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Electrophysiology and Arrhythmogenesis in the Human Right Ventricular Outflow Tract.

  • Academic Journal
  • Aras K; Department of Biomedical Engineering, George Washington University, Washington, DC (K.A., A.G., N.R.F., J.B., K.G., I.R.E.).
    Gams A; Department of Biomedical Engineering, George Washington University, Washington, DC (K.A., A.G., N.R.F., J.B., K.G., I.R.E.).
    Faye NR; Department of Biomedical Engineering, George Washington University, Washington, DC (K.A., A.G., N.R.F., J.B., K.G., I.R.E.).; Institut de rhythmologie et de modélisation cardiaque (LIRYC; The Rhythmology and Heart Modeling Institute), Bordeaux University, France (N.R.F., O.B.).
    Brennan J; Department of Biomedical Engineering, George Washington University, Washington, DC (K.A., A.G., N.R.F., J.B., K.G., I.R.E.).
    Goldrick K; Department of Biomedical Engineering, George Washington University, Washington, DC (K.A., A.G., N.R.F., J.B., K.G., I.R.E.).
    Li J; Department of Biomedical Engineering, Northwestern University, Evanston, IL (J.L., J.A.R.).; Department of Materials Science and Engineering, Ohio State University, Columbus, OH (J.L.).
    Zhong Y; Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign (Y.Z.).
    Chiang CH; Department of Biomedical Engineering, Duke University, Durham, NC (C.-H.C., J.V.).
    Smith EH; Department of Biomedical Sciences, East Tennessee State University, Johnson City (E.H.S., M.D.P., J.C., D.B.H.).
    Poston MD; Department of Biomedical Sciences, East Tennessee State University, Johnson City (E.H.S., M.D.P., J.C., D.B.H.).
    Chivers J; Department of Biomedical Sciences, East Tennessee State University, Johnson City (E.H.S., M.D.P., J.C., D.B.H.).
    Hanna P; University of California at Los Angeles Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, University of California, Los Angeles (P.H., S.M., O.A.A., K.S.).
    Mori S; University of California at Los Angeles Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, University of California, Los Angeles (P.H., S.M., O.A.A., K.S.).
    Ajijola OA; University of California at Los Angeles Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, University of California, Los Angeles (P.H., S.M., O.A.A., K.S.).
    Shivkumar K; University of California at Los Angeles Cardiac Arrhythmia Center and Neurocardiology Research Program of Excellence, University of California, Los Angeles (P.H., S.M., O.A.A., K.S.).
    Hoover DB; Department of Biomedical Sciences, East Tennessee State University, Johnson City (E.H.S., M.D.P., J.C., D.B.H.).
    Viventi J; Department of Biomedical Engineering, Duke University, Durham, NC (C.-H.C., J.V.).
    Rogers JA; Department of Biomedical Engineering, Northwestern University, Evanston, IL (J.L., J.A.R.).
    Bernus O; Institut de rhythmologie et de modélisation cardiaque (LIRYC; The Rhythmology and Heart Modeling Institute), Bordeaux University, France (N.R.F., O.B.).
    Efimov IR; Department of Biomedical Engineering, George Washington University, Washington, DC (K.A., A.G., N.R.F., J.B., K.G., I.R.E.).
  • Circulation. Arrhythmia and electrophysiology [Circ Arrhythm Electrophysiol] 2022 Mar; Vol. 15 (3), pp. e010630. Date of Electronic Publication: 2022 Mar 03.
  • English
  • Background: Right ventricular outflow tract (RVOT) is a common source of ventricular tachycardia, which often requires ablation. However, the mechanisms underlying the RVOT's unique arrhythmia susceptibility remain poorly understood due to lack of detailed electrophysiological and molecular studies of the human RVOT.
    Methods: We conducted optical mapping studies in 16 nondiseased donor human RVOT preparations subjected to pharmacologically induced adrenergic and cholinergic stimulation to evaluate susceptibility to arrhythmias and characterize arrhythmia dynamics.
    Results: We found that under control conditions, RVOT has shorter action potential duration at 80% repolarization relative to the right ventricular apical region. Treatment with isoproterenol (100 nM) shortened action potential duration at 80% repolarization and increased incidence of premature ventricular contractions ( P =0.003), whereas acetylcholine (100 μM) stimulation alone had no effect on action potential duration at 80% repolarization or premature ventricular contractions. However, acetylcholine treatment after isoproterenol stimulation reduced the incidence of premature ventricular contractions ( P =0.034) and partially reversed action potential duration at 80% repolarization shortening ( P =0.029). Immunolabeling of RVOT (n=4) confirmed the presence of cholinergic marker VAChT (vesicular acetylcholine transporter) in the region. Rapid pacing revealed RVOT susceptibility to both concordant and discordant alternans. Investigation into transmural arrhythmia dynamics showed that arrhythmia wave fronts and phase singularities (rotors) were relatively more organized in the endocardium than in the epicardium ( P =0.006). Moreover, there was a weak but positive spatiotemporal autocorrelation between epicardial and endocardial arrhythmic wave fronts and rotors. Transcriptome analysis (n=10 hearts) suggests a trend that MAPK (mitogen-activated protein kinase) signaling, calcium signaling, and cGMP-PKG (protein kinase G) signaling are among the pathways that may be enriched in the male RVOT, whereas pathways of neurodegeneration may be enriched in the female RVOT.
    Conclusions: Human RVOT electrophysiology is characterized by shorter action potential duration relative to the right ventricular apical region. Cholinergic right ventricular stimulation attenuates the arrhythmogenic effects of adrenergic stimulation, including increase in frequency of premature ventricular contractions and shortening of wavelength. Right ventricular arrhythmia is characterized by positive spatial-temporal autocorrelation between epicardial-endocardial arrhythmic wave fronts and rotors that are relatively more organized in the endocardium.
Additional Information
Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 101474365 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1941-3084 (Electronic) Linking ISSN: 19413084 NLM ISO Abbreviation: Circ Arrhythm Electrophysiol Subsets: MEDLINE
Original Publication: Hagerstown, MD : Lippincott Williams & Wilkins
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K99 HL148523 United States HL NHLBI NIH HHS
Keywords: acetylcholine*; arrhythmias, cardiac*; heart ventricles*; isoproterenol*; ventricular premature complexes*
0 (Adrenergic Agents)
0 (Cholinergic Agents)
L628TT009W (Isoproterenol)
N9YNS0M02X (Acetylcholine)
Date Created: 20220303 Latest Revision: 20220716
20220908
PMC9052172
10.1161/CIRCEP.121.010630
35238622

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