Cardiac Fibrillation: Mechanisms and Therapy

Summary

Principal Investigator: James N Weiss
Abstract: DESCRIPTION (provided by applicant): Ventricular fibrillation (VF) is the most common cause of sudden cardiac death (SCD), and accounts for over 300,000 deaths per year in the United States alone. However, despite 50 years of molecular and cellular research, no biological therapy has yet emerged with comparable efficacy to the implantable cardioverter- defibrillator. The objective of this proposed Program Project is to develop rational novel therapies to prevent SCD through a better understanding of the pathogenesis of VF at the mechanistic level. The proposal continues our efforts, which began with our SCOR in Sudden Cardiac Death (1995-2004) and has continued in the current Program Project (2005-2010), to address this objective by integrating information at the molecular, cellular, tissue and organism levels using a systems approach combining experimental and mathematical biology. Continuing along these lines, this Program Project will focus on trigger-substrate interactions, with the central theme related to how early (EADs) and delayed (DADs) afterdepolarizations, classically considered as arrhythmia triggers, simultaneously enhance the vulnerability of the tissue substrate to create the milieu leading to VF and SCD. We will analyze the synergism between dynamic factors and pre-existing tissue heterogeneities in this process. Project 1 (Multi-scale Modeling of Arrhythmias) will develop the theoretical framework, complemented by the experimental analysis at the molecular/cellular level in Project 2 (Cellular Mechanisms of Arrhythmias), the tissue level in Project 3 (Arrhythmias and Antiarrhythmic Targets in Failing Hearts), and therapeutic development in Project 4 (Molecular Approaches to Arrhythmia Therapy), facilitated by 3 cores (Computer and Math Core A, Biology and Bioengineering Core B, and Administrative Core C). Together, these studies will provide critical groundwork necessary to develop and advance novel therapies for this major complication and cause of mortality from heart disease.
Funding Period: 2005-01-01 - 2016-05-31
more information: NIH RePORT

Top Publications

  1. pmc Patterns of baseline autonomic nerve activity and the development of pacing-induced sustained atrial fibrillation
    Mark J Shen
    Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Heart Rhythm 8:583-9. 2011
  2. pmc The role of the calcium and the voltage clocks in sinoatrial node dysfunction
    Boyoung Joung
    Division of Cardiology, Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
    Yonsei Med J 52:211-9. 2011
  3. pmc Shaping a new Ca²⁺ conductance to suppress early afterdepolarizations in cardiac myocytes
    Roshni V Madhvani
    Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095 7115, USA
    J Physiol 589:6081-92. 2011
  4. pmc Abnormal response of superior sinoatrial node to sympathetic stimulation is a characteristic finding in patients with atrial fibrillation and symptomatic bradycardia
    Boyoung Joung
    Division of Cardiology, Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
    Circ Arrhythm Electrophysiol 4:799-807. 2011
  5. ncbi Short-duration therapeutic hypothermia causes prompt connexin43 gap junction remodeling in isolated rabbit hearts
    Yu Cheng Hsieh
    Cardiovascular Center, Taichung Veterans General Hospital and Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Cardiovascular Research Center, National Yang Ming University School of Medicine, Taipei, Taiwan
    Circ J 75:1706-16. 2011
  6. pmc Bidirectional ventricular tachycardia: ping pong in the His-Purkinje system
    Alex A Baher
    Cardiovascular Research Laboratory, Department of Medicine Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
    Heart Rhythm 8:599-605. 2011
  7. ncbi A new electrocardiographic marker for sympathetic nerve stimulation: modulation of repolarization by stimulation of stellate ganglia
    Rafael J Ramirez
    UCLA Cardiac Arrhythmia Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 7403, USA
    J Electrocardiol 44:694-9. 2011
  8. pmc Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines
    Mark J Shen
    Krannert Institute of Cardiology, Division of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
    Circulation 123:2204-12. 2011
  9. pmc Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts
    Norishige Morita
    Translational Arrhythmia Research Section, Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, 675 Charles E Young Dr South, MRL 3645 Mail Code 176022, Los Angeles, CA 90095, USA
    Am J Physiol Heart Circ Physiol 301:H180-91. 2011
  10. pmc Multi-scale modeling in biology: how to bridge the gaps between scales?
    Zhilin Qu
    Department of Medicine Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Prog Biophys Mol Biol 107:21-31. 2011

Research Grants

  1. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  2. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
  3. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
  4. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
  5. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013

Detail Information

Publications196 found, 100 shown here

  1. pmc Patterns of baseline autonomic nerve activity and the development of pacing-induced sustained atrial fibrillation
    Mark J Shen
    Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA
    Heart Rhythm 8:583-9. 2011
    ..Whether autonomic nerve activity is important in the development of pacing-induced sustained atrial fibrillation (AF) is unclear...
