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Annual Review of Physiology

Volume 82, 2020

Cardiac Pacemaker Activity and Aging

Abstract

A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness, and lifestyle, affecting in equal measure women and men, athletes and couch potatoes, spinach eaters and fast food enthusiasts. Importantly, the decline in mHR is the major determinant of the age-dependent decline in aerobic capacity that ultimately limits functional independence for many older individuals. The gradual reduction in mHR with age reflects a slowing of the intrinsic pacemaker activity of the sinoatrial node of the heart, which results from electrical remodeling of individual pacemaker cells along with structural remodeling and a blunted β-adrenergic response. In this review, we summarize current evidence about the tissue, cellular, and molecular mechanisms that underlie the reduction in pacemaker activity with age and highlight key areas for future work.

Keyword(s): aging, cardiac pacemaking, intrinsic heart rate, maximum heart rate, sinoatrial node
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/content/journals/10.1146/annurev-physiol-021119-034453
2020-02-10
2024-04-25
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Literature Cited

  1. 1. 
    Homer 1990. Iliad London: Penguin
  2. 2. 
    Robinson S. 1938. Experimental studies of physical fitness in relation to age. Eur. J. Appl. Physiol. 10:3251–323Seminal study showing age-dependent declines in mHR.
     [Google Scholar]
  3. 3. 
    Robinson S, Dill DB, Tzankoff SP, Wagner JA, Robinson RD 1975. Longitudinal studies of aging in 37 men. J. Appl. Physiol. 38:2263–67
     [Google Scholar]
  4. 4. 
    Heath GW, Hagberg JM, Ehsani AA, Holloszy JO 1981. A physiological comparison of young and older endurance athletes. J. Appl. Physiol. 51:3634–40
     [Google Scholar]
  5. 5. 
    Tanaka H, Monahan KD, Seals DR 2001. Age-predicted maximal heart rate revisited. J. Am. Coll. Cardiol. 37:1153–56
     [Google Scholar]
  6. 6. 
    Tanaka H, Desouza CA, Jones PP, Stevenson ET, Davy KP, Seals DR 1997. Greater rate of decline in maximal aerobic capacity with age in physically active versus sedentary healthy women. J. Appl. Physiol. 83:61947–53
     [Google Scholar]
  7. 7. 
    Fox SM, Naughton JP, Haskell WL 1971. Physical activity and the prevention of coronary heart disease. Ann. Clin. Res. 3:6404–32
     [Google Scholar]
  8. 8. 
    Nes BM, Janszky I, Wisløff U, Støylen A, Karlsen T 2013. Age-predicted maximal heart rate in healthy subjects: the HUNT fitness study. Scand. J. Med. Sci. Sports 23:6697–704
     [Google Scholar]
  9. 9. 
    Di Gennaro M, Bernabei R, Sgadari A, Carosella L, Carbonin PU 1987. Age-related differences in isolated rat sinus node function. Basic Res. Cardiol. 82:6530–36
     [Google Scholar]
  10. 10. 
    Alings AM, Bouman LN. 1993. Electrophysiology of the ageing rabbit and cat sinoatrial node—a comparative study. Eur. Heart J. 14:91278–88
     [Google Scholar]
  11. 11. 
    Liu J, Sirenko S, Juhaszova M, Sollott SJ, Shukla S et al. 2014. Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca2+ signaling. Am. J. Physiol. Heart Circ. Physiol. 306:10H1385–97
     [Google Scholar]
  12. 12. 
    Yaniv Y, Ahmet I, Tsutsui K, Behar J, Moen JM et al. 2016. Deterioration of autonomic neuronal receptor signaling and mechanisms intrinsic to heart pacemaker cells contribute to age-associated alterations in heart rate variability in vivo. Aging Cell 15:4716–24
     [Google Scholar]
  13. 13. 
    Larson ED, St Clair JR, Sumner WA, Bannister RA, Proenza C 2013. Depressed pacemaker activity of sinoatrial node myocytes contributes to the age-dependent decline in maximum heart rate. PNAS 110:4418011–16Description of age-dependent declines in pacemaking and membrane currents of isolated sinoatrial myocytes.
     [Google Scholar]
  14. 14. 
    Yin FC, Spurgeon HA, Greene HL, Lakatta EG, Weisfeldt ML 1979. Age-associated decrease in heart rate response to isoproterenol in dogs. Mech. Ageing Dev. 10:1–217–25
     [Google Scholar]
  15. 15. 
    Hagberg JM, Allen WK, Seals DR, Hurley BF, Ehsani AA, Holloszy JO 1985. A hemodynamic comparison of young and older endurance athletes during exercise. J. Appl. Physiol. 58:62041–46
     [Google Scholar]
  16. 16. 
    Tanaka H, Seals DR. 2008. Endurance exercise performance in Masters athletes: age-associated changes and underlying physiological mechanisms. J. Physiol. 586:155–63
     [Google Scholar]
  17. 17. 
    Paterson DH, Govindasamy D, Vidmar M, Cunningham DA, Koval JJ 2004. Longitudinal study of determinants of dependence in an elderly population. J. Am. Geriatr. Soc. 52:101632–38
     [Google Scholar]
  18. 18. 
