Skip to main content

Advertisement

SpringerLink
Log in

Pacing the Heart with Genes: Recent Progress in Biological Pacing

  • Invasive Electrophysiology and Pacing (EK Heist, Section Editor)
  • Published:
Current Cardiology Reports Aims and scope Submit manuscript

Abstract

The heartbeat originates within the sinoatrial node (SA node or SAN), a small highly specialized structure containing <10,000 genuine pacemaker cells. The ~5 billion working cardiomyocytes downstream of the SAN remain quiescent when it fails, leading to circulatory collapse and fueling a $6B/year electronic pacemaker industry. The electronic pacemaker devices work quite well. But, device-related problems persist. These include lead failure/repositioning, finite battery life, and infection. For pediatric patients, the children outgrow the length of the leads, necessitating replacement with longer leads. These pitfalls have motivated creation of biological pacing. that are free from all hardware. Toward this goal, we and others have tested the concept of biological pacemakers. Combined with efforts to create clinically relevant, large animal models of biological pacing, the field is moving beyond a conceptual novelty toward a future with clinical reality.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Bernstein AD, Parsonnet V. Survey of cardiac pacing and implanted defibrillator practice patterns in the United States in 1997. Pacing Clin Electrophysiol. 2001;24(5):842–55.

    Article  CAS  PubMed  Google Scholar 

  2. Ionta V, Liang W, Kim EH, Rafie R, Giacomello A, Marban E, et al. SHOX2 overexpression favors differentiation of embryonic stem cells into cardiac pacemaker cells, improving biological pacing ability. Stem Cell Rep. 2015;4(1):129–42. doi:10.1016/j.stemcr.2014.11.004.

    Article  CAS  Google Scholar 

  3. Kehat I, Khimovich L, Caspi O, Gepstein A, Shofti R, Arbel G, et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol. 2004;22(10):1282–9. doi:10.1038/nbt1014.

    Article  CAS  PubMed  Google Scholar 

  4. Xue T, Cho HC, Akar FG, Tsang SY, Jones SP, Marbán E, et al. Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell-based pacemakers. Circulation. 2005;111(1):11–20.

    Article  PubMed  Google Scholar 

  5. Miake J, Marban E, Nuss HB. Biological pacemaker created by gene transfer. Nature. 2002;419(6903):132–3.

    Article  CAS  PubMed  Google Scholar 

  6. Cho HC, Backx PH. Three-dimensional structure of a K+ channel pore: basis for ion selectivity and permeability. In: Archer SL, Rusch NJ, editors. Potassium channels in cardiovascular biology. New York: Kluwer Academic / Plenum Publishers; 2001. p. 17–34.

    Chapter  Google Scholar 

  7. Zobel C, Cho HC, Nguyen TT, Pekhletski R, Diaz RJ, Wilson GJ, et al. Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir2.2. J Physiol. 2003;550(Pt 2):365–72.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Cho HC, Tsushima RG, Nguyen TT, Guy HR, Backx PH. Two critical cysteine residues implicated in disulfide bond formation and proper folding of Kir2.1. Biochemistry. 2000;39(16):4649–57.

    Article  CAS  PubMed  Google Scholar 

  9. Mangoni ME, Nargeot J. Genesis and regulation of the heart automaticity. Physiol Rev. 2008;88(3):919–82. doi:10.1152/physrev.00018.2007.

    Article  CAS  PubMed  Google Scholar 

  10. Cho HC, Marbán E. Biological therapies for cardiac arrhythmias: can genes and cells replace drugs and devices? Circ Res. 2010;106(4):674–85. doi:10.1161/CIRCRESAHA.109.212936.

    Article  CAS  PubMed  Google Scholar 

  11. Lakatta EG, Vinogradova T, Lyashkov A, Sirenko S, Zhu W, Ruknudin A, et al. The integration of spontaneous intracellular Ca2+ cycling and surface membrane ion channel activation entrains normal automaticity in cells of the heart's pacemaker. Ann N Y Acad Sci. 2006;1080:178–206.