  2. pmc The role of the calcium and the voltage clocks in sinoatrial node dysfunction
    Boyoung Joung
    Division of Cardiology, Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
    Yonsei Med J 52:211-9. 2011
    ..The failure of DAD-like DD to consistently trigger a sinus beat is a novel mechanism of atrial arrhythmogenesis. We conclude that dysfunction of both the Ca(2+) clock and the voltage clock are important in sick sinus syndrome...
  3. pmc Shaping a new Ca²⁺ conductance to suppress early afterdepolarizations in cardiac myocytes
    Roshni V Madhvani
    Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095 7115, USA
    J Physiol 589:6081-92. 2011
    ..We propose that modifying the biophysical properties of I(Ca,L) has potential as a powerful therapeutic strategy for suppressing EADs and EAD-mediated arrhythmias...
  4. pmc Abnormal response of superior sinoatrial node to sympathetic stimulation is a characteristic finding in patients with atrial fibrillation and symptomatic bradycardia
    Boyoung Joung
    Division of Cardiology, Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
    Circ Arrhythm Electrophysiol 4:799-807. 2011
    ..We hypothesized that unresponsiveness of superior sinoatrial node (SAN) to sympathetic stimulation is strongly associated with the development of symptomatic bradycardia in patients with atrial fibrillation (AF)...
  5. ncbi Short-duration therapeutic hypothermia causes prompt connexin43 gap junction remodeling in isolated rabbit hearts
    Yu Cheng Hsieh
    Cardiovascular Center, Taichung Veterans General Hospital and Department of Internal Medicine, Faculty of Medicine, Institute of Clinical Medicine, Cardiovascular Research Center, National Yang Ming University School of Medicine, Taipei, Taiwan
    Circ J 75:1706-16. 2011
    ..Whether connexin43 gap junctions (Cx43 GJs) and spatial heterogeneity of conduction velocity (CV) restitutions are altered in hearts during moderate (MH; 33°C) and severe (SH; 30°C) hypothermia remains unclear...
  6. pmc Bidirectional ventricular tachycardia: ping pong in the His-Purkinje system
    Alex A Baher
    Cardiovascular Research Laboratory, Department of Medicine Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
    Heart Rhythm 8:599-605. 2011
    ..Evidence from human and animal studies attributes BVT to alternating ectopic foci originating from the distal His-Purkinje system in the left and/or right ventricle, respectively...
  7. ncbi A new electrocardiographic marker for sympathetic nerve stimulation: modulation of repolarization by stimulation of stellate ganglia
    Rafael J Ramirez
    UCLA Cardiac Arrhythmia Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 7403, USA
    J Electrocardiol 44:694-9. 2011
    ..Displaced repolarization vector and changes in T-wave morphometrics provide a novel marker of unilateral sympathetic nerve stimulation...
  8. pmc Continuous low-level vagus nerve stimulation reduces stellate ganglion nerve activity and paroxysmal atrial tachyarrhythmias in ambulatory canines
    Mark J Shen
    Krannert Institute of Cardiology, Division of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA
    Circulation 123:2204-12. 2011
    ..We hypothesize that left-sided low-level vagus nerve stimulation (LL-VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs...
  9. pmc Glycolytic inhibition causes spontaneous ventricular fibrillation in aged hearts
    Norishige Morita
    Translational Arrhythmia Research Section, Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, 675 Charles E Young Dr South, MRL 3645 Mail Code 176022, Los Angeles, CA 90095, USA
    Am J Physiol Heart Circ Physiol 301:H180-91. 2011
    ..05). We conclude that in aged fibrotic unlike in adult rat hearts, GI promotes EADs, triggered activity, and VF by activation of K(ATP) channels CaMKII and NCX...
  10. pmc Multi-scale modeling in biology: how to bridge the gaps between scales?
    Zhilin Qu
    Department of Medicine Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Prog Biophys Mol Biol 107:21-31. 2011
    ..We then discuss the gaps between different modeling methodologies and between scales, and discuss potential methods for bridging the gaps between scales...
  11. pmc "Good enough solutions" and the genetics of complex diseases
    James N Weiss
    Cardiovascular Research Laboratory and Atherosclerosis Research Unit, Department of Medicine Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Circ Res 111:493-504. 2012
    ..If validated, GMAS may imply that common polygenic diseases are related as much to group interactions between normal genes, as to multiple gene mutations...
  12. pmc Synchronization of early afterdepolarizations and arrhythmogenesis in heterogeneous cardiac tissue models
    Enno de Lange
    Cardiovascular Research Laboratory, Department of Medicine Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California, USA
    Biophys J 103:365-73. 2012
    ..The focal arrhythmias either spontaneously terminate or degenerate into reentrant arrhythmias due to heterogeneities and spatiotemporal chaotic dynamics of the foci...
  13. pmc Arrhythmogenic consequences of myofibroblast-myocyte coupling
    Thao P Nguyen
    UCLA Cardiovascular Research Laboratory, Division of Cardiology, Department of Medicine, Los Angeles, CA, USA
    Cardiovasc Res 93:242-51. 2012
    ....
