Autonomic Cardiovascular Assessment in Obstructive Sleep Apnea Using Beat-to-Beat Blood Pressure: A Pilot Study

Abstract

Objective

To perform autonomic cardiovascular tests on patients with suspected OSA.

Materials and Methods

In 2020, patients aged ≥18 years without difficult-to-control hypertension, cardiopathy, or pulmonary disease executed 6Hz deep breathing, 15-second Valsalva maneuver (40mmHg), and 5-minute active standing after the type 1 polysomnography at the Neurology (Federal University of São Paulo). The tests recorded blood pressure using beat-to-beat plethysmography, an electrocardiogram, and respiratory effort.

Results

Among the seventeen patients, ten had moderate OSA, and twelve were male. The mean age and disease duration were 52 and 14 years. Hypertension and obesity were frequent. They had mild autonomic symptom burden, mainly adrenergic sympathetic overactivity, and at least one-third of them had cardiovagal abnormalities.

Conclusion

A small sample of patients with untreated moderate-to-severe OSA had autonomic abnormalities in tests using beat-to-beat blood pressure. Sympathetic overdrive in long-term daytime was manifested as orthostatic hypertension. Emerging technologies contributed to diagnosing the OSA-related autonomic dysfunction beyond the polysomnographic approach.

 

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Keywords

autonomic - obstructive sleep apnea - cardiovagal - orthostatic hypertension - sympathetic

Introduction

Sleep-disordered breathing is strongly associated with hypertension. Hypoxia and hypercapnia during obstructive sleep apnea (OSA) respiratory events determine chemoreflex activation and sympathetic overactivity. Apnea-related autonomic dysfunction impacts cardiovascular risk.[1] Progressive bradycardia and abrupt tachycardia reflect autonomic modulation. Non-dipping blood pressure (BP) is involved in the onset of hypertension. The chronic hypertensive state is an adaptive autonomic response to recurrent sympathetic hyperactivation.[2]

The multiple comorbidities of patients with OSA also account for autonomic dysregulation. Autonomic dysfunction is a considerable feature of OSA in the long-term daytime. Increasing attention has been given to methods of autonomic assessment during wakefulness, such as heart rate (HR) variability as a marker of OSA severity. The screening of OSA by deep breathing was made in patients without obesity, diabetes, or cardiopathy. Facing the bidirectional association of OSA and HAS, BP recordings with cardiorespiratory variables could improve our knowledge about the autonomic responses of patients with OSA.

Arterial BP can be indirectly measured at the finger using beat-to-beat photoplethysmography. The change in infrared light transmitted through the finger is an index of the dynamic volume of blood flow. BP measurements for each pulse wave allow non-invasive recordings indistinguishable from those acquired intra-arterially. We hypothesized that OSA would be associated with abnormalities in daytime cardiovascular autonomic regulation using continuous BP monitoring.

We performed autonomic tests in patients undergoing polysomnography for suspected OSA. The objective was to measure the hemodynamic responses during orthostatic and respiratory challenges that influence the autonomic drive during wakefulness. We used the autonomic laboratory scoring instrument, Quantitative scale for grading cardiovascular reflex, transcranial Doppler ultrasound, sudomotor tests, and small fiber densities from skin biopsy (QASAT) to grade the abnormalities.[3]

 

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Materials and Methods

The Discipline of Neurology from the Federal University of São Paulo (Brazil) conducted the study (ethics approval n°611/2019). All participants signed the informed consent. We have prospectively screened 44 patients from the outpatient sleep clinic, aged ≥18 years, and referred for OSA. They completed polysomnography at the inpatient unit. Excluded were participants: 1) treated for OSA, 2) having difficult-to-control hypertension, cardiopathy, pulmonary disease, or disability. 17 participants were enrolled for autonomic tests, which were performed at the Pulmonary Function and Clinical Exercise Physiology Unit, Division of Respirology. The patients were recruited between February and March 2020, but the study was stopped because of COVID-19.