    Article  CAS  PubMed  Google Scholar 

  12. Miake J, Marban E, Nuss HB. Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression. J Clin Invest. 2003;111(10):1529–36. doi:10.1172/JCI17959.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Rohr S, Kucera JP, Fast VG, Kleber AG. Paradoxical improvement of impulse conduction in cardiac tissue by partial cellular uncoupling. Science. 1997;275(5301):841–4.

    Article  CAS  PubMed  Google Scholar 

  14. Unudurthi SD, Wolf RM, Hund TJ. Role of sinoatrial node architecture in maintaining a balanced source-sink relationship and synchronous cardiac pacemaking. Front Physiol. 2014;5:446. doi:10.3389/fphys.2014.00446.

    Article  PubMed Central  PubMed  Google Scholar 

  15. Lakatta EG, DiFrancesco D. What keeps us ticking: a funny current, a calcium clock, or both? J Mol Cell Cardiol. 2009;47(2):157–70.

    Article  CAS  PubMed  Google Scholar 

  16. Chien KR, Domian IJ, Parker KK. Cardiogenesis and the complex biology of regenerative cardiovascular medicine. Science. 2008;322(5907):1494–7. doi:10.1126/science.1163267.

    Article  CAS  PubMed  Google Scholar 

  17. Bleeker WK, Mackaay AJ, Masson-Pevet M, Bouman LN, Becker AE. Functional and morphological organization of the rabbit sinus node. Circ Res. 1980;46(1):11–22.

    Article  CAS  PubMed  Google Scholar 

  18. Christoffels VM, Smits GJ, Kispert A, Moorman AF. Development of the pacemaker tissues of the heart. Circ Res. 2010;106(2):240–54.

    Article  CAS  PubMed  Google Scholar 

  19. Blaschke RJ, Hahurij ND, Kuijper S, Just S, Wisse LJ, Deissler K, et al. Targeted mutation reveals essential functions of the homeodomain transcription factor Shox2 in sinoatrial and pacemaking development. Circulation. 2007;115(14):1830–8. doi:10.1161/CIRCULATIONAHA.106.637819.

    Article  CAS  PubMed  Google Scholar 

  20. Espinoza-Lewis RA, Yu L, He F, Liu H, Tang R, Shi J, et al. Shox2 is essential for the differentiation of cardiac pacemaker cells by repressing Nkx2-5. Dev Biol. 2009;327(2):376–85.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Hoogaars WM, Engel A, Brons JF, Verkerk AO, de Lange FJ, Wong LY, et al. Tbx3 controls the sinoatrial node gene program and imposes pacemaker function on the atria. Genes Dev. 2007;21(9):1098–112.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Mori AD, Zhu Y, Vahora I, Nieman B, Koshiba-Takeuchi K, Davidson L, et al. Tbx5-dependent rheostatic control of cardiac gene expression and morphogenesis. Dev Biol. 2006;297(2):566–86. doi:10.1016/j.ydbio.2006.05.023.

    Article  CAS  PubMed  Google Scholar 

  23. Wiese C, Grieskamp T, Airik R, Mommersteeg MT, Gardiwal A, de Gier-de VC, et al. Formation of the sinus node head and differentiation of sinus node myocardium are independently regulated by Tbx18 and Tbx3. Circ Res. 2009;104(3):388–97.

    Article  CAS  PubMed  Google Scholar 

  24. Kapoor N, Liang W, Marban E, Cho HC. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat Biotechnol. 2013;31(1):54–62. doi:10.1038/nbt.2465. This study provides the first proof-of-concept for a transcription factor-mediated reprogramming to transform ordinary cardiac myocytes to highly-specialized pacemaker cells.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Kapoor N, Galang G, Marbán E, Cho HC. Transcriptional suppression of Connexin43 by Tbx18 undermines cell-cell electrical coupling in postnatal cardiomyocytes. J Biol Chem. 2011. This study illuminates one of the key effects of re-expressing an embryonic transcription factor, Tbx18, in adult cardiac myocytes.

  26. Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ Res. 2010;106(4):659–73.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Cho HC, Kashiwakura Y, Marbán E. Creation of a biological pacemaker by cell fusion. Circ Res. 2007;100(8):1112–5.