  14. pmc Anisotropic conduction block and reentry in neonatal rat ventricular myocyte monolayers
    Carlos de Diego
    Cardiovascular Research Laboratory, Department of Medicine Cardiology and Physiology, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095, USA
    Am J Physiol Heart Circ Physiol 300:H271-8. 2011
    ....
  15. pmc Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome
    Mitsunori Maruyama
    Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    Circ Arrhythm Electrophysiol 4:103-11. 2011
    ..Both phase 2 and phase 3 early afterdepolarizations (EADs) occur in long-QT syndromes, but their respective roles in generating arrhythmias in intact cardiac tissue are incompletely understood...
  16. pmc FKBP12 is a critical regulator of the heart rhythm and the cardiac voltage-gated sodium current in mice
    Mitsunori Maruyama
    Department of Medicine, University School of Medicine, Indianapolis, IN 46202, USA
    Circ Res 108:1042-52. 2011
    ..FK506 binding protein (FKBP)12 is a known cis-trans peptidyl prolyl isomerase and highly expressed in the heart. Its role in regulating postnatal cardiac function remains largely unknown...
  17. pmc Chaos in the genesis and maintenance of cardiac arrhythmias
    Zhilin Qu
    Department of Medicine Cardiology, David Geffen School of Medicine at University of California, 650 Charles E Young Drive South, Los Angeles, CA 90095, USA
    Prog Biophys Mol Biol 105:247-57. 2011
    ....
  18. pmc Small-conductance calcium-activated potassium channel and recurrent ventricular fibrillation in failing rabbit ventricles
    Su Kiat Chua
    Krannert Institute of Cardiology, Division of Cardiology, Indiana University School of Medicine, Indianapolis, USA
    Circ Res 108:971-9. 2011
    ..Fibrillation/defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF)...
  19. pmc Alternans and arrhythmias: from cell to heart
    James N Weiss
    Department of Medicine, University of California at Los Angeles, 90095, USA
    Circ Res 108:98-112. 2011
    ..Throughout, we emphasize the qualitatively novel properties that emerge at each new scale of integration...
  20. pmc Intracellular calcium and the mechanism of anodal supernormal excitability in langendorff perfused rabbit ventricles
    Boyoung Joung
    Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Circ J 75:834-43. 2011
    ....
  21. pmc Delayed afterdepolarization in intact canine sinoatrial node as a novel mechanism for atrial arrhythmia
    Boyoung Joung
    Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    J Cardiovasc Electrophysiol 22:448-54. 2011
    ..The aim of this study is to test the hypothesis that spontaneous, nonvoltage gated, intracellular Ca (Ca(i)) elevation may induce delayed afterdepolarization (DAD) in intact SAN during isoproterenol infusion...
  22. ncbi Suppression of re-entrant and multifocal ventricular fibrillation by the late sodium current blocker ranolazine
    Norishige Morita
    Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
    J Am Coll Cardiol 57:366-75. 2011
    ..The purpose of this study was to test the hypothesis that the late Na current blocker ranolazine suppresses re-entrant and multifocal ventricular fibrillation (VF)...
  23. pmc Calcium dynamics and the mechanisms of atrioventricular junctional rhythm
    Daehyeok Kim
    Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana, USA
    J Am Coll Cardiol 56:805-12. 2010
    ..The purpose of this study was to test the hypothesis that rhythmic spontaneous sarcoplasmic reticulum calcium (Ca) release (the "Ca clock") plays an important role in atrioventricular junction (AVJ) automaticity...
  24. pmc So little source, so much sink: requirements for afterdepolarizations to propagate in tissue
    Yuanfang Xie
    University of California Los Angeles Cardiovascular Research Laboratory, Departments of Medicine Cardiology, Physiology and Integrative Biology and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
    Biophys J 99:1408-15. 2010
    ..Structural and electrophysiological remodeling decrease these numbers significantly but still require synchronization mechanisms for EADs and DADs to overcome the robust protective effects of source-sink mismatch...
  25. pmc Mapping cardiac pacemaker circuits: methodological puzzles of the sinoatrial node optical mapping
    Igor R Efimov
    Department of Biomedical Engineering, Washington University, One Brookings Dr, St Louis, MO 63130, USA
    Circ Res 106:255-71. 2010
    ..This overview aims to advance a common understanding of the basic principles of optical mapping in complex 3D anatomic structures...
  26. pmc T-wave Alternans and Arrhythmogenesis in Cardiac Diseases
    Zhilin Qu
    Department of Medicine Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095
    Front Physiol 1:1-15. 2010
    ..In this review, we summarize the cellular mechanisms of alternans arising from these different mechanisms, and discuss their roles in arrhythmogenesis in the setting of cardiac disease...
  27. pmc Diastolic intracellular calcium-membrane voltage coupling gain and postshock arrhythmias: role of purkinje fibers and triggered activity
    Mitsunori Maruyama
    Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, USA
    Circ Res 106:399-408. 2010
    ..Recurrent ventricular arrhythmias after initial successful defibrillation are associated with poor clinical outcome...
