Submitted:
11 July 2025
Posted:
14 July 2025
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Abstract
Keywords:
1. Introduction
2. Materials and Methods
2.1. Study Design
2.2. Settings
2.3. Participants
2.4. Data Collection
2.4.1. Demographic and Anthropometric Measurements
2.4.2. Assessment of Heart Rate Variability, Cardiac Parasympathetic Modulation, and Cardiac Baroreflex Gain
2.4.3. Heart Rate Variability
2.4.4. Cardiac Parasympathetic Modulation
2.4.5. Cardiac Baroreflex Gain
2.5. Sample Size
2.6. Statistical Analysis
3. Results
3.2. Cardiac Parasympathetic Modulation Responses During Active Standing Orthostatic Stress
3.3. Cardiac Baroreflex Gain Responses During Active Standing Orthostatic Stress Across Specific Phase Time Points
4. Discussion
4.1. Heart Rate Variability Responses
4.2. Cardiac Parasympathetic Modulation
4.3. Cardiac Baroreflex Gain Responses Across Specific Phase Time Points During Active Standing Orthostatic Stress
4.4. Symptoms of Orthostatic Intolerance
4.5. Implications for Older Adults’ Health and Clinical Practice
4.6. Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Conflicts of Interest
Abbreviations
References
- Ricci, F.; De Caterina, R.; Fedorowski, A. Orthostatic Hypotension: Epidemiology, Prognosis, and Treatment. J. Am. Coll. Cardiol. 2015, 66, 848–860. [CrossRef]
- Fedorowski, A.; Ricci, F.; Hamrefors, V.; Sandau, K.E.; Hwan Chung, T.; Muldowney, J.A.S.; Gopinathannair, R.; Olshansky, B. Orthostatic Hypotension: Management of a Complex, But Common, Medical Problem. Circ. Arrhythmia Electrophysiol. 2022, 15, E010573. [CrossRef]
- Finucane, C.; van Wijnen, V.K.; Fan, C.W.; Soraghan, C.; Byrne, L.; Westerhof, B.E.; Freeman, R.; Fedorowski, A.; Harms, M.P.M.; Wieling, W.; et al. A Practical Guide to Active Stand Testing and Analysis Using Continuous Beat-to-Beat Non-Invasive Blood Pressure Monitoring. Clin. Auton. Res. 2019, 29, 427–441. [CrossRef]
- Wehrwein, E.A.; Joyner, M.J. Regulation of Blood Pressure by the Arterial Baroreflex and Autonomic Nervous System. Handb. Clin. Neurol. 2013, 117, 89–102. [CrossRef]
- Wieling, W.; Karemaker, J.M. Measurement of Heart Rate and Blood Pressure to Evaluate Disturbances in Neurocardiovascular Control. Auton. Fail. 2013, 290–306. [CrossRef]
- David E. Mohrman; Lois Jane Hellet Cardiovascular Physiology; 8th ed.; McGraw-Hill Education: New York, 2010; ISBN 978-0-07-179312-4.
- Christopher J. Mathias and Roger Bannister Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System; 5th ed.; Oxford University Press, 2013; ISBN 9788578110796.
- Billman, G.E. Heart Rate Variability - A Historical Perspective. Front. Physiol. 2011, 2 NOV, 1–13. [CrossRef]
- Jandackova, V.K.; Scholes, S.; Britton, A.; Steptoe, A. Are Changes in Heart Rate Variability in Middle-Aged and Older People Normative or Caused by Pathological Conditions? Findings from a Large Population-Based Longitudinal Cohort Study. J. Am. Heart Assoc. 2016, 5, 1–13. [CrossRef]
- Parvaneh, S.; Howe, C.L.; Toosizadeh, N.; Honarvar, B.; Slepian, M.J.; Fain, M.; Mohler, J.; Najafi, B. Regulation of Cardiac Autonomic Nervous System Control across Frailty Statuses: A Systematic Review. Gerontology 2015, 62, 3–15. [CrossRef]
- Reardon, M.; Malik, M. Changes in Heart Rate Variability with Age. PACE - Pacing Clin. Electrophysiol. 1996, 19, 1863–1866. [CrossRef]
- Schmitt, D.T.; Ivanov, P.C. Fractal Scale-Invariant and Nonlinear Properties of Cardiac Dynamics Remain Stable with Advanced Age: A New Mechanistic Picture of Cardiac Control in Healthy Elderly. Am. J. Physiol. - Regul. Integr. Comp. Physiol. 2007, 293, 1–54. [CrossRef]
- Ewing, A.D.J.; Campbell, I.W.; Murray, A.; Neilson, J.M.M.; Clarke, B.F. Diabetes Immediate Autonomic Neuropathy In. 1978, 1, 145–147.
