Abstract
While electronic cardiac pacing in its various modalities represents standard of care for treatment of symptomatic bradyarrhythmias and heart failure, it has limitations ranging from absent or rudimentary autonomic modulation to severe complications. This has prompted experimental studies to design and validate a biological pacemaker that could supplement or replace electronic pacemakers. Advances in cardiac gene therapy have resulted in a number of strategies focused on β-adrenergic receptors as well as specific ion currents that contribute to pacemaker function. This article reviews basic pacemaker physiology, as well as studies in which gene transfer approaches to develop a biological pacemaker have been designed and validated in vivo. Additional requirements and refinements necessary for successful biopacemaker function by gene transfer are discussed.
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References
Anumonwo JM et al (1992) Gap junctional channels in adult mammalian sinus nodal cells. Immunolocalization and electrophysiology. Circ Res 71:229–239
Bauer A et al (2004) Inhibitory G protein overexpression provides physiologically relevant heart rate control in persistent atrial fibrillation. Circulation 110:3115–3120
Bekeredjian R, Shohet RV (2004) Cardiovascular gene therapy: angiogenesis and beyond. Am J Med Sci 327:139–148
Bogdanov KY et al (2006) Membrane potential fluctuations resulting from submembrane Ca2+ releases in rabbit sinoatrial nodal cells impart an exponential phase to the late diastolic depolarization that controls their chronotropic state. Circ Res. DOI 10.1161/01.RES.0000247933.66532.0b
Bonke FI (1973) Passive electrical properties of atrial fibers of the rabbit heart. Pflugers Arch 339:1–15
Boyett MR et al (1995) Ionic basis of the chronotropic effect of acetylcholine on the rabbit sinoatrial node. Cardiovasc Res 29:867–878
Boyett MR, Honjo H, Kodama I (2000) The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc Res 47:658–687
Brown H, DiFrancesco D (1980) Voltage-clamp investigations of membrane currents underlying pace-maker activity in rabbit sino-atrial node. J Physiol 308:331–351
Bunch TJ et al (2006) Impact of transforming growth factor-beta1 on atrioventricular node conduction modification by injected autologous fibroblasts in the canine heart. Circulation 113:2485–2494
Cai J et al (2006) Transplanted neonatal cardiomyocytes as a potential biological pacemaker in pigs with complete atrioventricular block. Transplantation 81:1022–1026
Capogrossi MC, Houser SR, Bahinski A, Lakatta EG (1987) Synchronous occurrence of spontaneous localized calcium release from the sarcoplasmic reticulum generates action potentials in rat cardiac ventricular myocytes at normal resting membrane potential. Circ Res 61:498–503
Champion HC et al (2003) Robust adenoviral and adeno-associated viral gene transfer to the in vivo murine heart: application to study of phospholamban physiology. Circulation 108:2790–2797
De Maziere AM, van Ginneken AC, Wilders R, Jongsma HJ, Bouman LN (1992) Spatial and functional relationship between myocytes and fibroblasts in the rabbit sinoatrial node. J Mol Cell Cardiol 24:567–578
DiFrancesco D, Ferroni A, Mazzanti M, Tromba C (1986) Properties of the hyperpolarizing-activated current (if) in cells isolated from the rabbit sino-atrial node. J Physiol 377:61–88
DiFrancesco D (1993) Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 55:455–472
DiFrancesco D (2006) Serious workings of the funny current. Prog Biophys Mol Biol 90:13–25
Difrancesco D (1991) The contribution of the ‘pacemaker’ current (if) to generation of spontaneous activity in rabbit sino-atrial node myocytes. J Physiol 434:23–40
