perinexal expansion in a genetically modified LQT3 (ΔKPQ) mouse heart model. Surprisingly, they found that high sodium shortened APD, instead of prolonging it, in both wild-type and ΔKPQ hearts. Although perinexal expansion significantly prolonged APD in ΔKPQ hearts, the combined effect of high sodium and perinexal expansion on APD was not synergistic, likely due to the shortening effect of high sodium. Patch clamping on isolated mouse cardiomyocytes showed that high sodium increased transient outward potassium current (Ito), which is responsible for early repolarization. Overall, Poelzing's lab results showed that high sodium regulates both Ito and INaL in ΔKPQ hearts, and produces opposing effects on APD. Since the electrophysiological properties of the mouse heart are distinct to human heart, selection of a proper animal model which functionally expresses Ito channels and has similar electrophysiology as the human heart is very important. Overall, the whole project deeply and diversely investigated the role of the perinexus in LQT3 under different conditions including sodium stress, aging and species. 

More About the Candidate and Project

Education

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

Qilu Medical University, Biomedical Engineering

Training

Graduate Research Assistant, Poelzing Lab

 

Mentor

Steven Poelzing, Ph.D.Professor, Fralin Biomedical Research Institute at VTC, and Co-Director, Translational Biology, Medicine, and Health Graduate Program, Virginia Tech

Committee Members

  • Robert Gourdie, Ph.D., Professor and Director, Center for Heart and Reparative Medicine Research, Fralin Biomedical Research Institute at VTC
  • James Smyth, Ph.D., Associate Professor, Fralin Biomedical Research Institute at VTC
  • David C. Sane, M.D., Professor of Internal Medicine, Virginia Tech Carilion School of Medicine

Presentations

  • Wu X, King D, Hoeker G, Johnstone S, Gourdie R, Weinberg S, Poelzing S. Age-dependent remodeling of the perinexus modulates the phenotype and arrhythmic risk of Long QT Syndrome Type 3 (poster). Basic Cardiovascular Sciences Scientific Sessions (BCVS); 2022 July 25-28; Chicago, IL
  • Wu X, Hoeker G, Gourdie R, Weinberg S, Poelzing S. Long QT Syndrome Type 3 phenotype dependence on extracellular sodium and the perinexus in a genetic mouse model (poster). Basic Cardiovascular Sciences Scientific Sessions (BCVS); 2022 July 25-28; Chicago, IL
  • Wu X. Age-dependent intercalated disc perinexal narrowing conceals long-qt syndrome type 3 phenotype (oral). The 1st annual virtual Muscle Group at Virginia Tech Symposium; 2021 April 23; [Virtual meeting].
  • Wu X, Gourdie R, Hoeker G, Weinberg S, Poelzing S. Age-dependent intercalated disc perinexal narrowing conceals long-qt syndrome type 3 phenotype (poster). Biophysical Society Annual Meeting; 2021 Feb 22-26; [Virtual meeting].
  • Wu X, Hoeker G, King D, Gourdie R, Weinberg S, Poelzing S. Increased Extracellular Sodium and Intercellular Cleft Separation Synergistically Prolong Repolarization in the Long-QT Syndrome Type 3 (poster). American Heart Association Scientific Sessions; 2020 Nov 13-17 [Virtual meeting]; Circulation. 2020;142:A13191.
  • Wu X. Extracellular sodium concentration and intercellular nanodomain separation modulate long QT syndrome type 3 phenotype (oral). Research in Progress Symposium at Fralin Biomedical Research Institute at VTC [Virtual meeting]. 2020 Oct. 13th.
  • Wu X, Gourdie R, Weinberg S, Poelzing S. Increased extracellular sodium and intercalated disc separation exacerbates the cardiac long-qt type 3 phenotype (oral). Heart Rhythm Society Scientific Sessions; 2020 May 6-9; San Diego CA [Conference canceled due to COVID-19 pandemic, virtual meeting].

Publications

  • Wu X, King D, Hoeker G, Johnstone S, Gourdie R, Weinberg S, Poelzing S. Age-dependent remodeling of the perinexus modulates the phenotype and arrhythmic risk of Long QT Syndrome Type 3 (in preparation).
  • Wu X, Swanger S, Hoeker G, Gourdie R, Weinberg S, Poelzing S. Extracellular sodium regulates transient outward potassium and late sodium currents in a mouse model of Long QT Syndrome Type 3 (in preparation).
  • Colucci-Chang K, Adams W, Wu X, Blair G, Bhagia S, Ragauskas AJ, Hanlon A, Keener JP, Gourdie RG, Hoeker G, Poelzing S. The Nonlinear Relationship Between Conduction Velocity and Excitability in Ventricular Myocardium (in preparation). Journal of Physiology 
  • Zhang Y, Wu X, Vadlamani R, Lim Y, Kim J, et al. Multifunctional ferromagnetic fiber robots for navigation, sensing, and treatment in minimally invasive surgery (in review). Nature Biomedical Engineering
  • Wu X, Hoeker G, Blair G, King D, Gourdie R, Weinberg S, Poelzing S. Hypernatremia and intercalated disc edema synergistically exacerbate long-QT syndrome type 3 phenotype (published). Am J Physiol Heart Circ Physiol 2021;321(6): H1042-H1055
  • Nowak M, Greer-Short A, Wan X, Wu X, Deschênes I, Weinberg S, Poelzing S. Intercellular sodium regulates repolarization in cardiac tissue with sodium channel gain-of-function (published). Biophys J. 2020;118(11):2829-2843.