The patients followed the usual instructions for autonomic tests.[4] We recorded respiratory effort (belt by Spes Medica), beat-to-beat non-invasive BP (Finapres NOVA), and HR (BioAmp). The data acquisition system was Powerlab8 (AD Instruments). Protocol: cardiac parasympathetic response to 6Hz deep breathing (DB) and Valsalva maneuver (VM) at 40 mm Hg for 15 seconds; sympathetic (adrenergic) responses to VM (HR and beat-to-beat BP); active standing (supine to five-minute upright with repeated HR and manual auscultatory BP).[5] Respiratory sinus arrhythmia and Valva ratio were calculated. VM's mean blood pressure (MBP) measurements were at baseline, phase II (maximum drop and end phase recovery), and phase IV. The VM four-phase pattern and variants were seen.[6]

Throughout this pilot study, there was no uniform definition among researchers regarding orthostatic hypertension. There were different cut-offs of BP to define exaggerated BP response to standing. Several studies used a ≥20 mm Hg systolic BP (SBP) increase and a ≥10 mm Hg diastolic BP increase after standing to identify orthostatic hypotension, isolated or combined, with or without absolute values of standing BP.[7] We used the criteria of upright SBP > 120% supine baseline SBP, as described by Novak.[3] [8] The American Autonomic Society recently established the consensus of an exaggerated orthostatic pressor response (orthostatic SBP increase ≥20 mm Hg) associated with an SBP ≥ 140 mm Hg while standing. The definition avoids the situation where a person with exaggerated BP response to standing without high orthostatic BP may be considered a hypertensive patient.[9]

Autonomic function testing evaluates an end-organ response to a specific physiological provocation to accurately diagnose dysautonomia.[4] Quantitative grading of testing has research and clinical relevance. QASAT is a laboratory grading scale for rating autonomic dysfunction, whether failure or hyperactivity, by expanded monitoring with end-tidal CO₂ and cerebral blood flow velocity from the middle cerebral artery during orthostatic stress.[3] QASAT uses the adrenergic and cardiovagal components of autonomic testing results that contribute to the Composite Autonomic Severity Score.[4] QASAT is grouped into cardiovascular, cerebral blood flow, and small fiber neuropathy categories. Giving numerical severity during each minute of standing, the instrument grades the abnormalities.[3] [8] QASAT has not yet been validated in populations with sleep disturbances.

Qpack software calculated QASAT scores. SPSS for Windows analyzed the other data. Pearson's chi-squared, Fisher's exact test, and one-way analysis were made for group comparisons concerning disease severity and hypertension. The data from this pilot study are reported as descriptive statistics. The results are presented as means ± standard deviation and percentages. Significance was set for p values <0.05.

 

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Results

[Table 1] summarizes the clinical characteristics and sleep parameters. Among the seventeen patients, ten had moderate OSA, and twelve were male. The mean age and disease duration were 52 and 14 years, respectively. The patients had mild to moderate compromised subjective sleep quality and mild autonomic symptom burden, mainly due to orthostatic intolerance. The mean apnea-hypopnea index was significantly higher in the severe group.

Table 1 Clinical characteristics and sleep parameters of patients with obstructive sleep apnea

	Number = 17
Male gender, %	12(70.6)
Age and disease duration, years	52.04 ± 14	14.33 ± 11
Hypertension and Diabetes mellitus, %	8(47)	4(23.5)
Regular medications, %	11(64.7)
Number of regular medications	1.76 ± 1.9
Body mass index kg/m2 and obesity %	30.63 ± 3	9(52.9)
Supine systolic and diastolic blood pressure, mmHg	132.71 ± 26	83.53 ± 11
Systolic ≥ 140 diastolic ≥ 90[a], %	8(47)
Resting heart rate, beats per minute	71.18 ± 11
Peak expiratory pressure cmH2O[b]	72.44 ± 31
Composite autonomic symptom scores 31 (0–100)	20.01 ± 18
Orthostatic intolerance domain (0–40)	7.52 ± 12
Epworth sleepiness scale (0–21)	8.71 ± 4
Pittsburgh sleep quality index (0–21)	9.24 ± 4
Apnea-hypopnea and respiratory disturbance index, event/h	39.30 ± 23	39.92 ± 24
Arousal index event/h and minimum SpO2%	36.36 ± 22	78.94 ± 9
Moderate and severe disease severity[c], %	10(58.8)	7(41.1)

Abbrevaitions: h, hour; SpO2, peripheral oxygen saturation.