Difrancesco D (1987) The pacemaker current in the sinus node. Eur Heart J 8(Suppl L):19–23
Donahue JK et al (2000) Focal modification of electrical conduction in the heart by viral gene transfer. Nat Med 6:1395–1398
Donahue JK, Bauer A, Kikuchi K, Sasano T (2005) Modification of cellular communication by gene transfer. Ann N Y Acad Sci 1047:157–165
Donahue JK, Kikuchi K, Sasano T (2005) Gene therapy for cardiac arrhythmias. Trends Cardiovasc Med 15:219–224
Edelberg JM, Aird WC, Rosenberg RD (1998) Enhancement of murine cardiac chronotropy by the molecular transfer of the human beta2 adrenergic receptor cDNA. J Clin Invest 101:337–343
Edelberg JM, Huang DT, Josephson ME, Rosenberg RD (2001) Molecular enhancement of porcine cardiac chronotropy. Heart 86:559–562
Elmqvist R (1978) Review of early pacemaker development. Pacing Clin Electrophysiol 1:535–536
Ertel EA et al (2000) Nomenclature of voltage-gated calcium channels. Neuron 25:533–535
Fermini B, Nathan RD (1991) Removal of sialic acid alters both T- and L-type calcium currents in cardiac myocytes. Am J Physiol 260:H735–H743
Freudenberger RS, Wilson AC, Lawrence-Nelson J, Hare JM, Kostis JB (2005) Permanent pacing is a risk factor for the development of heart failure. Am J Cardiol 95:671–674
Gilgenkrantz H et al (1995) Transient expression of genes transferred in vivo into heart using first-generation adenoviral vectors: role of the immune response. Hum Gene Ther 6:1265–1274
Gregoratos G et al (2002) ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmia devices: summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/NASPE Committee to Update the 1998 Pacemaker Guidelines). J Cardiovasc Electrophysiol 13:1183–1199
Guo J, Ono K, Noma A (1995) A sustained inward current activated at the diastolic potential range in rabbit sino-atrial node cells. J Physiol 483(Pt 1):1–13
Guo J, Mitsuiye T, Noma A (1997) The sustained inward current in sino-atrial node cells of guinea-pig heart. Pflugers Arch 433:390–396
Guo J, Noma A (1997) Existence of a low-threshold and sustained inward current in rabbit atrio-ventricular node cells. Jpn J Physiol 47:355–359
Hagiwara N, Irisawa H, Kameyama M (1988) Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol 395:233–253
Heubach JF et al (2004) Electrophysiological properties of human mesenchymal stem cells. J Physiol 554:659–672
Hirano Y, Fozzard HA, January CT (1989) Characteristics of L- and T-type Ca2+ currents in canine cardiac Purkinje cells. Am J Physiol 256:H1478–H1492
Hirano Y, Fozzard HA, January CT (1989) Inactivation properties of T-type calcium current in canine cardiac Purkinje cells. Biophys J 56:1007–1016
Holmer SR, Homcy CJ (1991) G proteins in the heart. A redundant and diverse transmembrane signaling network. Circulation 84:1891–1902
Hui A et al (1991) Molecular cloning of multiple subtypes of a novel rat brain isoform of the alpha 1 subunit of the voltage-dependent calcium channel. Neuron 7:35–44
Inagaki K et al (2006) Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther 14:45–53
Inglese J, Freedman NJ, Koch WJ, Lefkowitz RJ (1993) Structure and mechanism of the G protein-coupled receptor kinases. J Biol Chem 268:23735–23738
Irisawa H, Hagiwara N (1988) Pacemaker mechanism of mammalian sinoatrial node cells. Prog Clin Biol Res 275:33–52
Johns DC et al (1995) Adenovirus-mediated expression of a voltage-gated potassium channel in vitro (rat cardiac myocytes) and in vivo (rat liver). A novel strategy for modifying excitability. J Clin Invest 96:1152–1158
Johns DC, Nuss HB, Marban E (1997) Suppression of neuronal and cardiac transient outward currents by viral gene transfer of dominant-negative Kv4.2 constructs. J Biol Chem 272:31598–31603
Johns DC, Marban E, Nuss HB (1999) Virus-mediated modification of cellular excitability. Ann N Y Acad Sci 868:418–422
