The contribution of HCN4 to normal sinus node function in humans and animal models

PACE - Pacing and Clinical Electrophysiology

Volumn 33, Issue 1, 2010, Pages 100-106

  Nof, Eyal ^a,b   Antzelevitch, Charles ^a   Glikson, Michael ^b  

^a MASONIC MEDICAL RESEARCH LABORATORY   (United States)

^b TEL AVIV UNIVERSITY   (Israel)

Author keywords

Bradycardia; Genetics; Ion channels

Indexed keywords

CLONIDINE; CYCLIC AMP; CYCLIC NUCLEOTIDE GATED CHANNEL; CYCLIC NUCLEOTIDE GATED CHANNEL 4; ION CHANNEL; IVABRADINE; PLACEBO; THEOPHYLLINE; UNCLASSIFIED DRUG;

ACCELERATION; ACTION POTENTIAL; ADRENERGIC STIMULATION; CARDIOPULMONARY ARREST; CODON; CONSCIOUSNESS; DECELERATION; DEVELOPMENT; DRUG EFFECT; EXERCISE; EXON; GENE DELETION; GENE MUTATION; GENE SEQUENCE; GENETIC ANALYSIS; GENOTYPE PHENOTYPE CORRELATION; HEART ATRIUM FIBRILLATION; HEART LEFT VENTRICLE EJECTION FRACTION; HEART MUSCLE CONTRACTILITY; HEART RATE; HUMAN; HYPERPOLARIZATION; KNOCKOUT MOUSE; MISSENSE MUTATION; NONHUMAN; QT PROLONGATION; RETINA; REVIEW; SINUS BRADYCARDIA; SINUS NODE; SYMPATHETIC TONE; SYNCOPE; TACHYCARDIA; TORSADE DES POINTES; VAGUS NERVE STIMULATION; VISUAL DISORDER;

ANIMALS; CYCLIC NUCLEOTIDE-GATED CATION CHANNELS; HEART RATE; HUMANS; MICE; MUSCLE PROTEINS; SINOATRIAL NODE;

EID: 73649146591     PISSN: 01478389     EISSN: 15408159     Source Type: Journal    
DOI: 10.1111/j.1540-8159.2009.02563.x     Document Type: Review

References (64)

