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The end effector of circadian heart rate variation: the sinoatrial node pacemaker cell
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  • Journal title : BMB Reports
  • Volume 48, Issue 12,  2015, pp.677-684
  • Publisher : Korean Society for Biochemistry and Molecular Biology
  • DOI : 10.5483/BMBRep.2015.48.12.061
 Title & Authors
The end effector of circadian heart rate variation: the sinoatrial node pacemaker cell
Yaniv, Yael; Lakatta, Edward G.;
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Cardiovascular function is regulated by the rhythmicity of circadian, infradian and ultradian clocks. Specific time scales of different cell types drive their functions: circadian gene regulation at hours scale, activation-inactivation cycles of ion channels at millisecond scales, the heart`s beating rate at hundreds of millisecond scales, and low frequency autonomic signaling at cycles of tens of seconds. Heart rate and rhythm are modulated by a hierarchical clock system: autonomic signaling from the brain releases neurotransmitters from the vagus and sympathetic nerves to the heart`s pacemaker cells and activate receptors on the cell. These receptors activating ultradian clock functions embedded within pacemaker cells include sarcoplasmic reticulum rhythmic spontaneous Ca2+ cycling, rhythmic ion channel current activation and inactivation, and rhythmic oscillatory mitochondria ATP production. Here we summarize the evidence that intrinsic pacemaker cell mechanisms are the end effector of the hierarchical brain-heart circadian clock system.
Cardiac denervation;Coupled-clock pacemaker system;Fractal-like behavior;Heart rate variability;Ultradian rhythm of the heart rate;
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The Effects of Pharmacological Compounds on Beat Rate Variations in Human Long QT-Syndrome Cardiomyocytes, Stem Cell Reviews and Reports, 2016, 12, 6, 698  crossref(new windwow)
Bell-Pedersen D, Cassone VM, Earnest DJ et al (2005) Circadian rhythms from multiple oscillators: lessons from diverse organisms. Nat Rev Genet 6, 544-556 crossref(new window)

Reppert SM and Weaver DR (2002) Coordination of circadian timing in mammals. Nature 418, 935-941 crossref(new window)

Yaniv Y, Lakatta EG and Maltsev AV (2015) From two competing oscillators to one coupled-clock pacemaker cell system. Front Physiol 6, 47

Yaniv Y, Lyashkov AE and Lakatta EG (2013) The fractal-like complexity of heart rate variability beyond neurotransmitters and autonomic receptors: signaling intrinsic to sinoatrial node pacemaker cells. Cardiovasc Pharm Open Access 2, 11-14

Yaniv Y, Lyashkov AE and Lakatta EG (2013) Impaired Signaling Intrinsic to Sinoatrial Node Pacemaker Cells Affects Heart Rate Variability during Cardiac Disease. J Clin Trials 4, 2167

Bigger JT Jr, Steinman RC, Rolnitzky LM, Fleiss JL, Albrecht P and Cohen RJ (1996) Power law behavior of RR-interval variability in healthy middle-aged persons, patients with recent acute myocardial infarction, and patients with heart transplants. Circulation 93, 2142-2151 crossref(new window)

Monfredi O, Lyashkov AE, Johnsen AB et al (2014) Biophysical Characterization of the Underappreciated and Important Relationship Between Heart Rate Variability and Heart Rate. Hypertension 64, 1334-1343 crossref(new window)

Mandel Y, Weissman A, Schick R et al (2012) Human embryonic and induced pluripotent stem cell-derived cardiomyocytes exhibit beat rate variability and power-law behavior. Circulation 125, 883-893 crossref(new window)

Rocchetti M, Malfatto G, Lombardi F and Zaza A (2000) Role of the input/output relation of sinoatrial myocytes in cholinergic modulation of heart rate variability. J Cardiovasc Electrophysiol 11, 522-530 crossref(new window)

Yaniv Y, Ahmet I, Liu J et al (2014) Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals. Heart Rhythm 11, 1210-1219 crossref(new window)

Yaniv Y, Lyashkov AE, Sirenko S et al (2014) Stochasticity intrinsic to coupled-clock mechanisms underlies beat-tobeat variability of spontaneous action potential firing in sinoatrial node pacemaker cells. J Mol Cell Cardiol 77, 1-10 crossref(new window)

