Resting heart rate and heart rate variability in cardiovascular aging: Biomarkers and potential therapeutic targets

Resting heart rate and heart rate variability in cardiovascular aging: Biomarkers and potential therapeutic targets

Weiguo Zhang
*Correspondence to: Weiguo Zhang, Las Colinas Institutes, Irving, TX 75039, USA. E-mail: weiguozha@yahoo.com
Geromedicine. 2026;2:202617. 10.70401/Geromedicine.2026.0028
Received: March 24, 2026Accepted: June 29, 2026Published: June 29, 2026
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This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

Cardiovascular aging is characterized by progressive loss of regulatory capacity, reduced physiological reserve, and increased vulnerability to stress and disease. Resting heart rate (RHR) and heart rate variability (HRV) provide complementary measures of cardiac automaticity and autonomic regulation, capturing important dimensions of cardiovascular aging. Comparative and epidemiological evidence demonstrates that elevated RHR and reduced HRV predict morbidity and mortality across species and human populations, reflecting cumulative physiological stress and declining regulatory function. Biological pathways associated with these autonomic phenotypes include sympathetic overactivation, parasympathetic withdrawal, neuroendocrine dysregulation, impaired baroreflex function, chronic inflammation, oxidative stress, and mitochondrial dysfunction. Clinical and mechanistic studies indicate that behavioral interventions (e.g., exercise and dietary modulation), pharmacological therapies, and neuromodulatory approaches can favorably influence RHR and HRV, although their causal effects on aging trajectories remain uncertain. Recent advances in wearable technologies and machine-learning-based phenotyping enable continuous assessment of autonomic function in both research and real-world settings. Integrating RHR and HRV into geroscience frameworks may help link autonomic regulation with fundamental aging mechanisms and cardiovascular risk. As accessible, noninvasive measures of physiological resilience and adaptability, RHR and HRV have potential value for advancing precision approaches to healthy cardiovascular aging and longevity.

Keywords

Autonomic nervous system, cardiovascular aging, cardiovascular outcomes, heart rate variability, resting heart rate, risk factors

References

  • 1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243-278.
    [DOI]
  • 2. Zhao Y, Chen P, Zhang Y, Huo S, Yu D, Zeng X, et al. Heart rate variability and its modulation by nutrients: A narrative review on implications for cardiovascular aging. Front Neurosci. 2025;19:1654796.
    [DOI] [PubMed] [PMC]
  • 3. Arakaki X, Arechavala RJ, Choy EH, Bautista J, Bliss B, Molloy C, et al. The connection between heart rate variability (HRV), neurological health, and cognition: A literature review. Front Neurosci. 2023;17:1055445.
    [DOI] [PubMed] [PMC]
  • 4. Zhang W. Chronotropic effects and mechanisms of long-chain omega-3 polyunsaturated fatty acids on heartbeat: the latest insights. Nutr Rev. 2021;80(1):128-135.
    [DOI] [PubMed]
  • 5. Gibbons CH. Basics of autonomic nervous system function. In: Handb clin neurol. Amsterdam: Elsevier; 2019. p. 160:407-418.
    [DOI]
  • 6. Fajemiroye JO, da Cunha LC, Saavedra-Rodríguez R, Rodrigues KL, Naves LM, Mourão AA, et al. Aging-induced biological changes and cardiovascular diseases. BioMed Res Int. 2018;2018(1):7156435.
    [DOI]
  • 7. Zhang GQ, Zhang W. Heart rate, lifespan, and mortality risk. Ageing Res Rev. 2009;8(1):52-60.
    [DOI]
  • 8. Olshansky B, Ricci F, Fedorowski A. Importance of resting heart rate. Trends Cardiovasc Med. 2023;33(8):502-515.
    [DOI]
  • 9. Levine HJ. Rest heart rate and life expectancy. J Am Coll Cardiol. 1997;30(4):1104-1106.
    [DOI]
  • 10. Lindstedt SL, Calder WA III. Body size, physiological time, and longevity of homeothermic animals. Q Rev Biol. 1981;56(1):1-16.
    [DOI]
  • 11. Cook S, Togni M, Schaub MC, Wenaweser P, Hess OM. High heart rate: A cardiovascular risk factor? Eur Heart J. 2006;27(20):2387-2393.
    [DOI]
  • 12. Zhang QG. Hypertension and counter-hypertension mechanisms in giraffes. Cardiovasc Hematol Disord Drug Targets. 2006;6(1):63-67.
    [DOI] [PubMed]
  • 13. Hulbert AJ, Pamplona R, Buffenstein R, Buttemer WA. Life and death: metabolic rate, membrane composition, and life span of animals. Physiol Rev. 2007;87(4):1175-1213.
    [DOI] [PubMed]
  • 14. Calder WA. Size, function, and life history. North Chelmsford: Courier Corporation; 1996. Available from: https://books.google.com/books/about/Size_Function_and_Life_History.html?id=-iBS6-2OO3wC
  • 15. Healy K, Guillerme T, Finlay S, Kane A, Kelly SB, McClean D, et al. Ecology and mode-of-life explain lifespan variation in birds and mammals. Proc Biol Sci. 2014;281(1784):20140298.
