{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:24:52Z","timestamp":1790619892460,"version":"4.1.0"},"reference-count":118,"publisher":"Elsevier BV","issue":"6","license":[{"start":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T00:00:00Z","timestamp":1748736000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2025,6,1]],"date-time":"2025-06-01T00:00:00Z","timestamp":1748736000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2025,5,8]],"date-time":"2025-05-08T00:00:00Z","timestamp":1746662400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["clinicalkey.com","clinicalkey.com.au","clinicalkey.es","clinicalkey.fr","clinicalkey.jp","heartlungcirc.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Heart, Lung and Circulation"],"published-print":{"date-parts":[[2025,6]]},"DOI":"10.1016\/j.hlc.2025.04.084","type":"journal-article","created":{"date-parts":[[2025,5,11]],"date-time":"2025-05-11T15:00:01Z","timestamp":1746975601000},"page":"543-555","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":6,"title":["Heart Rhythm Harmony Becomes Discordant as We Age"],"prefix":"10.1016","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4772-0035","authenticated-orcid":false,"given":"Edward G.","family":"Lakatta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib1","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1016\/j.hrthm.2021.01.011","article-title":"Heartbeat music","volume":"18","author":"Lakatta","year":"2021","journal-title":"Heart Rhythm"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1113\/expphysiol.2007.041178","article-title":"Potential clinical relevance of the 'little brain' on the mammalian heart","volume":"93","author":"Armour","year":"2008","journal-title":"Exp Physiol"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib3","doi-asserted-by":"crossref","first-page":"9971","DOI":"10.1038\/s41598-020-66709-z","article-title":"Signatures of the autonomic nervous system and the heart's pacemaker cells in canine electrocardiograms and their applications to humans","volume":"10","author":"Rosenberg","year":"2020","journal-title":"Sci Rep"},{"key":"10.1016\/j.hlc.2025.04.084_bib4","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2021.665709","article-title":"Opening the Schr\u00f6dinger box: short- and long-range mammalian heart rate variability","volume":"12","author":"Weiser-Bitoun","year":"2021","journal-title":"Front Physiol"},{"issue":"14","key":"10.1016\/j.hlc.2025.04.084_bib5","doi-asserted-by":"crossref","first-page":"3911","DOI":"10.1113\/JP271870","article-title":"Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics","volume":"594","author":"Shivkumar","year":"2016","journal-title":"J Physiol"},{"issue":"9","key":"10.1016\/j.hlc.2025.04.084_bib6","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1161\/CIRCRESAHA.120.318458","article-title":"Innervation and neuronal control of the mammalian sinoatrial node a comprehensive atlas","volume":"128","author":"Hanna","year":"2021","journal-title":"Circ Res"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib7","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1152\/physrev.1993.73.2.413","article-title":"Cardiovascular regulatory mechanisms in advanced age","volume":"73","author":"Lakatta","year":"1993","journal-title":"Physiol Rev"},{"key":"10.1016\/j.hlc.2025.04.084_bib8","unstructured":"Lakatta EG. Chapter 40: Length modulation of muscle performance: Frank-Starling law of the heart. Fozzard HM HE, Jennings RB, Katz AM, Morgan HE editor. New York: Raven Press; 1986."},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib9","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1161\/01.RES.40.3.251","article-title":"Length-dependent activation: its effect on the length-tension relation in cat ventricular muscle","volume":"40","author":"Lakatta","year":"1977","journal-title":"Circ Res"},{"key":"10.1016\/j.hlc.2025.04.084_bib10","doi-asserted-by":"crossref","DOI":"10.3389\/fphys.2021.612770","article-title":"Ca(2+) and membrane potential transitions during action potentials are self-similar to each other and to variability of AP firing intervals across the broad physiologic range of AP intervals during autonomic receptor stimulation","volume":"12","author":"Yang","year":"2021","journal-title":"Front Physiol"},{"issue":"Suppl 1","key":"10.1016\/j.hlc.2025.04.084_bib11","doi-asserted-by":"crossref","first-page":"S48","DOI":"10.3949\/ccjm.74.Suppl_1.S48","article-title":"The little brain on the heart","volume":"74","author":"Armour","year":"2007","journal-title":"Cleve Clin J Med"},{"issue":"8","key":"10.1016\/j.hlc.2025.04.084_bib12","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.jacep.2020.06.022","article-title":"Synchronized cardiac impulses emerge from heterogeneous local calcium signals within and among cells of pacemaker tissue","volume":"6","author":"Bychkov","year":"2020","journal-title":"JACC Clin