Molecular Mechanisms of Cardiac Arrhythmias

Summary

Principal Investigator: Qing Kenneth Wang
Abstract: Cardiac arrhythmias account for more than 300,000 sudden deaths each year in the U.S. alone. Our laboratory is investigating the pathogenesis of cardiac arrhythmias. We focus on two arrhythmic disorders: long-QT syndrome (LQT) and idiopathic ventricular fibrillation (IVF), both of which cause sudden death in the young, otherwise healthy, individuals. During the past 8 years of this project, we focused on genetics and in vitro electrophysiology of LQT and IVF. Together with other scientists, we have defined a genetic pathway for pathogenesis of both LQT and IVF. Further exploration of pathogenic mechanisms of LQT and IVF at the tissue and organ level is impossible because of lack of fresh heart tissues from patients. In the proposed studies we plan to develop and characterize LQT- and IVF-animal models in which SCN5A (the cardiac sodium channel gene) mutations are engineered into the mouse genome to further explore the etiology of arrhythmogenesis. We have successfully established a mouse model for LQT and ventricular arrhythmias by targeting an SCN5A mutation (N1325S). Characterization of our arrhythmic mice has led to the working hypothesis that early and after depolarizations (EADs and DADs) are the substrate for ventricular tachycardia (VT) and ventricular fibrillation (VF). In the proposed studies we plan to continue to study the mouse model for LQT to uncover detailed molecular mechanisms of cardiac arrhythmias, and to generate and characterize mouse models for IVF and acquired LQT. Our specific aims are: (1) To investigate whether over-expression of an LQT-causing mutation of SCN5A in the mouse heart will trigger electrophysiological remodeling; (2) To systematically dissect EADs and DADs induced by a genetic LQT mutation; (3) To systematically determine the effects of representative agents from each class of antiarrhythmic drugs on VT/VF and correlate the findings with results on EADs/DADs; (4) To characterize SCN5A mutations associated with IVF and acquired LQT using the transgenic mouse technology. The successful accomplishment of goals in this proposal will provide a fundamental understanding of the pathogenic mechanisms of cardiac arrhythmias. Evaluation of animal models will help define the physiological and cellular processes involved in arrhythmogenesis, and bridge the gap between the in vitro biophysical defects and the in vivo whole animal phenotype characterized by arrhythmia susceptibility. These studies may provide a new framework for the rational design of therapeutic agents.
Funding Period: 2002-09-01 - 2008-06-30
more information: NIH RePORT

Top Publications

  1. ncbi Proteomics with two-dimensional gel electrophoresis and mass spectrometry analysis in cardiovascular research
    Sun Ah You
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:15-26. 2006
  2. pmc Cardiac-specific overexpression of SCN5A gene leads to shorter P wave duration and PR interval in transgenic mice
    Teng Zhang
    Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute NE40, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Biochem Biophys Res Commun 355:444-50. 2007
  3. pmc LQTS mutation N1325S in cardiac sodium channel gene SCN5A causes cardiomyocyte apoptosis, cardiac fibrosis and contractile dysfunction in mice
    Teng Zhang
    Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Int J Cardiol 147:239-45. 2011
  4. ncbi A robust hybrid between genetic algorithm and support vector machine for extracting an optimal feature gene subset
    Li Li
    Department of Bioinformatics, Harbin Medical University, Harbin 150086, People s Republic of China
    Genomics 85:16-23. 2005
  5. ncbi Generation of transgenic mice for cardiovascular research
    Xiao Li Tian
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:69-81. 2006
  6. pmc Characterization of the cardiac sodium channel SCN5A mutation, N1325S, in single murine ventricular myocytes
    Sandro L Yong
    Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Biochem Biophys Res Commun 352:378-83. 2007
  7. pmc Optical mapping of ventricular arrhythmias in LQTS mice with SCN5A mutation N1325S
    Xiao Li Tian
    Department of Molecular Cardiology, Lerner Research Institute and Center for Cardiovascular Genetics, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
    Biochem Biophys Res Commun 352:879-83. 2007
  8. pmc Induction of high STAT1 expression in transgenic mice with LQTS and heart failure
    Ling Wu
    Center for Cardiovascular Genetics and Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Biochem Biophys Res Commun 358:449-54. 2007
  9. pmc Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB
    Sudhiranjan Gupta
    Department of Molecular Cardiology, Lerner Research Institute, NB50, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
    J Mol Biol 375:637-49. 2008
  10. pmc Identification and functional characterization of a novel splicing mutation in RP gene PRPF31
    Jing Yu Liu
    Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
    Biochem Biophys Res Commun 367:420-6. 2008

