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The road to biological pacing

Nature Reviews Cardiology volume 8, pages 656–666 (2011)Cite this article

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Abstract

The field of biological pacing is entering its second decade of active investigation. The inception of this area of study was serendipitous, deriving largely from observations made by several teams of investigators, whose common interest was to understand the mechanisms governing cardiac impulse initiation. Research directions taken have fallen under the broad headings of gene therapy and cell therapy, and biomaterials research has also begun to enter the field. In this Review, we revisit certain milestones achieved through the construction of a 'roadmap' in biological pacing. Whether the end result will be a clinically applicable biological pacemaker is still uncertain. However, promising constructs that achieve physiologically relevant heart rates and good autonomic responsiveness are now available, and proof of principle studies are giving way to translation to large-animal models in long-term studies. Provided that interest in the field continues, the next decade should see either biological pacemakers become a clinical reality or the improvement of electronic pacemakers to a point where the biological approach is no longer a viable alternative.

Key Points

  • Biological pacing is a disruptive technology that aims first to improve upon, then to supplement and, eventually, to replace electronic pacing

  • Biological pacing utilizes the tools of gene and cell therapy to introduce pacemaker function to preselected regions of the heart

  • Gene therapy focuses on delivery via viral vectors; whereas cell therapy uses either mesenchymal stem cells as delivery systems or cells with sinoatrial node-like properties derived from pluripotent stem cells

  • Proof-of-concept has been achieved in studies of large animals in complete heart block and, in some instances, sinoatrial node dysfunction

  • Substantial barriers remain to be overcome before clinical trials of biological pacing can be begun, but the field is advancing steadily towards this goal

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Figure 1: Schematic of interactions among Ca2+, basal Ca2+-activated adenylyl cyclase, cAMP, phosphodiesterase activity, and protein kinase A and CaMKII activity, within the context of sarcoplasmic reticulum Ca2+ cycling, L-type Ca2+ channels, HCN channels, and other ion channels.
Figure 2: Pacemaker function in cells in two-cell syncytium in culture.
Figure 3: The auricular sling method used by Starzl and associates38 in an attempt to provide sinus beats to the ventricle.
Figure 4: 6-lead electrocardiograms from two dogs with radiofrequency ablation-induced CHB.
Figure 5: Histology of serial sections of an injection site of hMSCs loaded with HCN2 and GFP at 6 weeks.
Figure 6: 24 h heart rate variability studies of a dog in sinus rhythm (left), a dog in CHB that received HCN2-loaded hMSCs into the left ventricular anterior wall (center), and another dog in CHB that received an adenoviral HCN2 construct into the left bundle branch (right).

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References

  1. Hoffman, B. F. & Cranefield, P. F. Electrophysiology of the Heart (Futura Publishing, Armonk, 1960).

    Google Scholar 

  2. Jalife, J., Delmar, M., Davidenko, J. M. & Anumonwo, J. M. Basic Cardiac Electrophysiology for the Clinician (Futura Publishing, Armonk, 1999).

    Google Scholar 

  3. Tsien, R. W. & Carpenter, D. O. Ionic mechanisms of pacemaker activity in cardiac Purkinje fibers. Fed. Proc. 37, 2127–2131 (1978).

    CAS  PubMed  Google Scholar 

  4. Biel, M., Schneider, A. & Wahl, C. Cardiac HCN channels structure, function, and modulation. Trends Cardiovasc. Med. 12, 206–212 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Bogdanov, K. Y. et al. Membrane potential fluctuations resulting from submembrane Ca+ releases in rabbit sinoatrial nodal cells impart an exponential phase to the late diastolic depolarization that controls their chronotropic state. Circ. Res. 99, 979–987 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. DiFrancesco, D. A study of the ionic nature of the pacemaker current in calf Purkinje fibres. J. Physiol. 314, 377–393 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. DiFrancesco, D. The contribution of the 'pacemaker' current (If) to generation of spontaneous activity in rabbit sino-atrial node myocytes. J. Physiol. 434, 23–40 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lakatta, E. G., Maltsev, V. A. & Vinogradova, T. M. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker. Circ. Res. 106, 659–673 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lakatta, E. G. & DiFrancesco, D. What keeps us ticking: a funny current, a calcium clock, or both? J. Mol. Cell. Cardiol. 47, 157–170 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Joung, B. et al. Intracellular calcium dynamics and acceleration of sinus rhythm by beta-adrenergic stimulation. Circulation 119, 788–796 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Robinson, R. B. & Siegelbaum, S. A. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu. Rev. Physiol. 65, 453–480 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Chandler, N. J. et al. Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker. Circulation 119, 1562–1575 (2009).