Electrophysiol"},{"issue":"10","key":"10.1016\/j.hlc.2025.04.084_bib13","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.jacep.2022.07.003","article-title":"The heart's pacemaker mimics brain cytoarchitecture and function: novel interstitial cells expose complexity of the SAN","volume":"8","author":"Bychkov","year":"2022","journal-title":"JACC Clin Electrophysiol"},{"issue":"1879","key":"10.1016\/j.hlc.2025.04.084_bib14","doi-asserted-by":"crossref","DOI":"10.1098\/rstb.2022.0180","article-title":"What makes the sinoatrial node tick? A question not for the faint of heart","volume":"378","author":"Donald","year":"2023","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"10.1016\/j.hlc.2025.04.084_bib15","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.80949","article-title":"A remarkable adaptive paradigm of heart performance and protection emerges in response to marked cardiac-specific overexpression of ADCY8","volume":"11","author":"Tarasov","year":"2022","journal-title":"Elife"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib16","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1016\/j.bpj.2017.12.043","article-title":"Positive feedback mechanisms among local Ca releases, NCX, and I(CaL) ignite pacemaker action potentials","volume":"114","author":"Lyashkov","year":"2018","journal-title":"Biophys J"},{"issue":"12","key":"10.1016\/j.hlc.2025.04.084_bib17","doi-asserted-by":"crossref","first-page":"1254","DOI":"10.1161\/hh1201.092095","article-title":"Sinoatrial nodal cell ryanodine receptor and Na(+)-Ca(2+) exchanger: molecular partners in pacemaker regulation","volume":"88","author":"Bogdanov","year":"2001","journal-title":"Circ Res"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib18","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1161\/CIRCRESAHA.109.206078","article-title":"A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart's pacemaker","volume":"106","author":"Lakatta","year":"2010","journal-title":"Circ Res"},{"key":"10.1016\/j.hlc.2025.04.084_bib19","unstructured":"Lakata EG, Maltsev VA. A new functional paradigm for the heart\u2019s pacemaker: mutual entrainment of intracellular calcium clocks and surface membrane ion channel clocks. 5 ed. DP Z, J J, editors. Philadelphia: Saunders; 2009."},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib20","doi-asserted-by":"crossref","first-page":"5555","DOI":"10.1038\/s41467-020-19304-9","article-title":"cAMP-dependent regulation of HCN4 controls the tonic entrainment process in sinoatrial node pacemaker cells","volume":"11","author":"Fenske","year":"2020","journal-title":"Nat Commun"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib21","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1016\/j.hrthm.2020.11.026","article-title":"A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate","volume":"18","author":"D'Souza","year":"2021","journal-title":"Heart Rhythm"},{"issue":"24","key":"10.1016\/j.hlc.2025.04.084_bib22","doi-asserted-by":"crossref","first-page":"3449","DOI":"10.1001\/jama.1985.03360240061035","article-title":"Characteristics and prognosis of lone atrial fibrillation. 30-year follow-up in the Framingham Study","volume":"254","author":"Brand","year":"1985","journal-title":"JAMA"},{"issue":"10","key":"10.1016\/j.hlc.2025.04.084_bib23","doi-asserted-by":"crossref","first-page":"C941","DOI":"10.1152\/ajpcell.00072.2013","article-title":"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\"","volume":"304","author":"Lakatta","year":"2013","journal-title":"Am J Physiol Cell Physiol"},{"issue":"9","key":"10.1016\/j.hlc.2025.04.084_bib24","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0045250","article-title":"The neuron-astrocyte-microglia triad in normal brain ageing and in a model of neuroinflammation in the rat hippocampus","volume":"7","author":"Cerbai","year":"2012","journal-title":"PLoS One"},{"issue":"Pt 2","key":"10.1016\/j.hlc.2025.04.084_bib25","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1113\/jphysiol.2007.144121","article-title":"The relevance of non-excitable cells for cardiac pacemaker function","volume":"585","author":"Fahrenbach","year":"2007","journal-title":"J Physiol"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib26","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1038\/s42254-019-0040-8","article-title":"The physics of brain network structure, function and control","volume":"1","author":"Lynn","year":"2019","journal-title":"Nat Rev Phys"},{"issue":"12","key":"10.1016\/j.hlc.2025.04.084_bib27","doi-asserted-by":"crossref","first-page":"2990","DOI":"10.1111\/j.1582-4934.2012.01626.x","article-title":"Characterization of the tissue\u2013level Ca2+ signals in spontaneously contracting human myometrium","volume":"16","author":"Bru-Mercier","year":"2012","journal-title":"J Cell Mol Med"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib28","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1113\/jphysiol.2014.277632","article-title":"Facing the challenge