    Shephard RJ. 2009. Maximal oxygen intake and independence in old age. Br. J. Sports Med. 43:5342–46
     [Google Scholar]
  19. 19. 
    Hawkins S, Wiswell R. 2003. Rate and mechanism of maximal oxygen consumption decline with aging: implications for exercise training. Sports Med 33:12877–88
     [Google Scholar]
  20. 20. 
    Jose AD, Collison D. 1970. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc. Res. 4:2160–67Seminal study on age-dependent declines in iHR.
     [Google Scholar]
  21. 21. 
    Jose AD, Stitt F, Collison D 1970. The effects of exercise and changes in body temperature on the intrinsic heart rate in man. Am. Heart J. 79:4488–98
     [Google Scholar]
  22. 22. 
    Christou DD, Seals DR. 2008. Decreased maximal heart rate with aging is related to reduced β-adrenergic responsiveness but is largely explained by a reduction in intrinsic heart rate. J. Appl. Physiol. 105:124–29Study measuring the contribution of decreased iHR and βAR agonist sensitivity to declines in mHR.
     [Google Scholar]
  23. 23. 
    Silverman ME, Hollman A. 2007. Discovery of the sinus node by Keith and Flack: on the centennial of their 1907 publication. Heart 93:101184–87
     [Google Scholar]
  24. 24. 
    Fye WB. 1987. The origin of the heart beat: a tale of frogs, jellyfish, and turtles. Circulation 76:3493–500
     [Google Scholar]
  25. 25. 
    Keith A, Flack M. 1907. The form and nature of the muscular connections between the primary divisions of the vertebrate heart. J. Anat. Physiol. 41:Part 3172–89Description of SAN anatomy in multiple species.
     [Google Scholar]
  26. 26. 
    Bexton RS, Nathan AW, Hellestrand KJ, Cory-Pearce R, Spurrell RA et al. 1984. Sinoatrial function after cardiac transplantation. J. Am. Coll. Cardiol. 3:3712–23
     [Google Scholar]
  27. 27. 
    Strobel JS, Epstein AE, Bourge RC, Kirklin JK, Kay GN 1999. Nonpharmacologic validation of the intrinsic heart rate in cardiac transplant recipients. J. Interv. Card. Electrophysiol. Int. J. Arrhythm. Pacing 3:115–18
     [Google Scholar]
  28. 28. 
    Robinson BF, Epstein SE, Beiser GD, Braunwald E 1966. Control of heart rate by the autonomic nervous system. Studies in man on the interrelation between baroreceptor mechanisms and exercise. Circ. Res. 19:2400–11
     [Google Scholar]
  29. 29. 
    Masson-Pévet M, Bleeker WK, Gros D 1979. The plasma membrane of leading pacemaker cells in the rabbit sinus node. A qualitative and quantitative ultrastructural analysis. Circ. Res. 45:5621–29
     [Google Scholar]
  30. 30. 
    James TN, Sherf L, Fine G, Morales AR 1966. Comparative ultrastructure of the sinus node in man and dog. Circulation 34:1139–63
     [Google Scholar]
  31. 31. 
    Opthof T, de Jonge B, Jongsma HJ, Bouman LN 1987. Functional morphology of the mammalian sinuatrial node. Eur. Heart J. 8:111249–59
     [Google Scholar]
  32. 32. 
    Boyett MR, Honjo H, Kodama I 2000. The sinoatrial node, a heterogeneous pacemaker structure. Cardiovasc. Res. 47:4658–87
     [Google Scholar]
  33. 33. 
    Csepe TA, Zhao J, Hansen BJ, Li N, Sul LV et al. 2016. Human sinoatrial node structure: 3D microanatomy of sinoatrial conduction pathways. Prog. Biophys. Mol. Biol. 120:1–3164–78
     [Google Scholar]
  34. 34. 
    Kwong KF, Schuessler RB, Green KG, Laing JG, Beyer EC et al. 1998. Differential expression of gap junction proteins in the canine sinus node. Circ. Res. 82:5604–12
     [Google Scholar]
  35. 35. 
    Coppen SR, Kodama I, Boyett MR, Dobrzynski H, Takagishi Y et al. 1999. Connexin45, a major connexin of the rabbit sinoatrial node, is co-expressed with connexin43 in a restricted zone at the nodal-crista terminalis border. J. Histochem. Cytochem. 47:7907–18
     [Google Scholar]
  36. 36. 
    Kreuzberg MM, Söhl G, Kim J-S, Verselis VK, Willecke K, Bukauskas FF 2005. Functional properties of mouse connexin30.2 expressed in the conduction system of the heart. Circ. Res. 96:111169–77
     [Google Scholar]
  37. 37. 
    Haubrich S, Schwarz HJ, Bukauskas F, Lichtenberg-Fraté H, Traub O et al. 1996. Incompatibility of connexin 40 and 43 Hemichannels in gap junctions between mammalian cells is determined by intracellular domains. Mol. Biol. Cell 7:121995–2006
     [Google Scholar]
  38. 38. 
