Kedar Aras1, Anna Gams1, Ndeye Rokhaya Faye1,2, Jaclyn Brennan1, Katherine Goldrick1, Jinghua Li3,4, Yishan Zhong5, Chia-Han Chiang6, Elizabeth H Smith7, Megan D Poston7, Jacqueline Chivers7, Peter Hanna8, Shumpei Mori8, Olujimi A Ajijola8, Kalyanam Shivkumar8, Donald B Hoover7, Jonathan Viventi6, John A Rogers3, Olivier Bernus2, Igor R Efimov1. 1. Department of Biomedical Engineering, George Washington University, Washington, DC (K.A., A.G., N.R.F., J.B., K.G., I.R.E.). 2. Institut de rhythmologie et de modélisation cardiaque (LIRYC; The Rhythmology and Heart Modeling Institute), Bordeaux University, France (N.R.F., O.B.). 3. Department of Biomedical Engineering, Northwestern University, Evanston, IL (J.L., J.A.R.). 4. Department of Materials Science and Engineering, Ohio State University, Columbus, OH (J.L.). 5. Department of Electrical and Computer Engineering, University of Illinois at Urbana-Champaign (Y.Z.). 6. Department of Biomedical Engineering, Duke University, Durham, NC (C.-H.C., J.V.). 7. Department of Biomedical Sciences, East Tennessee State University, Johnson City (E.H.S., M.D.P., J.C., D.B.H.). 8. 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.).
Abstract
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.
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.
Authors: Joseph S Ulphani; Jack H Cain; Firdous Inderyas; David Gordon; Peter V Gikas; Gregory Shade; David Mayor; Rishi Arora; Alan H Kadish; Jeffrey J Goldberger Journal: Heart Rhythm Date: 2010-04-08 Impact factor: 6.343
Authors: Hiroshi Morita; Douglas P Zipes; John Lopshire; Shiho T Morita; Jiashin Wu Journal: Am J Physiol Heart Circ Physiol Date: 2006-04-28 Impact factor: 4.733