    Article  PubMed  Google Scholar 

  13. Scherf, D. & Schott, A. Extrasystoles and Allied Arrhythmias 2nd edn (Year Book Medical Publishers, Chicago, 1973).

    Google Scholar 

  14. Osler, W. Stokes–Adams disease. Ann. Noninvasive Electrocardiol. 7, 79–81 (2002).

    Article  PubMed  Google Scholar 

  15. Adams, R. Cases of diseases of the heart accompanied with pathological observations. Dublin Hospital Reports 4, 353–453 (1827).

    Google Scholar 

  16. Stokes, W. Observations on some cases of permanently slow pulse. Dublin Quarterly Journal of Medical Science 2, 73–85 (1846).

    Article  Google Scholar 

  17. Zoll, P. M. Resuscitation of the heart in ventricular standstill by external electric stimulation. N. Engl. J. Med. 247, 768–771 (1952).

    Article  CAS  PubMed  Google Scholar 

  18. Furman, S. & Schwedel, J. B. An intracardiac pacemaker for Stokes–Adams seizures. N. Engl. J. Med. 261, 943–947 (1959).

    Article  CAS  PubMed  Google Scholar 

  19. Zivin, A., Mehra, R. & Bardy, G. H. in Foundations of Cardiac Arrhythmias: Basic Concepts and Clinical Approaches (Eds Spooner, P. M. & Rosen, M. R.) 571–598 (Marcel Dekker Inc., New York, 2001).

    Google Scholar 

  20. Rosen, M. R., Brink, P. R., Cohen, I. S. & Robinson, R. B. Cardiac pacing: from biological to electronic … to biological? Circ. Arrhythmia Electrophysiol. 1, 54–61 (2008).

    Article  Google Scholar 

  21. Kolata, G. In Fixing Faulty Medical Devices, the Cure Can Be Worse Than the Disease. New York Times (6 April 1998).

  22. Binggeli, C. et al. Autonomic nervous system-controlled cardiac pacing: a comparison between intracardiac impedance signal and muscle sympathetic nerve activity. Pacing Clin. Electrophysiol. 23, 1632–1637 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Lee, K. L. In the wireless era: leadless pacing. Expert Rev. Cardiovasc. Ther. 8, 171–174 (2010).

    Article  PubMed  Google Scholar 

  24. Rosen, M. R., Brink, P. R., Cohen, I. S. & Robinson, R. B. Genes, stem cells and biological pacemakers. Cardiovasc. Res. 64, 12–23 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Siu, C. W., Lieu, D. K. & Li, R. A. HCN-encoded pacemaker channels: from physiology and biophysics to bioengineering. J. Membr. Biol. 214, 115–122 (2006).

    Article  CAS  PubMed  Google Scholar 

  26. Marbán, E. & Cho, H. C. Biological pacemakers as a therapy for cardiac arrhythmias. Curr. Opin. Cardiol. 23, 46–54 (2008).

    Article  PubMed  Google Scholar 

  27. Cingolani, E. et al. Biological pacemaker created by percutaneous gene delivery via venous catheters in a porcine model of complete heart block [poster PO 01–25]. Heart Rhythm 8, S112 (2011).

    Google Scholar 

  28. Bucchi, A. et al. Wild-type and mutant HCN channels in a tandem biological-electronic cardiac pacemaker. Circulation 114, 992–999 (2006).

    Article  PubMed  Google Scholar 

  29. Zhang, H., Holden, A. V. & Boyett, M. R. Gradient model versus mosaic model of the sinoatrial node. Circulation 103, 584–588 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Cohen, I. S. & Robinson, R. B. Pacemaker current and automatic rhythms: toward a molecular understanding. Handb. Exp. Pharmacol. 171, 41–71 (2006).

    Article  Google Scholar 

  31. Qu, J. et al. HCN2 overexpression in newborn and adult ventricular myocytes: distinct effects on gating and excitability. Circ. Res. 89, E8–E14 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Jansen, J. A., van Veen, T. A., de Bakker, J. M. & van Rijen, H. V. Cardiac connexins and impulse propagation. J. Mol. Cell Cardiol. 48, 76–82 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Valiunas, V. et al. Human mesenchymal stem cells make cardiac connexins and form functional gap junctions. J. Physiol. 555, 617–626 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Valiunas, V. et al. Coupling an HCN2-expressing cell to a myocyte creates a two-cell pacing unit. J. Physiol. 587, 5211–5226 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Plotnikov, A. N. et al. Xenografted adult human mesenchymal stem cells provide a platform for sustained biological pacemaker function in canine heart. Circulation 116, 706–713 (2007).

