A Novel Method Predicting Parasympathetic Nerve Dysfunction in Subjects with Apneic Events - Instantaneous Time-Frequency Analysis

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Kazuhiro Yamaguchi http://orcid.org/0000-0002-9135-2161 Mizuha Haraguchi Haruki Sekiguchi Takao Tsuji Kazutetsu Aoshiba Atsushi Nagai


The pathophysiological aspects of parasympathetic nerve (PN) function during sleep in patients with morbid apneas/hypopneas studied by classical methods, including power-spectrum and/or time-domain analysis on heart rate variability (HRV), are highly controversial. This controversy is attributed to methodological problems such as poor time resolution in classical methods. In the present review, we describe a reliable method for investigating the PN function in patients with apneas/hypopneas, which has recently been elaborated and named “instantaneous time-frequency analysis (ITF)”. The ITF was established based on the complex demodulation (CD) algorism, which enables us to measure the transitional change in amplitude of a target frequency domain in a practically continuous manner. Among high frequency (HF) domains between 0.15 and 0.40 Hz contained in R-R intervals of electrocardiogram tracing (representative of HRV), the HF domain with the maximum amplitude was used as an approximate measure of PN activity. Based on density-spectrum-array map for main HF peak constructed with time scale of 1 sec and frequency resolution of 0.002 Hz (HF-DSA map), shift in central frequency of main HF peak over time was continuously monitored. When the main HF peak with the same central frequency lasted for more than 20 seconds or 5 minutes on HF-DSA map, the PN function was assumed “stable” or “very stable”, respectively. Based on the ITF, we elucidated the qualitative and quantitative abnormalities in PN function in patients with obstructive sleep apnea (OSA), while it was not possible to evaluate PN abnormalities in patients with central sleep apnea (CSA). Furthermore, we certified the effects of various confounding factors on PN function in OSA patients, i.e., PN activity was inhibited by aging and obesity, while PN stability was distorted by apneas/hypopneas. To establish the clinical importance of ITF, we also determined normal reference values regarding the activity and stability of PN function.

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YAMAGUCHI, Kazuhiro et al. A Novel Method Predicting Parasympathetic Nerve Dysfunction in Subjects with Apneic Events - Instantaneous Time-Frequency Analysis. Medical Research Archives, [S.l.], v. 4, n. 7, nov. 2016. ISSN 2375-1924. Available at: <https://journals.ke-i.org/index.php/mra/article/view/736>. Date accessed: 21 july 2018.
power-spectrum analysis; time-domain analysis; complex demodulation method; parasympathetic nerve activity; parasympathetic nerve stability; obstructive sleep apnea; central sleep apnea; continuous positive airway pressure (CPAP) treatment
Review Articles