Tong M, Watanabe E, Yamamoto N et al (2013) Circadian expressions of cardiac ion channel genes in mouse might be associated with the central clock in the SCN but not the peripheral clock in the heart. Biol Rhythm Res 44, 519-530 crossref(new window)

Jeyaraj D, Haldar SM, Wan X et al (2012) Circadian rhythms govern cardiac repolarization and arrhythmogenesis. Nature 483, 96-99 crossref(new window)

Leibetseder V, Humpeler S, Svoboda M et al (2009) Clock genes display rhythmic expression in human hearts. Chronobiol Int 26, 621-636 crossref(new window)

Lakatta EG, Yaniv Y and Maltsev VA (2013) Minding the gaps that link intrinsic circadian clock within the heart to its intrinsic ultradian pacemaker clocks. Focus on "The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility". Am J Physiol Cell Physiol 304, C941-944 crossref(new window)

Schroder EA, Lefta M, Zhang X et al (2013) The cardiomyocyte molecular clock, regulation of Scn5a, and arrhythmia susceptibility. Am J Physiol Cell Physiol 304, C954-965 crossref(new window)

Kraft IA, Alexander S, Foster D, Leachman RD and Lipscomb HS (1970) Circadian rhythms in human heart homograft. Science 169, 694-696 crossref(new window)

Kotsis VT, Stabouli SV, Pitiriga V et al (2005) Impact of cardiac transplantation in 24 hours circadian blood pressure and heart rate profile. Transplant Proc 37, 2244-2246 crossref(new window)

Young ME, Razeghi P, Cedars AM, Guthrie PH and Taegtmeyer H (2001) Intrinsic diurnal variations in cardiac metabolism and contractile function. Circ Res 89, 1199-1208 crossref(new window)

DiFrancesco D (1993) Pacemaker mechanisms in cardiac tissue. Annu Rev Physiol 55, 455-472 crossref(new window)

DiFrancesco D and Tortora P (1991) Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 351, 145-147 crossref(new window)

Lyashkov AE, Vinogradova TM, Zahanich I et al (2009) Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca(2+) cycling and I(KACh). Am J Physiol Heart Circ Physiol 297, H949-959 crossref(new window)

Vinogradova TM, Bogdanov KY and Lakatta EG (2002) beta-Adrenergic stimulation modulates ryanodine receptor Ca(2+) release during diastolic depolarization to accelerate pacemaker activity in rabbit sinoatrial nodal cells. Circ Res 90, 73-79 crossref(new window)

Yaniv Y, Ganesan A, Yang D, Ziman B, Zhang J and Lakatta EG (2014) Parallel increase in PKA activation kinetics and spontaneous beating rate in sinoatrial node cell in response to chronotropic stimuli. Heart Rhythm 11, S164 crossref(new window)

Zaza A, Robinson RB and DiFrancesco D (1996) Basal responses of the L-type Ca2+ and hyperpolarization- activated currents to autonomic agonists in the rabbit sino-atrial node. J Physiol 491(Pt 2), 347-355 crossref(new window)

Zaza A and Lombardi F (2001) Autonomic indexes based on the analysis of heart rate variability: a view from the sinus node. Cardiovasc Res 50, 434-442 crossref(new window)

Christ JE (1979) An analysis of circadian rhythmicity of heart rate in tetraplegic human subjects. Paraplegia 17, 251-258 crossref(new window)

Boudreau P, Yeh WH, Dumont GA and Boivin DB (2012) A circadian rhythm in heart rate variability contributes to the increased cardiac sympathovagal response to awakening in the morning. Chronobiol Int 29, 757-768 crossref(new window)

Prinz PN, Halter J, Benedetti C and Raskind M (1979) Circadian variation of plasma catecholamines in young and old men: relation to rapid eye movement and slow wave sleep. J Clin Endocrinol Metab 49, 300-304 crossref(new window)

Linsell CR, Lightman SL, Mullen PE, Brown MJ and Causon RC (1985) Circadian rhythms of epinephrine and norepinephrine in man. J Clin Endocrinol Metab 60, 1210-1215 crossref(new window)

Cinca J, Moya A, Figueras J, Roma F and Rius J (1986) Circadian variations in the electrical properties of the human heart assessed by sequential bedside electrophysiologic testing. Am Heart J 112, 315-321 crossref(new window)