of mammalian neural microcircuits: taking a few breaths may help","volume":"593","author":"Feldman","year":"2015","journal-title":"J Physiol"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib29","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0176031","article-title":"Transcriptome of interstitial cells of Cajal reveals unique and selective gene signatures","volume":"12","author":"Lee","year":"2017","journal-title":"PLoS One"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib30","doi-asserted-by":"crossref","DOI":"10.1083\/jcb.201902014","article-title":"Ca2+ transients in melanocyte dendrites and dendritic spine-like structures evoked by cell-to-cell signaling","volume":"219","author":"Belote","year":"2020","journal-title":"J Cell Biol"},{"key":"10.1016\/j.hlc.2025.04.084_bib31","series-title":"Heart Rate and Rhythm","article-title":"Cardiac pacemaking is an emergent property of complex synchronized singaling on multiple scales","author":"Monfredi","year":"2023"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib32","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1113\/JP285582","article-title":"Inspiratory and sigh breathing rhythms depend on distinct cellular signalling mechanisms in the preB\u00f6tzinger complex","volume":"602","author":"Borrus","year":"2024","journal-title":"J Physiol"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib33","doi-asserted-by":"crossref","first-page":"1017","DOI":"10.1523\/JNEUROSCI.4731-10.2011","article-title":"Dendritic calcium activity precedes inspiratory bursts in preBotzinger complex neurons","volume":"31","author":"Del","year":"2011","journal-title":"J Neurosci"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib34","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1093\/cvr\/4.2.160","article-title":"The normal range and determinants of the intrinsic heart rate in man","volume":"4","author":"Jose","year":"1970","journal-title":"Cardiovasc Res"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11357-021-00420-3","article-title":"Slowing down as we age: aging of the cardiac pacemaker's neural control","volume":"44","author":"Choi","year":"2022","journal-title":"Geroscience"},{"key":"10.1016\/j.hlc.2025.04.084_bib36","doi-asserted-by":"crossref","first-page":"255","DOI":"10.3389\/fphys.2017.00255","article-title":"Heart rate fragmentation: a new approach to the analysis of cardiac interbeat interval dynamics","volume":"8","author":"Costa","year":"2017","journal-title":"Front Physiol"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib37","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1161\/CIRCULATIONAHA.105.545459","article-title":"Accelerated longitudinal decline of aerobic capacity in healthy older adults","volume":"112","author":"Fleg","year":"2005","journal-title":"Circulation"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib38","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1159\/000435947","article-title":"Heart rate, life expectancy and the cardiovascular system: therapeutic considerations","volume":"132","author":"Boudoulas","year":"2015","journal-title":"Cardiology"},{"key":"10.1016\/j.hlc.2025.04.084_bib39","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.yjmcc.2015.04.005","article-title":"So! What's aging? Is cardiovascular aging a disease?","volume":"83","author":"Lakatta","year":"2015","journal-title":"J Mol Cell Cardiol"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib40","doi-asserted-by":"crossref","first-page":"M21","DOI":"10.1093\/geronj\/43.1.M21","article-title":"Spectral analysis of heart rate indicates reduced baroreceptor\u2013related heart rate variability in elderly persons","volume":"43","author":"Simpson","year":"1988","journal-title":"J Gerontol"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib41","doi-asserted-by":"crossref","first-page":"M95","DOI":"10.1093\/geronj\/45.3.M95","article-title":"Age-associated changes in the components of atrioventricular conduction in apparently healthy volunteers","volume":"45","author":"Fleg","year":"1990","journal-title":"J Gerontol"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib42","doi-asserted-by":"crossref","first-page":"M99","DOI":"10.1093\/geronj\/46.3.M99","article-title":"Aging effects on heart rate variation","volume":"46","author":"Schwartz","year":"1991","journal-title":"J Gerontol"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib43","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1159\/000245563","article-title":"Respiratory change in heart rate, sinus arrhythmia in the elderly","volume":"17","author":"Davies","year":"1975","journal-title":"Gerontol Clin (Basel)"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib44","first-page":"H461","article-title":"Cardiac function and morphology with aging in the spontaneously hypertensive rat","volume":"237","author":"Pfeffer","year":"1979","journal-title":"Am J