    Kreuzberg MM, Willecke K, Bukauskas FF 2006. Connexin-mediated cardiac impulse propagation: connexin 30.2 slows atrioventricular conduction in mouse heart. Trends Cardiovasc. Med. 16:8266–72
     [Google Scholar]
  39. 39. 
    Anumonwo JM, Wang HZ, Trabka-Janik E, Dunham B, Veenstra RD et al. 1992. Gap junctional channels in adult mammalian sinus nodal cells. Immunolocalization and electrophysiology. Circ. Res. 71:2229–39
     [Google Scholar]
  40. 40. 
    Joyner RW, van Capelle FJ 1986. Propagation through electrically coupled cells. How a small SA node drives a large atrium. Biophys. J. 50:61157–64
     [Google Scholar]
  41. 41. 
    Yamamoto M, Honjo H, Niwa R, Kodama I 1998. Low-frequency extracellular potentials recorded from the sinoatrial node. Cardiovasc. Res. 39:2360–72
     [Google Scholar]
  42. 42. 
    Fedorov VV, Glukhov AV, Chang R, Kostecki G, Aferol H et al. 2010. Optical mapping of the isolated coronary-perfused human sinus node. J. Am. Coll. Cardiol. 56:171386–94
     [Google Scholar]
  43. 43. 
    Csepe TA, Kalyanasundaram A, Hansen BJ, Zhao J, Fedorov VV 2015. Fibrosis: a structural modulator of sinoatrial node physiology and dysfunction. Front. Physiol. 6:37Review of fibrosis in the dysfunction of aging SAN.
     [Google Scholar]
  44. 44. 
    Valiunas V, Weingart R, Brink PR 2000. Formation of heterotypic gap junction channels by connexins 40 and 43. Circ. Res. 86:2E42–49
     [Google Scholar]
  45. 45. 
    Bukauskas FF, Angele AB, Verselis VK, Bennett MVL 2002. Coupling asymmetry of heterotypic connexin 45/connexin 43-EGFP gap junctions: properties of fast and slow gating mechanisms. PNAS 99:107113–18
     [Google Scholar]
  46. 46. 
    Jones SA, Lancaster MK, Boyett MR 2004. Ageing-related changes of connexins and conduction within the sinoatrial node. J. Physiol. 560:Part 2429–37
     [Google Scholar]
  47. 47. 
    Moghtadaei M, Jansen HJ, Mackasey M, Rafferty SA, Bogachev O et al. 2016. The impacts of age and frailty on heart rate and sinoatrial node function. J. Physiol. 594:237105–26
     [Google Scholar]
  48. 48. 
    Tellez JO, Mączewski M, Yanni J, Sutyagin P, Mackiewicz U et al. 2011. Ageing-dependent remodelling of ion channel and Ca2+ clock genes underlying sino-atrial node pacemaking. Exp. Physiol. 96:111163–78Large-scale transcript analysis of young and aged SAN tissue.
     [Google Scholar]
  49. 49. 
    Cavoto FV, Kelliher GJ, Roberts J 1974. Electrophysiological changes in the rat atrium with age. Am. J. Physiol. 226:61293–97
     [Google Scholar]
  50. 50. 
    Rickert C, Proenza C. 2017. ParamAP: standardized parameterization of sinoatrial node myocyte action potentials. Biophys. J. 113:4765–69
     [Google Scholar]
  51. 51. 
    Mangoni ME, Nargeot J. 2008. Genesis and regulation of the heart automaticity. Physiol. Rev. 88:3919–82
     [Google Scholar]
  52. 52. 
    Lakatta EG, DiFrancesco D. 2009. JMCC point-counterpoint. J. Mol. Cell. Cardiol. 47:2157–70
     [Google Scholar]
  53. 53. 
    Monfredi O, Dobrzynski H, Mondal T, Boyett MR, Morris GM 2010. The anatomy and physiology of the sinoatrial node—a contemporary review. PACE Pacing Clin. Electrophysiol. 33:111392–406
     [Google Scholar]
  54. 54. 
    Brown H, DiFrancesco D, Noble S 1979. Cardiac pacemaker oscillation and its modulation by autonomic transmitters. J. Exp. Biol. 81:175–204
     [Google Scholar]
  55. 55. 
    Moosmang S, Biel M, Hofmann F, Ludwig A 1999. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol. Chem. 380:7–8975–80
     [Google Scholar]
  56. 56. 
    Moosmang S, Stieber J, Zong X, Biel M, Hofmann F, Ludwig A 2001. Cellular expression and functional characterization of four hyperpolarization-activated pacemaker channels in cardiac and neuronal tissues. Eur. J. Biochem. 268:61646–52
     [Google Scholar]
  57. 57. 
    Li N, Csepe TA, Hansen BJ, Dobrzynski H, Higgins RSD et al. 2015. Molecular mapping of sinoatrial node HCN channel expression in the human heart. Circ. Arrhythm. Electrophysiol. 8:51219–27
     [Google Scholar]
  58. 58. 