    [DOI] [PubMed] [PMC]
  • 16. Speakman JR. Body size, energy metabolism and lifespan. J Exp Biol. 2005;208(9):1717-1730.
    [DOI]
  • 17. Schmidt-Nielsen K. Scaling: Why is animal size so important? New York: Cambridge University Press; 1984. Available from: https://academic.oup.com/auk/article-abstract/102/3/661/5191417?redirectedFrom=fulltext
  • 18. Sidhu S, Marine JE. Evaluating and managing bradycardia. Trends Cardiovasc Med. 2020;30(5):265-272.
    [DOI]
  • 19. Kannel WB, Kannel C, Paffenbarger RSJ, Cupples LA. Heart rate and cardiovascular mortality: The Framingham study. Am Heart J. 1987;113(6):1489-1494.
    [DOI]
  • 20. Wulsin LR, Horn PS, Perry JL, Massaro JM, D’Agostino RB. Autonomic imbalance as a predictor of metabolic risks, cardiovascular disease, diabetes, and mortality. J Clin Endocrinol Metab. 2015;100(6):2443-2448.
    [DOI]
  • 21. Dyer AR, Persky V, Stamler J, Paul O, Shekelle RB, Berkson DM, et al. Heart rate as a prognostic factor for coronary heart disease and mortality: Findings in three Chicago epidemiologic studies. Am J Epidemiol. 1980;112(6):736-749.
    [DOI] [PubMed]
  • 22. Gillum RF, Makuc DM, Feldman JJ. Pulse rate, coronary heart disease, and death: The NHANES I Epidemiologic Follow-up Study. Am Heart J. 1991;121(1):172-177.
    [DOI]
  • 23. Benetos A, Rudnichi A, Thomas F, Safar M, Guize L. Influence of heart rate on mortality in a French population: Role of age, gender, and blood pressure. Hypertension. 1999;33(1):44-52.
    [DOI]
  • 24. Jouven X, Empana JP, Schwartz PJ, Desnos M, Courbon D, Ducimetière P. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med. 2005;352(19):1951-1958.
    [DOI] [PubMed]
  • 25. Cooney MT, Vartiainen E, Laakitainen T, Juolevi A, Dudina A, Graham IM. Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women. Am Heart J. 2010;159(4):612-619.e3.
    [DOI]
  • 26. Chen XJ, Barywani SB, Hansson PO, Östgärd Thunström E, Rosengren A, Ergatoudes C, et al. Impact of changes in heart rate with age on all-cause death and cardiovascular events in 50-year-old men from the general population. Open Heart. 2019;6(1):e000856.
    [PubMed] [PMC]
  • 27. Wang A, Chen S, Wang C, Zhou Y, Wu Y, Xing A, et al. Resting heart rate and risk of cardiovascular diseases and all-cause death: The Kailuan study. PLoS One. 2014;9(10):e110985.
    [DOI] [PubMed] [PMC]
  • 28. Okamura T, Hayakawa T, Kadowaki T, Kita Y, Okayama A, Elliott P, et al. Resting heart rate and cause-specific death in a 16.5-year cohort study of the Japanese general population. Am Heart J. 2004;147(6):1024-1032.
    [DOI]
  • 29. Choi Y, Kim G, Yoon J, Kim YS. Association of resting heart rate and physical activity with cardiovascular mortality: A population-based cohort study of Korean adults. J Sports Sci. 2024;42(16):1529-1537.
    [DOI] [PubMed]
  • 30. Wen CP, Chen CH, Nauman J, Wai JPM, Tsai MK, Lee JH, et al. Resting heart rate–The forgotten risk factor? Comparison of resting heart rate and hypertension as predictors of all-cause mortality in 692, 217 adults in Asia and Europe. Prog Cardiovasc Dis. 2025;89:35-44.
    [DOI]
  • 31. Jiang X, Liu X, Wu S, Zhang GQ, Peng M, Wu Y, et al. Metabolic syndrome is associated with and predicted by resting heart rate: A cross-sectional and longitudinal study. Heart. 2015;101(1):44-49.
    [DOI] [PubMed]
  • 32. Wang Y, Yin L, Hu B, Tse LA, Liu Y, Ma H, et al. Association of heart rate with cardiovascular events and mortality in hypertensive and normotensive population: A nationwide prospective cohort study. Ann Transl Med. 2021;9(11):917.
    [DOI] [PubMed] [PMC]
  • 33. Jensen MT, Marott JL, Allin KH, Nordestgaard BG, Jensen GB. Resting heart rate is associated with cardiovascular and all-cause mortality after adjusting for inflammatory markers: The Copenhagen City Heart Study. Eur J Prev Cardiol. 2012;19(1):102-108.
    [DOI] [PubMed]
  • 34. Ho JE, Larson MG, Ghorbani A, Cheng S, Coglianese EE, Vasan RS, et al. Long-term cardiovascular risks associated with an elevated heart rate: The Framingham heart study. JAHA. 2014;3(3):e000668.