- Monahan, K.D. Effect of Aging on Baroreflex Function in Humans. Am. J. Physiol. - Regul. Integr. Comp. Physiol. 2007, 293. [CrossRef]
- Mol, A.; Maier, A.B.; van Wezel, R.J.A.; Meskers, C.G.M. Multimodal Monitoring of Cardiovascular Responses to Postural Changes. Front. Physiol. 2020, 11, 1–13. [CrossRef]
- Borst, C.; Van Brederode, J.F.M.; Wieling, W. Mechanisms of Initial Blood Pressure Response to Postural Change. Clin. Sci. 1984, 67, 321–327. [CrossRef]
- von Elm, E.; Altman, D.G.; Egger, M.; Pocock, S.J.; Gøtzsche, P.C.; Vandenbroucke, J.P. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies. Int. J. Surg. 2014. [CrossRef]
- Heidari, S.; Babor, T.F.; De Castro, P.; Tort, S.; Curno, M. Sex and Gender Equity in Research: Rationale for the SAGER Guidelines and Recommended Use. Res. Integr. Peer Rev. 2016. [CrossRef]
- Canadian Society for Exercise Physiology Canadian Physical Activity Guidelines for Older Adults 65 Years and Older; CSEP, Ed.; Ottawa, 2011;
- Guelen, I.; Westerhof, B.E.; Van Der Sar, G.L.; Van Montfrans, G.A.; Kiemeneij, F.; Wesseling, K.H.; Bos, W.J.W. Finometer, Finger Pressure Measurements with the Possibility to Reconstruct Brachial Pressure. Blood Press. Monit. 2003, 8, 27–30. [CrossRef]
- Van Der Velde, N.; Van Den Meiracker, A.H.; Stricker, B.H.C.; Van Der Cammen, T.J.M. Measuring Orthostatic Hypotension with the Finometer Device: Is a Blood Pressure Drop of One Heartbeat Clinically Relevant? Blood Press. Monit. 2007, 12, 167–171. [CrossRef]
- Mol, A.; Slangen, L.R.N.; Trappenburg, M.C.; Reijnierse, E.M.; van Wezel, R.J.A.; Meskers, C.G.M.; Maier, A.B. Blood Pressure Drop Rate after Standing up Is Associated with Frailty and Number of Falls in Geriatric Outpatients. J. Am. Heart Assoc. 2020, 9. [CrossRef]
- Malik, M.; Camm, A.J.; Bigger, J.T.; Breithardt, G.; Cerutti, S.; Cohen, R.J.; Coumel, P.; Fallen, E.L.; Kennedy, H.L.; Kleiger, R.E.; et al. Heart Rate Variability. Standards of Measurement, Physiological Interpretation, and Clinical Use. Eur. Heart J. 1996, 17, 354–381. [CrossRef]
- Balcıoğlu, A.S. Diabetes and Cardiac Autonomic Neuropathy: Clinical Manifestations, Cardiovascular Consequences, Diagnosis and Treatment. World J. Diabetes 2015, 6, 80. [CrossRef]
- Duque, A.; Mediano, M.F.F.; De Lorenzo, A.; Rodrigues Jr, L.F. Cardiovascular Autonomic Neuropathy in Diabetes: Pathophysiology, Clinical Assessment and Implications. World J. Diabetes 2021, 12, 855–867. [CrossRef]
- Norcliffe-Kaufmann, L.; Kaufmann, H.; Palma, J.A.; Shibao, C.A.; Biaggioni, I.; Peltier, A.C.; Singer, W.; Low, P.A.; Goldstein, D.S.; Gibbons, C.H.; et al. Orthostatic Heart Rate Changes in Patients with Autonomic Failure Caused by Neurodegenerative Synucleinopathies. Ann. Neurol. 2018, 83, 522–531. [CrossRef]
- La Rovere, M.T.; Pinna, G.D.; Raczak, G. Baroreflex Sensitivity: Measurement and Clinical Implications. Ann. Noninvasive Electrocardiol. 2008, 13, 191–207. [CrossRef]
- Faul, F.; Erdfelder, E.; Lang, A.-G.; Buchner, A. G*Power 3: A Flexible Statistical Power Analysis Program for the Social, Behavioral, and Biomedical Sciences. Behav. Res. Methods 2007, 39, 175–191. [CrossRef]
- Yoav Benjamini and Yosef Hochberg Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing. 1995, 57, 289–300.