    Huang X, Yang P, Yang Z, Zhang H, Ma A 2016. Age-associated expression of HCN channel isoforms in rat sinoatrial node. Exp. Biol. Med. 241:3331–39
     [Google Scholar]
  59. 59. 
    Herrmann S, Layh B, Ludwig A 2011. Novel insights into the distribution of cardiac HCN channels: an expression study in the mouse heart. J. Mol. Cell. Cardiol. 51:6997–1006
     [Google Scholar]
  60. 60. 
    Moroni A, Gorza L, Beltrame M, Gravante B, Vaccari T et al. 2001. Hyperpolarization-activated cyclic nucleotide-gated channel 1 is a molecular determinant of the cardiac pacemaker current If. J. Biol. Chem. 276:3129233–41
     [Google Scholar]
  61. 61. 
    Ludwig A, Budde T, Stieber J, Moosmang S, Wahl C et al. 2003. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J 22:2216–24
     [Google Scholar]
  62. 62. 
    Flynn GE, Zagotta WN. 2018. Insights into the molecular mechanism for hyperpolarization-dependent activation of HCN channels. PNAS 115:34E8086–95
     [Google Scholar]
  63. 63. 
    Bucchi A, Barbuti A, Difrancesco D, Baruscotti M 2012. Funny current and cardiac rhythm: insights from HCN knockout and transgenic mouse models. Front. Physiol. 3:240
     [Google Scholar]
  64. 64. 
    Verkerk AO, Wilders R. 2013. Hyperpolarization-activated current, If, in mathematical models of rabbit sinoatrial node pacemaker cells. BioMed. Res. Int. 2013:872454
     [Google Scholar]
  65. 65. 
    Sharpe EJ, Gantz SC, Liu P, Bean BP, Proenza C 2017. Characteristics of ivabradine-sensitive currents in mouse sinoatrial node myocytes. Biophys. J. 112:335a–36a
     [Google Scholar]
  66. 66. 
    Sharpe EJ, Larson ED, Proenza C 2017. Cyclic AMP reverses the effects of aging on pacemaker activity and If in sinoatrial node myocytes. J. Gen. Physiol. 149:2237–47Study showing cAMP can restore If and the firing rate of aged SAMs to youthful levels.
     [Google Scholar]
  67. 67. 
    Robertson GA. 2017. It's not funny: how changes in If limit maximum heart rate with aging. J. Gen. Physiol. 149:2177–79
     [Google Scholar]
  68. 68. 
    Yanni J, Tellez JO, Sutyagin PV, Boyett MR, Dobrzynski H 2010. Structural remodelling of the sinoatrial node in obese old rats. J. Mol. Cell. Cardiol. 48:4653–62
     [Google Scholar]
  69. 69. 
    Huang X, Yang P, Du Y, Zhang J, Ma A 2007. Age-related down-regulation of HCN channels in rat sinoatrial node. Basic Res. Cardiol. 102:5429–35
     [Google Scholar]
  70. 70. 
    Li Y-D, Hong Y-F, Yusufuaji Y, Tang B-P, Zhou X-H et al. 2015. Altered expression of hyperpolarization-activated cyclic nucleotide-gated channels and microRNA-1 and -133 in patients with age-associated atrial fibrillation. Mol. Med. Rep. 12:33243–48
     [Google Scholar]
  71. 71. 
    Ragueneau I, Laveille C, Jochemsen R, Resplandy G, Funck-Brentano C, Jaillon P 1998. Pharmacokinetic-pharmacodynamic modeling of the effects of ivabradine, a direct sinus node inhibitor, on heart rate in healthy volunteers. Clin. Pharmacol. Ther. 64:2192–203
     [Google Scholar]
  72. 72. 
    Baruscotti M, Bucchi A, Viscomi C, Mandelli G, Consalez G et al. 2011. Deep bradycardia and heart block caused by inducible cardiac-specific knockout of the pacemaker channel gene Hcn4. PNAS 108:41705–10
     [Google Scholar]
  73. 73. 
    Milano A, Vermeer AMC, Lodder EM, Barc J, Verkerk AO et al. 2014. HCN4 mutations in multiple families with bradycardia and left ventricular noncompaction cardiomyopathy. J. Am. Coll. Cardiol. 64:8745–56
     [Google Scholar]
  74. 74. 
    Pilcher JD. 1912. The action of caffein on the mammalian heart. J. Pharmacol. Exp. Ther. 3:6609–24
     [Google Scholar]
  75. 75. 
    Tsien RW, Kass RS, Weingart R 1979. Cellular and subcellular mechanisms of cardiac pacemaker oscillations. J. Exp. Biol. 81:205–15
     [Google Scholar]
  76. 76. 
    Rapp PE, Berridge MJ. 1977. Oscillations in calcium-cyclic AMP control loops form the basis of pacemaker activity and other high frequency biological rhythms. J. Theor. Biol. 66:3497–525
     [Google Scholar]
  77. 77. 
    Rubenstein DS, Lipsius SL. 1989. Mechanisms of automaticity in subsidiary pacemakers from cat right atrium. Circ. Res. 64:4648–57
     [Google Scholar]
  78. 78. 