    [DOI]
  • 35. Seviiri M, Lynch BM, Hodge AM, Yang Y, Liew D, English DR, et al. Resting heart rate, temporal changes in resting heart rate, and overall and cause-specific mortality. Heart. 2018;104(13):1076-1085.
    [DOI] [PubMed]
  • 36. Abhishekh HA, Nisarga P, Kisan R, Meghana A, Chandran S, Raju T, et al. Influence of age and gender on autonomic regulation of heart. J Clin Monit Comput. 2013;27(3):259-264.
    [DOI]
  • 37. Fox K, Borer JS, Camm AJ, Danchin N, Ferrari R, Sendon JLL, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50(9):823-830.
    [DOI]
  • 38. Zhang D, Shen X, Qi X. Resting heart rate and all-cause and cardiovascular mortality in the general population: A meta-analysis. CMAJ. 2016;188(3):E53-E63.
    [DOI] [PubMed] [PMC]
  • 39. Palatini P. Heart rate as an independent risk factor for cardiovascular disease. Drugs. 2007;67(2):3-13.
    [DOI]
  • 40. Lonn EM, Rambihar S, Gao P, Custodis FF, Sliwa K, Teo KK, et al. Heart rate is associated with increased risk of major cardiovascular events, cardiovascular and all-cause death in patients with stable chronic cardiovascular disease: An analysis of ONTARGET/TRANSCEND. Clin Res Cardiol. 2014;103(2):149-159.
    [DOI] [PubMed]
  • 41. Zhang D, Wang W, Li F. Association between resting heart rate and coronary artery disease, stroke, sudden death and noncardiovascular diseases: A meta-analysis. CMAJ. 2016;188(15):E384-E392.
    [DOI]
  • 42. Fox K, Ford I, Steg PG, Tendera M, Ferrari R. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): A randomised, double-blind, placebo-controlled trial. Lancet. 2008;372(9641):807-816.
    [DOI] [PubMed]
  • 43. DiFrancesco D, Camm JA. Heart rate lowering by specific and selective If current inhibition with ivabradine: A new therapeutic perspective in cardiovascular disease. Drugs. 2004;64(16):1757-1765.
    [DOI] [PubMed]
  • 44. Palatini P, Thijs L, Staessen JA, Fagard RH, Bulpitt CJ, Clement DL, et al. Predictive value of clinic and ambulatory heart rate for mortality in elderly subjects with systolic hypertension. Arch Intern Med. 2002;162(20):2313-2321.
    [DOI] [PubMed]
  • 45. Kolloch R, Legler UF, Champion A, Cooper-Dehoff RM, Handberg E, Zhou Q, et al. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: Findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eur Heart J. 2008;29(10):1327-1334.
    [DOI] [PubMed] [PMC]
  • 46. Zhang W. Can we use calcium antagonist better in antihypertensive therapy? Circadian consideration. Pharmacol Res. 1996;34(5-6):187-191.
    [DOI]
  • 47. Zhang W, Wang Z. Resetting baroreceptors to a lower arterial pressure level by enalapril avoids baroreflex mediated activation of sympathetic nervous system by nifedipine. Life Sci. 2001;68(25):2769-2779.
    [DOI] [PubMed]
  • 48. Böhm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, et al. Heart rate as a risk factor in chronic heart failure (SHIFT): The association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet. 2010;376(9744):886-894.
    [DOI]
  • 49. Hillis GS, Woodward M, Rodgers A, Chow CK, Li Q, Zoungas S, et al. Resting heart rate and the risk of death and cardiovascular complications in patients with type 2 diabetes mellitus. Diabetologia. 2012;55(5):1283-1290.
    [DOI]
  • 50. Saito H, Tanaka K, Ejiri H, Kimura H, Shimabukuro M, Asahi K, et al. Elevated resting heart rate is associated with mortality in patients with chronic kidney disease. Sci Rep. 2024;14:17372.
    [DOI]
  • 51. Jensen MT, Pereira M, Araujo C, Malmivaara A, Ferrieres J, Degano IR, et al. Heart rate at admission is a predictor of in-hospital mortality in patients with acute coronary syndromes: Results from 58 European hospitals: The European Hospital Benchmarking by Outcomes in acute coronary syndrome Processes study. Eur Heart J Acute Cardiovasc Care. 2018;7(2):149-157.
    [DOI] [PubMed]
  • 52. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: Principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113(9):1213-1225.
    [DOI] [PubMed]
  • 53. Gazzaniga G, Menichelli D, Scaglione F, Farcomeni A, Pani A, Pastori D. Effect of digoxin on all-cause and cardiovascular mortality in patients with atrial fibrillation with and without heart failure: An umbrella review of systematic reviews and 12 meta-analyses. Eur J Clin Pharmacol. 2023;79(4):473-483.
    [DOI] [PubMed] [PMC]
  • 54. Quinn TA, Kohl P. Cardiac mechano-electric coupling: Acute effects of mechanical stimulation on heart rate and rhythm. Physiol Rev. 2021;101(1):37-92.