  28. pmc Electrophysiological characteristics of the Marshall bundle in humans
    Seongwook Han
    Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Heart Rhythm 7:786-93. 2010
    ..Marshall bundles (MBs) are the muscle bundles within the ligament of Marshall...
  29. pmc Intrinsic cardiac nerve activity and paroxysmal atrial tachyarrhythmia in ambulatory dogs
    Eue Keun Choi
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, 1801 N Capitol Avenue, Indianapolis, IN 46202, USA
    Circulation 121:2615-23. 2010
    ..Little is known about the relationship between intrinsic cardiac nerve activity (ICNA) and spontaneous arrhythmias in ambulatory animals...
  30. ncbi Cardiac resynchronization therapy for treatment of heart failure
    Jonathan K Ho
    Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles CA 90095 7403, USA
    Anesth Analg 111:1353-61. 2010
    ..With increasing use, understanding of cardiac resynchronization therapy devices and the principles behind the therapy are important for physicians providing perioperative and intensive care for patients with heart failure...
  31. pmc Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation
    Boyoung Joung
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Heart Rhythm 7:88-95. 2010
    ..The mechanism of sinoatrial node (SAN) dysfunction in atrial fibrillation (AF) is unclear...
  32. pmc Off-site control of repolarization alternans in cardiac fibers
    Trine Krogh-Madsen
    Greenberg Division of Cardiology, Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA
    Phys Rev E Stat Nonlin Soft Matter Phys 81:011915. 2010
    ....
  33. pmc Ca2+ clock malfunction in a canine model of pacing-induced heart failure
    Tetsuji Shinohara
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Am J Physiol Heart Circ Physiol 299:H1805-11. 2010
    ..HF also increases the ectopic pacemaking activity by activating the I(f) at the latent pacemaking sites in lower crista terminalis...
  34. ncbi Prolonged central venous desaturation measured by continuous oximetry is associated with adverse outcomes in pediatric cardiac surgery
    Ryan Crowley
    Department of Anesthesiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA
    Anesthesiology 115:1033-43. 2011
    ..We hypothesized that central venous oxygen desaturations are associated with adverse clinical outcomes...
  35. pmc Induction of atrial ectopic beats with calcium release inhibition: Local hierarchy of automaticity in the right atrium
    Tetsuji Shinohara
    Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Heart Rhythm 7:110-6. 2010
    ..Whether or not the same mechanism applies to atrial ectopic pacemakers (AEPs) remains unclear...
  36. pmc Tachybradycardia in the isolated canine right atrium induced by chronic sympathetic stimulation and pacemaker current inhibition
    Boyoung Joung
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University Schoolof Medicine, Indianapolis, Indiana 46202, USA
    Am J Physiol Heart Circ Physiol 299:H634-42. 2010
    ..Combined malfunction of both membrane and Ca(2+) clocks underlies the mechanisms of PSPs...
  37. pmc Early afterdepolarizations and cardiac arrhythmias
    James N Weiss
    UCLA Cardiovascular Research Laboratory, Departments of Medicine Cardiology, Physiology and Integrative Biology and Physiology, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
    Heart Rhythm 7:1891-9. 2010
    ....
  38. pmc Spark-induced sparks as a mechanism of intracellular calcium alternans in cardiac myocytes
    Robert Rovetti
    Department of Mathematics, Loyola Marymount University, Los Angeles, Calif, USA
    Circ Res 106:1582-91. 2010
    ..Intracellular calcium (Ca) alternans has been widely studied in cardiac myocytes and tissue, yet the underlying mechanism remains controversial...
  39. ncbi The initiation of the heart beat
    Peng Sheng Chen
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Circ J 74:221-5. 2010
    ..Malfunction of the clocks is associated with sinus node dysfunction in heart failure and atrial fibrillation. More studies are needed to determine how both clocks work together to initiate heart beat under normal and disease conditions...
  40. pmc Atrioventricular conduction and arrhythmias at the initiation of beating in embryonic mouse hearts
    Fuhua Chen
    UCLA Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California Los Angeles, 675 Charles Young Drive South, Los Angeles, CA 90095, USA
    Dev Dyn 239:1941-9. 2010
    ..In summary, at the onset of beating, I(f)-dependent pacemaking drives both AP propagation and Ca(i) transient generation through activation of voltage-dependent Ca channels. Na channels and intracellular Ca cycling have minor roles...
  41. pmc Selective inhibition of late sodium current suppresses ventricular tachycardia and fibrillation in intact rat hearts
    Arash Pezhouman
    Translational Arrhythmia Research Section, UCLA Cardiovascular Research Laboratory, Department of Medicine Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, California
    Heart Rhythm 11:492-501. 2014
    ..Enhanced late inward Na current (INa-L) modulates action potential duration (APD) and plays a key role in the genesis of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs) and triggered activity...