Physiol"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib45","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1161\/01.CIR.65.1.141","article-title":"The effect of age on heart rate in subjects free of heart disease. Studies by ambulatory electrocardiography and maximal exercise stress test","volume":"65","author":"Kostis","year":"1982","journal-title":"Circulation"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib46","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1161\/01.HYP.13.5.401","article-title":"Cardiovascular regulatory functions in elderly patients with hypertension","volume":"13","author":"Kawamoto","year":"1989","journal-title":"Hypertension"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib47","first-page":"177","article-title":"Changes in heart rhythm power spectrum during human aging","volume":"3","author":"Korkushko","year":"1991","journal-title":"Aging (Milano)"},{"key":"10.1016\/j.hlc.2025.04.084_bib48","article-title":"Heart rate fragmentation gives novel insights into non-autonomic mechanisms governing beat-to-beat control of the heart's rhythm","volume":"9","author":"Lensen","year":"2020","journal-title":"JRSM Cardiovasc Dis"},{"key":"10.1016\/j.hlc.2025.04.084_bib49","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1109\/CIC.2002.1166860","article-title":"A new method to detect erratic sinus rhythm in RR-interval files generated from Holter recordings","author":"Domitrovich","year":"2002","journal-title":"Computers in Cardiology"},{"key":"10.1016\/j.hlc.2025.04.084_bib50","first-page":"669","year":"2002","journal-title":"Computers in Cardiology"},{"key":"10.1016\/j.hlc.2025.04.084_bib51","doi-asserted-by":"crossref","first-page":"827","DOI":"10.3389\/fphys.2017.00827","article-title":"Heart Rate Fragmentation: A Symbolic Dynamical Approach","volume":"8","author":"Costa","year":"2017","journal-title":"Front Physiol"},{"issue":"6","key":"10.1016\/j.hlc.2025.04.084_bib52","doi-asserted-by":"crossref","first-page":"H1341","DOI":"10.1152\/ajpheart.00110.2019","article-title":"Heart rate fragmentation: using cardiac pacemaker dynamics to probe the pace of biological aging","volume":"316","author":"Costa","year":"2019","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib53","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-023-45101-7","article-title":"Age-dependent contribution of intrinsic mechanisms to sinoatrial node function in humans","volume":"13","author":"Weiser-Bitoun","year":"2023","journal-title":"Sci Rep"},{"issue":"7","key":"10.1016\/j.hlc.2025.04.084_bib54","doi-asserted-by":"crossref","first-page":"1659","DOI":"10.1016\/0735-1097(89)90012-0","article-title":"Prevalence and long-term significance of exercise-induced frequent or repetitive ventricular ectopic beats in apparently healthy volunteers","volume":"14","author":"Busby","year":"1989","journal-title":"J Am Coll Cardiol"},{"issue":"12","key":"10.1016\/j.hlc.2025.04.084_bib55","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/S0002-9149(99)80412-3","article-title":"Prevalence and prognostic significance of exercise-induced supraventricular tachycardia in apparently healthy volunteers","volume":"75","author":"Maurer","year":"1995","journal-title":"Am J Cardiol"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib56","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1161\/01.CIR.0000048893.62841.F7","article-title":"Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: links to heart disease","volume":"107","author":"Lakatta","year":"2003","journal-title":"Circulation"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib57","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1378\/chest.81.3.302","article-title":"Cardiac arrhythmias in a healthy elderly population: detection by 24-hour ambulatory electrocardiography","volume":"81","author":"Fleg","year":"1982","journal-title":"Chest"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib58","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1016\/0735-1097(94)90638-6","article-title":"Cardiac arrhythmias on 24-h ambulatory electrocardiography in older women and men: the Cardiovascular Health Study","volume":"23","author":"Manolio","year":"1994","journal-title":"J Am Coll Cardiol"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib59","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1161\/01.CIR.56.2.273","article-title":"Echocardiographic assessment of a normal adult aging population","volume":"56","author":"Gerstenblith","year":"1977","journal-title":"Circulation"},{"issue":"Pt 3","key":"10.1016\/j.hlc.2025.04.084_bib60","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/j.1469-7793.2000.00407.x","article-title":"Human ageing and the sympathoadrenal system","volume":"528","author":"Seals","year":"2000","journal-title":"J Physiol"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib61","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s12017-008-8034-1","article-title":"Autonomic control of the aging