Jones JM, Wilson KH, Steenbergen C, Koch WJ, Milano CA (2004) Dose dependent effects of cardiac beta2 adrenoceptor gene therapy. J Surg Res 122:113–120
Joyner RW, van Capelle FJ (1986) Propagation through electrically coupled cells. How a small SA node drives a large atrium. Biophys J 50:1157–1164
Kizana E, Ginn SL, Allen DG, Ross DL, Alexander IE (2005) Fibroblasts can be genetically modified to produce excitable cells capable of electrical coupling. Circulation 111:394–398
Kodama I et al (1997) Regional differences in the role of the Ca2+ and Na+ currents in pacemaker activity in the sinoatrial node. Am J Physiol 272:H2793–H2806
Kurata Y, Hisatome I, Imanishi S, Shibamoto T (2003) Roles of L-type Ca2+ and delayed-rectifier K+ currents in sinoatrial node pacemaking: insights from stability and bifurcation analyses of a mathematical model. Am J Physiol Heart Circ Physiol 285:H2804–H2819
Kurata Y, Matsuda H, Hisatome I, Shibamoto T (2006) Effects of pacemaker currents on creation and modulation of human ventricular pacemaker: a theoretical study with application to biological pacemaker engineering. Am J Physiol Heart Circ Physiol
Kusumoto FM, Goldschlager N (1996) Cardiac pacing. N Engl J Med 334:89–97
Lakatta EG, Maltsev VA, Bogdanov KY, Stern MD, Vinogradova TM (2003) Cyclic variation of intracellular calcium: a critical factor for cardiac pacemaker cell dominance. Circ Res 92:e45–e50
Lawrence JH, Johns DC, Chiamvimonvat N, Nuss HB, Marban E (1995) Prospects for genetic manipulation of cardiac excitability. Adv Exp Med Biol 382:41–48
Liechty KW et al (2000) Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 6:1282–1286
Lin G et al (2005) Biological pacemaker created by fetal cardiomyocyte transplantation. J Biomed Sci 12:513–519
Maltsev VA, Vinogradova TM, Bogdanov KY, Lakatta EG, Stern MD (2004) Diastolic calcium release controls the beating rate of rabbit sinoatrial node cells: numerical modeling of the coupling process. Biophys J 86:2596–2605
Maltsev VA, Vinogradova TM, Lakatta EG (2006) The emergence of a general theory of the initiation and strength of the heartbeat. J Pharmacol Sci 100:338–369
Mangoni ME et al (2000) Facilitation of the L-type calcium current in rabbit sino-atrial cells: effect on cardiac automaticity. Cardiovasc Res 48:375–392
Mangoni ME et al (2003) Functional role of L-type Cav1.3 Ca2+ channels in cardiac pacemaker activity. Proc Natl Acad Sci USA 100:5543–5548
Mangoni ME et al (2006) Voltage-dependent calcium channels and cardiac pacemaker activity: from ionic currents to genes. Prog Biophys Mol Biol 90:38–63
Marionneau C et al (2005) Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart. J Physiol 562:223–234
Matsuura H, Ehara T, Ding WG, Omatsu-Kanbe M, Isono T (2002) Rapidly and slowly activating components of delayed rectifier K(+) current in guinea-pig sino-atrial node pacemaker cells. J Physiol 540:815–830
Matthes J et al (2004) Disturbed atrio-ventricular conduction and normal contractile function in isolated hearts from Cav1.3-knockout mice. Naunyn Schmiedebergs Arch Pharmacol 369:554–562
Miake J, Marban E, Nuss HB (2002) Biological pacemaker created by gene transfer. Nature 419:132–133
Mitsuiye T, Shinagawa Y, Noma A (2000) Sustained inward current during pacemaker depolarization in mammalian sinoatrial node cells. Circ Res 87:88–91
Noma A, Morad M, Irisawa H (1983) Does the “pacemaker current” generate the diastolic depolarization in the rabbit SA node cells? Pflugers Arch 397:190–194
Nuss HB et al (1996) Reversal of potassium channel deficiency in cells from failing hearts by adenoviral gene transfer: a prototype for gene therapy for disorders of cardiac excitability and contractility. Gene Ther 3:900–912