1. Albin G, Hayes DL, Holmes DR, Jr. Sinus node dysfunction in pediatric and young adult patients: Treatment by implantation of a permanent pacemaker in 39 cases. Mayo Clin Proc 1985 60 : 667 672.
2. Yabek SM, Jarmakani JM. Sinus node dysfunction in children, adolescents, and young adults. Pediatrics 1978 61 : 593 598.
3. Beder SD, Gillette PC, Garson A, Jr., Porter CB, McNamara DG. Symptomatic sick sinus syndrome in children and adolescents as the only manifestation of cardiac abnormality or associated with unoperated congenital heart disease. Am J Cardiol 1983 51 : 1133 1136.
4. Onat A. Familial sinus node disease and degenerative myopia-a new hereditary syndrome? Hum Genet 1986 72 : 182 184.
5. von Zur MF, Klass C, Kreuzer H, Mall G, Giese A, Reimers CD. Cardiac involvement in proximal myotonic myopathy. Heart 1998 79 : 619 621.
6. Gulotta SJ, Gupta RD, Padmanabhan VT, Morrison J. Familial occurrence of sinus bradycardia, short PR interval, intraventricular conduction defects, recurrent supraventricular tachycardia, and cardiomegaly. Am Heart J 1977 93 : 19 29.
7. Schneider MD, Roller DH, Morganroth J, Josephson ME. The syndromes of familial atrioventricular block with sinus bradycardia: Prognostic indices, electrophysiologic and histopathologic correlates. Eur J Cardiol 1978 7 : 337 351.
8. Isobe M, Oka T, Takenaka H, Imamura H, Kinoshita O, Kasanuki H, Sekiguchi M. Familial sick sinus syndrome with atrioventricular conduction disturbance. Jpn Circ J 1998 62 : 788 790.
9. Shi W, Wymore R, Yu H, Wu J, Wymore RT, Pan Z, Robinson RB, et al. Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ Res 1999 85 : e1 e6.
10. Hagiwara N, Irisawa H, Kameyama M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J Physiol 1988 395 : 233 253.
11. + current in the ferret heart. Circ Res 1997 81 : 128 135.
12. Brahmajothi MV, Morales MJ, Liu R, Rasmusson RL, Campbell DL, Strauss HC. In situ hybridization reveals extensive diversity of K+ channel mRNA in isolated ferret cardiac myocytes. Circ Res 1996 78 : 1083 1089.
13. + channel proteins Kir3.1 and Kir3.4 in the ventricle, atrium, and sinoatrial node of heart. J Histochem Cytochem 2001 49 : 1221 1234.
14. Wickman K, Nemec J, Gendler SJ, Clapham DE. Abnormal heart rate regulation in GIRK4 knockout mice. Neuron 1998 20 : 103 114.
15. Sarachek NS, Leonard JL. Familial heart block and sinus bradycardia. Classification and natural history. Am J Cardiol 1972 29 : 451 458.
16. Lorber A, Maisuls E, Palant A. Autosomal dominant inheritance of sinus node disease. Int J Cardiol 1987 15 : 252 256.
17. Mehta AV, Chidambaram B, Garrett A. Familial symptomatic sinus bradycardia: Autosomal dominant inheritance. Pediatr Cardiol 1995 16 : 231 234.
18. Caralis DG, Varghese PJ. Familial sinoatrial node dysfunction. Increased vagal tone a possible aetiology. Br Heart J 1976 38 : 951 956.
19. Milanesi R, Baruscotti M, Gnecchi-Ruscone T, DiFrancesco D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N Engl J Med 2006 354 : 151 157.
20. Schulze-Bahr E, Neu A, Friederich P, Kaupp UB, Breithardt G, Pongs O, Isbrandt D. Pacemaker channel dysfunction in a patient with sinus node disease. J Clin Invest 2003 111 : 1537 1545.
21. Ueda K, Nakamura K, Hayashi T, Inagaki N, Takahashi M, Arimura T, Morita H, et al. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem 2004 1 26.
22. Nof E, Luria D, Brass D, Marek D, Lahat H, Reznik-Wolf H, Pras E, et al. Point mutation in the HCN4 cardiac ion channel pore affecting synthesis, trafficking, and functional expression is associated with familial asymptomatic sinus bradycardia. Circulation 2007 116 : 463 470.
23. Stieber J, Herrmann S, Feil S, Loster J, Feil R, Biel M, Hofmann F, et al. The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc Natl Acad Sci USA 2003 100 : 15235 15240.
24. DiFrancesco D, Tortora P. Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 1991 351 : 145 147.
25. DiFrancesco D. Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 1993 55 : 455 472.
26. Baruscotti M, Bucchi A, DiFrancesco D. Physiology and pharmacology of the cardiac pacemaker ("funny") current. Pharmacol Ther 2005 107 : 59 79.
27. Accili EA, Proenza C, Baruscotti M, DiFrancesco D. From funny current to HCN channels: 20 years of excitation. News Physiol Sci 2002 17 : 32 37.
28. 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 1652.
29. Mistrik P, Mader R, Michalakis S, Weidinger M, Pfeifer A, Biel M. The murine HCN3 gene encodes a hyperpolarization-activated cation channel with slow kinetics and unique response to cyclic nucleotides. J Biol Chem 2005 280 : 27056 27061.
30. Moroni A, Gorza L, Beltrame M, Gravante B, Vaccari T, Bianchi ME, Altomare C, et al. Hyperpolarization-activated cyclic nucleotide-gated channel 1 is a molecular determinant of the cardiac pacemaker current I(f). J Biol Chem 2001 276 : 29233 29241.
31. Herrmann S, Stieber J, Ludwig A. Pathophysiology of HCN channels. Pflugers Arch 2007 454 : 517 522.
32. Ludwig A, Budde T, Stieber J, Moosmang S, Wahl C, Holthoff K, Langebartels A, et al. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J 2003 22 : 216 224.
33. Ludwig A, Zong X, Stieber J, Hullin R, Hofmann F, Biel M. Two pacemaker channels from human heart with profoundly different activation kinetics. EMBO J 1999 18 : 2323 2329.