Values are expressed as the mean ± standard deviation or percentage (%) from analysis of variance and Pearson's chi-squared or Fisher's exact tests within the groups.

^a Hypertension according to Brazilian guideline.

^b MicroRPM respiratory pressure meter (CareFusion, USA).

^c p = 0.0001.

The autonomic cardiovascular assessment is presented in [Table 2]. QASAT sub scores were: 1.0 ± 0.7 for adrenergic sympathetic overactivity (0–2); 0.41 ± 0.6 for cardiovagal failure (0–3). Fourteen patients had adrenergic sympathetic overactivity (ten supine hypertension and four orthostatic hypertension). One patient had a mild adrenergic sympathetic failure. All patients had normal VM patterns, with seven of them having an absent MBP drop (flat top variant). HR responses to DB were abnormal in 6 patients (35.2%). 9 patients had an abnormal Valsalva ratio (52.9%). There was no significant difference in the autonomic findings related to OSA severity.

Table 2 Autonomic cardiovascular assessment in patients with obstructive sleep apnea

	Number = 17
QASAT sub scores
Supine and orthostatic hypertension (adrenergic, 0–2)	1 ± 0.7
Deep breathing (cardiovagal parasympathetic, 0–3)	0.41 ± 0.6
Adrenergic sympathetic
Overactivity (supine and/or orthostatic hypertension), %	14 (88.2)
Supine hypetension[a], %	10 (58.8)
Orthostatic hypertension[b], %	4(23.5)
Active standing test
Manual auscultatory (3-minute upright – supine) blood pressure, mmHg
SBP	5.71 ± 10
DBP	7.06 ± 10
Heart rate (3-minute upright – supine), beats per minute	8.88 ± 6
Failure (Valsalva maneuver and orthostatic hypotension) %	1(5.9)
Valsalva maneuver measurements
Baseline beat-to-beat blood pressure, mmHg
SBP	145.90 ± 24
MBP[c]	110.50 ± 16
DBP	92.73 ± 14
Absent drop (flat top response)[d], %	7 (41.1)
Pressure recovery time, second	1.38 ± 0.4
Cardiovagal parasympathetic
Respiratory sinus arrhythmia[e], bpm	13.53 ± 8
Failure (deep breathing), %	6(35.2)
Valsalva ratio[f]	1.44 ± 0.31
Abnormal Valsalva ratio, %	9 (52.9)

Abbreviations: DBP, diastolic blood pressure; MBP, mean blood pressure; QASAT, quantitative scale for grading cardiovascular reflex, transcranial Doppler ultrasound, sudomotor tests, and small fiber densities from skin biopsy; SBP, systolic blood pressure.

Values are expressed as the mean ± standard deviation or percentage (%) from analysis of variance and Pearson's chi-squared or Fisher's exact tests within the groups of disease severity.

^a National Institute of Health criteria elevated and high = systolic blood pressure ≥120mmHg and diastolic blood pressure ≥ 80mmHg.

^b Systolic >120% of baseline.

^c diastolic + ⅓ pulse pressure (systolic – diastolic).

^d below baseline.

^e difference between the heart rate at the end of expiration and the inspiration of six consecutive respiratory cycles.

^f maximum/minimum heart rate.

In a subgroup analysis, the nine patients without hypertension were significantly younger than the 8 patients with hypertension (41.07 ± 10 versus 64.38 ± 6, p = 0.0001). However, there was no significant difference regarding disease severity [moderate 66.7% versus 50% and severe 33.3% versus 50%, p = 0.486] or cardiovagal abnormalities [DB 33.3% versus 37.5% p = 0.858; VM 44.4% versus 62.5% p = 0.457]. The four patients with diabetes had hypertension.

 

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Discussion

Our patients were predominantly adult males with a long duration of untreated moderate-to-severe OSA. A few patients had developed comorbidities, mainly hypertension and/or obesity. The participants without hypertension were younger, but there was no difference regarding disease severity or cardiovagal abnormalities related to hypertension.

