Sudden cardiac death during heart failure is a major concern in the United States and other Western Nations. The broad long term objectives of this study are to understand the time course and impact of heterogeneous gap junction and extracellular space remodeling during heart failure. It has been recently demonstrated that gap junction functional remodeling precedes conduction velocity changes by approximately two weeks.1 Since conduction slowing is implicated as a mechanism of sudden cardiac death, and the relationship between gap junctions and conduction velocity is a topic of significant controversy and debate, it is imperative to understand all the mechanisms that modify this relationship. Even more broadly speaking, the gap junction-conduction velocity (Gj-?) relationship is important for understanding sudden cardiac death in diseases such as ischemia, hypertrophy, and heart failure, because all three are associated with gap junctional remodeling and altered conduction. If the extracellular space significantly modulates the gap junction conduction velocity relationship as preliminarily demonstrated in this application, then modulating the cardiac extracellular space may be a previously untapped therapeutic target for heart failure. Our approach to address this hypothesis will bring together three state of the art methodologies and associated experts. 1. Dr. Steven Poelzing (PI), an expert on quantifying the Cx43-conduction velocity relationship, will be responsible for demonstrating that pharmacologically modulating ventricular ECS modulates Gj-? relationship in pharmacologic and genetic models of Cx43 functional down-regulation. 2. Dr. Mohamed Salama (collaborator), an expert on morphometric analysis of cell structure and the extracellular matrix, will be responsible for determining how the ex-vivo interventions implemented by Dr. Poelzing changes cell size and the ECS. 3. Finally, Dr. James Keener, an expert of mathematically modeling cardiac conduction will develop a model of cardiac conduction that includes electric-field coupling in addition to gap junctional coupling. This model will include all the data collected from Drs. Poelzing, and Salama. The mathematical model will be validated against all interventions proposed in the animal experiments.

Public Health Relevance

Ventricular arrhythmias account for 80%2 of over 450,000 cases of sudden cardiac death that occur in the U.S. each year.3 While there is an established association between aberrant conduction and arrhythmias, the mechanisms of conduction failure in diseases such as heart failure and ischemia remain unknown. Interestingly, two common findings in heart failure and ischemia are an increased extracellular volume (i.e. edema)4 and impairment of intercellular coupling.1;5 The role of intercellular coupling is well researched, but controversial,6 and the role of the extracellular volume has been largely ignored until recently.7 The purpose of this proposal is to demonstrate that the extracellular space is an important determinant of risk for sudden cardiac death since it modulates the relationship between intercellular coupling and cardiac conduction. Modulating the extracellular space represents a novel therapeutic target for heart failure and sudden cardiac death.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Wang, Lan-Hsiang
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Virginia Polytechnic Institute and State University
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United States
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Raisch, Tristan; Khan, Momina; Poelzing, Steven (2018) Quantifying Intermembrane Distances with Serial Image Dilations. J Vis Exp :
Raisch, Tristan B; Yanoff, Matthew S; Larsen, Timothy R et al. (2018) Intercalated Disk Extracellular Nanodomain Expansion in Patients With Atrial Fibrillation. Front Physiol 9:398
Veeraraghavan, Rengasayee; Hoeker, Gregory S; Alvarez-Laviada, Anita et al. (2018) The adhesion function of the sodium channel beta subunit (?1) contributes to cardiac action potential propagation. Elife 7:
Entz 2nd, Michael; King, D Ryan; Poelzing, Steven (2017) Design and validation of a tissue bath 3-D printed with PLA for optically mapping suspended whole heart preparations. Am J Physiol Heart Circ Physiol 313:H1190-H1198
Greer-Short, Amara; George, Sharon A; Poelzing, Steven et al. (2017) Revealing the Concealed Nature of Long-QT Type 3 Syndrome. Circ Arrhythm Electrophysiol 10:e004400
Hoeker, Gregory S; Skarsfeldt, Mark A; Jespersen, Thomas et al. (2017) Electrophysiologic effects of the IK1 inhibitor PA-6 are modulated by extracellular potassium in isolated guinea pig hearts. Physiol Rep 5:
Abdullah, Osama M; Gomez, Arnold David; Merchant, Samer et al. (2016) Orientation dependence of microcirculation-induced diffusion signal in anisotropic tissues. Magn Reson Med 76:1252-62
George, Sharon A; Bonakdar, Mohammad; Zeitz, Michael et al. (2016) Extracellular sodium dependence of the conduction velocity-calcium relationship: evidence of ephaptic self-attenuation. Am J Physiol Heart Circ Physiol 310:H1129-39
Veeraraghavan, Rengasayee; Lin, Joyce; Keener, James P et al. (2016) Potassium channels in the Cx43 gap junction perinexus modulate ephaptic coupling: an experimental and modeling study. Pflugers Arch 468:1651-61
George, Sharon A; Poelzing, Steven (2016) Cardiac conduction in isolated hearts of genetically modified mice--Connexin43 and salts. Prog Biophys Mol Biol 120:189-98

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