    Article  PubMed  Google Scholar 

  36. Zhang, H. et al. Implantation of sinoatrial node cells into canine right ventricle:biological pacing appears limited by the substrate. Cell Transplant. doi:10.3727/096368911X565038.

    Article  CAS  PubMed  Google Scholar 

  37. Rylant, M. Contribution a l'etude de l'automatisme et de la conduction dans le Coeur. Bull. Acad. Med. Belgique 7, 161–200 (1927).

    Google Scholar 

  38. Starzl, T. E., Hermann, G., Axtell, H. K., Marchioro, T. L. & Waddell, W. R. Failure of sino-atrial nodal transplantation for the treatment of experimental complete heart block in dogs. J. Thorac. Cardiovasc. Surg. 46, 201–205 (1963).

    PubMed  PubMed Central  Google Scholar 

  39. Ernst, R. W. Pedicle grafting of the sino-auricular node to the right ventricle for the treatment of complete atrioventricular block. J. Thorac. Surg. 44, 681–698 (1962).

    Google Scholar 

  40. Morishita, Y., Poirier, R. A. & Rohner, R. F. Sinoatrial node transplantation in the dog. Vasc. Endovasc. Surg. 15, 388–393 (1981).

    Google Scholar 

  41. Edelberg, J. M., Aird, W. C. & Rosenberg, R. D. Enhancement of murine cardiac chronotropy by the molecular transfer of the human beta2 adrenergic receptor cDNA. J. Clin. Invest. 101, 337–343 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Edelberg, J. M., Huang, D. T., Josephson, M. E. & Rosenberg, R. D. Molecular enhancement of porcine cardiac chronotropy. Heart 86, 559–562 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ruhpawar, A. et al. Transplanted fetal cardiomyocytes as cardiac pacemaker. Eur. J. Cardiothorac. Surg. 21, 853–857 (2002).

    Article  Google Scholar 

  44. Ruhparwar, A. et al. Adenylate-cyclase VI transforms ventricular cardiomyocytes into biological pacemaker cells. Tissue Eng. Part A 16, 1867–1872 (2010).

    Article  CAS  PubMed  Google Scholar 

  45. Mattick, P. et al. Ca2+-stimulated adenylyl cyclase isoform AC1 is preferentially expressed in guinea-pig sino-atrial node cells and modulates the I(f) pacemaker current. J. Physiol. 582, 1195–1203 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Younes, A. et al. Ca2+ -stimulated basal adenylyl cyclase activity localization in membrane lipid microdomains of cardiac sinoatrial nodal pacemaker cells. J. Biol. Chem. 283, 14461–14468 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kryukova, Y. & Robinson, R. B. A key role of Ca2+-activated adenylyl cyclase I in Ca2+-dependence of β-adrenergic modulation of pacemaker current [abstract 2330]. Circulation 120, S625 (2009).

    Google Scholar 

  48. Boink, G. J. et al. Introducing the Ca2+-stimulated adenylyl cyclase AC1 into HCN2-based biological pacemakers enhances their function [abstract A16415]. Circulation 122, A16415 (2010).

    Google Scholar 

  49. Miake, J., Marbán, E., Nuss, H. B. Biological pacemaker created by gene transfer. Nature 419, 132–133 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Miake, J., Marbán, E. & Nuss, H. B. Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative-suppression. J. Clin. Invest. 111, 1529–1536 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Qu, J. et al. Expression and function of a biological pacemaker in canine heart. Circulation 107, 1106–1109 (2003).

    Article  PubMed  Google Scholar 

  52. Plotnikov, A. N. et al. Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation 109, 506–512 (2004).

    Article  PubMed  Google Scholar 

  53. Tse, H. F. 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 114, 1000–1011 (2006).

    Article  CAS  PubMed  Google Scholar 

  54. Plotnikov, A. N. et al. HCN212-channel biological pacemakers manifesting ventricular tachyarrhythmias are responsive to treatment with I(f) blockade. Heart Rhythm 5, 282–288 (2008).