heart","volume":"10","author":"Kaye","year":"2008","journal-title":"Neuromolecular Med"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib62","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1161\/01.CIR.87.2.631","article-title":"Deficient neuroendocrine regulation of the cardiovascular system with advancing age in healthy humans","volume":"87","author":"Lakatta","year":"1993","journal-title":"Circulation"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib63","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1152\/jappl.1985.59.4.1033","article-title":"Age-related augmentation of plasma catecholamines during dynamic exercise in healthy males","volume":"59","author":"Fleg","year":"1985","journal-title":"J Appl Physiol (1985)"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib64","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1210\/edrv-1-2-167","article-title":"Sympathetic nervous system and aging in man","volume":"1","author":"Rowe","year":"1980","journal-title":"Endocr Rev"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib65","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/j.1365-2362.1982.tb00948.x","article-title":"Noradrenaline release and clearance in relation to age and blood pressure in man","volume":"12","author":"Rubin","year":"1982","journal-title":"Eur J Clin Invest"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib66","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1161\/01.HYP.5.1.100","article-title":"Age-dependence of hypertensive-normotensive differences in plasma norepinephrine","volume":"5","author":"Goldstein","year":"1983","journal-title":"Hypertension"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib67","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1093\/geronj\/38.3.315","article-title":"Plasma norepinephrine responses to posture and isometric exercise increase with age in the absence of obesity","volume":"38","author":"Sowers","year":"1983","journal-title":"J Gerontol"},{"issue":"13","key":"10.1016\/j.hlc.2025.04.084_bib68","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1056\/NEJM198403293101303","article-title":"Alterations in leukocyte beta-receptor affinity with aging. A potential explanation for altered beta-adrenergic sensitivity in the elderly","volume":"310","author":"Feldman","year":"1984","journal-title":"N Engl J Med"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib69","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1161\/01.CIR.86.2.504","article-title":"Differences in cardiovascular responses to isoproterenol in relation to age and exercise training in healthy men","volume":"86","author":"Stratton","year":"1992","journal-title":"Circulation"},{"issue":"2, Supplement 1","key":"10.1016\/j.hlc.2025.04.084_bib70","doi-asserted-by":"crossref","DOI":"10.1016\/0735-1097(95)93216-Y","article-title":"807-2 Effect of age on left ventricular diastolic filling patterns during orthostatic stress","volume":"25","author":"Swinne","year":"1995","journal-title":"J Am Coll Cardiol"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib71","first-page":"257","article-title":"Effect of body fat on exercise hemodynamics in sedentary older men","volume":"6","author":"O'Connor","year":"1994","journal-title":"Aging (Milano)"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib72","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1152\/jappl.1988.64.2.585","article-title":"Baroreflex function in endurance- and static exercise-trained men","volume":"64","author":"Smith","year":"1988","journal-title":"J Appl Physiol (1985)"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib73","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1152\/jappl.1994.77.3.1500","article-title":"Cardiovascular responses to exhaustive upright cycle exercise in highly trained older men","volume":"77","author":"Fleg","year":"1994","journal-title":"J Appl Physiol (1985)"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib74","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1161\/01.CIR.94.3.359","article-title":"Continuum of cardiovascular performance across a broad range of fitness levels in healthy older men","volume":"94","author":"Schulman","year":"1996","journal-title":"Circulation"},{"key":"10.1016\/j.hlc.2025.04.084_bib75","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1146\/annurev-physiol-021119-034453","article-title":"Cardiac Pacemaker Activity and Aging","volume":"82","author":"Peters","year":"2020","journal-title":"Annu Rev Physiol"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib76","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1161\/01.CIR.69.2.203","article-title":"Exercise cardiac output is maintained with advancing age in healthy human subjects: cardiac dilatation and increased stroke volume compensate for a diminished heart rate","volume":"69","author":"Rodeheffer","year":"1984","journal-title":"Circulation"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib77","first-page":"H1863","article-title":"Hemodynamic