Factors that Initiate Arrhythamias in Long QT Syndrome

Summary

Principal Investigator: G Salama
Affiliation: University of Pittsburgh
Country: USA
Abstract: DESCRIPTION (provided by applicant): The role of the autonomic nervous system in the genesis of life-threatening arrhythmias has been the subject of intense investigation yet remains incomplete and fragmented. Sympathetic imbalance has been implicated as a trigger of ventricular arrhythmias in the long QT syndrome (LQTS) by enhancing spatial heterogeneities of i) action potential durations (APDs), ii) dispersion of repolarization (DOR) and iii) perhaps conduction. The project will address fundamental questions regarding the neuromodulation of cardiac function by autonomic activity, the effects of intra-cardiac reflex responses and their role in LQT-related arrhythmias. Rabbit hearts will be isolated with bilateral innervation of sympathetic and parasympathetic branches, will be perfused, stained with voltage and Ca 2+ - sensitive dyes to simultaneously map action potentials (APs) and intracellular Ca 2v(Cai) transients from 256 sites at high spatial and temporal resolution. The sympathetic system will be stimulated bilaterally with electrodes inserted in the vertebral column and the parasympathetic system with electrodes on the right and left vagus nerves. Innervated hearts will be perfused with inhibitors of IKs (HMR 1556), IKr (E4031) or INa inactivation kinetics (Anthopleurin A) (e.g. models of LQTS types 1-3) to elucidate the role of autonomic activity on Torsade de Pointes (TdP). The specific aims are: 1) To test the hypothesis that autonomic activity to the heart modulates APDs, DOR and to determine the mechanisms underlying this neuromodulation by mapping simultaneously cardiac APs and Cai from 256 sites of innervated, Langendorff rabbit hearts. Sympathetic and parasympathetic modulation of heart rate, conduction of the specialized conduction system and ventricular myocardium, AP upstroke velocity, APDs, DOR, and Cai transients will be analyzed during various autonomic nerve stimulation paradigms. Stimulation nerve paradigms will be developed to obtain a spectrum of cardiac responses. Pharmacological interventions will be used to identify the receptors mediating the cardiac responses (131,132,cq-adrenergic receptors: AR; muscarinic cholinergic; peptidergic and puronergic) and the contribution of efferent and afferent fibers involved in this neuromodulation by blocking ganglionic transmission with hexamethonium. 2) To test the hypothesis that intra-cardiac reflexes via afferent and efferent neurons and ganglia in the heart muscle regulate electrical and contractile properties. We will apply a focal sensory stimulus (mechanical or chemical) at a site on the heart (i.e. the apex of the left ventricle) while recording changes in electrical and contractile parameters mediated by cardiac reflex responses in other regions of the heart. Pharmacological agents will then be per'fused to block specific neural pathways to identify the underlying neuronal mechanisms. 3) The synergistic effects of right and left sympathetic or right-left vagus nerves activation and the cross-interactions between the sympathetic and parasympathetic branches are central to our understanding of the neuromodulation of the heart. We will compare the changes in APs and Ca_ at a constant heart rate during i) bilateral versus unilateral (right or left) vagal stimulation; ii) vertebral column stimulation (bilateral sympathetic activation) and bilateral versus unilateral vagus stimulation; iii) vertebral column stimulation with right or left stellectomy. Sympathetic inputs to the heart are fractionated and emanate from different thoracic segments that target different regions of the heart. We will selectively stimulate a single sympathetic branch without activating the others inputs (up to 4) to identify the targets on the heart of each input. The convergence or divergence of sympathetic inputs to the heart may be important for normal cardiac function and enhance QT dispersion and TdP in the LQTS. 4) The role of 'autonomic imbalance' on the genesis of LQT-related arrhythmias will be determined in rabbit heart with LQTS type 1,2 or 3 by measuring changes in APDs, DOR, the propensity to fire early afterdepolarizations (EADs) and the initiation of TdP before and during various nerve stimulation paradigms (determined in aim 1). Stimulation paradigms that i) enhance DOR or ii) elicit a bradycardia followed by a tachycardia are more likely to increase the incidence of EADs and TdP. The specific aims are: 1) To test the hypothesis that autonomic activity to the heart modulates APDs, DOR and to determine the mechanisms underlying this neuromodulation by mapping simultaneously cardiac APs and CaI from 256 sites of innervated, Langendorff rabbit hearts. Sympathetic and parasympathetic modulation of heart rate, conduction of the specialized conduction system and ventricular myocardium, AP upstroke velocity, APDs, DOR, and CaI transients will be analyzed during various autonomic nerve stimulation paradigms. Stimulation nerve paradigms will be developed to obtain a spectrum of cardiac responses. Pharmacological interventions will be used to identify the receptors mediating the cardiac responses (beta1, beta2, alpha1-adrenergic receptors: AR; muscarinic cholinergic; peptidergic and puronergic) and the contribution of efferent and afferent fibers involved in this neuromodulation by blocking ganglionic transmission with hexamethonium. 2) To test the hypothesis that intra-cardiac reflexes via afferent and efferent neurons and ganglia in the heart muscle regulate electrical and contractile properties. We will apply a focal sensory stimulus (mechanical or chemical) at a site on the heart (i.e. the apex of the left ventricle) while recording changes in electrical and contractile parameters mediated by cardiac reflex responses in other regions of the heart. Pharmacological agents will then be perfused to block specific neural pathways to identify the underlying neuronal mechanisms. 3) The synergistic effects of right and left sympathetic or right-left vagus nerves activation and the cross-interactions between the sympathetic and parasympathetic branches are central to our understanding of the neuromodulation of the heart. We will compare the changes in APs and Cai at a constant heart rate during i) bilateral versus unilateral vagus stimulation; ii) vertebral column stimulation (bilateral sympathetic activation) and bilateral versus unilateral vagus stimulation; iii) vertebral column stimulation with right or left stellectomy. Sympathetic inputs to the heart are fractionated and emanate from different thoracic segments that target different regions of the heart. We will selectively stimulate a single sympathetic branch without activating the others inputs (up to 4) to identify the targets on the heart of each input. The convergence or divergence of sympathetic inputs to the heart may be important for normal cardiac function and enhance QT dispersion and TdP in the LQTS. 4) The role of 'autonomic imbalance' on the genesis of LQT-related arrhythmias will be determined in rabbit heart with LQTS type 1, 2, or 3 by measuring changes in APDs, DOR, the propensity to fire early afterdepolarizations (EADs) and the initiation of TdP before and during various nerve stimulation paradigms (determined in aim 1). Stimulation paradigms that i) enhance DOR or ii) elicit a bradycardia followed by a tachycardia are more likely to increase the incidence of EADs or TdP.
Funding Period: 1998-02-01 - 2008-03-31
more information: NIH RePORT