  42. pmc Carvedilol analog modulates both basal and stimulated sinoatrial node automaticity
    Tetsuji Shinohara
    Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, 1801 N Capitol Ave, E 308, Indianapolis, IN, 46202, USA
    Heart Vessels 29:396-403. 2014
    ..01), and it suppressed the ISO-induced increase in sinus rate (P = 0.02). Our results suggest that the sinus rate may be partly controlled by the Ca(2+) clock via SR Ca(2+) release during β-adrenergic stimulation...
  43. pmc Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium
    Po Cheng Chang
    Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital and Chang Gung University School of Medicine, Taoyuan, Taiwan
    Heart Rhythm 10:1516-24. 2013
    ..We hypothesize that apamin, a specific I(KAS) blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai...
  44. pmc Chronic amiodarone therapy impairs the function of the superior sinoatrial node in patients with atrial fibrillation
    Hee Sun Mun
    Division of Cardiology, Department of Medicine, Yonsei University College of Medicine
    Circ J 77:2255-63. 2013
    ..The mechanisms underlying amiodarone-induced sinoatrial node (SAN) dysfunction remain unclear, so we used 3-dimensional endocardial mapping of the right atrium (RA) to investigate...
  45. pmc Calcium alternans in cardiac myocytes: order from disorder
    Zhilin Qu
    Department of Medicine Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
    J Mol Cell Cardiol 58:100-9. 2013
    ..We also illustrate how this '3R theory' can reconcile many seemingly contradictory experimental observations...
  46. ncbi Effect of pharmacologic increases in afterload on left ventricular rotation and strain in a rabbit model
    Jonathan K Ho
    Department of Anesthesiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA
    J Am Soc Echocardiogr 26:674-82. 2013
    ..The aim of this study was to identify the changes in left ventricular function and rotational mechanics during increasing pharmacologic afterload...
  47. ncbi Pro- and antiarrhythmic effects of ATP-sensitive potassium current activation on reentry during early afterdepolarization-mediated arrhythmias
    Marvin G Chang
    Department of Medicine Cardiology, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
    Heart Rhythm 10:575-82. 2013
    ..ATP-sensitive K current (IKATP) activation suppresses EADs, but the effects on ICa,L-mediated reentry are unknown...
  48. pmc Sympathetic nerve fibers and ganglia in canine cervical vagus nerves: localization and quantitation
    Patrick Onkka
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine Indianapolis, IN 46202 1228, USA
    Heart Rhythm 10:585-91. 2013
    ..Cervical vagal nerve (CVN) stimulation may improve left ventricular ejection fraction in patients with heart failure...
  49. pmc Heterogeneous upregulation of apamin-sensitive potassium currents in failing human ventricles
    Po Cheng Chang
    Division of Cardiology, Krannert Institute of Cardiology, Indianapolis, IN
    J Am Heart Assoc 2:e004713. 2013
    ..This study goal is to test the hypothesis that subtype 2 of the small-conductance Ca(2+) activated K(+) (SK2) channel and apamin-sensitive K(+) currents (IKAS) are upregulated in failing human ventricles...
  50. pmc Apamin-sensitive potassium current modulates action potential duration restitution and arrhythmogenesis of failing rabbit ventricles
    Yu Cheng Hsieh
    Department of Medicine, Division of Cardiology, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Circ Arrhythm Electrophysiol 6:410-8. 2013
    ..Apamin-sensitive K currents (I(KAS)) are upregulated in heart failure. We hypothesize that apamin can flatten action potential duration restitution (APDR) curve and can reduce ventricular fibrillation duration in failing ventricles...
  51. pmc Proarrhythmic effect of blocking the small conductance calcium activated potassium channel in isolated canine left atrium
    Chia Hsiang Hsueh
    Krannert Institute of Cardiology and Division of Cardiology, Indiana University, Indianapolis, Indiana 46202, USA
    Heart Rhythm 10:891-8. 2013
    ..Genome-wide association studies revealed that a variant of SKCa is associated with lone atrial fibrillation in humans. Roles of SKCa in atrial arrhythmias remain unclear...
  52. pmc Early afterdepolarizations in cardiac myocytes: beyond reduced repolarization reserve
    Zhilin Qu
    Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Cardiovasc Res 99:6-15. 2013
    ..We also summarize different mechanisms of phase-3 EADs. Based on the dynamical theory, we discuss the roles of each of the major ionic currents in the genesis of EADs, and potential therapeutic targets. ..
  53. pmc Hypokalemia promotes late phase 3 early afterdepolarization and recurrent ventricular fibrillation during isoproterenol infusion in Langendorff perfused rabbit ventricles
    Mitsunori Maruyama
    Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Cardiovascular Center, Chiba Hokusoh Hospital, Nippon Medical School, Chiba, Japan
    Heart Rhythm 11:697-706. 2014
    ..Hypokalemia and sympathetic activation are commonly associated with electrical storm (ES) in normal and diseased hearts. The mechanisms remain unclear...