    Article  CAS  PubMed  Google Scholar 

  28. Kashiwakura Y, Cho HC, Barth AS, Azene E, Marbán E. Gene transfer of a synthetic pacemaker channel into the heart: a novel strategy for biological pacing. Circulation. 2006;114(16):1682–6.

    Article  PubMed  Google Scholar 

  29. Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126(4):663–76.

    Article  CAS  PubMed  Google Scholar 

  30. Yu J, Vodyanik MA, Smuga-Otto K, Antosiewicz-Bourget J, Frane JL, Tian S, et al. Induced pluripotent stem cell lines derived from human somatic cells. Science. 2007;318(5858):1917–20.

    Article  CAS  PubMed  Google Scholar 

  31. Bakker ML, Boink GJ, Boukens BJ, Verkerk AO, van den Boogaard M, den Haan AD, et al. T-box transcription factor TBX3 reprogrammes mature cardiac myocytes into pacemaker-like cells. Cardiovasc Res. 2012;94(3):439–49. doi:10.1093/cvr/cvs120.

    Article  CAS  PubMed  Google Scholar 

  32. Chardack WM, Gage AA, Greatbatch W. A transistorized, self-contained, implantable pacemaker for the long-term correction of complete heart block. Surgery. 1960;48:643–54.

    CAS  PubMed  Google Scholar 

  33. Epstein AE, DiMarco JP, Ellenbogen KA, Estes 3rd NA, Freedman RA, Gettes LS, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation. 2013;127(3):e283–352. doi:10.1161/CIR.0b013e318276ce9b.

    Article  PubMed  Google Scholar 

  34. Bucchi A, Plotnikov AN, Shlapakova I, Danilo Jr P, Kryukova Y, Qu J, et al. Wild-type and mutant HCN channels in a tandem biological-electronic cardiac pacemaker. Circulation. 2006;114(10):992–9.

    Article  PubMed  Google Scholar 

  35. Cingolani E, Yee K, Shehata M, Chugh SS, Marban E, Cho HC. Biological pacemaker created by percutaneous gene delivery via venous catheters in a porcine model of complete heart block. Heart RhytHm J. 2012;9(8):1310–8. doi:10.1016/j.hrthm.2012.04.020.

    Article  Google Scholar 

  36. Tse HF, Xue T, Lau CP, Siu CW, Wang K, Zhang QY, et al. Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model. Circulation. 2006;114(10):1000–11.

    Article  CAS  PubMed  Google Scholar 

  37. Boink GJ, Nearing BD, Shlapakova IN, Duan L, Kryukova Y, Bobkov Y, et al. Ca(2+)-stimulated adenylyl cyclase AC1 generates efficient biological pacing as single gene therapy and in combination with HCN2. Circulation. 2012;126(5):528–36. doi:10.1161/CIRCULATIONAHA.111.083584. As an extension of their previous works, this study utilizes an ion channel-based approach to generating cardiac automaticity in a large animal model.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Hu YF, Dawkins JF, Cho HC, Marban E, Cingolani E. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci Transl Med. 2014;6(245):245ra94. doi:10.1126/scitranslmed.3008681. The work builds on the groundbreaking results of Tbx18-mediated reprogramming (ref. 24), and demonstrates Tbx18-mediated biological pacemaking in a clinically-realistic large animal model.

    Article  PubMed  Google Scholar 

  39. Cinca J, Moya A, Figueras J, Roma F, Rius J. Circadian variations in the electrical properties of the human heart assessed by sequential bedside electrophysiologic testing. Am Heart J. 1986;112(2):315–21.

    Article  CAS  PubMed  Google Scholar 

  40. Narula OS, Samet P, Javier RP. Significance of the sinus-node recovery time. Circulation. 1972;45(1):140–58.

    Article  CAS  PubMed  Google Scholar 

  41. Montano N, Ruscone TG, Porta A, Lombardi F, Pagani M, Malliani A. Power spectrum analysis of heart rate variability to assess the changes in sympathovagal balance during graded orthostatic tilt. Circulation. 1994;90(4):1826–31.