Goetze JP, Georg B, Jorgensen HL and Fahrenkrug J (2010) Chamber-dependent circadian expression of cardiac natriuretic peptides. Regul Pept 160, 140-145 crossref(new window)

Sato R, Mizuno M, Miura T et al (2013) Angiotensin receptor blockers regulate the synchronization of circadian rhythms in heart rate and blood pressure. J Hypertens 31, 1233-1238 crossref(new window)

Yaniv Y, Sirenko S, Ziman BD, Spurgeon HA, Maltsev VA and Lakatta EG (2013) New evidence for coupled clock regulation of the normal automaticity of sinoatrial nodal pacemaker cells: bradycardic effects of ivabradine are linked to suppression of intracellular Ca(2)(+) cycling. J Mol Cell Cardiol 62, 80-89 crossref(new window)

Maltsev VA, Yaniv Y, Maltsev AV, Stern MD and Lakatta EG (2014) Modern perspectives on numerical modeling of cardiac pacemaker cell. J Pharmacol Sci 125, 6-38 crossref(new window)

Massin MM, Maeyns K, Withofs N, Ravet F and Gerard P (2000) Circadian rhythm of heart rate and heart rate variability. Arch Dis Child 83, 179-182 crossref(new window)

Bilan A, Witczak A, Palusinski R, Myslinski W and Hanzlik J (2005) Circadian rhythm of spectral indices of eart rate variability in healthy subjects. J Electrocardiol 38, 239-243 crossref(new window)

Hu K, Scheer FA, Buijs RM and Shea SA (2008) The circadian pacemaker generates similar circadian rhythms in the fractal structure of heart rate in humans and rats. Cardiovasc Res 80, 62-68 crossref(new window)

Younes A, Lyashkov AE, Graham D et al (2008) Ca(2+)-stimulated basal adenylyl cyclase activity localization in membrane lipid microdomains of cardiac sinoatrial nodal pacemaker cells. J Biol Chem 283, 14461-14468 crossref(new window)

Mattick P, Parrington J, Odia E, Simpson A, Collins T and Terrar D (2007) 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 crossref(new window)

Ko GY, Ko ML and Dryer SE (2001) Circadian regulation of cGMP-gated cationic channels of chick retinal cones. Erk MAP Kinase and Ca2+/calmodulin-dependent protein kinase II. Neuron 29, 255-266 crossref(new window)

Ko ML, Shi L, Grushin K, Nigussie F and Ko GY (2010) Circadian profiles in the embryonic chick heart: L-type voltage-gated calcium channels and signaling pathways. Chronobiol Int 27, 1673-1696 crossref(new window)

Welsh DK, Takahashi JS and Kay SA (2010) Suprachiasmatic nucleus: cell autonomy and network properties. Annu Rev Physiol 72, 551-577 crossref(new window)

Ikeda M (2004) Calcium dynamics and circadian rhythms in suprachiasmatic nucleus neurons. Neuroscientist 10, 315-324 crossref(new window)

Colwell CS (2000) Circadian modulation of calcium levels in cells in the suprachiasmatic nucleus. Eur J Neurosci 12, 571-576 crossref(new window)

Pennartz CM, de Jeu MT, Bos NP, Schaap J and Geurtsen AM (2002) Diurnal modulation of pacemaker potentials and calcium current in the mammalian circadian clock. Nature 416, 286-290 crossref(new window)

Yamashita T, Sekiguchi A, Iwasaki YK et al (2003) Circadian variation of cardiac K+ channel gene expression. Circulation 107, 1917-1922 crossref(new window)

Isobe Y, Hida H and Nishino H (2011) Circadian rhythm of enolase in suprachiasmatic nucleus depends on mitochondrial function. J Neurosci Res 89, 936-944 crossref(new window)

Yaniv Y, Juhaszova M, Lyashkov AE, Spurgeon H, Sollott SJ and Lakatta EG (2011) Ca2+-regulated-cAMP/PKA signaling in cardiac pacemaker cells links ATP supply to demand. J Mol Cell Cardiol 51, 740-748 crossref(new window)

Aon MA, Cortassa S and O’Rourke B (2006) The fundamental organization of cardiac mitochondria as a network of coupled oscillators. Biophys J 91, 4317-4327 crossref(new window)