    Article  PubMed  Google Scholar 

  55. Potapova, I. et al. Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ. Res. 94, 952–959 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Lau, D. H. et al. Epicardial border zone overexpression of skeletal muscle sodium channel, SkM1, normalizes activation, preserves conduction and suppresses ventricular arrhythmia: an in silico, in vivo, in vitro study. Circulation 119, 19–27 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Protas, L. et al. Expression of skeletal but not cardiac Na+ channel isoform preserves normal conduction in a depolarized cardiac syncytium. Cardiovasc. Res. 81, 528–535 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Coronel, R. et al. Cardiac expression of skeletal muscle sodium channels increases longitudinal conduction velocity in the canine 1-week myocardial infarction. Heart Rhythm 7, 1104–1110 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Boink, G. J. et al. HCN2/SkM1 gene transfer into the canine left bundle branch induces highly stable biological pacing at physiological beating rates [abstract AB24–2]. Heart Rhythm 8, S54 (2011).

    Google Scholar 

  60. Kashiwakura, Y., Cho, H. C., Barth, A. S., Azene, E. & Marbán, E. Gene transfer of a synthetic pacemaker channel into the heart: a novel strategy for biological pacing. Circulation 114, 1682–1686 (2006).

    Article  PubMed  Google Scholar 

  61. Kehat, I. et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat. Biotechnol. 22, 1282–1289 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. Zhang, J. et al. Functional cardiomyocytes derived from human induced pluripotent stem cells. Circ. Res. 104, e30–e41 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Novak, A. et al. Enhanced reprogramming and cardiac differentiation of human keratinocytes derived from plucked hair follicles, using a single excisable lentivirus. Cell Reprogram. 12, 665–678 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Efe, J. E. et al. Conversion of mouse fibroblasts into cardiomyocytes using a direct reprogramming strategy. Nat. Cell Biol. 13, 215–222 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Warren, L. et al. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7, 618–630 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Leda, M. et al. Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142, 375–386 (2010).

    Article  Google Scholar 

  67. Mummery, C. Induced pluripotent stem cells—a cautionary note. N. Engl. J. Med. 364, 2160–2162 (2011).

    Article  CAS  PubMed  Google Scholar 

  68. Pera, M. F. Stem cells: the dark side of induced pluripotency. Nature 471, 46–47 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Shlapakova, I. N. et al. Biological pacemakers in canines exhibit positive chronotropic response to emotional arousal. Heart Rhythm 7, 1835–1840 (2010).

    Article  PubMed  Google Scholar 

  70. Cho, H. C., Kashiwakura, Y. & Marbán, E. Creation of a biological pacemaker by cell fusion. Circ. Res. 100, 1112–1115 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Rezai, N. et al. Methods for examining stem cells in post-ischemic and transplanted hearts. Methods Mol. Med. 112, 223–238 (2005).

    PubMed  Google Scholar 

  72. Proulx, M. K. et al. Fibrin microthreads support mesenchymal stem cell growth while maintaining differentiation potential. J. Biomed. Mater. Res. A. 96, 301–312 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Rosen, A. B. et al. Finding fluorescent needles in the cardiac haystack: tracking human mesenchymal stem cells labeled with quantum dots for quantitative in vivo three-dimensional fluorescence analysis. Stem Cells 25, 2128–2138 (2007).

    Article  CAS  PubMed  Google Scholar 

  74. Kraitchman, D. L. & Wu, J. C. (Eds) Stem Cell Labeling for Delivery and Tracking Using Non-Invasive Imaging. (CRC Press, New York, 2011).

    Book  Google Scholar 

  75. Climbing Mount Everest is work for supermen. New York Times (18 March 1923).

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Authors and Affiliations

  1. Departments of Pharmacology and Pediatrics, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, PH7 West-321, New York, 10032, NY, USA

    Michael R. Rosen

  2. Department of Pharmacology, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, 630 West 168th Street, PH7 West-321, New York, 10032, NY, USA

    Richard B. Robinson

  3. Department of Physiology and Biophysics, Institute for Molecular Cardiology, Stony Brook University Medical Center, East Loop Road, Stony Brook, 11794, NY, USA

    Peter R. Brink & Ira S. Cohen

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M. R. Rosen and R. B. Robinson researched data for the article. M. R. Rosen and I. S. Cohen discussed the content. The article was written by M. R. Rosen. All authors reviewed/edited the article before submission.

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Correspondence to Michael R. Rosen.

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Rosen, M., Robinson, R., Brink, P. et al. The road to biological pacing. Nat Rev Cardiol 8, 656–666 (2011). https://doi.org/10.1038/nrcardio.2011.120

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