Top Publications

  1. doi Vagal modulation of cardiac ventricular arrhythmia
    G Andre Ng
    Department of Cardiovascular Sciences, Cardiology Group, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester LE3 9QP, UK
    Exp Physiol 99:295-9. 2014
  2. pmc Calcium oscillations and T-wave lability precede ventricular arrhythmias in acquired long QT type 2
    Jan Nemec
    Department of Medicine, Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    Heart Rhythm 7:1686-94. 2010
  3. pmc Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen
    Guojun Chen
    University of Pittsburgh, School of Medicine, Cardiovascular Institute, 3550 Terrace Street, Suite S 628 Scaife Hall, Pittsburgh, PA 15261, USA
    J Physiol 589:1061-80. 2011
  4. pmc Oestrogen upregulates L-type Ca²⁺ channels via oestrogen-receptor- by a regional genomic mechanism in female rabbit hearts
    Xiaoyan Yang
    University of Pittsburgh, Department of Medicine, Cardiovascular Institute, 3550 Terrace Street, Suite S 628 Scaife Hall, Pittsburgh, PA 15261, USA
    J Physiol 590:493-508. 2012
  5. doi Sympathetic nerve stimulation produces spatial heterogeneities of action potential restitution
    G Andre Ng
    Department of Cardiovascular Sciences, Cardiology Group, University of Leicester, UK
    Heart Rhythm 6:696-706. 2009
  6. doi Arrhythmia phenotype in mouse models of human long QT
    Guy Salama
    Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh, S312 Biomedical Science Tower, 200 Lothrop St, Pittsburgh, PA 15261, USA
    J Interv Card Electrophysiol 24:77-87. 2009
  7. pmc Sex, age, and regional differences in L-type calcium current are important determinants of arrhythmia phenotype in rabbit hearts with drug-induced long QT type 2
    Carl Sims
    University of Pittsburgh, School of Medicine, Department of Cell Biology and Physiology, Pittsburgh, PA 15261, USA
    Circ Res 102:e86-100. 2008
  8. pmc Imaging ventricular fibrillation
    Guy Salama
    Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA
    J Electrocardiol 40:S56-61. 2007
  9. ncbi Dual-dye optical mapping after myocardial infarction: does the site of ventricular stimulation alter the properties of electrical propagation?
    Samir Saba
    Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    J Cardiovasc Electrophysiol 19:197-202. 2008
  10. ncbi Calcium transients modulate action potential repolarizations in ventricular fibrillation
    Bum Rak Choi
    University of Pittsburgh, PA 15261, USA
    Conf Proc IEEE Eng Med Biol Soc 1:2264-7. 2006