    [DOI] [PubMed]
  • 55. Al-Rashed F, Sindhu S, Al Madhoun A, Ahmad Z, AlMekhled D, Azim R, et al. Elevated resting heart rate as a predictor of inflammation and cardiovascular risk in healthy obese individuals. Sci Rep. 2021;11:13883.
    [DOI]
  • 56. Lakatta EG, Levy D. Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part II: The aging heart in health: Links to heart disease. Circulation. 2003;107(2):346-354.
    [DOI] [PubMed]
  • 57. Thayer JF, Lane RD. Claude Bernard and the heart–brain connection: Further elaboration of a model of neurovisceral integration. Neurosci Biobehav Rev. 2009;33(2):81-88.
    [DOI]
  • 58. Junior EC, Oliveira FM. Attenuation of vagal modulation with aging: Univariate and bivariate analysis of HRV. Annu Int Conf IEEE Eng Med Biol Soc. 2017;2017:3178-3181.
    [DOI] [PubMed]
  • 59. Tanaka H, Monahan KD, Seals DR. Age-predicted maximal heart rate revisited. J Am Coll Cardiol. 2001;37(1):153-156.
    [DOI]
  • 60. Michael S, Graham KS, Davis GMO. Cardiac autonomic responses during exercise and post-exercise recovery using heart rate variability and systolic time intervals-a review. Front Physiol. 2017;8:301.
    [DOI] [PubMed] [PMC]
  • 61. Zhang W, Huang BS, Leenen FHH. Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction. Am J Physiol Heart Circ Physiol. 1999;276(5):H1608-H1615.
    [DOI]
  • 62. Tuncel M, Augustyniak R, Zhang W, Toto RD, Victor RG. Sympathetic nervous system function in renal hypertension. Curr Hypertens Rep. 2002;4(3):229-236.
    [DOI]
  • 63. Herzog MJ, Müller P, Lechner K, Stiebler M, Arndt P, Kunz M, et al. Arterial stiffness and vascular aging: Mechanisms, prevention, and therapy. Sig Transduct Target Ther. 2025;10:282.
    [DOI]
  • 64. Zhang W, Thorén P. Hyper-responsiveness of adrenal sympathetic nerve activity in spontaneously hypertensive rats to ganglionic blockade, mental stress and neuronglucopenia. Pflugers Arch. 1998;437(1):56-60.
    [DOI] [PubMed]
  • 65. Parker HW, Abreu AM, Sullivan MC, Vadiveloo MK. Allostatic load and mortality: A systematic review and meta-analysis. Am J Prev Med. 2022;63(1):131-140.
    [DOI] [PubMed]
  • 66. Jeong EM, Liu M, Sturdy M, Gao G, Varghese ST, Sovari AA, et al. Metabolic stress, reactive oxygen species, and arrhythmia. J Mol Cell Cardiol. 2012;52(2):454-463.
    [DOI]
  • 67. North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res. 2012;110(8):1097-1108.
    [DOI]
  • 68. Whelton SP, Narla V, Blaha MJ, Nasir K, Blumenthal RS, Jenny NS, et al. Association between resting heart rate and inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin-6, and fibrinogen) (from the Multi-Ethnic Study of Atherosclerosis). Am J Cardiol. 2014;113(4):644-649.
    [DOI] [PubMed] [PMC]
  • 69. Sajadieh A, Nielsen OW, Rasmussen V, Hein HO, Abedini S, Hansen JF. Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J. 2004;25(5):363-370.
    [DOI] [PubMed]
  • 70. Giunta S, Xia S, Pelliccioni G, Olivieri F. Autonomic nervous system imbalance during aging contributes to impair endogenous anti-inflammaging strategies. Geroscience. 2024;46(1):113-127.
    [DOI] [PubMed] [PMC]
  • 71. Jensen MT. Resting heart rate and relation to disease and longevity: Past, present and future. Scand J Clin Lab Invest. 2019;79(1-2):108-116.
    [DOI] [PubMed]
  • 72. Giannoglou GD, Chatzizisis YS, Zamboulis C, Parcharidis GE, Mikhailidis DP, Louridas GE. Elevated heart rate and atherosclerosis: An overview of the pathogenetic mechanisms. Int J Cardiol. 2008;126(3):302-312.
    [DOI] [PubMed]
  • 73. Opthof T. The normal range and determinants of the intrinsic heart rate in man. Cardiovasc Res. 2000;45(1):177-184.
    [DOI]
  • 74. Steenman M, Lande G. Cardiac aging and heart disease in humans. Biophys Rev. 2017;9(2):131-137.
    [DOI]
  • 75. Ribeiro ASF, Zerolo BE, López-Espuela F, Sánchez R, Fernandes VS. Cardiac system during the aging process. Aging Dis. 2023;14(4):1105.
    [DOI]
  • 76. Dun W, Boyden PA. Aged atria: Electrical remodeling conducive to atrial fibrillation. J Interv Card Electrophysiol. 2009;25(1):9-18.
    [DOI] [PubMed] [PMC]
  • 77. Palatini P. Need for a revision of the normal limits of resting heart rate. Hypertension. 1999;33(2):622-625.