1) Arnardottir ES, Mackiewicz M, Gislason T, Teff KL, Pack AI. Molecular signatures of obstructive sleep apnea in adults. Sleep 2009; 32:447-470.
2) Arai Y, Saul JP, Albrecht P. Modulation of cardiac autonomic activity during and immediately after exercise. Am J Physiol 1989; 256:H132-H141.
3) Balachandran JS, Bakker JP, Rahangdale S, Yim-Yeh S, Mietus JE, et al. Effect of mild, asymptomatic obstructive sleep apnea on daytime heart rate variability and impedance cardiography measurements. Am J Cardiol 2012; 109:140-145.
4) Barutcu I, Esen AM, Kaya D, Turkmen M, Karakaya O, et al. Cigarette Smoking and Heart Rate Variability: Dynamic Influence of Parasympathetic and Sympathetic Maneuvers. Ann Noninvasive Electrocardiol 2005; 10:324-329.
5) Bédard ME, Marquis K, Poirier P, Provencher S. Reduced heart rate variability in patients with chronic obstructive pulmonary disease independent of anticholinergic or β-agonist medications. COPD 2010; 7:391-397.
6) Berger RD, Saul JP, Cohen RJ. Transfer function analysis of autonomic regulation, I: canine atrial rate response. Am J Physiol 1989; 256:H142-H152.
7) Berntson GG, Cacioppo JT, Quigley KS. Respiratory sinus arrhythmia: autonomic origins, physiological mechanisms, and psychophysiological implications. Psychophysiology 1993; 30:183-196.
8) Chrysostomakis SI, Simantirakis EN, Schiza SE, Karalis IK, Klapsinos NC, Siafakas NM, Vardas PE. Continuous positive airway pressure therapy lowers vagal tone in patients with obstructive sleep apnoea-hypopnoea syndrome. Hellenic J Cardiol 2006; 47:13-20.
9) Cooke WH, Hoag JB, Crossman AA, Kuusela TA, Tahvanainen KU, Eckberg DL. Human responses to upright tilt: a window on central autonomic integration. J Physiol 1999; 517:617-628.
10) Eckberg DL. Sympathovagal balance: a critical appraisal. Circulation 1997; 96:3224-3232.
11) Furlan R, Dell’Orto S, Crivellaro W. Effects of tilt and treadmill exercise on short-term variability in systolic arterial pressure in hypertensive men. J Hypertension 1987; 5 (Suppl 5):S423-S425.
12) Gula LJ, Krahn AD, Skanes A. Heart rate variability in obstructive sleep apnea: a prospective study and frequency domain analysis. Ann Noninvasive Electrocardiol 2003; 8:144-149.
13) Hayano J, Sakakibara Y, Yamada A. Accuracy of assessment of cardiac vagal tone by heart rate variability in normal subjects. Am J Cardiol 1991; 67:199-204.
14) Hayano J, Taylor JA, Yamada A. Continuous assessment of hemodynamic control by complex demodulation of cardiovascular variability. Am J Physiol 1993; 264:H1229-H1238.
15) Hayano J, Taylor JA, Mukai S. Assessment of frequency shifts in R-R interval variability and respiration with complex demodulation. J Appl Physiol 1994; 77:2879-2888.
16) Hayano J. Analysis of autonomic-nerve function by heart rate variability. In: Inoue H, editor. Cardiac diseases and autonomic nerve function. Tokyo: Igaku-Shoin, 2010; p.71-109 (Japanese).
17) Hilton MF, Chappell MJ, Bartlett WA, Malhotra A, Beattie JM, Cayton RM. The sleep apnoea/hypopnoea syndrome depresses waking vagal tone independent of sympathetic activation. Eur Respir J 2001; 17:1258-1266.
18) Hopf H-B, Skyschally A, Heuesh G. Low-frequency spectral power of heart rate variability is not a specific marker of cardiac sympathetic modulation. Anesthesiol 1995; 82:609-619.
19) Houle MS, Billman GE. Low-frequency component of the heart rate variability spectrum: a poor maker of sympathetic activity. Am J Physiol 1999; 276:H215-H223.
20) Hrushesky WJM, Fader D, Schmitt O. The respiratory sinus arrhythmia: a measure of cardiac age. Science 1984; 224:1001-1004.
21) Jensen-Urstad K, Storck N, Bouvier F, Ericson M, Lindbland E, et al. Heart rate variability in healthy subjects is related to age and gender. Acta Physiologica Scand 1997; 160:235-241.
22) Katona PG, Jih F. Respiratory sinus arrhythmia: noninvasive measure of parasympathetic cardiac control. J Appl Physiol 1975; 39:801-805.
23) Khoo MCK, Kim T, Berry RB. Spectral indices of cardiac autonomic function in obstructive sleep apnea. Sleep 1999; 22:443-451.
24) Kim JA, Park Y-G, Cho K-H, Hong M-H, Han H-C, et al. Heart rate variability and obesity indices: emphasis on the response to noise and standing. J Am Board Fam Pract 2005; 18:97-103.
25) Lombardi F, Montano N, Finocchiaro ML, Gnecchi-Ruscone T, Baselli G, Cerutti S, Malliani A. Spectral analysis of sympathetic discharge in decerebrate cats. J Auton Nerve Syst 1990; 30(suppl):S97-S99.
26) Lu W-A, Kuo J, Wang Y-M, Lien T-C, Liu Y-B, Jang-Zern Tsai J-Z, Kuo C-D. Reduced enhancement of high-frequency component in the cross spectrum of ECG and nostril airflow signals in patients with chronic obstructive pulmonary disease. Physiol Report 2016; e12763. DOI:10.14814/phy2.12.
27) Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation 1991; 84:482-492.
28) Molfino A, Fiorentini A, Tubani L, Martuscelli M, Fanelli FR, et al. Body mass index is related to autonomic nervous system activity as measured by heart rate variability. Eur J Clin Nutrition 2009; 63:1263-1265.
29) Muralikrishnani K, Balasubramanian K, Jawahar SM, Ali SM, Rao BV. Poincare plot of heart rate variability: an approach towards explaining the cardiovascular autonomic function in obesity. Indian J Physiol Pharmacol 2013; 57:31-37.