We performed autonomic tests available for clinical practice in a few countries. This study combined sleep assessments with daytime autonomic testing to evaluate cardiovascular regulation. The QASAT quantified sympathetic hyperfunction, showing overactivity in most patients and confirming orthostatic hypertension in some. The Brazilian Guideline defines systolic BP≥140 and diastolic BP≥90 mm Hg as the cut-off values for hypertension, similar to the European.[10] The National Institutes of Health uses SBP≥130 and diastolic BP > 90 mm Hg.

Almost a quarter of our patients had orthostatic hypertension. They also met the criteria of the recent consensus.[9] Orthostatic hypertension has been increasingly recognized in medical literature, but different definitions have been applied over the years.[7] SBP change with standing revealed the association of orthostatic hypertension with an increased risk of masked and sustained hypertension, target organ damage, poor cardiovascular outcome, and mortality. Orthostatic hypertension is bidirectionally linked to essential hypertension.[11] [12] Hypertension-associated morbidity influences the development and progression of OSA.

Orthostatic hypertension (BP rise upon standing ≥5mmHg) was an independent risk factor associated with masked hypertension (office BP < 140 × 90 with home BP≥135 × 85mmHg).[13] Patients with orthostatic hypertension were likely to have masked hypertension unrelated to pharmacotherapy.[14] Orthostatic hypertension (systolic BP≥20mmHg) was an underestimated cause of orthostatic intolerance among patients referred to autonomic testing.[15]

The mechanisms leading to masked hypertension indicate psychosocial factors in its development. Stressful lifestyle factors (smoking, alcohol, physical inactivity, anxiety) and conditioned stress response specific to out-of-clinic settings are relevant. The effect of sympathetic activation remains not completely understood. OSA-related hypertension is characterized by masked hypertension, elevated, and non-dipper nocturnal BP. The pathological mechanism between OSA and masked hypertension is associated with hypoxia/hypercapnia-related sympathetic activation.

Autonomic dysfunction is a crucial mechanism in the pathogenesis of orthostatic hypertension. Conditions enhancing sympathetic activation and/or baroreflex dysregulation (aging, diabetes, neurological disorders) are risk factors for orthostatic hypertension.[12] OSA may also be a clinical promoter of orthostatic hypertension. Rapid eye movement sleep breathing events are associated with morning hypertensive BP levels.[16] A cohort study about orthostatic reactivity demonstrated that childhood OSA persisting in this developmental period is associated with adolescent hypertension.[17]

We agree that patients with OSA could benefit from BP monitoring protocols to optimize decision-making concerning pharmacotherapy. Patients with isolated orthostatic hypertension with non-dipping BP or masked morning hypertension in 24-hour ambulatory BP monitoring should be screened for OSA. More intensive blood pressure treatment modestly reduced orthostatic hypertension in adults with elevated blood pressure or hypertension. The effect of antihypertensives for seated hypertension may also prevent hypertension on standing. However, there is no evidence to support the use of a drug class for cardiovascular protection in patients with orthostatic hypertension. There is a need for studies about exaggerated orthostatic pressor responses to guide clinical practice.

Our patient's continuous non-invasive finger BP measurements confirmed the sustained BP elevation during the steady-state period of the active standing test. The first 3 minutes of the test provide a simple means to clinically assess short-term neurocardiovascular control. The test is a powerful tool to identify the hemodynamic correlations of patient symptoms to detect autonomic dysfunction. The practical guide to active standing test with beat-to-beat continuous BP monitoring defines orthostatic hypertension as a sustained increase (>1 minute) in SBP ≥20 mm Hg or above 140/90 mm Hg, if the patient is normotensive supine. The criteria combine both absolute SBP increase and conversion from normal supine BP to hypertension on standing.[5]

Novel beat-to-beat BP approaches can identify syncope, orthostatic hypotension (classical, initial, or delayed), and hyperadrenergic states such as postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia.[18] The increased BP in a few patients, regardless of disease severity or hypertension, may indicate an augmented autonomic response. The beat-to-beat BP could improve the early diagnosis of hypertension and OSA-related impairments in research and clinical care.