    [DOI] [PubMed]
  • 78. Nanchen D. Resting heart rate: What is normal? Heart. 2018;104(13):1048-1049.
    [DOI]
  • 79. Billman GE, Huikuri HV, Sacha J, Trimmel K. An introduction to heart rate variability: Methodological considerations and clinical applications. Front Physiol. 2015;6:55.
    [DOI] [PubMed] [PMC]
  • 80. Hon EH, Lee ST. Electronic evaluation of the fetal heart rate. VIII. Am J Obstet Gynecol. 1963;87:814-826.
    [PubMed]
  • 81. Brockmann L, Hunt KJ. Heart rate variability changes with respect to time and exercise intensity during heart-rate-controlled steady-state treadmill running. Sci Rep. 2023;13(1):8515.
    [DOI] [PubMed] [PMC]
  • 82. Eckstein ML, Brockfeld A, Haupt S, Schierbauer JR, Zimmer RT, Wachsmuth NB, et al. Acute changes in heart rate variability to glucose and fructose supplementation in healthy individuals: A double-blind randomized crossover placebo-controlled trial. Biology. 2022;11(2):338.
    [DOI] [PubMed] [PMC]
  • 83. Umetani K, Singer DH, McCraty R, Atkinson M. Twenty-four hour time domain heart rate variability and heart rate: Relations to age and gender over nine decades. J Am Coll Cardiol. 1998;31(3):593-601.
    [DOI] [PubMed]
  • 84. Liao D, Cai J, Rosamond WD, Barnes RW, Hutchinson RG, Whitsel EA, et al. Cardiac autonomic function and incident coronary heart disease: A population-based case-cohort study. The ARIC Study. Am J Epidemiol. 1997;145(8):696-706.
    [DOI] [PubMed]
  • 85. Antelmi I, De Paula RS, Shinzato AR, Peres CA, Mansur AJ, Grupi CJ. Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease. Am J Cardiol. 2004;93(3):381-385.
    [DOI]
  • 86. Tsuji H, Larson MG, Venditti FJ, Manders ES, Evans JC, Feldman CL, et al. Impact of reduced heart rate variability on risk for cardiac events: The Framingham heart study. Circulation. 1996;94(11):2850-2855.
    [DOI]
  • 87. Tsuji H, Venditti FJ, Manders ES, Evans JC, Larson MG, Feldman CL, et al. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation. 1994;90(2):878-883.
    [DOI]
  • 88. Dekker JM, Schouten EG, Klootwijk P, Pool J, Swenne CA, Kromhout D. Heart rate variability from short electrocardiographic recordings predicts mortality from all causes in middle-aged and elderly men. The Zutphen Study. Am J Epidemiol. 1997;145(10):899-908.
    [DOI] [PubMed]
  • 89. Dekker JM, Crow RS, Folsom AR, Hannan PJ, Liao D, Swenne CA, et al. Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes: The ARIC study. Circulation. 2000;102(11):1239-1244.
    [DOI]
  • 90. Greiser KH, Kluttig A, Schumann B, Swenne CA, Kors JA, Kuss O, et al. Cardiovascular diseases, risk factors and short-term heart rate variability in an elderly general population: The CARLA study 2002–2006. Eur J Epidemiol. 2009;24(3):123-142.
    [DOI]
  • 91. de Bruyne MC, Kors JA, Hoes AW, Klootwijk P, Dekker JM, Hofman A, et al. Both decreased and increased heart rate variability on the standard 10-second electrocardiogram predict cardiac mortality in the elderly: The Rotterdam Study. Am J Epidemiol. 1999;150(12):1282-1288.
    [DOI] [PubMed]
  • 92. Jiang Y, Yabluchanskiy A, Deng J, Amil FA, Po SS, Dasari TW. The role of age-associated autonomic dysfunction in inflammation and endothelial dysfunction. Geroscience. 2022;44(6):2655-2670.
    [DOI] [PubMed] [PMC]
  • 93. Kleiger RE, Miller JP, Bigger JT, Moss AJ. Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol. 1987;59(4):256-262.
    [DOI]
  • 94. Bigger JTJ, Fleiss JL, Steinman RC, Rolnitzky LM, Kleiger RE, Rottman JN. Frequency domain measures of heart period variability and mortality after myocardial infarction. Circulation. 1992;85(1):164-171.
    [DOI]
  • 95. La Rovere MT, Bigger JTJ, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet. 1998;351(9101):478-484.
    [DOI] [PubMed]
  • 96. Grassi G, Drager LF. Sympathetic overactivity, hypertension and cardiovascular disease: State of the art. Curr Med Res Opin. 2024;40:5-13.
    [DOI] [PubMed]
  • 97. Thayer JF, Yamamoto SS, Brosschot JF. The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol. 2010;141(2):122-131.
    [DOI]
  • 98. Nolan J, Batin PD, Andrews R, Lindsay SJ, Brooksby P, Mullen M, et al. Prospective study of heart rate variability and mortality in chronic heart failure: Results of the United Kingdom heart failure evaluation and assessment of risk trial (UK-heart). Circulation. 1998;98(15):1510-1516.