30) Nagai N, Matsumoto T, Kita H, Moritani T. Autonomic nervous system activity and the state and development of obesity in Japanese school children. Obes Res 2003; 11:25-32.
31) Narkiewicz K, Montano N, Cogliati C, van de Borne PJ, Dyken ME, Somers VK. Altered cardiovascular variability in obstructive sleep apnea. Circulation 1998; 98:1071-1077.
32) Narkiewicz K, Kato M, Phillips BG, Pesek CA, Davison DE, Somers VK. Nocturnal continuous positive airway pressure decreases daytime sympathetic traffic in obstructive sleep apnea. Circulation 1999; 100:2332-2335.
33) Notarius CF, Butler GC, Ando S. Dissociation between microneurographic and heart rate variability estimates of sympathetic tone in normal subjects and patients with heart failure. Clin Sci 1999; 96:557-565.
34) O'brien I, O'hare P, Corrall RJM. Heart rate variability in healthy subjects: effect of age and the derivation of normal ranges for tests of autonomic function. Br Heart J 1987; 55:348-354.
35) Pagani M, Lombardi F, Guzzetti S. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Cir Res 1986; 59:178-193.
36) Pagani M, Lucini D, Pizzinelli P, Sergi M, Bosisio E, Mela GS, Malliani A. Effects of aging and of chronic obstructive pulmonary disease on RR interval variability. J Auton Nerv Syst 1996; 59:125-132.
37) Park D-H, Shin C-J, Hong S-C, Yu J, Ryu S-H, et al. Correlation between the severity of obstructive sleep apnea and heart rate variability indices. J Korean Med Sci 2008; 23:226-231.
38) Piestrzeniewicz K, Łuczak K, Lelonek M, Wranicz KJ, Goch JH. Obesity and heart rate variability in men with myocardial infarction. Cardiol J 2008 15:43-49.
39) Pomeranz B, Macaulay RJB, Caudill MA. Assessment of autonomic function in humans by heart rate spectral analysis. Am J Physiol 1985; 248:H151-H153.
40) Postma DS, Keyzer JJ, Hoeter GH, Sluiter HJ, Vries KDE. Influence of parasympathetic and sympathetic nervous system on nocturnal bronchial obstruction. Clin Sci 1985; 69:251-258.
41) Rajalakshmi R, VijayaVageesh Y, Nataraj SM, MuraliDhar, Srinath CG. Heart rate variability in Indian obese young adults. Pak J Physiol 2012; 8:39-44.
42) Reardon M, Malk M. Changes in heart rate variability with age. Pacing Clin Electrophysiol 1996; 19:1863-1866.
43) Sakakibara M, Takeuchi S, Hayano J. Effect of relaxation training on crdiac parasympathetic tone. Psychophysiology 1994; 31:223-228.
44) Saul JP, Berger RD, Albrecht P. Transfer function analysis of the circulation: unique insights into cardiovascular regulation. Am J Physiol Heart Cir Physiol 1991; 261:H1231-H1245.
45) Shannon DC, Carley DW, Benson H. Aging of modulation of heart rate. Am J Physiol 1987; 253:H874-H877.
46) Sloan RP, Shapiro PA, Bagiella E. Relationships between circulating catecholamines and low frequency heart period variability as indices of cardiac sympathetic activity during mental stress. Psychosom Med 1996; 58:25-31.
47) Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897-1904.
48) Song M-K, Hao JH, Ryu S-H, Yu J, Park D-H. The effect of aging and severity of sleep apnea on heart rate variability indices in obstructive sleep apnea syndrome. Psychiatry Investig 2012; 9:65-72.
49) Stein PK, Kleiger RE, Rottman JN. Differing effects of age on heart rate variability in men and women. Am J Cardiol 1997; 80:302-305.
50) Stein PK, Domtrovich PP, Hui N, Rataharju P, Gottdiener J. Sometimes higher heart rate variability is not better heart rate variability: results of graphical and nonlinear analyses. J Cardiovasc Electrophysiol 2005; 16:954-959.
51) Taha BH, Simon PM, Dempsey JA. Respiratory sinus arrhythmia in humans: an obligatory role for vagal feedback from the lungs. J Appl Physiol 1995; 78:638-645.
52) Vanninen E, Tuunaianen A, Kansanen M, Uusitupa M, Laensimies E. Cardiac sympathovagal balance during sleep apnea episodes. Clin Physiol 1996; 16:209-216.
53) Vanoli E, Adamson PB. Heart rate variability during specific sleep stages: a comparison of healthy subjects with patients after myocardial infarction. Circulation 1995; 91:1918-1922.
54) Yamaguchi K, Ohki N, Kobayashi, M, Satoya N, Inoue Y, Onizawa S, Maeda Y, Sekiguchi H, Suzuki M, Tsuji T, Aoshiba K, Nagai A. Estimation of parasympathetic nerve function during sleep in patients with obstructive sleep apnea by instantaneous time-frequency analysis. Sleep Medicine 2014; 15:33-41.
55) Yamaguchi K, Inoue Y, Ohki N, Satoya N, Inoue F, Maeda Y, Sekiguchi H, Suzuki M, Tsuji T, Aoshiba K, Nagai A. Gender-specific impacts of apnea, age and BMI on parasympathetic nerve dysfunction during sleep in patients with obstructive sleep apnea. PLoS ONE 2014; 9: e92808. DOI:10.1371/journal.pone.0092808.
56) Yasuma F, Hayano J. Respiratory sinus arrhythmia. Why does heartbeat synchronize with respiratory rhythm? Chest 2004; 125:683-690.
57) Zamarrón C, Lado MJ, Teijeiro T, Morete E, Vila XA, Lamas PF. Heart rate variability in patients with severe chronic obstructive pulmonary disease in a home care program. Technol Health Care 2014; 22:91-98.
58) Zhang J, Fang SC, Mittleman MA, Christiani DC, Jennifer M, et al. (2013). Secondhand tobacco smoke exposure and heart rate variability and inflammation among non-smoking construction workers: a repeated measures study. Environ Health 2013; 12:83. Ehjournal website. Available: http://www.ehjournal.net/content/pdf/1476-069X-12-83.pdf.

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