creators_name: G, Rajesh creators_name: Francis, Johnson editors_name: Singh, Balbir editors_name: Lokhandwala, Yash editors_name: Francis, Johnson editors_name: Gupta, Anup type: journalp datestamp: 2006-01-06 lastmod: 2011-03-11 08:56:13 metadata_visibility: show title: Biological Pacemakers ispublished: pub subjects: ipej full_text_status: public keywords: Gene therapy, Pacemaker current, HCN channels abstract: Genetically engineered pacemakers could be a possible alternative to implantable electronic devices for the treatment of bradyarrhythmias. The strategies include upregulation of beta adrenergic receptors, conversion of myocytes into pacemaker cells and stem cell therapy. Pacemaker activity in adult ventricular myocytes is normally repressed by the inward rectifier potassium current (IK1). The IK1 current is encoded by the Kir2 gene family. Use of a negative construct that suppresses current when expressed with wild-type Kir2.1 is an experimental approach for genesis of genetic pacemaker. hyperpolarisation activated cyclic nucleotide gated (HCN) channels which generate If current, the pacemaker current of heart can be delivered to heart by using stem cell therapy approach and viral vectors. The unresolved issues include longevity and stability of pacemaker genes, limitations involved in adenoviral and stem cell therapy and creation of genetic pacemakers which can compete with the electronic units. date: 2005-01 date_type: published publication: Indian Pacing and Electrophysiology Journal volume: 6 number: 1 publisher: Indian Pacing and Electrophysiology Group pagerange: 1-5 refereed: TRUE referencetext: 1. Edelberg JM, Aird WC, Rosenberg RD. Enhancement of murine cardiac chronotropy by molecular transfer of the human b2 adrenergic receptor cDNA. J Clin Invest. 1998;101:337-343. 2. Miake J, Marban E, Nuss HB. Gene therapy: biological pacemaker created by gene transfer. Nature. 2002;419:132-133. 3. Potapova I, Plotnikov A, Lu Z. Human mesenchymal stem cells as a gene delivery system to crate cardiac pacemakers. Circulation research. 2004;952-959. 4. Zhou YY,Wang SQ, Zhu WZ,Chruscinski A, Kobilka BK, Ziman B,Wang S,Lakatta EG, Cheng H, Xiao PP. Culture and adenoviral infection of adult mouse cardiac myocytes;methods for cellular genetic physiology. Am J Physiol (Heart Circ physiol). 2000;279:H429-H436. 5. Hamm A, Krott N, Breibach I, Blindt R, Bosserfoff AK. Efficient transfection method for primary cells. Tissue ENG. 2002;8:235-245. 6. Di Francesco D. Pacemaker mechanism in cardiac tissue. Annu Rev Physiol. 1993; 55:455-472. 7. Ludwig A, Zong X,Jeglitsch M. A family of hyperpolarisation activated mammalian cation channels. Nature 1998; 393:587-591. 8. Andreas Ludig et al. HCN channels, From genes to function. In: Douglas p . Zipes, Jose Jalife, ed: Cardiac electrophysiology, From cell to bedside. Fourth edition. Saunders. pp. 59-65. 9. Moosmang S, Stieber J, Zong X, Biel M, Hofmann F, Ludwig A. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem. 2001;268:1646-52 10. Biel M, Schneider A, Wahl C. Cardiac HCN channels: structure, function, and modulation. Trends Cardiovasc Med. 2002;12:206-12. 11. Lopatin AN, Nichols CG. Inward rectifiers in the heart: an update on I(K1). J Mol Cell Cardiol. 2001 ;33:625-38. 12. Nichols CG, Makhina EN, Pearson WL, Sha Q, Lopatin A. Inward rectification and implications for cardiac excitability. Circ Res. 1996 ;78(1):1-7. 13. Qu J, Plotnikov AN, Danilo P Jr, Shlapakova I, Cohen IS, Robinson RB, Rosen MR. Expression and function of a biological pacemaker in canine heart. Circulation. 2003; 107(8):1106-9. 14. Plotnikov AN, Sosunov EA, Qu J, Shlapakova IN, Anyukhovsky EP, Liu L, Janse MJ, Brink PR, Cohen IS, Robinson RB, Danilo P Jr, Rosen MR. Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation. 2004;109 (4):506-12. 15. Valiunas V, Weingart R, Brink PR. Formation of heterotypic gap junction channels by connexins 40 and 43. Circ Res. 2000; 86(2):E42-9. citation: G, Rajesh and Francis, Johnson (2005) Biological Pacemakers. [Journal (Paginated)] document_url: http://cogprints.org/4599/1/rajesh.htm document_url: http://cogprints.org/4599/2/rajesh.pdf