    [DOI] [PubMed]
  • 99. Benichou T, Pereira B, Mermillod M, Tauveron I, Pfabigan D, Maqdasy S, et al. Heart rate variability in type 2 diabetes mellitus: A systematic review and meta–analysis. PLoS One. 2018;13(4):e0195166.
    [DOI]
  • 100. Duque A, Mediano MFF, De Lorenzo A, Rodrigues LF. Cardiovascular autonomic neuropathy in diabetes: Pathophysiology, clinical assessment and implications. World J Diabetes. 2021;12(6):855-867.
    [DOI]
  • 101. Chowdhury M, Nevitt S, Eleftheriadou A, Kanagala P, Esa H, Cuthbertson DJ, et al. Cardiac autonomic neuropathy and risk of cardiovascular disease and mortality in type 1 and type 2 diabetes: A meta-analysis. BMJ Open Diabetes Res Care. 2021;9(2):e002480.
    [DOI] [PubMed] [PMC]
  • 102. Drawz PE, Babineau DC, Brecklin C, He J, Kallem RR, Soliman EZ, et al. Heart rate variability is a predictor of mortality in chronic kidney disease: A report from the CRIC Study. Am J Nephrol. 2013;38(6):517-528.
    [DOI] [PubMed] [PMC]
  • 103. Yugar LBT, Yugar-Toledo JC, Dinamarco N, Sedenho-Prado LG, Moreno BVD, Rubio TA, et al. The role of heart rate variability (HRV) in different hypertensive syndromes. Diagnostics. 2023;13(4):785.
    [DOI] [PubMed] [PMC]
  • 104. Hämmerle P, Eick C, Blum S, Schlageter V, Bauer A, Rizas KD, et al. Heart rate variability triangular index as a predictor of cardiovascular mortality in patients with atrial fibrillation. J Am Heart Assoc. 2020;9(15):e016075.
    [DOI] [PubMed] [PMC]
  • 105. Lees T, Shad-Kaneez F, Simpson AM, Nassif NT, Lin Y, Lal S. Heart rate variability as a biomarker for predicting stroke, post-stroke complications and functionality. Biomark Insights. 2018;13:1177271918786931.
    [DOI] [PubMed] [PMC]
  • 106. Saleem S, Khandoker AH, Alkhodari M, Hadjileontiadis LJ, Jelinek HF. Investigating the effects of beta-blockers on circadian heart rhythm using heart rate variability in ischemic heart disease with preserved ejection fraction. Sci Rep. 2023;13(1):5828.
    [DOI] [PubMed] [PMC]
  • 107. Amekran Y, El hangouche AJ. Effects of exercise training on heart rate variability in healthy adults: A systematic review and meta-analysis of randomized controlled trials. Cureus. 2024;16(6):e62465.
    [DOI]
  • 108. Deng Y, Zeng X, Tang C, Hou X, Zhang Y, Shi L. The effect of exercise training on heart rate variability in patients with hypertension: A systematic review and meta-analysis. J Sports Sci. 2024;42(13):1272-1287.
    [DOI] [PubMed]
  • 109. Schmaußer M, Hoffmann S, Raab M, Laborde S. The effects of noninvasive brain stimulation on heart rate and heart rate variability: A systematic review and meta-analysis. J Neurosci Res. 2022;100(9):1664-1694.
    [DOI] [PubMed]
  • 110. Polito R, Valenzano A, Monda V, Cibelli G, Monda M, Messina G, et al. Heart rate variability and sympathetic activity is modulated by very low-calorie ketogenic diet. Int J Environ Res Public Health. 2022;19(4):2253.
    [DOI] [PubMed] [PMC]
  • 111. De Meersman RE, Stein PK. Vagal modulation and aging. Biol Psychol. 2007;74(2):165-173.
    [DOI]
  • 112. Wolf V, Kühnel A, Teckentrup V, Koenig J, Kroemer NB. Does transcutaneous auricular vagus nerve stimulation affect vagally mediated heart rate variability? A living and interactive Bayesian meta-analysis. Psychophysiology. 2021;58(11):e13933.
    [DOI] [PubMed]
  • 113. Zhang W, Gan D, Huo S, Chen P. Unraveling the discrepancies between REDUCE-IT and STRENGTH trials with omega-3 fatty acids: New analytical approaches. Front Nutr. 2024;11:1490953.
    [DOI] [PubMed] [PMC]
  • 114. Wang BX, Brennand E, Le Page P, Mitchell ARJ. Heart rate variability in cardiovascular disease diagnosis, prognosis and management. Front Cardiovasc Med. 2026;12:1680783.
    [DOI]
  • 115. Monahan KD. Effect of aging on baroreflex function in humans. Am J Physiol Regul Integr Comp Physiol. 2007;293(1):R3-R12.
    [DOI]
  • 116. Elia A, Cannavo A, Gambino G, Cimini M, Ferrara N, Kishore R, et al. Aging is associated with cardiac autonomic nerve fiber depletion and reduced cardiac and circulating BDNF levels. J Geriatr Cardiol. 2021;18(7):549-559.