QASAT enhanced our analysis by computing orthostatic responses. QASAT is an objective, validated instrument for grading the severity and distribution of sudomotor, cardiovagal, and adrenergic dysfunctions. The tool facilitates the reproducibility and quality of autonomic studies that can be incorporated into routine clinical or research testing.[3] QASAT could be useful in early diagnosis and monitoring the course of autonomic disorder in OSA, in addition to the response to treatment. QASAT quantifies sympathetic overactivity, orthostatic cerebral hypoperfusion, and cerebral vasoreactivity, which could bring fundamental discoveries from the laboratory to the understanding of the research questions related to OSA.

We found 2-fold more flat top response in VM than described previously. VM is influenced by position and heart failure, but late-phase II is unaffected by posture.[19] The high BP during straining in some of our patients could be associated with hypertension or indicate masked hypertension. 35.4% of patients with newly diagnosed OSA had high ambulatory 24-hour BP, termed masked hypertension.[20] Our findings align with the pathogenesis of hypertension, related to the increased peripheral chemoreceptor sensitivity before its onset. VM sympathetic neurocirculatory failure markers are phase II fall without recovery and phase IV delayed return to baseline without overshoot. One patient with severe OSA had a VM response consistent with mild adrenergic failure. Even though the elevated phase IV of hyperadrenergic states is described, the normal range is not standardized.[6] OSA hyperadrenergic profile was described invasively with the heightened muscle sympathetic nerve activity in wakefulness and sleep, mainly N2 and REM.[21]

We confirmed cardiovagal abnormalities in at least one-third of our patients, unrelated to hypertension or diabetes. Impaired cardiovascular variability was identified in OSA regardless of other comorbidities, and it was dependent on the disease severity.[22] Patients with newly diagnosed and untreated OSA have lower amplitude, delayed onset, and slower HR changes.[23] DB and VM beat-to-beat HR responses provide the cardiovagal index in laboratory grading of autonomic failure. The laboratory scoring of OSA autonomic abnormalities can determine the extent of the dysfunction, the need for follow-up, and the cardiovascular risk.

The strengths of this study are that all patients were free of medications that could interfere with the tests; unlike most studies with OSA, all measures were obtained during wakefulness, avoiding desaturation or respiratory influence.

However, this preliminary study has limitations, mainly its design and selection bias. The study recruitment was interrupted due to COVID-19. The small sample size and early study termination due to COVID-19 limit the generalizability and the sensitivity of the findings to the broader OSA population. We propose a future large cohort investigation. Moreover, the absence of a control group restricts our analysis. Subsequent matched control studies are needed to assess the factors associated with the abnormalities. Additionally, supine and plasma levels of catecholamines to investigate excessive neurohumoral activation while standing were not measured. Echocardiograms to evaluate preload failure were not performed.

 

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Conclusion

Cardiovascular autonomic tests using beat-to-beat BP confirmed cardiovagal and sympathetic adrenergic abnormalities during wakefulness in patients with untreated moderate-to-severe OSA. Orthostatic hypertension draws attention to investigate underlying HTN in these patients. Emerging technologies can contribute to diagnosing OSA-related autonomic dysfunction beyond the polysomnographic approach.

 

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Abbreviations

• Obstructive sleep apnea (OSA)

• Blood pressure (BP)

• Heart rate (HR)

• Quantitative scale for grading cardiovascular reflex, transcranial Doppler, sudomotor tests, and small fiber densities from skin biopsy (QASAT)

• Deep breathing (DB)

• Valsalva maneuver (VM)

• Mean blood pressure (MBP)

• Systolic blood pressure (SBP)

 

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Conflict of Interest

The authors report no conflict of interest.

Acknowledgments

The authors thank Professor Bruno Moreira Silva from the Department of Physiology and Medicine at the Federal University of São Paulo (Brazil) for equipment support and the laboratory room.