    Rigg L, Terrar DA. 1996. Possible role of calcium release from the sarcoplasmic reticulum in pacemaking in guinea-pig sino-atrial node. Exp. Physiol. 81:5877–80
     [Google Scholar]
  79. 79. 
    Chen B, Wu Y, Mohler PJ, Anderson ME, Song LS 2009. Local control of Ca2+-induced Ca2+ release in mouse sinoatrial node cells. J. Mol. Cell. Cardiol. 47:5706–15
     [Google Scholar]
  80. 80. 
    Bogdanov KY, Vinogradova TM, Lakatta EG 2001. Sinoatrial nodal cell ryanodine receptor and Na+-Ca2+ exchanger. Circ. Res. 88:121254–58
     [Google Scholar]
  81. 81. 
    Li J, Qu J, Nathan RD 1997. Ionic basis of ryanodine's negative chronotropic effect on pacemaker cells isolated from the sinoatrial node. Am. J. Physiol. Heart Circ. Physiol. 273:5H2481–89
     [Google Scholar]
  82. 82. 
    Vinogradova TM, Brochet D, Sirenko S, Li Y, Spurgeon H, Lakatta EG 2010. Sarcoplasmic reticulum Ca2+ pumping kinetics regulates timing of local Ca2+ releases and spontaneous beating rate of rabbit sinoatrial node pacemaker cells. Circ. Res. 107:6767–75
     [Google Scholar]
  83. 83. 
    Dun W, Yagi T, Rosen MR, Boyden PA 2003. Calcium and potassium currents in cells from adult and aged canine right atria. Cardiovasc. Res. 58:3526–34
     [Google Scholar]
  84. 84. 
    Xu G-J, Gan T-Y, Tang B-P, Chen Z-H, Jiang T et al. 2013. Age-related changes in cellular electrophysiology and calcium handling for atrial fibrillation. J. Cell. Mol. Med. 17:91109–18
     [Google Scholar]
  85. 85. 
    Herraiz-Martínez A, Álvarez-García J, Llach A, Molina CE, Fernandes J et al. 2015. Ageing is associated with deterioration of calcium homeostasis in isolated human right atrial myocytes. Cardiovasc. Res. 106:176–86
     [Google Scholar]
  86. 86. 
    Jones SA, Boyett MR, Lancaster MK 2007. Declining into failure the age-dependent loss of the L-type calcium channel within the sinoatrial node. Circulation 115:101183–90
     [Google Scholar]
  87. 87. 
    Lipsius SL, Vassalle M. 1978. Dual excitatory channels in the sinus node. J. Mol. Cell. Cardiol. 10:8753–67
     [Google Scholar]
  88. 88. 
    Muramatsu H, Zou AR, Berkowitz GA, Nathan RD 1996. Characterization of a TTX-sensitive Na+ current in pacemaker cells isolated from rabbit sinoatrial node. Am. J. Physiol. Heart Circ. Physiol. 270:6H2108–19
     [Google Scholar]
  89. 89. 
    Maier SKG, Westenbroek RE, Yamanushi TT, Dobrzynski H, Boyett MR et al. 2003. An unexpected requirement for brain-type sodium channels for control of heart rate in the mouse sinoatrial node. PNAS 100:63507–12
     [Google Scholar]
  90. 90. 
    Ruan Y, Liu N, Priori SG 2009. Sodium channel mutations and arrhythmias. Nat. Rev. Cardiol. 6:5337–48
     [Google Scholar]
  91. 91. 
    Wu J, Zhang Y, Zhang X, Cheng L, Lammers WJ et al. 2012. Altered sinoatrial node function and intra-atrial conduction in murine gain-of-function Scn5a+/ΔKPQ hearts suggest an overlap syndrome. Am. J. Physiol. Heart Circ. Physiol. 302:7H1510–23
     [Google Scholar]
  92. 92. 
    Protas L, Oren RV, Clancy CE, Robinson RB 2010. Age-dependent changes in Na current magnitude and TTX-sensitivity in the canine sinoatrial node. J. Mol. Cell. Cardiol. 48:1172–80
     [Google Scholar]
  93. 93. 
    Bettahi I, Marker CL, Roman MI, Wickman K 2002. Contribution of the Kir3.1 subunit to the muscarinic-gated atrial potassium channel IKACh. J. Biol. Chem. 277:5048282–88
     [Google Scholar]
  94. 94. 
    Weisbrod D, Peretz A, Ziskind A, Menaker N, Oz S et al. 2013. SK4 Ca2+ activated K+ channel is a critical player in cardiac pacemaker derived from human embryonic stem cells. PNAS 110:18E1685–94
     [Google Scholar]
  95. 95. 
    Lai MH, Wu Y, Gao Z, Anderson ME, Dalziel JE, Meredith AL 2014. BK channels regulate sinoatrial node firing rate and cardiac pacing in vivo. Am. J. Physiol. Heart Circ. Physiol. 307:9H1327–38
     [Google Scholar]
  96. 96. 
    Weisbrod D, Khun SH, Bueno H, Peretz A, Attali B 2016. Mechanisms underlying the cardiac pacemaker: the role of SK4 calcium-activated potassium channels. Acta Pharmacol. Sin. 37:182–97
     [Google Scholar]
  97. 97. 