Scientific Experts

  • G Salama
  • SAMIR F SABA
  • Michael J Patrick
  • Bum Rak Choi
  • G Andre Ng
  • Yvonne N Tallini
  • Xiaoyan Yang
  • Guojun Chen
  • Rajkumar Mantravadi
  • Tong Liu
  • Jan Nemec
  • William H Walker
  • Carl Sims
  • Junichi Nakai
  • Michael I Kotlikoff
  • Robert Doran
  • Polina S Petkova-Kirova
  • Eunji Cheong
  • Rita Papp
  • Donald B DeFranco
  • Fandian Zeng
  • Sean Alber
  • Vladimir Shusterman
  • Beth Gabris
  • Jong J Kim
  • Waldo G Ortin
  • William de Groat
  • Prakash C Viswanathan
  • Steven Reisenweber
  • Steven S Segal
  • Seong min Hwang
  • William C de Groat
  • Bethann Gabris
  • Bo Shui
  • Johan Fredrik Brekke
  • Keiji Imoto
  • Barry London
  • Haider Mehdi
  • Erdal Gursoy
  • Jeffrey Robbins
  • Charles F McTiernan
  • Masamichi Ohkura
  • Guangju Ji
  • John Mathai
  • Jane Lee
  • Jason Wilson
  • Atsushi Sanbe
  • Hong Bo Xin
  • James Gulick
  • Patricia Plan
  • Milou Daniel Drici
  • Vassil Tumbev
  • Detcho Stoyanovsky