Scientific Experts

  • Qing Kenneth Wang
  • Xia Li
  • Kathryn A Glatter
  • Su Zhang
  • Zheng Guo
  • Xianqin Zhang
  • Teng Zhang
  • Sandro L Yong
  • Gong Qing Shen
  • Xiao Li Tian
  • Tie Ke
  • Ling Wu
  • Ayse Anil Timur
  • Shaoqi Rao
  • Sun Ah You
  • Stephen R Archacki
  • A A Timur
  • Zoran B Popovic
  • Y Hu
  • Jing Yu Liu
  • Qian qian Liu
  • Sudhiranjan Gupta
  • Ying Ni
  • L Li
  • D J Driscoll
  • A Melamud
  • Lin Li
  • Liping Luo
  • Li Li
  • Jeanne K Drinko
  • John C Shryock
  • Luiz Belardinelli
  • Cladelis Rubio Gomez
  • Heidi Eliana Mateus
  • Juan Andres Castano
  • Kalil G Abdullah
  • Carlos Oberti
  • Anasuya Gupta
  • Xin Cui
  • Hyun Jin Rho
  • Subha Sen
  • Stephen W Jones
  • Przemyslaw Szafranski
  • Ratan K Maitra
  • Jiqun Sheng
  • Xiaohua Dai
  • Carlos A Obejero-Paz
  • S B Seidelmann
  • Anjuli Mahajan
  • Qiuyun Chen
  • Chun Fan
  • Yan Bai
  • Melvin Scheinman
  • David Young
  • Xueqing Jiang
  • Shin Yoo
  • Xu Wang
  • Da yi Hu
  • Mugen Liu
  • Zhaohui Tang
  • Xin Tu
  • P H Shen
  • Michael J Ackerman
  • Yuanna Cheng
  • Mei Ling Chang Liao
  • David J Tester
  • S A Hagstrom
  • Theresa P Pretlow
  • G Q Shen
  • Q Xi
  • N S Peachey
  • Thomas G Pretlow
  • E Simpson
  • Karen A Stiffler
  • D Chung
  • Albert Luo
  • H Zegarra
  • E I Traboulsi
  • Lei Du
  • Eric J Topol
  • Kathy L Moser
  • Wei Jiang