    Aziz Q, Li Y, Tinker A 2018. Potassium channels in the sinoatrial node and their role in heart rate control. Channels 12:1356–66
     [Google Scholar]
  98. 98. 
    Thomas D, Wimmer A-B, Karle CA, Licka M, Alter M et al. 2005. Dominant-negative IKs suppression by KCNQ1-ΔF339 potassium channels linked to Romano-Ward syndrome. Cardiovasc. Res. 67:3487–97
     [Google Scholar]
  99. 99. 
    Horigome H, Nagashima M, Sumitomo N, Yoshinaga M, Ushinohama H et al. 2010. Clinical characteristics and genetic background of congenital long-QT syndrome diagnosed in fetal, neonatal, and infantile life: a nationwide questionnaire survey in Japan. Circ. Arrhythm. Electrophysiol. 3:110–17
     [Google Scholar]
  100. 100. 
    Wilders R, Verkerk AO. 2018. Long QT syndrome and sinus bradycardia—a mini review. Front. Cardiovasc. Med. 5:106
     [Google Scholar]
  101. 101. 
    Wang L, Swirp S, Duff H 2000. Age-dependent response of the electrocardiogram to K+ channel blockers in mice. Am. J. Physiol. Cell Physiol. 278:1C73–80
     [Google Scholar]
  102. 102. 
    Furukawa Y, Miyashita Y, Nakajima K, Hirose M, Kurogouchi F, Chiba S 1999. Effects of verapamil, zatebradine, and E-4031 on the pacemaker location and rate in response to sympathetic stimulation in dog hearts. J. Pharmacol. Exp. Ther. 289:31334–42
     [Google Scholar]
  103. 103. 
    Kuß J, Stallmeyer B, Goldstein M, Rinné S, Pees C et al. 2019. Familial sinus node disease caused by a gain of GIRK (G-protein activated inwardly rectifying K+ channel) channel function. Circ. Genomic Precis. Med. 12:1e002238
     [Google Scholar]
  104. 104. 
    Wickman K, Nemec J, Gendler SJ, Clapham DE 1998. Abnormal heart rate regulation in GIRK4 knockout mice. Neuron 20:1103–14
     [Google Scholar]
  105. 105. 
    Liu Y, Beyer A, Aebersold R 2016. On the dependency of cellular protein levels on mRNA abundance. Cell 165:3535–50
     [Google Scholar]
  106. 106. 
    Shiraishi I, Takamatsu T, Minamikawa T, Onouchi Z, Fujita S 1992. Quantitative histological analysis of the human sinoatrial node during growth and aging. Circulation 85:62176–84
     [Google Scholar]
  107. 107. 
    Thery C, Gosselin B, Lekieffre J, Warembourg H 1977. Pathology of sinoatrial node. Correlations with electrocardiographic findings in 111 patients. Am. Heart J. 93:6735–40
     [Google Scholar]
  108. 108. 
    Inoue S, Shinohara F, Niitani H, Gotoh K 1986. A new method for the histological study of aging changes in the sinoatrial node. Jpn. Heart J. 27:5653–60
     [Google Scholar]
  109. 109. 
    Kistler PM, Sanders P, Fynn SP, Stevenson IH, Spence SJ et al. 2004. Electrophysiologic and electroanatomic changes in the human atrium associated with age. J. Am. Coll. Cardiol. 44:1109–16
     [Google Scholar]
  110. 110. 
    Sanders P, Morton JB, Kistler PM, Spence SJ, Davidson NC et al. 2004. Electrophysiological and electroanatomic characterization of the atria in sinus node disease. Circulation 109:121514–22
     [Google Scholar]
  111. 111. 
    Monfredi O, Boyett MR. 2015. Sick sinus syndrome and atrial fibrillation in older persons—a view from the sinoatrial nodal myocyte. J. Mol. Cell. Cardiol. 83:88–100
     [Google Scholar]
  112. 112. 
    Hao X, Zhang Y, Zhang X, Nirmalan M, Davies L et al. 2011. TGF-β1-mediated fibrosis and ion channel remodeling are key mechanisms in producing the sinus node dysfunction associated with SCN5A deficiency and aging. Circ. Arrhythm. Electrophysiol. 4:3397–406
     [Google Scholar]
  113. 113. 
    Glukhov AV, Kalyanasundaram A, Lou Q, Hage LT, Hansen BJ et al. 2015. Calsequestrin 2 deletion causes sinoatrial node dysfunction and atrial arrhythmias associated with altered sarcoplasmic reticulum calcium cycling and degenerative fibrosis within the mouse atrial pacemaker complex. Eur. Heart J. 36:11686–97
     [Google Scholar]
  114. 114. 
    de Melo SR, de Souza RR, Mandarim-de-Lacerda CA 2002. Stereologic study of the sinoatrial node of rats—age related changes. Biogerontology 3:6383–90
     [Google Scholar]
  115. 115. 