- Cohen, J. Statistical Power Analysis. Curr. Dir. Psychol. Sci. 1992, 1, 98–101. [CrossRef]
- Kerby, D.S. The Simple Difference Formula: An Approach to Teaching Nonparametric Correlation. Compr. Psychol. 2014, 3, 11.IT.3.1. [CrossRef]
- Freeman, R.; Wieling, W.; Axelrod, F.B.; Benditt, D.G.; Benarroch, E.; Biaggioni, I.; Cheshire, W.P.; Chelimsky, T.; Cortelli, P.; Gibbons, C.H.; et al. Consensus Statement on the Definition of Orthostatic Hypotension, Neurally Mediated Syncope and the Postural Tachycardia Syndrome. Auton. Neurosci. Basic Clin. 2011, 161, 46–48. [CrossRef]
- Kawaguchi, T.; Uyama, O.; Konishi, M.; Nishiyama, T.; Iida, T. Orthostatic Hypotension in Elderly Persons during Passive Standing: A Comparison with Young Persons. Journals Gerontol. - Ser. A Biol. Sci. Med. Sci. 2001, 56, 273–280. [CrossRef]
- Grässler, B.; Dordevic, M.; Darius, S.; Vogelmann, L.; Herold, F.; Langhans, C.; Halfpaap, N.; Böckelmann, I.; Müller, N.G.; Hökelmann, A. Age-Related Differences in Cardiac Autonomic Control at Resting State and in Response to Mental Stress. Diagnostics 2021, 11. [CrossRef]
- Droguett, V.S.L.; Santos, A.D.C.; de Medeiros, C.E.; Marques, D.P.; do Nascimento, L.S.; Brasileiro-Santos, M.D.S. Cardiac Autonomic Modulation in Healthy Elderly after Different Intensities of Dynamic Exercise. Clin. Interv. Aging 2015, 10, 203–208. [CrossRef]
- Acharya, U.R.; Joseph, K.P.; Kannathal, N.; Lim, C.M.; Suri, J.S. Heart Rate Variability: A Review. Med. Biol. Eng. Comput. 2006, 44, 1031–1051. [CrossRef]
- Mohrman;, D.L.H. Cardiovascular Physiology; 8th ed.; McGraw-Hill Education, 2013; ISBN 0071793119.