    [DOI] [PubMed] [PMC]
  • 117. Luu N, Bajpai A, Li R, Park S, Noor M, Ma X, et al. Aging-associated decline in vascular smooth muscle cell mechanosensation is mediated by Piezo1 channel. Aging Cell. 2024;23(2):e14036.
    [DOI] [PubMed] [PMC]
  • 118. Mesquita T, Miguel-Dos-Santos R, Cingolani E. Aging and sinus node dysfunction: Mechanisms and future directions. Clin Sci. 2025;139(11):577-593.
    [DOI] [PubMed] [PMC]
  • 119. Paniccia M, Paniccia D, Thomas S, Taha T, Reed N. Clinical and non-clinical depression and anxiety in young people: A scoping review on heart rate variability. Auton Neurosci. 2017;208:1-14.
    [DOI]
  • 120. Civieri G, Abohashem S, Grewal SS, Aldosoky W, Qamar I, Hanlon E, et al. Anxiety and depression associated with increased cardiovascular disease risk through accelerated development of risk factors. JACC Adv. 2024;3(9):101208.
    [DOI]
  • 121. Gao X, Geng T, Jiang M, Huang N, Zheng Y, Belsky DW, et al. Accelerated biological aging and risk of depression and anxiety: Evidence from 424, 299 UK Biobank participants. Nat Commun. 2023;14:2277.
    [DOI]
  • 122. Mueller B, Figueroa A, Robinson-Papp J. Structural and functional connections between the autonomic nervous system, hypothalamic-pituitary-adrenal axis, and the immune system: A context and time dependent stress response network. Neurol Sci. 2022;43(2):951-960.
    [DOI] [PubMed]
  • 123. Solano-Atehortua JM, Castrillón G, Suarez-Revelo JX, Sánchez-López JD, Vargas-Tejada DA, Valentina HC, et al. Linking allostatic load, heart rate variability and brain functional networks and structures in healthy men. Psychoneuroendocrinology. 2026;186:107759.
    [DOI] [PubMed]
  • 124. López-Otín C, Kroemer G. Hallmarks of aging: Integrating molecular and social determinants. Geromedicine. 2025;1(1):202507.
    [DOI]
  • 125. Olivieri F, Biscetti L, Pimpini L, Pelliccioni G, Sabbatinelli J, Giunta S. Heart rate variability and autonomic nervous system imbalance: Potential biomarkers and detectable hallmarks of aging and inflammaging. Ageing Res Rev. 2024;101:102521.
    [DOI] [PubMed]
  • 126. Baechle JJ, Chen N, Makhijani P, Winer S, Furman D, Winer DA. Chronic inflammation and the hallmarks of aging. Mol Metab. 2023;74:101755.
    [DOI]
  • 127. Yelisyeyeva O, Kaminskyy D, Semen M, Chelpanova I, Semen KO. Redox metabolism and autonomic regulation during aging: Can heart rate variability be used to monitor healthy longevity? Biomedicines. 2025;13(1):161.
    [DOI] [PubMed] [PMC]
  • 128. Johnston GR, Webster NR. Cytokines and the immunomodulatory function of the vagus nerve. Br J Anaesth. 2009;102(4):453-462.
    [DOI]
  • 129. Huston JM, Tracey KJ. The pulse of inflammation: Heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J Intern Med. 2011;269(1):45-53.
    [DOI]
  • 130. Haensel A, Mills PJ, Nelesen RA, Ziegler MG, Dimsdale JE. The relationship between heart rate variability and inflammatory markers in cardiovascular diseases. Psychoneuroendocrinology. 2008;33(10):1305-1312.
    [DOI]
  • 131. Williams DP, Koenig J, Carnevali L, Sgoifo A, Jarczok MN, Sternberg EM, et al. Heart rate variability and inflammation: A meta-analysis of human studies. Brain Behav Immun. 2019;80:219-226.
    [DOI]
  • 132. Augustyniak R, Thomas G, Victor R, Zhang W. Nitric oxide pathway as new drug targets for refractory hypertension. Curr Pharm Des. 2005;11(25):3307-3315.
    [DOI]
  • 133. Augustyniak RA, Victor RG, Morgan DA, Zhang W. L-NAME- and ADMA-induced sympathetic neural activation in conscious rats. Am J Physiol Regul Integr Comp Physiol. 2006;290(3):R726-R732.
    [DOI] [PubMed]
  • 134. Hirooka Y, Kishi T, Sakai K, Takeshita A, Sunagawa K. Imbalance of central nitric oxide and reactive oxygen species in the regulation of sympathetic activity and neural mechanisms of hypertension. Am J Physiol Regul Integr Comp Physiol. 2011;300(4):R818-R826.
    [DOI] [PubMed]
  • 135. Kullmann FA, McDonnell BM, Wolf-Johnston AS, Kanai AJ, Shiva S, Chelimsky T, et al. Stress-induced autonomic dysregulation of mitochondrial function in the rat urothelium. Neurourol Urodyn. 2019;38(2):572-581.