    Swaminathan PD, Purohit A, Soni S, Voigt N, Singh MV et al. 2011. Oxidized CaMKII causes cardiac sinus node dysfunction in mice. J. Clin. Investig. 121:83277–88
     [Google Scholar]
  116. 116. 
    Kharche S, Beling J, Biktasheva IV, Zhang H, Biktashev VN 2013. Simulating cell apoptosis induced sinus node dysfunction Paper presented at the 35th Annual International Conference of the IEEE Engineering in Medicine and Biology Society Osaka, Japan: July 3–7
  117. 117. 
    Lakatta EG, Gerstenblith G, Angell CS, Shock NW, Weisfeldt ML 1975. Diminished inotropic response of aged myocardium to catecholamines. Circ. Res. 36:2262–69
     [Google Scholar]
  118. 118. 
    Stratton JR, Cerqueira MD, Schwartz RS, Levy WC, Veith RC et al. 1992. Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men. Circulation 86:2504–12
     [Google Scholar]
  119. 119. 
    Fleg JL, Schulman S, O'Connor F, Becker LC, Gerstenblith G et al. 1994. Effects of acute beta-adrenergic receptor blockade on age-associated changes in cardiovascular performance during dynamic exercise. Circulation 90:52333–41
     [Google Scholar]
  120. 120. 
    Abhishekh HA, Nisarga P, Kisan R, Meghana A, Chandran S et al. 2013. Influence of age and gender on autonomic regulation of heart. J. Clin. Monit. Comput. 27:3259–64
     [Google Scholar]
  121. 121. 
    Freeling JL, Li Y. 2015. Age-related attenuation of parasympathetic control of the heart in mice. Int. J. Physiol. Pathophysiol. Pharmacol. 7:3126–35
     [Google Scholar]
  122. 122. 
    Baker SE, Limberg JK, Dillon GA, Curry TB, Joyner MJ, Nicholson WT 2018. Aging alters the relative contributions of the sympathetic and parasympathetic nervous system to blood pressure control in women. Hypertension 72:51236–42
     [Google Scholar]
  123. 123. 
    Vestal RE, Wood AJJ, Shand DG 1979. Reduced β-adrenoceptor sensitivity in the elderly. Clin. Pharmacol. Ther. 26:2181–86
     [Google Scholar]
  124. 124. 
    Alboni P, Malcarne C, Pedroni P, Masoni A, Narula OS 1982. Electrophysiology of normal sinus node with and without autonomic blockade. Circulation 65:61236–42
     [Google Scholar]
  125. 125. 
    St. Clair JR, Liao Z, Larson ED, Proenza C. 2013. PKA-independent activation of If by cAMP in mouse sinoatrial myocytes. Channels 7:4318–21
     [Google Scholar]
  126. 126. 
    Striessnig J, Pinggera A, Kaur G, Bock G, Tuluc P 2014. L-type Ca2+ channels in heart and brain. Wiley Interdiscip. Rev. Membr. Transp. Signal. 3:215–38
     [Google Scholar]
  127. 127. 
    Vinogradova TM, Bogdanov KY, Lakatta EG 2002. β-Adrenergic stimulation modulates ryanodine receptor Ca2+ release during diastolic depolarization to accelerate pacemaker activity in rabbit sinoatrial nodal cells. Circ. Res. 90:173–79
     [Google Scholar]
  128. 128. 
    Shen J. 2006. Isoprenaline enhances local Ca2+ release in cardiac myocytes. Acta Pharmacol. Sin. 27:7927–32
     [Google Scholar]
  129. 129. 
    Yoshida A, Takahashi M, Imagawa T, Shigekawa M, Takisawa H, Nakamura T 1992. Phosphorylation of ryanodine receptors in rat myocytes during beta-adrenergic stimulation. J. Biochem. 111:2186–90
     [Google Scholar]
  130. 130. 
    Uehara A, Yasukochi M, Mejía-Alvarez R, Fill M, Imanaga I 2002. Gating kinetics and ligand sensitivity modified by phosphorylation of cardiac ryanodine receptors. Pflügers Arch 444:1–2202–12
     [Google Scholar]
  131. 131. 
    Kaese S, Bögeholz N, Pauls P, Dechering D, Olligs J et al. 2017. Increased sodium/calcium exchanger activity enhances beta-adrenergic-mediated increase in heart rate: whole-heart study in a homozygous sodium/calcium exchanger overexpressor mouse model. Heart Rhythm 14:81247–53
     [Google Scholar]
  132. 132. 
    Sanders L, Rakovic S, Lowe M, Mattick PAD, Terrar DA 2006. Fundamental importance of Na+−Ca2+ exchange for the pacemaking mechanism in guinea-pig sino-atrial node. J. Physiol. 571:Part 3639–49
     [Google Scholar]
  133. 133. 
    Liao Z, Lockhead D, Larson E, Proenza C 2010. Phosphorylation and modulation of hyperpolarization-activated HCN4 channels by protein kinase A in the mouse sinoatrial node. J. Gen. Physiol. 136:3247–58
     [Google Scholar]
  134. 134. 