- Kim, Y.S.; Bogert, L.W.J.; Immink, R. V.; Harms, M.P.M.; Colier, W.N.J.M.; Van Lieshout, J.J. Effects of Aging on the Cerebrovascular Orthostatic Response. Neurobiol. Aging 2011, 32, 344–353. [CrossRef]
- Lai, Y.H.; Yuan, Y.; Liang, Y.X.; Yu, J.H. Comparison of Aging Effect between Cardiac Complexity and Baroreceptor Sensitivity. Proc. - 2021 Int. Conf. Inf. Technol. Biomed. Eng. ICITBE 2021 2021, 287–291. [CrossRef]
- Monahan, K.D.; Dinenno, F.A.; Seals, D.R.; Clevenger, C.M.; Desouza, C.A.; Tanaka, H. Age-Associated Changes in Cardiovagal Baroreflex Sensitivity Are Related to Central Arterial Compliance. Am. J. Physiol. - Hear. Circ. Physiol. 2001, 281, 284–289. [CrossRef]
- Kim, Y.S.; Bogert, L.W.J.; Immink, R. V.; Harms, M.P.M.; Colier, W.N.J.M.; Van Lieshout, J.J. Effects of Aging on the Cerebrovascular Orthostatic Response. Neurobiol. Aging 2011, 32, 344–353. [CrossRef]
- Dani, M.; Dirksen, A.; Taraborrelli, P.; Panagopolous, D.; Torocastro, M.; Sutton, R.; Lim, P.B. Orthostatic Hypotension in Older People: Considerations, Diagnosis and Management. Clin. Med. J. R. Coll. Physicians London 2021, 21, E275–E282. [CrossRef]
- Liguori, I.; Russo, G.; Coscia, V.; Aran, L.; Bulli, G.; Curcio, F.; Della-Morte, D.; Gargiulo, G.; Testa, G.; Cacciatore, F.; et al. Orthostatic Hypotension in the Elderly: A Marker of Clinical Frailty? J. Am. Med. Dir. Assoc. 2018, 19, 779–785. [CrossRef]
- Krediet, C.T.P.; Van Lieshout, J.J.; Bogert, L.W.J.; Immink, R. V.; Kim, Y.S.; Wieling, W. Leg Crossing Improves Orthostatic Tolerance in Healthy Subjects: A Placebo-Controlled Crossover Study. Am. J. Physiol. - Hear. Circ. Physiol. 2006, 291, 1768–1772. [CrossRef]
- Ten Harkel, A.D.J.; Van Lieshout, J.J.; Wieling, W. Effects of Leg Muscle Pumping and Tensing on Orthostatic Arterial Pressure: A Study in Normal Subjects and Patients with Autonomic Failure. Clin. Sci. 1994, 87, 553–558. [CrossRef]
- Logan, A.; Freeman, J.; Pooler, J.; Kent, B.; Gunn, H.; Billings, S.; Cork, E.; Marsden, J. Effectiveness of Non-Pharmacological Interventions to Treat Orthostatic Hypotension in Elderly People and People with a Neurological Condition: A Systematic Review. JBI Evid. Synth. 2020, 18, 2556–2617. [CrossRef]
- Fu, Q.; Levine, B.D. Exercise and the Autonomic Nervous System. Handb. Clin. Neurol. 2013, 117, 147–160. [CrossRef]
- Fecchio, R.Y.; de Sousa, J.C.S.; Oliveira-Silva, L.; da Silva Junior, N.D.; Pio-Abreu, A.; da Silva, G. V.; Drager, L.F.; Low, D.A.; Forjaz, C.L.M. Effects of Dynamic, Isometric and Combined Resistance Training on Blood Pressure and Its Mechanisms in Hypertensive Men. Hypertens. Res. 2023, 46, 1031–1043. [CrossRef]
- Bellavere, F.; Cacciatori, V.; Bacchi, E.; Gemma, M.L.; Raimondo, D.; Negri, C.; Thomaseth, K.; Muggeo, M.; Bonora, E.; Moghetti, P. Effects of Aerobic or Resistance Exercise Training on Cardiovascular Autonomic Function of Subjects with Type 2 Diabetes: A Pilot Study. Nutr. Metab. Cardiovasc. Dis. 2018, 28, 226–233. [CrossRef]