34. Michels G, Er F, Khan I, Sudkamp M, Herzig S, Hoppe UC. Single-channel properties support a potential contribution of hyperpolarization-activated cyclic nucleotide-gated channels and If to cardiac arrhythmias. Circulation 2005 111 : 399 404.
35. f and undermines spontaneous beating of neonatal cardiomyocytes. Circulation 2003 107 : 485 489.
36. Chandler NJ, Greener ID, Tellez JO, Inada S, Musa H, Molenaar P, DiFrancesco D, et al. Molecular architecture of the human sinus node: Insights into the function of the cardiac pacemaker. Circulation 2009 119 : 1562 1575.
37. Guo J, Ono K, Noma A. A sustained inward current activated at the diastolic potential range in rabbit sino-atrial node cells. J Physiol 1995 483 : 1 13.
38. 1D) calcium channel in sinoatrial nodes: Insight gained using gene-targeted null mutant mice. Circ Res 2002 90 : 981 987.
39. Maltsev VA, Vinogradova TM, Lakatta EG. The emergence of a general theory of the initiation and strength of the heartbeat. J Pharmacol Sci 2006 100 : 338 369.
40. Harzheim D, Pfeiffer KH, Fabritz L, Kremmer E, Buch T, Waisman A, Kirchhof P, et al. Cardiac pacemaker function of HCN4 channels in mice is confined to embryonic development and requires cyclic AMP. EMBO J 2008 27 : 692 703.
41. Herrmann S, Stieber J, Stockl G, Hofmann F, Ludwig A. HCN4 provides a 'depolarization reserve' and is not required for heart rate acceleration in mice. EMBO J 2007 26 : 4423 4432.
42. Redfern WS, Carlsson L, Davis AS, Lynch WG, MacKenzie I, Palethorpe S, Siegl PK, et al. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development. Cardiovasc Res 2003 58 : 32 45.
43. Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J 2005 26 : 2529 2536.
44. Stieber J, Wieland K, Stockl G, Ludwig A, Hofmann F. Bradycardic and proarrhythmic properties of sinus node inhibitors. Mol Pharmacol 2006 69 : 1328 1337.
45. Topilski I, Rogowski O, Rosso R, Justo D, Copperman Y, Glikson M, Belhassen B, et al. The morphology of the QT interval predicts torsade de pointes during acquired bradyarrhythmias. J Am Coll Cardiol 2007 49 : 320 328.
46. Laish-Farkash A, Marek D, Brass D, Pras E, Dascal N, Arad M, Nof E, et al. A novel mutation in the HCN4 gene causes familial sinus bradycardia in two unrelated Moroccan families. (abstract) Heart Rhythm 2008 5S : S275.
47. Zicha S, Fernandez-Velasco M, Lonardo G, L'Heureux N, Nattel S. Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. Cardiovasc Res 2005 66 : 472 481.
48. Cerbai E, Barbieri M, Mugelli A. Occurrence and properties of the hyperpolarization-activated current if in ventricular myocytes from normotensive and hypertensive rats during aging. Circulation 1996 94 : 1674 1681.
49. Yamamoto M, Dobrzynski H, Tellez J, Niwa R, Billeter R, Honjo H, Kodama I, et al. Extended atrial conduction system characterised by the expression of the HCN4 channel and connexin45. Cardiovasc Res 2006 72 : 271 281.
50. Goethals M, Raes A, Van Bogaert PP. Use-dependent block of the pacemaker current I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS 49). On the mode of action of sinus node inhibitors. Circulation 1993 88 : 2389 2401.
51. f current inhibition with ivabradine: A new therapeutic perspective in cardiovascular disease. Drugs 2004 64 : 1757 1765.
52. f inhibitor, in stable angina: A randomized, double-blind, multicentered, placebo-controlled trial. Circulation 2003 107 : 817 823.
53. f inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology 2003 100 : 149 155.
54. f current inhibition by ivabradine. Drugs 2007 67 : 35 41.
55. Fox K, Ferrari R, Tendera M, Steg PG, Ford I. Rationale and design of a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: The morBidity-mortality EvAlUaTion of the I(f) inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study. Am Heart J 2006 152 : 860 866.
56. f inhibition by ivabradine in cardiology. Drugs 2007 67 : 43 49.
57. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A randomised, double-blind, placebo-controlled trial. Lancet 2008 372 : 807 816.
58. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A subgroup analysis of a randomised controlled trial. Lancet 2008 372 : 817 821.
59. Schulze V, Steiner S, Hennersdorf M, Strauer BE. Ivabradine as an alternative therapeutic trial in the therapy of inappropriate sinus tachycardia. A case report. Cardiology 2007 110 : 206 208.
60. Knaus A, Zong X, Beetz N, Jahns R, Lohse MJ, Biel M, Hein L. Direct inhibition of cardiac hyperpolarization-activated cyclic nucleotide-gated pacemaker channels by clonidine. Circulation 2007 115 : 872 880.
61. Alboni P, Menozzi C, Brignole M, Paparella N, Gaggioli G, Lolli G, Cappato R. Effects of permanent pacemaker and oral theophylline in sick sinus syndrome the THEOPACE study: A randomized controlled trial. Circulation 1997 96 : 260 266.
62. Bucchi A, Plotnikov AN, Shlapakova I, Danilo P, Jr., Kryukova Y, Qu J, Lu Z, et al. Wild-type and mutant HCN channels in a tandem biological-electronic cardiac pacemaker. Circulation 2006 114 : 992 999.
63. Tse HF, Xue T, Lau CP, Siu CW, Wang K, Zhang QY, Tomaselli GF, 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 : 1000 1011.
64. Cai J, Yi FF, Li YH, Yang XC, Song J, Jiang XJ, Jiang H, et al. Adenoviral gene transfer of HCN4 creates a genetic pacemaker in pigs with complete atrioventricular block. Life Sci 2007 80 : 1746 1753.