effects of unloading the old heart","volume":"277","author":"Nussbacher","year":"1999","journal-title":"Am J Physiol"},{"issue":"6 Pt 2","key":"10.1016\/j.hlc.2025.04.084_bib78","first-page":"H1932","article-title":"Age-related decline in left ventricular filling at rest and exercise","volume":"263","author":"Schulman","year":"1992","journal-title":"Am J Physiol"},{"issue":"7","key":"10.1016\/j.hlc.2025.04.084_bib79","doi-asserted-by":"crossref","first-page":"1290","DOI":"10.1016\/S0735-1097(02)02132-0","article-title":"Attenuated cardiovascular reserve during prolonged submaximal cycle exercise in healthy older subjects","volume":"40","author":"Correia","year":"2002","journal-title":"J Am Coll Cardiol"},{"issue":"6","key":"10.1016\/j.hlc.2025.04.084_bib80","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.1007\/s11357-022-00605-4","article-title":"Emergence of heartbeat frailty in advanced age I: perspectives from life-long EKG recordings in adult mice","volume":"44","author":"Moen","year":"2022","journal-title":"Geroscience"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib81","doi-asserted-by":"crossref","first-page":"2589","DOI":"10.1007\/s11357-023-00787-5","article-title":"cAMP signaling affects age-associated deterioration of pacemaker beating interval dynamics","volume":"45","author":"Segal","year":"2023","journal-title":"GeroScience"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib82","first-page":"126","article-title":"Age-related attenuation of parasympathetic control of the heart in mice","volume":"7","author":"Freeling","year":"2015","journal-title":"Int J Physiol Pathophysiol Pharmacol"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib83","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1111\/acel.12483","article-title":"Deterioration of autonomic neuronal receptor signaling and mechanisms intrinsic to heart pacemaker cells contribute to age-associated alterations in heart rate variability in vivo","volume":"15","author":"Yaniv","year":"2016","journal-title":"Aging Cell"},{"issue":"11","key":"10.1016\/j.hlc.2025.04.084_bib84","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1016\/j.hrthm.2021.07.069","article-title":"Impacts of frailty on heart rate variability in aging mice: Roles of the autonomic nervous system and sinoatrial node","volume":"18","author":"Dorey","year":"2021","journal-title":"Heart Rhythm"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib87","doi-asserted-by":"crossref","first-page":"5085","DOI":"10.1007\/s11357-024-01267-0","article-title":"Lifelong longitudinal assessment of the contribution of multi-fractal fluctuations to heart rate and heart rate variability in aging mice: role of the sinoatrial node and autonomic nervous system","volume":"46","author":"Moghtadaei","year":"2024","journal-title":"Geroscience"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib85","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/0002-9149(91)90445-Q","article-title":"Accuracy of assessment of cardiac vagal tone by heart rate variability in normal subjects","volume":"67","author":"Hayano","year":"1991","journal-title":"Am J Cardiol"},{"issue":"7","key":"10.1016\/j.hlc.2025.04.084_bib86","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1016\/j.hrthm.2014.03.049","article-title":"Synchronization of sinoatrial node pacemaker cell clocks and its autonomic modulation impart complexity to heart beating intervals","volume":"11","author":"Yaniv","year":"2014","journal-title":"Heart Rhythm"},{"issue":"12","key":"10.1016\/j.hlc.2025.04.084_bib88","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1016\/0022-2828(89)90678-0","article-title":"Decrease with senescence in the norepinephrine-induced phosphorylation of myofilament proteins in isolated rat cardiac myocytes","volume":"21","author":"Sakai","year":"1989","journal-title":"J Mol Cell Cardiol"},{"issue":"1 Pt 2","key":"10.1016\/j.hlc.2025.04.084_bib89","first-page":"H184","article-title":"Contractile response of individual cardiac myocytes to norepinephrine declines with senescence","volume":"262","author":"Sakai","year":"1992","journal-title":"Am J Physiol"},{"issue":"2","key":"10.1016\/j.hlc.2025.04.084_bib90","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1038\/scientificamerican0290-42","article-title":"Chaos and fractals in human physiology","volume":"262","author":"Goldberger","year":"1990","journal-title":"Sci Am"},{"issue":"11","key":"10.1016\/j.hlc.2025.04.084_bib91","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/j.jacep.2021.02.016","article-title":"Self-similar synchronization of calcium and membrane potential transitions during action potential cycles predict heart rate across species","volume":"7","author":"Tagirova Sirenko","year":"2021","journal-title":"JACC Clin Electrophysiol"},{"issue":"534","key":"10.1016\/j.hlc.2025.04.084_bib93","doi-asserted-by":"crossref","DOI":"10.1126\/scisignal.aap7608","article-title":"A