• References

• 1 Milagro J, Deviaene M, Gil E. et al. Autonomic Dysfunction Increases Cardiovascular Risk in the Presence of Sleep Apnea. Front Physiol 2019; 10: 620
• 2 Lombardi C, Pengo MF, Parati G. Obstructive sleep apnea syndrome and autonomic dysfunction. Auton Neurosci 2019; 221: 102563
• 3 Novak P. Qpack-a Python package for QASAT-quantitative scale for grading cerebral blood flow, autonomic testing, and skin biopsies. Neurol Sci 2022; 43 (08) 4821-4828
• 4 Cheshire WP, Freeman R, Gibbons CH. et al. Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology. Clin Neurophysiol 2021; 132 (02) 666-682
• 5 Finucane C, van Wijnen VK, Fan CW. 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 (04) 427-441
• 6 Novak P. Quantitative autonomic testing. J Vis Exp 2011; 53 (53) x
• 7 Jordan J, Ricci F, Hoffmann F, Hamrefors V, Fedorowski A. Orthostatic Hypertension: Critical Appraisal of an Overlooked Condition. Hypertension 2020; 75 (05) 1151-1158
• 8 Novak P. Quantitative Scale for Grading of Cardiovascular Autonomic Reflex Tests and Small Fibers from Skin Biopsies (QASAT). J Neurol Disord 3: 2
• 9 Jordan J, Biaggioni I, Kotsis V. et al. Consensus statement on the definition of orthostatic hypertension endorsed by the American Autonomic Society and the Japanese Society of Hypertension. Hypertens Res 2023; 46 (02) 291-294
• 10 Barroso WKS, Rodrigues CIS, Bortolotto LA. et al. Brazilian Guidelines of Hypertension - 2020. Arq Bras Cardiol 2021; 116 (03) 516-658
• 11 Magkas N, Tsioufis C, Thomopoulos C. et al. Orthostatic hypertension: From pathophysiology to clinical applications and therapeutic considerations. J Clin Hypertens (Greenwich) 2019; 21 (03) 426-433
• 12 Palatini P. Orthostatic Hypertension: A Newcomer Among the Hypertension Phenotypes. Hypertension 2023; 80 (10) 1993-2002
• 13 Barochiner J, Cuffaro PE, Aparicio LS. et al. Predictors of masked hypertension among treated hypertensive patients: an interesting association with orthostatic hypertension. Am J Hypertens 2013; 26 (07) 872-878
• 14 Tabara Y, Igase M, Miki T, Ohyagi Y, Matsuda F, Kohara K. J-SHIPP study group. Orthostatic hypertension as a predisposing factor for masked hypertension: the J-SHIPP study. Hypertens Res 2016; 39 (09) 664-669
• 15 Lee H, Kim HA. Orthostatic hypertension: An underestimated cause of orthostatic intolerance. Clin Neurophysiol 2016; 127 (04) 2102-2107
• 16 Falla C, Young A, Pope A, O'Driscoll DM. Obstructive sleep apnea during REM sleep: effects on morning and evening blood pressure. Sleep 2023; 46 (03) zsac259
• 17 Fernandez-Mendoza J, He F, Calhoun SL, Vgontzas AN, Liao D, Bixler EO. Association of Pediatric Obstructive Sleep Apnea With Elevated Blood Pressure and Orthostatic Hypertension in Adolescence. JAMA Cardiol 2021; 6 (10) 1144-1151
• 18 Shibao C, Arzubiaga C, Roberts II LJ. et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 2005; 45 (03) 385-390
• 19 Singer W, OpferGgehrking TL, McPhee BR, Hilz MJ, Low PA. Influence of posture on the Valsalva manoeuvre. Clin Sci (Lond) 2001; 100 (04) 433-440
• 20 Baguet JP, Lévy P, Barone-Rochette G. et al. Masked hypertension in obstructive sleep apnea syndrome. J Hypertens 2008; 26 (05) 885-892
• 21 Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96 (04) 1897-1904
• 22 Narkiewicz K, Montano N, Cogliati C, van de Borne PJ, Dyken ME, Somers VK. Altered cardiovascular variability in obstructive sleep apnea. Circulation 1998; 98 (11) 1071-1077
• 23 Macey PM, Kumar R, Woo MA, Yan-Go FL, Harper RM. Heart rate responses to autonomic challenges in obstructive sleep apnea. PLoS One 2013; 8 (10) e76631

Publication History

Received: 01 November 2024

Accepted: 20 June 2025

Article published online:
18 August 2025