    [DOI] [PubMed] [PMC]
  • 136. de Matos DG, de Santana JL, Aidar FJ, Cornish SM, Giesbrecht GG, Nunes-Silva A, et al. Changes in autonomic balance, cardiac parasympathetic modulation, and cardiac baroreflex gain in older adults under different orthostatic stress conditions. Healthcare. 2025;13(19):2404.
    [DOI] [PubMed] [PMC]
  • 137. Siepmann M, Weidner K, Petrowski K, Siepmann T. Heart rate variability: A measure of cardiovascular health and possible therapeutic target in dysautonomic mental and neurological disorders. Appl Psychophysiol Biofeedback. 2022;47(4):273-287.
    [DOI] [PubMed] [PMC]
  • 138. Yang F, Ma Y, Liang S, Shi Y, Wang C. Effect of exercise modality on heart rate variability in adults: A systematic review and network meta-analysis. Rev Cardiovasc Med. 2024;25(1):9.
    [DOI] [PubMed] [PMC]
  • 139. Han S, Qiu Y, Zhang GQ, Lian F, Zhang W. A meta-analysis and systematic review of randomized clinical trials on the effect of coffee consumption on heart rate. Nutr Rev. 2024;82(8):1046-1055.
    [DOI] [PubMed]
  • 140. Han S, Li Y, Song R, Gao H, Zhang W. Effect of probiotics supplementation on heart rate: A systematic review and meta-analysis of randomized clinical trials. Front Nutr. 2022;9:829703.
    [DOI] [PubMed] [PMC]
  • 141. Costa GS, Julião-Silva LS, Belo VS, de Oliveira HCF, Chaves VE. A systematic review and meta-analyses on the effects of atorvastatin on blood pressure and heart rate. Eur Heart J Cardiovasc Pharmacother. 2022;9(1):100-115.
    [DOI] [PubMed]
  • 142. Sehgal D, Bonifanti L, Tran J, Lound M, Manfredi A, Mayrovitz HN. The effects of hypertension treatment on heart rate variability: A scoping review. Cureus. 2025;17(9):e91659.
    [DOI] [PubMed] [PMC]
  • 143. Ikram MA, Kieboom BCT, Brouwer WP, Brusselle G, Chaker L, Ghanbari M, et al. The Rotterdam Study. Design update and major findings between 2020 and 2024. Eur J Epidemiol. 2024;39(2):183-206.
    [DOI]
  • 144. Shaffer F, Ginsberg JP. An overview of heart rate variability metrics and norms. Front Public Health. 2017;5:258.
    [DOI] [PubMed] [PMC]
  • 145. Almeida-Santos MA, Barreto-Filho JA, Oliveira JLM, Reis FP, da Cunha Oliveira CC, Sousa ACS. Aging, heart rate variability and patterns of autonomic regulation of the heart. Arch Gerontol Geriatr. 2016;63:1-8.
    [DOI]
  • 146. Calderón-Juárez M, González-Gómez GH, Echeverría JC, Lerma C. Revisiting nonlinearity of heart rate variability in healthy aging. Sci Rep. 2023;13(1):13185.
    [DOI] [PubMed] [PMC]
  • 147. Brubaker PH, Kitzman DW. Chronotropic incompetence: Causes, consequences, and management. Circulation. 2011;123(9):1010-1020.
    [DOI] [PubMed] [PMC]
  • 148. Kardos A, Johnson C, Leeson P. Chronotropic incompetency during stress echocardiography: A new paradigm for mortality and cardiac event prediction? Eur J Prev Cardiol. 2025.
    [DOI] [PubMed]
  • 149. Abdellatif M, Rainer PP, Sedej S, Kroemer G. Hallmarks of cardiovascular ageing. Nat Rev Cardiol. 2023;20(11):754-777.
    [DOI]
  • 150. Lee S, Chu Y, Ryu J, Park YJ, Yang S, Koh SB. Artificial intelligence for detection of cardiovascular-related diseases from wearable devices: A systematic review and meta-analysis. Yonsei Med J. 2022;63:S93-S107.
    [DOI] [PubMed] [PMC]
  • 151. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: A new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. 2018;14(10):576-590.
    [DOI] [PubMed]
  • 152. Understand your risks to prevent a heart attack [Internet]. Dallas: American Heart Association; 2024 [cited 2026 Mar 15]. Available from: https://www.heart.org/en/health-topics/heart-attack/understand-your-risks-to-prevent-a-heart-attack
  • 153. Hamczyk MR, Nevado RM, Barettino A, Fuster V, Andrés V. Biological versus chronological aging: JACC focus seminar. J Am Coll Cardiol. 2020;75(8):919-930.
    [DOI] [PubMed]
  • 154. Galambos DA, Li K, Miliard Y, Valdes GM. A leap in longevity? The future of aging research in the United States. MIT Sci Policy Rev. 2025;6:60-70.
    [DOI]

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Zhang W. Resting heart rate and heart rate variability in cardiovascular aging: Biomarkers and potential therapeutic targets. Geromedicine. 2026;2:202617. https://doi.org/10.70401/Geromedicine.2026.0028

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