coupled-clock system drives the automaticity of human sinoatrial nodal pacemaker cells","volume":"11","author":"Tsutsui","year":"2018","journal-title":"Sci Signal"},{"issue":"14","key":"10.1016\/j.hlc.2025.04.084_bib94","doi-asserted-by":"crossref","first-page":"1841","DOI":"10.1016\/j.jacep.2020.09.017","article-title":"The Sinus Node: Still Mysterious After All These Years","volume":"6","author":"Weiss","year":"2020","journal-title":"JACC Clin Electrophysiol"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib95","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1038\/nbt.2480","article-title":"Reprogramming paces the heart","volume":"31","author":"Lakatta","year":"2013","journal-title":"Nat Biotechnol"},{"issue":"11","key":"10.1016\/j.hlc.2025.04.084_bib92","doi-asserted-by":"crossref","first-page":"3106","DOI":"10.3390\/cells10113106","article-title":"Phosphoprotein phosphatase 1 but not 2A activity modulates coupled-clock mechanisms to impact on intrinsic automaticity of sinoatrial nodal pacemaker cells","volume":"10","author":"Sirenko","year":"2021","journal-title":"Cells"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib96","doi-asserted-by":"crossref","first-page":"734A","DOI":"10.1016\/j.bpj.2009.12.4026","article-title":"Cardiac pacemaker cells uniquely match ATP supply to demand","volume":"98","author":"Yaniv","year":"2010","journal-title":"Biophys J"},{"key":"10.1016\/j.hlc.2025.04.084_bib97","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1111\/j.1749-6632.2009.05093.x","article-title":"Matching ATP supply and demand in mammalian heart: in vivo, in vitro, and in silico perspectives","volume":"1188","author":"Yaniv","year":"2010","journal-title":"Ann N Y Acad Sci"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib98","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.yjmcc.2011.07.018","article-title":"Ca2+-regulated-cAMP\/PKA signaling in cardiac pacemaker cells links ATP supply to demand","volume":"51","author":"Yaniv","year":"2011","journal-title":"J Mol Cell Cardiol"},{"issue":"11","key":"10.1016\/j.hlc.2025.04.084_bib99","doi-asserted-by":"crossref","first-page":"H1428","DOI":"10.1152\/ajpheart.00969.2012","article-title":"Mechanisms that match ATP supply to demand in cardiac pacemaker cells during high ATP demand","volume":"304","author":"Yaniv","year":"2013","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"6","key":"10.1016\/j.hlc.2025.04.084_bib100","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.ceca.2004.01.017","article-title":"Beyond Bowditch: the convergence of cardiac chronotropy and inotropy","volume":"35","author":"Lakatta","year":"2004","journal-title":"Cell Calcium"},{"key":"10.1016\/j.hlc.2025.04.084_bib101","doi-asserted-by":"crossref","first-page":"615","DOI":"10.3389\/fnins.2019.00615","article-title":"Overexpression of a neuronal type adenylyl cyclase (type 8) in sinoatrial node markedly impacts heart rate and rhythm","volume":"13","author":"Moen","year":"2019","journal-title":"Front Neurosci"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib102","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1016\/j.yjmcc.2009.08.023","article-title":"Structural remodelling of the sinoatrial node in obese old rats","volume":"48","author":"Yanni","year":"2010","journal-title":"J Mol Cell Cardiol"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib103","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1161\/CIRCEP.110.960807","article-title":"TGF-\u03b21-mediated fibrosis and ion channel remodeling are key mechanisms in producing the sinus node dysfunction associated with SCN5A deficiency and aging","volume":"4","author":"Hao","year":"2011","journal-title":"Circ Arrhythm Electrophysiol"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib104","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s00395-007-0660-5","article-title":"Age-related down-regulation of HCN channels in rat sinoatrial node","volume":"102","author":"Huang","year":"2007","journal-title":"Basic Res Cardiol"},{"issue":"10","key":"10.1016\/j.hlc.2025.04.084_bib105","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1161\/CIRCULATIONAHA.106.663070","article-title":"Declining into failure: the age-dependent loss of the L-type calcium channel within the sinoatrial node","volume":"115","author":"Jones","year":"2007","journal-title":"Circulation"},{"issue":"10","key":"10.1016\/j.hlc.2025.04.084_bib106","doi-asserted-by":"crossref","first-page":"H1385","DOI":"10.1152\/ajpheart.00088.2014","article-title":"Age-associated abnormalities of intrinsic automaticity of sinoatrial nodal cells are linked to deficient cAMP-PKA-Ca(2+) signaling","volume":"306","author":"Liu","year":"2014","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"12","key":"10.1016\/j.hlc.2025.04.084_bib107","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1161\/01.RES.0000251717.98379.69","article-title":"Differential expression