    Article  CAS  PubMed  Google Scholar 

  42. Nicolini P, Ciulla MM, De Asmundis C, Magrini F, Brugada P. The prognostic value of heart rate variability in the elderly, changing the perspective: from sympathovagal balance to chaos theory. Pacing Clin Electrophysiol. 2012;35(5):622–38. doi:10.1111/j.1540-8159.2012.03335.x.

    Article  PubMed  Google Scholar 

  43. McGavigan AD, Roberts-Thomson KC, Hillock RJ, Stevenson IH, Mond HG. Right ventricular outflow tract pacing: radiographic and electrocardiographic correlates of lead position. Pacing Clin Electrophysiol. 2006;29(10):1063–8. doi:10.1111/j.1540-8159.2006.00499.x.

    Article  PubMed  Google Scholar 

  44. Rajappan K. Permanent pacemaker implantation technique: part I: arrhythmias. Heart. 2009;95(3):259–64. doi:10.1136/hrt.2007.132753.

    Article  PubMed  Google Scholar 

  45. Rosen MR, Robinson RB, Brink PR, Cohen IS. The road to biological pacing. Nat Rev Cardiol. 2011;8(11):656–66. doi:10.1038/nrcardio.2011.120.

    Article  PubMed  Google Scholar 

  46. Kozhevnikov D, Caref EB, El-Sherif N. Mechanisms of enhanced arrhythmogenicity of regional ischemia in the hypertrophied heart. Heart Rhythm. 2009;6(4):522–7. doi:10.1016/j.hrthm.2008.12.021.

    Article  CAS  PubMed  Google Scholar 

  47. Antzelevitch C, Oliva A. Amplification of spatial dispersion of repolarization underlies sudden cardiac death associated with catecholaminergic polymorphic VT, long QT, short QT and Brugada syndromes. J Intern Med. 2006;259(1):48–58. doi:10.1111/j.1365-2796.2005.01587.x.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Losordo DW, Henry TD, Davidson C, Sup Lee J, Costa MA, Bass T, et al. Intramyocardial, autologous CD34+ cell therapy for refractory angina. Circ Res. 2011;109(4):428–36. doi:10.1161/CIRCRESAHA.111.245993.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation. 2003;107(18):2294–302. doi:10.1161/01.CIR.0000070596.30552.8B.

    Article  PubMed  Google Scholar 

  50. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Silva GV, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation. 2004;110(11 Suppl 1):II213–8. doi:10.1161/01.CIR.0000138398.77550.62.

    PubMed  Google Scholar 

  51. Mitani K, Graham FL, Caskey CT, Kochanek S. Rescue, propagation, and partial purification of a helper virus-dependent adenovirus vector. Proc Natl Acad Sci U S A. 1995;92(9):3854–8.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Gray SJ, Samulski RJ. Optimizing gene delivery vectors for the treatment of heart disease. Expert Opin Biol Ther. 2008;8(7):911–22.

    Article  CAS  PubMed  Google Scholar 

  53. Reddy VY, Knops RE, Sperzel J, Miller MA, Petru J, Simon J, et al. Permanent leadless cardiac pacing: results of the LEADLESS trial. Circulation. 2014;129(14):1466–71. doi:10.1161/CIRCULATIONAHA.113.006987.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Supported by the Urowsky-Sahr Foundation, NHLBI, and AHA.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Hee Cheol Cho declares that he has no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Emory University, HSRB E-184, 1760 Haygood Drive, Atlanta, GA, 30322, USA

    Hee Cheol Cho

  2. Department of Pediatrics, Emory University, HSRB E-184, 1760 Haygood Drive, Atlanta, GA, 30322, USA

    Hee Cheol Cho

Authors
  1. Hee Cheol Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hee Cheol Cho.

Additional information

This article is part of the Topical Collection on Invasive Electrophysiology and Pacing

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cho, H.C. Pacing the Heart with Genes: Recent Progress in Biological Pacing. Curr Cardiol Rep 17, 65 (2015). https://doi.org/10.1007/s11886-015-0620-x

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11886-015-0620-x

Keywords

Search

Navigation