Nuss HB, Marban E, Johns DC (1999) Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes. J Clin Invest 103:889–896
Oosthoek PW et al (1993) Immunohistochemical delineation of the conduction system. I: The sinoatrial node. Circ Res 73:473–481
Platzer J et al (2000) Congenital deafness and sinoatrial node dysfunction in mice lacking class D L-type Ca2+ channels. Cell 102:89–97
Plotnikov AN et al (2004) Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation 109:506–512
Pogwizd SM, Schlotthauer K, Li L, Yuan W, Bers DM (2001) Arrhythmogenesis and contractile dysfunction in heart failure: roles of sodium–calcium exchange, inward rectifier potassium current, and residual beta-adrenergic responsiveness. Circ Res 88:1159–1167
Potapova I et al (2004) Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ Res 94:952–959
Qu J et al (2003) Expression and function of a biological pacemaker in canine heart. Circulation 107:1106–1109
Qu J et al (2004) MiRP1 modulates HCN2 channel expression and gating in cardiac myocytes. J Biol Chem 279:43497–43502
Qu J et al (2001) HCN2 overexpression in newborn and adult ventricular myocytes: distinct effects on gating and excitability. Circ Res 89:E8–E14
Ravens U (2006) Electrophysiological properties of stem cells. Herz 31:123–126
Rosen MR (2005) 15th annual Gordon K. Moe Lecture. Biological pacemaking: in our lifetime? Heart Rhythm 2:418–428
Satoh H (2003) Sino-atrial nodal cells of mammalian hearts: ionic currents and gene expression of pacemaker ionic channels. J Smooth Muscle Res 39:175–193
Satoh H, Tsuchida K (1993) Comparison of a calcium antagonist, CD-349, with nifedipine, diltiazem, and verapamil in rabbit spontaneously beating sinoatrial node cells. J Cardiovasc Pharmacol 21:685–692
Shi W et al (1999) Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res 85:e1–e6
Shukla HH et al (2005) Heart failure hospitalization is more common in pacemaker patients with sinus node dysfunction and a prolonged paced QRS duration. Heart Rhythm 2:245–251
Silva J, Rudy Y (2003) Mechanism of pacemaking in I(K1)-downregulated myocytes. Circ Res 92:261–263
Sweeney MO, Hellkamp AS, Lee KL, Lamas GA (2005) Association of prolonged QRS duration with death in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 111:2418–2423
Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105:93–98
Valiunas V et al (2004) Human mesenchymal stem cells make cardiac connexins and form functional gap junctions. J Physiol 555:617–626
Verheijck EE, van Ginneken AC, Wilders R, Bouman LN (1999) Contribution of L-type Ca2+ current to electrical activity in sinoatrial nodal myocytes of rabbits. Am J Physiol 276:H1064–H1077
Vinogradova TM, Maltsev VA, Bogdanov KY, Lyashkov AE, Lakatta EG (2005) Rhythmic Ca2+ oscillations drive sinoatrial nodal cell pacemaker function to make the heart tick. Ann N Y Acad Sci 1047:138–156
Xue T et al (2005) 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 111:11–20
Yu H, Chang F, Cohen IS (1993) Phosphatase inhibition by calyculin A increases i(f) in canine Purkinje fibers and myocytes. Pflugers Arch 422:614–616
Zhang Z et al (2002) Functional Roles of Ca(v)1.3 (alpha(1D)) calcium channel in sinoatrial nodes: insight gained using gene-targeted null mutant mice. Circ Res 90:981–987
Zhang YM, Hartzell C, Narlow M, Dudley SC Jr (2002) Stem cell-derived cardiomyocytes demonstrate arrhythmic potential. Circulation 106:1294–1299
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Anghel, T.M., Pogwizd, S.M. Creating a cardiac pacemaker by gene therapy . Med Bio Eng Comput 45, 145–155 (2007). https://doi.org/10.1007/s11517-006-0135-0
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DOI: https://doi.org/10.1007/s11517-006-0135-0