  54. pmc Autonomic nerve activity and blood pressure in ambulatory dogs
    Jessica Hellyer
    Division of Cardiology, Department of Medicine, Krannert Institute of Cardiology, Indianapolis, Indiana
    Heart Rhythm 11:307-13. 2014
    ..The relationship between cardiac autonomic nerve activity and blood pressure (BP) changes in ambulatory dogs is unclear...
  55. pmc Myocardial repolarization dispersion and autonomic nerve activity in a canine experimental acute myocardial infarction model
    Gianfranco Piccirillo
    Dipartimento di Scienze Cardiovascolari, respiratorie, nefrologiche, Anestesiologiche e Geriatriche, Policlinico Umberto I, Sapienza University of Rome, Rome, Italy Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Electronic address
    Heart Rhythm 11:110-8. 2014
    ..Evidence from a canine experimental acute myocardial infarction (MI) model shows that until the seventh week after MI, the relationship between stellate ganglion nerve activity (SGNA) and vagal nerve activity (VNA) progressively increases...
  56. pmc Apamin does not inhibit human cardiac Na+ current, L-type Ca2+ current or other major K+ currents
    Chih Chieh Yu
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America Department of Integrated Diagnostic and Therapeutics, National Taiwan University, Taipei, Taiwan
    PLoS ONE 9:e96691. 2014
    ..Apamin is commonly used as a small-conductance Ca2+-activated K+ (SK) current inhibitor. However, the specificity of apamin in cardiac tissues remains unclear...
  57. pmc Sympathetic nerve fibers in human cervical and thoracic vagus nerves
    Atsuko Seki
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California Electronic address
    Heart Rhythm 11:1411-7. 2014
    ..Although it is known that there is neural communication between the VN and the cervical sympathetic trunk, there are few data regarding the quantity and/or distribution of the sympathetic components within the vagus nerve (VN)...
  58. pmc Utilization rates of implantable cardioverter-defibrillators for primary prevention of sudden cardiac death: a 2012 calculation for a midwestern health referral region
    Allen Hoang
    Krannert Institute of Cardiology and Division of Cardiology, Indiana University, Indianapolis, Indiana
    Heart Rhythm 11:849-55. 2014
    ..Utilization rates (URs) for implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death (PPSCD) are lacking in the community...
  59. pmc Role of the autonomic nervous system in atrial fibrillation: pathophysiology and therapy
    Peng Sheng Chen
    From the Department of Medicine, Division of Cardiology, The Krannert Institute of Cardiology P S C, S F L and Department of Neurology L S C, Indiana University School of Medicine, Indianapolis Department of Pathology and Laboratory Medicine, University of California, Los Angeles M C F Institute of Biomedical Engineering, National Chiao Tung University, Hsinchu, Taiwan S F L and Department of Medicine, Montreal Heart Institute and Universite de Montreal, Montreal, Quebec, Canada S N
    Circ Res 114:1500-15. 2014
    ..Although the role of the autonomic nervous system has long been recognized, new science and new technologies promise exciting prospects for the future. ..
  60. pmc Cardiac fibrosis and arrhythmogenesis: the road to repair is paved with perils
    Thao P Nguyen
    UCLA Cardiovascular Research Laboratory and the Departments of Medicine Division of Cardiology and Physiology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA Electronic address
    J Mol Cell Cardiol 70:83-91. 2014
    ..This article is part of a Special Issue entitled "Myocyte-Fibroblast Signaling in Myocardium." ..
  61. pmc The emergence of subcellular pacemaker sites for calcium waves and oscillations
    Michael Nivala
    Z Qu Department of Medicine, David Geffen School of Medicine at UCLA, A2 237 CHS, 650 Charles E Young Drive South, Los Angeles, CA 90095
    J Physiol 591:5305-20. 2013
    ..Using these results, we develop a theory for the entrainment of random oscillators which provides a unified explanation for the experimental observations underlying the emergence of pacemaker sites and Ca(2+) oscillations...
  62. pmc Amiodarone inhibits apamin-sensitive potassium currents
    Isik Turker
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    PLoS ONE 8:e70450. 2013
    ....
  63. pmc Low-level vagus nerve stimulation upregulates small conductance calcium-activated potassium channels in the stellate ganglion
    Mark J Shen
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
    Heart Rhythm 10:910-5. 2013
    ..Small conductance calcium-activated potassium (SK) channels are responsible for afterhyperpolarization that suppresses nerve discharges...
  64. pmc Carvedilol analogue inhibits triggered activities evoked by both early and delayed afterdepolarizations
    Mitsunori Maruyama
    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Heart Rhythm 10:101-7. 2013
    ..Carvedilol and its analogues suppress delayed afterdepolarizations (DADs) and catecholaminergic polymorphic ventricular tachycardias by direct action on the cardiac ryanodine receptor type 2 (RyR2)...