Detail Information

Publications22

  1. doi Vagal modulation of cardiac ventricular arrhythmia
    G Andre Ng
    Department of Cardiovascular Sciences, Cardiology Group, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester LE3 9QP, UK
    Exp Physiol 99:295-9. 2014
    ....
  2. pmc Calcium oscillations and T-wave lability precede ventricular arrhythmias in acquired long QT type 2
    Jan Nemec
    Department of Medicine, Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    Heart Rhythm 7:1686-94. 2010
    ..A related phenomenon, T-wave lability (TWL), precedes torsades de pointes (TdP) in patients and animal models with impaired repolarization. However, the role of Ca(i) in TWL remains unexplored...
  3. pmc Regional genomic regulation of cardiac sodium-calcium exchanger by oestrogen
    Guojun Chen
    University of Pittsburgh, School of Medicine, Cardiovascular Institute, 3550 Terrace Street, Suite S 628 Scaife Hall, Pittsburgh, PA 15261, USA
    J Physiol 589:1061-80. 2011
    ..Thus, E2 upregulates NCX1 by a genomic mechanism mediated by ERs, and de novo mRNA and protein biosynthesis, in a sex- and region-dependent manner which contributes to the enhanced propensity to EADs and TdP in female hearts...
  4. pmc Oestrogen upregulates L-type Ca²⁺ channels via oestrogen-receptor- by a regional genomic mechanism in female rabbit hearts
    Xiaoyan Yang
    University of Pittsburgh, Department of Medicine, Cardiovascular Institute, 3550 Terrace Street, Suite S 628 Scaife Hall, Pittsburgh, PA 15261, USA
    J Physiol 590:493-508. 2012
    ..Therefore, E2 upregulates I(Ca,L) by a regional genomic mechanism involving ERα which is a known determinant of sex differences in TdP risk in LQT2...
  5. doi Sympathetic nerve stimulation produces spatial heterogeneities of action potential restitution
    G Andre Ng
    Department of Cardiovascular Sciences, Cardiology Group, University of Leicester, UK
    Heart Rhythm 6:696-706. 2009
    ..Restitution kinetics (RK) of action potential duration (APD) are classically studied by applying an extra impulse at varying diastolic intervals (DI) and might differ from RK elicited by sympathetic nerve stimulation (SNRK)...
  6. doi Arrhythmia phenotype in mouse models of human long QT
    Guy Salama
    Department of Cell Biology and Physiology, School of Medicine, University of Pittsburgh, S312 Biomedical Science Tower, 200 Lothrop St, Pittsburgh, PA 15261, USA
    J Interv Card Electrophysiol 24:77-87. 2009
    ..10%). A comparison of mouse models of LQT based on K(+) channel mutations important to human and mouse repolarization emphasizes DR as a major determinant of arrhythmia vulnerability...
  7. pmc Sex, age, and regional differences in L-type calcium current are important determinants of arrhythmia phenotype in rabbit hearts with drug-induced long QT type 2
    Carl Sims
    University of Pittsburgh, School of Medicine, Department of Cell Biology and Physiology, Pittsburgh, PA 15261, USA
    Circ Res 102:e86-100. 2008
    ....
  8. pmc Imaging ventricular fibrillation
    Guy Salama
    Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA
    J Electrocardiol 40:S56-61. 2007
    ..Finally, recent image analysis routines were used to identify wavebreak sites and revealed that wavebreaks are caused by abrupt spatial dispersion of voltage (V(m)) oscillations...
  9. ncbi Dual-dye optical mapping after myocardial infarction: does the site of ventricular stimulation alter the properties of electrical propagation?
    Samir Saba
    Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
    J Cardiovasc Electrophysiol 19:197-202. 2008
    ..We investigated the effect of MI on the regional voltage and calcium (Ca) signals and their propagation properties, with special attention to the effect of the site of ventricular pacing on these properties...
  10. ncbi Calcium transients modulate action potential repolarizations in ventricular fibrillation
    Bum Rak Choi
    University of Pittsburgh, PA 15261, USA
    Conf Proc IEEE Eng Med Biol Soc 1:2264-7. 2006
    ..In conclusion, Cai can influence action potential durations, which may promote wave breaks in VF...
  11. ncbi Effects of pO2 on the activation of skeletal muscle ryanodine receptors by NO: a cautionary note
    Eunji Cheong
    Department of Cell Biology and Physiology, University of Pittsburgh, School of Medicine, 3500 Terrace Street, Room S314 Biomedical Science Tower, Pittsburgh, PA 15261, USA
    Cell Calcium 38:481-8. 2005
    ..We discuss the significance of these findings and propose that caution should be taken when considering a role for pO2 and nitrosation by NO as mechanisms that tune RyRs in striated muscles...
  12. ncbi Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha
    Polina S Petkova-Kirova
    Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Am J Physiol Heart Circ Physiol 290:H2098-107. 2006
    ..2, Kv4.3, and Kv1.5. Thus decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias...
  13. pmc Imaging cellular signals in the heart in vivo: Cardiac expression of the high-signal Ca2+ indicator GCaMP2
    Yvonne N Tallini
    Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14850, USA
    Proc Natl Acad Sci U S A 103:4753-8. 2006
    ..d. 13.5, atrioventricular conduction through the canal was abolished at this stage. These studies demonstrate that GCaMP2 will have broad utility in the dissection of numerous complex cellular interactions in mammals, in vivo...
  14. ncbi Low osmolarity transforms ventricular fibrillation from complex to highly organized, with a dominant high-frequency source
    Bum Rak Choi
    Department of Biomedical Engineering, Tulane University, New Orleans, Louisiana, USA
    Heart Rhythm 3:1210-20. 2006
    ..I(Cl,vol) is activated in ischemia/reperfusion, but the effects of osmotic challenges and I(Cl,vol) on ventricular fibrillation (VF) are unknown...
  15. pmc Mouse models of long QT syndrome
    Guy Salama
    Cardiovascular Institute, University of Pittsburgh Medical Center, Scaife S 572, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    J Physiol 578:43-53. 2007
    ..Our goal is to provide the reader with a comprehensive overview of mouse models with long QT syndrome and to emphasize the advantages and limitations of these models...
  16. pmc Autonomic nerve stimulation reverses ventricular repolarization sequence in rabbit hearts
    Rajkumar Mantravadi
    Department of Cardiovascular Sciences, Cardiology Group, University of Leicester, UK
    Circ Res 100:e72-80. 2007
    ....
  17. pmc Spatially discordant voltage alternans cause wavebreaks in ventricular fibrillation
    Bum Rak Choi
    Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Heart Rhythm 4:1057-68. 2007
    ..The incessant breakup and creation of new daughter waves (wavebreaks) perpetuate VF. Dispersion of refractoriness (static or dynamic) has been implicated as a mechanism underlying wavebreaks...
  18. pmc Enhanced aqueous solubility of long wavelength voltage-sensitive dyes by covalent attachment of polyethylene glycol
    Michael J Patrick
    Molecular Biosensor and Imaging Center, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA 15213, USA
    Org Biomol Chem 5:3347-53. 2007
    ..Thus, the solubility of VSDs can be considerably improved with small polyethyleneglycol chains and can provide an effective approach to improve staining of excitable tissues and optical recordings of membrane potential...
  19. ncbi Propagated endothelial Ca2+ waves and arteriolar dilation in vivo: measurements in Cx40BAC GCaMP2 transgenic mice
    Yvonne N Tallini
    Biomedical Sciences Department, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
    Circ Res 101:1300-9. 2007
    ....
  20. ncbi Sex modulates the arrhythmogenic substrate in prepubertal rabbit hearts with Long QT 2
    Tong Liu
    Department of Cell Biology and Physiology, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania 15261, USA
    J Cardiovasc Electrophysiol 16:516-24. 2005
    ..Thus, sex differences are opposite in prepubertal versus adult rabbits with respect to E4031-induced APD prolongation, EADs and PVT, underscoring the fact that APD prolongation alone is insufficient to predict arrhythmia susceptibility...