    Simmerman HKB, Jones LR. 1998. Phospholamban: protein structure, mechanism of action, and role in cardiac function. Physiol. Rev. 78:4921–47
     [Google Scholar]
  135. 135. 
    O'Connor SW, Scarpace PJ, Abrass IB 1981. Age-associated decrease of adenylate cyclase activity in rat myocardium. Mech. Ageing Dev. 16:191–95
     [Google Scholar]
  136. 136. 
    Hardouin S, Bourgeois F, Toraasson M, Oubenaissa A, Elalouf JM et al. 1998. β-Adrenergic and muscarinic receptor mRNA accumulation in the sinoatrial node area of adult and senescent rat hearts. Mech. Ageing Dev. 100:3277–97
     [Google Scholar]
  137. 137. 
    Yaniv Y, Ahmet I, Liu J, Lyashkov AE, Guiriba T-R et al. 2014. Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals. Heart Rhythm 11:71210–19
     [Google Scholar]
  138. 138. 
    Behar J, Yaniv Y. 2017. Age-related pacemaker deterioration is due to impaired intracellular and membrane mechanisms: insights from numerical modeling. J. Gen. Physiol. 149:10935–49
     [Google Scholar]
  139. 139. 
    Ortman JM, Velkoff VA, Hogan H 2014. An aging nation: the older population in the United States Curr. Pop. Rep. P25-1140, US Dep. Commer Washington, DC: https://www.census.gov/prod/2014pubs/p25-1140.pdf
  140. 140. 
    Semelka M, Gera J, Usman S 2013. Sick sinus syndrome: a review. Am. Fam. Physician 87:10691–96
     [Google Scholar]
  141. 141. 
    Sideris S, Archontakis S, Dilaveris P, Gatzoulis KA, Trachanas K et al. 2017. Leadless cardiac pacemakers: current status of a modern approach in pacing. Hellenic J. Cardiol. 58:6403–10
     [Google Scholar]
  142. 142. 
    Stieber J, Wieland K, Stöckl G, Ludwig A, Hofmann F 2006. Bradycardic and proarrhythmic properties of sinus node inhibitors. Mol. Pharmacol. 69:41328–37
     [Google Scholar]
  143. 143. 
    Lees-Miller JP, Guo J, Wang Y, Perissinotti LL, Noskov SY, Duff HJ 2015. Ivabradine prolongs phase 3 of cardiac repolarization and blocks the HERG1 (KCNH2) current over a concentration-range overlapping with that required to block HCN4. J. Mol. Cell. Cardiol. 85:71–78
     [Google Scholar]
  144. 144. 
    Melgari D, Brack KE, Zhang C, Zhang Y, El Harchi A et al. 2015. hERG potassium channel blockade by the HCN channel inhibitor bradycardic agent ivabradine.. J. Am. Heart Assoc. 4:4e001813
     [Google Scholar]
  145. 145. 
    Kragie L, Sekovski B. 1992. Theophylline—an alternative therapy for bradyarrhythmia in the elderly. Pharmacotherapy 12:4324–30
     [Google Scholar]
  146. 146. 
    Pasnoori VR, Leesar MA. 2004. Use of aminophylline in the treatment of severe symptomatic bradycardia resistant to atropine. Cardiol. Rev. 12:265–68
     [Google Scholar]
  147. 147. 
    Proenza C. 2018. Ion channels: exploiting natural regulation. eLife 7:e39664
     [Google Scholar]
  148. 148. 
    Kane AE, Howlett SE. 2018. Differences in cardiovascular aging in men and women. Adv. Exp. Med. Biol. 1065:389–411
     [Google Scholar]
  149. 149. 
    Burke JH, Goldberger JJ, Ehlert FA, Kruse JT, Parker MA, Kadish AH 1996. Gender differences in heart rate before and after autonomic blockade: evidence against an intrinsic gender effect. Am. J. Med. 100:5537–43
     [Google Scholar]
  150. 150. 
    Nowak B, Misselwitz B, Erdogan A, Funck R et al. 2010. Do gender differences exist in pacemaker implantation?—results of an obligatory external quality control program. Europace 12:2210–15
     [Google Scholar]
  151. 151. 
    Tamargo J, Rosano G, Walther T, Duarte J, Niessner A et al. 2017. Gender differences in the effects of cardiovascular drugs. Eur. Heart J. Cardiovasc. Pharmacother. 3:3163–82
     [Google Scholar]
  152. 152. 
    Park DS, Fishman GI. 2017. Development and function of the cardiac conduction system in health and disease. J. Cardiovasc. Dev. Dis. 4:27
     [Google Scholar]
  153. 153. 
    Kharche SR, Vigmond E, Efimov IR, Dobrzynski H 2017. Computational assessment of the functional role of sinoatrial node exit pathways in the human heart. PLOS ONE 12:9e0183727
     [Google Scholar]
/content/journals/10.1146/annurev-physiol-021119-034453
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Cardiac Pacemaker Activity and Aging
Annual Review of Physiology 82, 21 (2020); https://doi.org/10.1146/annurev-physiol-021119-034453
/content/journals/10.1146/annurev-physiol-021119-034453
/content/journals/10.1146/annurev-physiol-021119-034453
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