of ion channel transcripts in atrial muscle and sinoatrial node in rabbit","volume":"99","author":"Tellez","year":"2006","journal-title":"Circ Res"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib108","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1007\/s11357-022-00609-0","article-title":"Changes in cAMP signaling are associated with age-related downregulation of spontaneously beating atrial tissue energetic indices","volume":"45","author":"Kirschner Peretz","year":"2023","journal-title":"Geroscience"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib109","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s00395-012-0279-z","article-title":"Constitutive phosphorylation of inhibitor-1 at Ser67 and Thr75 depresses calcium cycling in cardiomyocytes and leads to remodeling upon aging","volume":"107","author":"Florea","year":"2012","journal-title":"Basic Res Cardiol"},{"issue":"11","key":"10.1016\/j.hlc.2025.04.084_bib110","doi-asserted-by":"crossref","first-page":"1576","DOI":"10.1093\/cvr\/cvz112","article-title":"Complexities in cardiovascular rhythmicity: perspectives on circadian normality, ageing and disease","volume":"115","author":"Monfredi","year":"2019","journal-title":"Cardiovasc Res"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib111","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/0022-2828(78)90364-4","article-title":"Studies of sarcoplasmic reticulum function and contraction duration in young adult and aged rat myocardium","volume":"10","author":"Froehlich","year":"1978","journal-title":"J Mol Cell Cardiol"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib112","doi-asserted-by":"crossref","first-page":"453","DOI":"10.33549\/physiolres.932320","article-title":"Age-associated changes in Ca(2+)-ATPase and oxidative damage in sarcoplasmic reticulum of rat heart","volume":"61","author":"Babu\u0161\u00edkov\u00e1","year":"2012","journal-title":"Physiol Res"},{"issue":"5","key":"10.1016\/j.hlc.2025.04.084_bib113","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1172\/JCI117559","article-title":"Age-associated changes in beta-adrenergic modulation on rat cardiac excitation-contraction coupling","volume":"94","author":"Xiao","year":"1994","journal-title":"J Clin Invest"},{"issue":"4","key":"10.1016\/j.hlc.2025.04.084_bib114","first-page":"H501","article-title":"Contractile and biochemical correlates of beta-adrenergic stimulation of the aged heart","volume":"239","author":"Guarnieri","year":"1980","journal-title":"Am J Physiol"},{"issue":"1","key":"10.1016\/j.hlc.2025.04.084_bib115","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1161\/01.CIR.0000048892.83521.58","article-title":"Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a \"set up\" for vascular disease","volume":"107","author":"Lakatta","year":"2003","journal-title":"Circulation"},{"issue":"3","key":"10.1016\/j.hlc.2025.04.084_bib116","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1161\/01.CIR.0000048894.99865.02","article-title":"Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part III: cellular and molecular clues to heart and arterial aging","volume":"107","author":"Lakatta","year":"2003","journal-title":"Circulation"},{"issue":"9","key":"10.1016\/j.hlc.2025.04.084_bib117","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1038\/s41569-018-0068-y","article-title":"The reality of getting old","volume":"15","author":"Lakatta","year":"2018","journal-title":"Nat Rev Cardiol"},{"key":"10.1016\/j.hlc.2025.04.084_bib118","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1038\/nmeth.4305","article-title":"Fast high-resolution miniature two-photon microscopy for brain imaging in freely behaving mice","volume":"14","author":"Zong","year":"2017","journal-title":"Nat Methods"}],"container-title":["Heart, Lung and Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1443950625003245?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S1443950625003245?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,8,22]],"date-time":"2025-08-22T22:55:41Z","timestamp":1755903341000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S1443950625003245"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6]]},"references-count":118,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2025,6]]}},"alternative-id":["S1443950625003245"],"URL":"https:\/\/doi.org\/10.1016\/j.hlc.2025.04.084","relation":{},"ISSN":["1443-9506"],"issn-type":[{"value":"1443-9506","type":"print"}],"subject":[],"published":{"date-parts":[[2025,6]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Heart Rhythm Harmony Becomes Discordant as We Age","name":"articletitle","label":"Article Title"},{"value":"Heart, Lung and Circulation","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.hlc.2025.04.084","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"Published by Elsevier B.V. on behalf of Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ).","name":"copyright","label":"Copyright"}]}}