- Wahba, A.; Shibao, C.A.; Muldowney, J.A.S.; Peltier, A.; Habermann, R.; Biaggioni, I. Management of Orthostatic Hypotension in the Hospitalized Patient: A Narrative Review. Am. J. Med. 2022, 135, 24–31. [CrossRef]
- Fedorowski, A.; Melander, O. Syndromes of Orthostatic Intolerance: A Hidden Danger. J. Intern. Med. 2013, 273, 322–335. [CrossRef]



| Variable | Younger adults | Older adults | p | ||||
| Sex | n | % | n | % | |||
| Experiment 1 | ---- | ---- | ---- | ---- | ---- | ---- | ---- |
| Female | 13 | 50 | ---- | 35 | 71.5↑ | ---- | <0.001* |
| Male | 13 | 50 | ---- | 14 | 28.5 | ---- | <0.001* |
| Experiment 2 | ---- | ---- | ---- | ---- | ---- | ---- | ---- |
| Female | 13 | 50 | ---- | 35 | 70↑ | ---- | <0.001* |
| Male | 13 | 50 | ---- | 15 | 30 | ---- | <0.001* |
| Anthropometric data | Mean ± SD | CI 95% | Min; Max | Mean ± | CI 95% | Min; Max | |
| Age (years) | 21.0 ± 2.3 | 20.8; 22.6 | 18.0; 28.0 | 70.5 ± 3.9↑ | 69.3; 71.5 | 63.0; 78.0 | <0.001* |
| Height (m) | 1.73 ± 0.07 | 1.69; 1.76 | 1.56; 1.86 | 1.64 ± 0.08↓ | 1.62; 1.66 | 1.46; 1.84 | <0.001* |
| Body mass (kg) | 67.6 ± 11.9 | 62.9-72.2 | 42.6; 90.5 | 73.7 ± 15.4 | 69.4; 78.0 | 42.5; 110.0 | 0.07 |
| BMI (kg/m2) | 22.6 ± 3.38 | 21.3-23.9 | 16.5; 30.4 | 27.3 ± 5.6↑ | 25.8; 28.9 | 17.1; 48.4 | <0.001* |
| Orthostatic Intolerance* | n | % | ---- | n | % | ---- | |
| No | 26 | 100↑ | ---- | 43 | 86 | ---- | 0.041* |
| Yes | 0 | 0 | ---- | 7 | 14↑ | ---- | |
| HRV (time domain) | ||||
| Lie-to-stand | Stats | |||
| Younger adults | Older | p | ES | |
| RR (ms) | 888.7 | 316.6 (977.9; 1.01) |
825.0 | 898.8 (999.7; 1.01) |
0.213 | -0.480 |
| SDRR (ms) | 63.9 ± 24.0 (54.1; 73.6) |
36.0 ± 15.9↓ (31.5; 40.6) |
<0.001* | -1.462 |
| RMSSD (ms) | 77.7 | 51.2 (20.9; 141.0) |
24.9 | 19.2↓ (7.2; 86.2) |
<0.001* | -1.758 |
| HRV (frequency domain) | ||||
| Lie-to-stand | Stats | |||
| Younger adults | Older | p | ES | |
| LF (ms) | 1060.0 | 1417.7 (95.8; 5352.0) |
342.3 | 460.1↓ (31.4; 2226.0) |
<0.001* | -1.029 |
| HF (ms) | 2893.0 | 3984.7 (1.0; 9555.0) |
402.5 | 640.0↓ (13.1; 5756.0) |
<0.001* | -1.322 |
| LF/HF | 0.4 | 0.2 (0.0; 0.8) |
0.7 | 0.9↑ (0.1; 3.6) |
0.002* | 1.306 |
| Sit-to-Stand | |||||
| Variable | Group | Phase 1 | Phase 2 | Phase 3 | Phase 4 |
|
CBG (bpm.mmHg-1) |
Younger adults | 0.6 | 0.2 (0.4; 1.1) |
0.6 | 0.2 (0.4; 1.1) |
0.7 | 0.1 (0.5; 1.1) |
0.7 | 0.2 (0.5; 1.0) |
| Older adults |
0.5 | 0.1 (0.3; 0.9) |
0.5 | 0.1↓ (0.3; 0.9) |
0.5 | 0.1↓ (0.3; 0.8) |
0.6 | 0.9↓ (0.3; 0.8) |
|
| Adj p | 0.10 | 0.0013* | 0.0013* | 0.0013* | |
| ES | 0.2 | 0.4 | 0.7 | 0.7 | |
| Lie-to-Stand | |||||
| CBG (bpm.mmHg-1) |
Younger adults | 0.5 | 0.1 (0.4; 1.4) |
0.6 | 0.1 (0.4; 1.2) |
0.6 | 0.2 (0.5; 1.1) |
0.7 | 0.1 (0.4; 1.2) |
| Older adults |
0.5 | 0.1 (0.3; 1.0) |
0.5 | 0.1 (0.3; 1.1) |
0.5 | 0.1↓ (0.3; 0.9) |
0.5 | 0.1↓ (0.3; 1.0) |
|
| Adj p | 0.6 | 0.06 | 0.002* | 0.002* | |
| ES | 0.07 | 0.3 | 0.5 | 0.7 | |
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