Durgan DJ, Trexler NA, Egbejimi O et al (2006) The circadian clock within the cardiomyocyte is essential for responsiveness of the heart to fatty acids. J Biol Chem 281, 24254-24269 crossref(new window)

Yaniv Y, Juhaszova M, Nuss HB et al (2010) Matching ATP supply and demand in mammalian heart In vivo, in vitro, and in silico perspectives. Ann N Y Acad Sci 1188, 133-142 crossref(new window)

Levy C, Ter Keurs HE, Yaniv Y and Landesberg A (2005) The sarcomeric control of energy conversion. Ann N Y Acad Sci 1047, 219-231 crossref(new window)

Yaniv Y, Spurgeon HA, Ziman BD, Lyashkov AE and Lakatta EG (2013) Mechanisms that match ATP supply to demand in cardiac pacemaker cells during high ATP demand. Am J Physiol Heart Circ Physiol 304, H1428-1438 crossref(new window)

Yaniv Y, Spurgeon HA, Ziman BD and Lakatta EG (2013) Ca(2)+/calmodulin-dependent protein kinase II (CaMKII) activity and sinoatrial nodal pacemaker cell energetics. PLoS One 8, e57079 crossref(new window)

Burkeen JF, Womac AD, Earnest DJ and Zoran MJ (2011) Mitochondrial calcium signaling mediates rhythmic extracellular ATP accumulation in suprachiasmatic nucleus astrocytes. J Neurosci 31, 8432-8440 crossref(new window)

Custodis F, Reil JC, Laufs U and Bohm M (2013) Heart rate: a global target for cardiovascular disease and therapy along the cardiovascular disease continuum. J Cardiol 62, 183-187 crossref(new window)

Hillebrand S, Gast KB, de Mutsert R et al (2013) Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose-response meta-regression. Europace 15, 742-749 crossref(new window)

Bassiouny HS, Zarins CK, Lee DC, Skelly CL, Fortunato JE and Glagov S (2002) Diurnal heart rate reactivity: a predictor of severity of experimental coronary and carotid atherosclerosis. J Cardiovasc Risk 9, 331-338 crossref(new window)

Furlan R, Barbic F, Piazza S, Tinelli M, Seghizzi P and Malliani A (2000) Modifications of cardiac autonomic profile associated with a shift schedule of work. Circulation 102, 1912-1916 crossref(new window)

Yaniv Y, Tsutsui K and Lakatta EG (2015) Potential effects of intrinsic heart pacemaker cell mechanisms on dysrhythmic cardiac action potential firing. Front Physiol 6, 1-7

Rydlewska A, Jankowska EA, Ponikowska B, Borodulin-Nadzieja L, Banasiak W and Ponikowski P (2011) Changes in autonomic balance in patients with decompensated chronic heart failure. Clin Auton Res 21, 47-54 crossref(new window)

Wu GQ, Shen LL, Tang DK, Zheng DA and Poon CS (2006) Circadian rhythms of spectral components of heart rate variability. Conf Proc IEEE Eng Med Biol Soc 1, 3557-3560

Peng CK, Havlin S, Hausdorff JM, Mietus JE, Stanley HE and Goldberger AL (1995) Fractal mechanisms and heart rate dynamics. Long-range correlations and their breakdown with disease. J Electrocardiol 28 Suppl, 59-65 crossref(new window)

Verkerk AO, Wilders R, Coronel R, Ravesloot JH and Verheijck EE (2003) Ionic remodeling of sinoatrial node cells by heart failure. Circulation 108, 760-766 crossref(new window)

Burger AJ, Charlamb M and Sherman HB (1999) Circadian patterns of heart rate variability in normals, chronic stable angina and diabetes mellitus. Int J Cardiol 71, 41-48 crossref(new window)

Pikkujamsa SM, Makikallio TH, Sourander LB et al (1999) Cardiac interbeat interval dynamics from childhood to senescence : comparison of conventional and new measures based on fractals and chaos theory. Circulation 100, 393-399 crossref(new window)

Santulli G and Iaccarino G (2013) Pinpointing beta adrenergic receptor in ageing pathophysiology: victim or executioner? Evidence from crime scenes. Immun Ageing 10, 10 crossref(new window)

Liu J, Sirenko S, Juhaszova M et al (2014) Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca(2+) signaling. Am J Physiol Heart Circ Physiol 306, H1385-1397 crossref(new window)