Gender-Differences in Cardiac Repolarization/Arrhythmias

Summary

Principal Investigator: G Salama
Abstract: The long-term goal is to elucidate gender differences in the expression and spatial distribution of cardiac ionic channels and their functional consequences on the electrical and intracellular free Ca2+ (Cai) handling properties of the heart. Clinical studies have shown that women have longer corrected QT intervals (QTc), a greater propensity to drug-induced long QT syndrome (LQTS) and a higher incidence of sudden cardiac death than men. Differences in APD diminish after menopause implicating a modulation of ion channels by estrogen and/or testosterone. The effect of estrogen-replacement in post- menopausal women on arrhythmia vulnerability remains unknown. Female rabbits have longer APDs and QT intervals than males and a greater vulnerability to LQT-related arrhythmias. Differences in the expression and spatial distribution of IKr, IKs and/or ICa most likely account for differences in repolarization sequence, QT prolongation and enhanced susceptibility of females to arrhythmias. To characterize gender differences in Cai handling and dispersion of repolarization (DR), we propose to apply imaging techniques at high spatial and temporal resolution to simultaneously map voltage and intracellular Ca2+ transients from perfused rabbit hearts. Optical maps of APs and Cai transients q selective blockers for IKr, IKs and ICa will elucidate gender differences in the spatial distribution of these channels and will be correlated with measurements of Ito, IKr, IKs and ICa, by voltage clamping of ventricular myocytes isolated from various regions of the heart. These data will also be correlated with distributions of mRNA and protein using selective probes and antibodies for individual ion channel subunits. The specific aims are: 1) To characterize gender differences in the spatial distribution of Ito, IKr, IKs, and ICa and their functional effects on APD, repolarization and Cai handling that can be attributed to gonadal hormones. Hearts from female (q ovariectomy (OVX)), and male (q orchiectomy (ORX)) rabbits will be optically mapped (approximately 1 month later) to obtain baseline values for electrical and Cai handling. Hearts will then be treated with an IKr, IKs, and/or ICa blockers to measure changes in APD, repolarization patterns, and susceptibility to arrhythmias. Optical maps will be correlated with the distribution of ionic currents, channel mRNA levels and channel protein distribution using voltage clamp, Northern and Western blot techniques. 2) To investigate the effects of hormone replacement on the dispersion of repolarization and arrhythmia susceptibility by treating OVX and ORX rabbits with 17-beta estradiol (EST), 5alpha-dihydroxy-testosterone (DHT) for 2-3 weeks. Hearts will be examined for altered electrical and Cai handling properties, which will be correlated with changes in the distribution of ion channel currents, mRNA and protein levels. 3) To study gender differences in response to ischemic injury by determining the effects of acute and chronic ischemia (rabbit infarct model) on dispersion of repolarization and arrhythmias on males (q ORX) compared to females (q OVX). 4) To determine possible protective effects of estrogen replacement on ischemic injury. Changes in APD, dispersion of repolarization and arrhythmia susceptibility will be measured in an acute and chronic infarct model using rabbit hearts from OVX females with or without estrogen replacement. Such an investigation will analyze the functional effects of cardiac repolarization, a parameter that has been implicated in an underlying mechanism for the initiation and maintenance of arrhythmias and thus, will address a fundamental problem in women's health.
Funding Period: 2002-07-20 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. 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
  2. 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
  3. 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
  4. ncbi 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
  5. pmc Bradycardia alters Ca(2+) dynamics enhancing dispersion of repolarization and arrhythmia risk
    Jong J Kim
    Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Am J Physiol Heart Circ Physiol 304:H848-60. 2013
  6. 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
  7. 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
  8. pmc Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α
    Polina S Petkova-Kirova
    Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Am J Physiol Heart Circ Physiol 302:H934-52. 2012
  9. 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
  10. ncbi 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

Scientific Experts

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

Detail Information

Publications21

  1. 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...
  2. 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...
  3. 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
    ....
  4. ncbi 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)...
  5. pmc Bradycardia alters Ca(2+) dynamics enhancing dispersion of repolarization and arrhythmia risk
    Jong J Kim
    Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15261, USA
    Am J Physiol Heart Circ Physiol 304:H848-60. 2013
    ..In conclusion, acute bradycardia elicits synchronized subcellular SCRs of sufficient magnitude to overcome the source-sink mismatch and to promote afterdepolarizations...
  6. 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...
  7. 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...
  8. pmc Mathematical modeling mechanisms of arrhythmias in transgenic mouse heart overexpressing TNF-α
    Polina S Petkova-Kirova
    Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
    Am J Physiol Heart Circ Physiol 302:H934-52. 2012
    ....
  9. 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...
  10. ncbi 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...
  11. 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...
  12. 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...
  13. 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
    ....
  14. pmc Properties of new, long-wavelength, voltage-sensitive dyes in the heart
    G Salama
    Department of Cell Biology and Physiology, University of Pittsburgh, School of Medicine, S314 Biomedical Science Tower, PA 15261, USA
    J Membr Biol 208:125-40. 2005
    ..The long wavelengths, large Stokes shifts, high DeltaF/F and low baseline fluorescence make PGH dyes a valuable tool in optical mapping and for simultaneous mapping of APs and intracellular Ca(2+)...
  15. 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...
  16. 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...
  17. pmc Dispersion of repolarization and refractoriness are determinants of arrhythmia phenotype in transgenic mice with long QT
    Barry London
    University of Pittsburgh, Cardiovascular Institute, Pittsburgh, PA 15213, USA
    J Physiol 578:115-29. 2007
    ..2DN mice. Thus, dispersion of repolarization (DR) appears to be an important determinant of arrhythmia vulnerability...
  18. 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
    ....
  19. 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...
  20. 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...