Detail Information

Publications34

  1. ncbi Proteomics with two-dimensional gel electrophoresis and mass spectrometry analysis in cardiovascular research
    Sun Ah You
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:15-26. 2006
    ..This technique should be useful in characterizing cardiovascular diseases and in defining signaling pathways for cardiovascular development and physiology...
  2. pmc Cardiac-specific overexpression of SCN5A gene leads to shorter P wave duration and PR interval in transgenic mice
    Teng Zhang
    Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute NE40, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Biochem Biophys Res Commun 355:444-50. 2007
    ..These results suggest that the expression level of the SCN5A gene is a determinant for the length of the P wave duration and PR interval on electrocardiograms (ECG)...
  3. pmc LQTS mutation N1325S in cardiac sodium channel gene SCN5A causes cardiomyocyte apoptosis, cardiac fibrosis and contractile dysfunction in mice
    Teng Zhang
    Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Int J Cardiol 147:239-45. 2011
    ..However, the long-term prognosis of LQTS on the structure of the heart has not been investigated in this or any other LQTS models and human patients...
  4. ncbi A robust hybrid between genetic algorithm and support vector machine for extracting an optimal feature gene subset
    Li Li
    Department of Bioinformatics, Harbin Medical University, Harbin 150086, People s Republic of China
    Genomics 85:16-23. 2005
    ....
  5. ncbi Generation of transgenic mice for cardiovascular research
    Xiao Li Tian
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:69-81. 2006
    ....
  6. pmc Characterization of the cardiac sodium channel SCN5A mutation, N1325S, in single murine ventricular myocytes
    Sandro L Yong
    Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Biochem Biophys Res Commun 352:378-83. 2007
    ..This implies that Ca2+ influx and intracellular Ca2+ ([Ca2+]i) ions are involved and that [Ca2+]i inhomogeneity may be the underlying mechanisms behind non-bradycardia LQT3 arrhythmogenesis associated with mutation N(1325)S...
  7. pmc Optical mapping of ventricular arrhythmias in LQTS mice with SCN5A mutation N1325S
    Xiao Li Tian
    Department of Molecular Cardiology, Lerner Research Institute and Center for Cardiovascular Genetics, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA
    Biochem Biophys Res Commun 352:879-83. 2007
    ..Nifedipine, an L-type calcium channel blocker, decreased the frequency of VT, indicating the involvement of abnormalities of the calcium homeostasis in the genesis of VT in TG-NS/LQT3 mice...
  8. pmc Induction of high STAT1 expression in transgenic mice with LQTS and heart failure
    Ling Wu
    Center for Cardiovascular Genetics and Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Biochem Biophys Res Commun 358:449-54. 2007
    ..This study represents the first microarray analysis for LQTS and implicates STAT1 in the pathogenesis and progression of LQTS and heart failure...
  9. pmc Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB
    Sudhiranjan Gupta
    Department of Molecular Cardiology, Lerner Research Institute, NB50, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
    J Mol Biol 375:637-49. 2008
    ..Our data suggest, for the first time, that inhibition of NF-kappaB using direct gene delivery of sh-p65 RNA results in regression of cardiac hypertrophy. These data validate NF-kappaB as a therapeutic target to prevent hypertrophy/HF...
  10. pmc Identification and functional characterization of a novel splicing mutation in RP gene PRPF31
    Jing Yu Liu
    Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, 1037 Luoyu Road, Wuhan 430074, PR China
    Biochem Biophys Res Commun 367:420-6. 2008
    ..Our studies identify a novel splicing mutation in PRPF31 associated with adRP and suggest that the penetrance of RP11 mutations may be correlated with the expression level of the PRPF31 mRNA...
  11. ncbi Identification of a new co-factor, MOG1, required for the full function of cardiac sodium channel Nav 1.5
    Ling Wu
    Department of Molecular Cardiology, Lerner Research Institute, Center for Cardiovascular Genetics, Tausig Cancer Center, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Biol Chem 283:6968-78. 2008
    ..This study further demonstrates the functional diversity of Nav1.5-binding proteins, which serve important functions for Nav1.5 under different cellular conditions...
  12. pmc Identification of a novel KCNQ1 mutation associated with both Jervell and Lange-Nielsen and Romano-Ward forms of long QT syndrome in a Chinese family
    Su Zhang
    Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, PR China
    BMC Med Genet 9:24. 2008
    ....
  13. ncbi [A Novel mutation of F189L in CASQ2 in families with catecholaminergic polymorphic ventricular tachycardia]
    Qian qian Liu
    Department of Cardiology, Peopleos Hospital of Peking University, Beijing, 100044 People s Republic of China
    Zhonghua Yi Xue Yi Chuan Xue Za Zhi 25:334-7. 2008
    ..To identify mutations and variants in CASQ2 gene in 27 CPVT patients/family members...
  14. pmc Identification of association of common AGGF1 variants with susceptibility for Klippel-Trenaunay syndrome using the structure association program
    Y Hu
    Center for Cardiovascular Genetics, Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA
    Ann Hum Genet 72:636-43. 2008
    ..These results suggest that common AGGF1 variants confer risk of KTS...
  15. pmc Protective effect of KCNH2 single nucleotide polymorphism K897T in LQTS families and identification of novel KCNQ1 and KCNH2 mutations
    Xianqin Zhang
    Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China
    BMC Med Genet 9:87. 2008
    ..To investigate the disease expressivity, this study aimed to identify mutations and common variants that can modify LQTS phenotype...
  16. ncbi The TaqMan method for SNP genotyping
    Gong Qing Shen
    Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
    Methods Mol Biol 578:293-306. 2009
    ..Here, we describe the detailed procedures for TaqMan SNP genotyping assay, including preparation of high-quality DNA samples, the operating protocol, clarification of technical issues, and discussion of several cautionary notes...
  17. ncbi Microarray analysis of cardiovascular diseases
    Stephen R Archacki