  65. pmc Electroanatomic remodeling of the left stellate ganglion after myocardial infarction
    Seongwook Han
    Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University, School of Medicine, Indianapolis, Indiana, USA
    J Am Coll Cardiol 59:954-61. 2012
    ..The purpose of this study was to evaluate the changes of left stellate ganglionic nerve activity (SGNA) and left thoracic vagal nerve activity (VNA) after acute myocardial infarction (MI)...
  66. pmc Enhanced sensitivity of aged fibrotic hearts to angiotensin II- and hypokalemia-induced early afterdepolarization-mediated ventricular arrhythmias
    Aneesh Bapat
    Translational Arrhythmia Research Section, University of California Los Angeles Cardiovascular Research Laboratory, USA
    Am J Physiol Heart Circ Physiol 302:H2331-40. 2012
    ....
  67. pmc Ryanodine receptor inhibition potentiates the activity of Na channel blockers against spontaneous calcium elevations and delayed afterdepolarizations in Langendorff-perfused rabbit ventricles
    Young Soo Lee
    Department of Medicine, Krannert Institute of Cardiology and Division of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    Heart Rhythm 9:1125-32. 2012
    ..However, in isolated mouse ventricular myocytes lacking calsequestrin, only those Na channel blockers that also inhibit type 2 ryanodine receptor channels were effective against spontaneous Ca elevation (SCaE) and DADs...
  68. pmc Role of the transient outward potassium current in the genesis of early afterdepolarizations in cardiac cells
    Zhenghang Zhao
    Department of Pharmacology, School of Medicine, Xi an Jiaotong University, Xi an, China
    Cardiovasc Res 95:308-16. 2012
    ..We aimed to study the effects and mechanisms of I(to) on EAD genesis in cardiac cells using combined experimental and computational approaches...
  69. pmc Resonance drifts of spiral waves on media of periodic excitability
    Lida Xu
    Center for Complexity Research, Department of Systems Science, School of Management, Beijing Normal University, Beijing, China
    Phys Rev E Stat Nonlin Soft Matter Phys 85:046216. 2012
    ..The theoretical results are in good quantitative agreement with numerical simulations. The model could be widely used in different excitable systems...
  70. ncbi Autonomic nerve activity and the short-term variability of the Tpeak-Tend interval in dogs with pacing-induced heart failure
    Gianfranco Piccirillo
    Dipartimento di Scienze Cardiovascolari, respiratorie, Anestesiologiche, Nefrologiche e Geriatriche, Policlinico Umberto I, Universita degli Studi di Roma La Sapienza, Rome, Italy
    Heart Rhythm 9:2044-50. 2012
    ..An increased interval between the peak and the end of the T wave (T(peak)-T(end)) has been reported to increase the incidence of sudden cardiac death. However, the ANS influence on the T(peak)-T(end) interval remains unclear...
  71. pmc Triggered firing and atrial fibrillation in transgenic mice with selective atrial fibrosis induced by overexpression of TGF-β1
    Eue Keun Choi
    Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
    Circ J 76:1354-62. 2012
    ..We hypothesized that CTTF underlies the mechanisms of early afterdepolarization (EAD) and spontaneous recurrent atrial fibrillation (AF) in transgenic (Tx) mice with overexpression of transforming growth factor β1 (TGF-β1)...
  72. pmc Bi-stable wave propagation and early afterdepolarization-mediated cardiac arrhythmias
    Marvin G Chang
    Department of Medicine Cardiology, David Geffen School of Medicine at University of California, Los Angeles, California 90095, USA
    Heart Rhythm 9:115-22. 2012
    ..However, it has not been shown whether the same tissue can exhibit both the I(Na)-mediated and the I(Ca,L)-mediated conduction...
  73. ncbi Unidirectional pinning and hysteresis of spatially discordant alternans in cardiac tissue
    Per Sebastian Skardal
    Department of Applied Mathematics, University of Colorado at Boulder, Boulder, Colorado 80309, USA
    Phys Rev Lett 108:108103. 2012
    ..This unidirectional pinning leads to strongly history-dependent node motion that is strongly arrhythmogenic...
  74. pmc Neural control of ventricular rate in ambulatory dogs with pacing-induced sustained atrial fibrillation
    Hyung Wook Park
    Krannert Institute of Cardiology, Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
    Circ Arrhythm Electrophysiol 5:571-80. 2012
    ..We hypothesize that inferior vena cava-inferior atrial ganglionated plexus nerve activity (IVC-IAGPNA) is responsible for ventricular rate (VR) control during atrial fibrillation (AF) in ambulatory dogs...
  75. pmc Mechanisms and determinants of ultralong action potential duration and slow rate-dependence in cardiac myocytes
    Zhilin Qu
    Department of Medicine Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
    PLoS ONE 7:e43587. 2012
    ....
  76. pmc Intracellular calcium dynamics, shortened action potential duration, and late-phase 3 early afterdepolarization in Langendorff-perfused rabbit ventricles
    Liang Tang
    Department of Biomedical Engineering, University of Texas at San Antonio, TX, USA
    J Cardiovasc Electrophysiol 23:1364-71. 2012
    ....