    Center for Molecular Genetics, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 129:1-13. 2006
    ....
  18. ncbi High-throughput single-nucleotide polymorphisms genotyping: TaqMan assay and pyrosequencing assay
    Gong Qing Shen
    Center for Molecular Genetics, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:209-24. 2006
    ..Here, we present the operative protocol, clarify the key technical issues, and highlight certain cautionary notes for high throughput SNP genotyping using TaqMan and pyrosequencing assays...
  19. pmc Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a Chinese family
    Qiufen Wang
    Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, China
    J Mol Med (Berl) 83:203-8. 2005
    ..This study identifies a novel Arg528Gly mutation in the CACNA1S gene that causes HypoPP in a Chinese family, expands the spectrum of mutations causing HypoPP, and demonstrates a gender difference in the penetrance of the disease...
  20. pmc Towards precise classification of cancers based on robust gene functional expression profiles
    Zheng Guo
    Department of Computer Science, Harbin Institute of Technology, Harbin 150001, China
    BMC Bioinformatics 6:58. 2005
    ..Therefore, there is an open space for development of the timely and relevant computational algorithms that use robust functional expression profiles towards precise classification of complex human diseases at the modular level...
  21. pmc Advances in the genetic basis of coronary artery disease
    Qing Wang
    Department of Molecular Cardiology, Lerner Research Institute ND4 38, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Curr Atheroscler Rep 7:235-41. 2005
    ..These studies identify a new mechanism, the myocyte enhancer factor 2 (MEF2) signaling pathway of vascular endothelium, for the pathogenesis of CAD, and also confirm the role of inflammation in the disease process...
  22. pmc Molecular genetics of coronary artery disease
    Qing Wang
    Department of Molecular Cardiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
    Curr Opin Cardiol 20:182-8. 2005
    ..Many advances have recently been made, however, and these are reviewed here...
  23. pmc Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis
    A A Timur
    Center for Molecular Genetics, ND40, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA
    Cell Mol Life Sci 62:1434-47. 2005
    ....
  24. ncbi Ferritin in atherosclerosis
    Sun Ah You
    Center for Molecular Genetics, Department of Molecular Cardiology, ND4 38, Lerner Research Institute, and Center for Cardiovascular Genetics, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
    Clin Chim Acta 357:1-16. 2005
    ..Future studies will determine whether increased ferritin levels can serve as a distinct biomarker for the incidence of CAD/MI and distinguish whether increased ferritin levels are a cause of CAD or a consequence of the disease process...
  25. pmc Risk stratification in Brugada syndrome
    Kathryn A Glatter
    Department of Cardiology, University of California, Davis, Sacramento, CA 95817, USA
    Lancet 366:530-1. 2005
  26. pmc Update on the molecular genetics of vascular anomalies
    Qing K Wang
    Department of Molecular Cardiology and Center for Cardiovascular Genetics, Lerner Research Institute ND 40, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
    Lymphat Res Biol 3:226-33. 2005
    ..Furthermore, these studies have identified critical genes involved in vascular morphogenesis, and provided fundamental understanding of the molecular mechanisms underlying vasculogenesis and angiogenesis...
  27. pmc Discovery of Time-Delayed Gene Regulatory Networks based on temporal gene expression profiling
    Xia Li
    Department of Bioinformatics, Harbin Medical University, Harbin 150086, PR China
    BMC Bioinformatics 7:26. 2006
    ..The vast amount of large-scale and genome-wide time-resolved data is becoming increasing available, which provides the golden opportunity to unravel the challenging reverse-engineering problem of time-delayed gene regulatory networks...
  28. ncbi Loss of heterozygosity in human aberrant crypt foci (ACF), a putative precursor of colon cancer
    Liping Luo
    Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
    Carcinogenesis 27:1153-9. 2006
    ..The finding of 3 of 4 of the losses of heterozygosity at 11p11 for PTPRJ and half of all the losses of heterozygosity in this study at PTPRJ suggest that this gene plays a role early in colon neoplasia...
  29. pmc Mapping a new genetic locus for X linked retinitis pigmentosa to Xq28
    A Melamud
    J Med Genet 43:e27. 2006
    ..06, 2.17, and 2.20, respectively. Haplotype analysis revealed segregation of the disease phenotype with markers at Xq28...
  30. ncbi Fluorescence in situ hybridization in cardiovascular disease
    Ayse Anil Timur
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:11-21. 2006
    ..FISH is also widely used in clinical diagnosis of chromosomal disorders...
  31. ncbi Construction of somatic cell hybrid lines: fusion of mouse thymidine kinase-deficient 3T3 fibroblasts and human lymphoblastoid cells
    Ayse Anil Timur
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:33-40. 2006
    ..These hybrid cells serve as an excellent tool with which to define the exact chromosomal breakpoints involved in a cytogenetic abnormality and to identify genes at the breakpoints...
  32. ncbi LINKAGE programs: linkage analysis for monogenic cardiovascular diseases
    Lin Li
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:41-60. 2006
    ..Then, we demonstrate the usages of the programs by analyzing several examples of hypothetical pedigrees with the inheritance modes of autosomal-dominant, autosomal-recessive, and genetic heterogeneity...
  33. ncbi SAGE programs: model-free linkage analysis for complex cardiovascular phenotypes
    Shaoqi Rao
    Department of Molecular Cardiology, The Cleveland Clinic Foundation, OH, USA
    Methods Mol Med 128:61-89. 2006
    ..In particular, the Haseman-Elston sib-pair regression method is introduced and implemented with examples to demonstrate how to identify susceptibility loci for complex traits...
  34. ncbi Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a South American family
    Tie Ke
    Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
    J Hum Genet 54:660-4. 2009
    ..These results identify a new mutation in CACNA1S and expand the spectrum of CACNA1S mutations associated with HypoPP...