  77. pmc Neural mechanisms of atrial fibrillation
    Hyung Wook Park
    Department of Cardiovascular Medicine, Chonnam National University Medical School, Gwangju, Korea
    Curr Opin Cardiol 27:24-8. 2012
    ..The autonomic nerve system is a potentially potent modulator of the initiation and perpetuation of atrial fibrillation. This review will briefly summarize the neural mechanisms of atrial fibrillation...
  78. pmc Imaging arrhythmogenic calcium signaling in intact hearts
    Peng Sheng Chen
    Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, 1800 N Capitol Ave, E475, Indianapolis, IN 46202, USA
    Pediatr Cardiol 33:968-74. 2012
    ..The latter findings suggest that I (KAS) may be a novel antiarrhythmic targets in patients with heart failure and electrical storms...
  79. ncbi Neural mechanisms of atrial arrhythmias
    Mark J Shen
    Department of Internal Medicine, University of Illinois at Chicago Advocate Christ Medical Center, 4440 West 95th Street, 131 NO, Oak Lawn, IL 60453, USA
    Nat Rev Cardiol 9:30-9. 2012
    ..In this article, we review the role of the ANS in the induction and maintenance of atrial arrhythmias and the role of neural modulation as a treatment strategy for atrial arrhythmias...
  80. pmc Criticality in intracellular calcium signaling in cardiac myocytes
    Michael Nivala
    Cardiology Division, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California, USA
    Biophys J 102:2433-42. 2012
    ....
  81. ncbi Selective sinoatrial node optical mapping and the mechanism of sinus rate acceleration
    Tetsuji Shinohara
    The Krannert Institute of Cardiology, Indianapolis, IN, USA
    Circ J 76:309-16. 2012
    ..The aim of this study was to use a novel approach to selectively mapping the intact SAN to examine the Ca clock mechanism...
  82. pmc Heart failure decreases nerve activity in the right atrial ganglionated plexus
    Tetsuji Shinohara
    Division of Cardiology, Department of Medicine, Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana, USA
    J Cardiovasc Electrophysiol 23:404-12. 2012
    ..We tested the hypothesis that heart failure (HF) results in right atrial ganglionated plexus (RAGP) denervation that contributes to sinoatrial node dysfunction...
  83. pmc Dynamics of early afterdepolarization-mediated triggered activity in cardiac monolayers
    Marvin G Chang
    Cardiovascular Research Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
    Biophys J 102:2706-14. 2012
    ....
  84. pmc Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load
    Michael Nivala
    Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, USA
    Am J Physiol Heart Circ Physiol 303:H341-52. 2012
    ....
  85. ncbi Spontaneous atrial fibrillation initiated by tyramine in canine atria with increased sympathetic nerve sprouting
    Ayaka Numata
    Division of Cardiovascular Medicine, Ohashi Medical Center, Toho University, Tokyo, Japan
    J Cardiovasc Electrophysiol 23:415-22. 2012
    ..Chronic left ventricular myocardial infarction (LVMI) promotes atrial and pulmonary veins (PV) sympathetic nerve sprouting...
  86. pmc Virtual electrodes and the induction of fibrillation in Langendorff-perfused rabbit ventricles: the role of intracellular calcium
    Hideki Hayashi
    Division of Cardiology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA
    Am J Physiol Heart Circ Physiol 295:H1422-8. 2008
    ..However, the inhibition of the sarcoplasmic reticulum function also reduced VFT, indicating that the [Ca(2+)](i) dynamics modulate, but are not essential, to ventricular vulnerability...
  87. doi Vulnerability to re-entry in simulated two-dimensional cardiac tissue: effects of electrical restitution and stimulation sequence
    Diana X Tran
    Cardiovascular Research Laboratories, Department of Physiological Science, David Geffen School of Medicine at UCLA, University of California, Los Angeles, California 90095, USA
    Chaos 17:043115. 2007
    ..When APD restitution is even steeper, the vulnerable window is reduced due to collision of the spiral tips...
  88. ncbi Left stellate ganglion and vagal nerve activity and cardiac arrhythmias in ambulatory dogs with pacing-induced congestive heart failure
    Masahiro Ogawa
    Division of Cardiology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA
    J Am Coll Cardiol 50:335-43. 2007
    ..The purpose of this study was to determine the patterns of autonomic nerve activity in congestive heart failure (CHF)...

Research Grants30

  1. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  2. Blood Pressure Regulation: Novel Roles for the Kidney
    Pablo A Ortiz; Fiscal Year: 2013
    ..Thus it will accelerate acquisition of knowledge of the novel mechanisms by which the kidney regulates blood pressure, and may provide new targets for anti-hypertensive drugs. ..
  3. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  4. Neurohumoral control of veins in hypertension
    Gregory D Fink; Fiscal Year: 2013
    ..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
  5. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..