International Journal of Cardiology 186 (2015) 216–218

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Letter to the Editor

Heart rate response to simulated obstructive apnea while awake predicts bradycardia during spontaneous obstructive sleep apnea Miriam Huettner b, Ulrich Koehler b, Christoph Nell b, Karl Kesper b, Olaf Hildebrandt b, Wolfram Grimm a,⁎ a b

Department of Cardiology, University Hospital of Marburg and Gießen, Philipps-University Marburg, Marburg, Germany Sleep Disorder Unit of the Department of Pneumology, University Hospital of Marburg and Gießen, Philipps-University Marburg, Marburg, Germany

a r t i c l e

i n f o

Article history: Received 29 January 2015 Accepted 7 March 2015 Available online 18 March 2015 Keywords: Bradycardia Obstructive sleep apnea Mueller maneuver

Bradycardia during obstructive sleep apnea (OSA) is a common finding and is thought to be due to enhanced vagal tone rather than structural abnormalities of sinus node or atrioventricular conduction system [1]. Simulated obstructive apnea by attempts to inhale against voluntarily closed upper airways known as Mueller maneuver has been shown to increase vagal tone with subsequent bradycardia in animal experiments, healthy controls and in patients with sleep apnea [2–10]. To date, the correlation between Mueller maneuver induced bradycardia and OSA induced bradycardia in patients with OSA is unknown. We prospectively compared the heart rate response using beat-tobeat heart rate analyses during repeated Mueller maneuvers and spontaneous OSA in 34 patients with severe OSA (Table 1). Mueller maneuvers were performed using a nasal clip and a mouth occluder which incorporated a pressure sensor (Fig. 1). The number of inspiratory efforts and the duration of airway occlusion during Mueller maneuvers in each patient were similar to the average number of inspiratory efforts and apnea length during 10 randomly selected OSA episodes of each study patient. Mueller maneuvers were performed aiming at a submaximal inspiratory pressure of − 50 mm Hg and a maximal inspiratory pressure in each patient. Mean heart rate was determined from a 5 s period preceding and following each Mueller maneuver and each OSA episode and from the time during each Mueller maneuver and OSA episode. The maximum heart rate response to each Mueller maneuver ⁎ Corresponding author at: Department of Cardiology, Philipps-University Marburg, Baldingerstraße, 35033 Marburg, Germany. E-mail address: [email protected] (W. Grimm).

http://dx.doi.org/10.1016/j.ijcard.2015.03.245 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

or OSA episode was calculated by the difference between the longest RR interval during the Mueller maneuver or OSA episode and the shortest RR interval during the 5 s period before and after the Mueller maneuver or OSA episode (Fig. 2). Polysomnography revealed severe OSA with a mean AHI of 52.9 ± 62.0/h in the 34 study patients. Mean apnea length during OSA was 23.7 ± 5.3 s with a mean number of 6.1 ± 1.9 inspiratory efforts against closed airways in 10 randomly selected apnea episodes (Table 1). Mueller maneuvers using submaximal inspiratory pressures of −50 mm Hg, Mueller maneuvers using maximal inspiratory pressures and spontaneous OSA episodes all resulted in a significant decrease in minimal heart rate during the apnea episodes (Table 2, Fig. 2). The maximum heart rate decrease during Mueller maneuvers and subsequent heart rate increase following Mueller maneuvers showed a significant correlation with the maximum heart rate decrease and subsequent heart rate increase during spontaneous OSA episodes (Fig. 2). In contrast to heart rate, minimal oxygen saturation decreased significantly only during spontaneous OSA episodes, but not during Mueller maneuvers (Table 2). Similar to a previous smaller study in 9 patients with OSA reported by Hanly et al. [4], our study examined the relationship between heart rate response during spontaneous OSA episodes and simulated obstructive apnea using similar apnea lengths and similar numbers of inspiratory efforts for Mueller maneuvers as in spontaneous OSA episodes. In addition, our study exclusively enrolled obese patients with severe OSA, who are known to be at particularly high risk for pronounced

Table 1 Clinical characteristics of 34 study patients with obstructive sleep apnea. Patients with obstructive sleep apnea (%)

34 (100)

Gender: male/female Age, years Body mass index, kg/m2 Sinus rhythm, n Arterial hypertension, n Active smoking, n Diabetes mellitus, n ß-Blockers, n Antiarrhythmic drugs, n Apnea–hypopnea index Apnea length, s Inspiratory efforts during apnea, n

31/3 49.5 ± 10.2 33.9 ± 7.3 34 (100) 17 (50) 13 (38) 0 (0) 0 (0) 0 (0) 52.9 ± 62.0 23.7 ± 5.3 6.1 ± 1.9

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Fig. 1. Simulated obstructive apnea by Mueller maneuver using 6 inspiratory efforts with submaximal intrathoracic pressure of −50 mm Hg. Note the occurrence of bradycardia at the end of the apnea episode.

nocturnal bradycardia [1]. The major finding of our study is a significant correlation between OSA associated bradycardia and Mueller maneuver induced bradycardia. This correlation was significant for both, Mueller maneuvers with submaximal negative pressures of − 50 mm Hg and Mueller maneuvers with maximal negative pressures. In our study, we adjusted the number of inspiratory efforts during Mueller maneuver to the number of inspiratory efforts during OSA in each patient, which resulted in comparable total apnea lengths between Mueller maneuvers and OSA in each patient. This concept is based on the observation by Zwillich et al. [3] that heart rate slowing during obstructive sleep apnea critically depends on apnea length, which also correlates with

the extent of oxygen desaturation during OSA. The role of oxygen desaturation as trigger of severe bradycardia during OSA, however, remains controversial. The first small study investigating the impact of oxygen supplementation in OSA was reported by Zwillich et al. [3] in 1982. As a result, oxygen administration completely prevented bradycardia during apnea in 4 out of 6 study patients with OSA [3]. In our present study, Mueller maneuvers lead to a significant heart rate decrease during apnea in the absence of significant oxygen desaturations as shown in Table 2. Our findings suggest that prolonged negative intrathoracic pressures during obstructive apnea are more important than oxygen desaturations as triggers of increased of vagal tone and subsequent

A) Heart rate response to obstructive sleep apnea and Mueller Maneuver using submaximal negative intrathoracic pressure of -50 mmHg

B) Heart rate response to obstructive sleep apnea and Mueller maneuver using maximal negative intrathoracic pressure.

Fig. 2. Correlation between maximum heart rate response to obstructive sleep apnea and simulated obstructive apnea using Mueller maneuver. A) Heart rate response to obstructive sleep apnea and Mueller Maneuver using submaximal negative intrathoracic pressure of −50 mm Hg. B) Heart rate response to obstructive sleep apnea and Mueller maneuver using maximal negative intrathoracic pressure.

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Table 2 Heart rate and O2 saturation during Mueller maneuver and obstructive apnea. Pre-apnea

During-apnea

Post-apnea

Mueller maneuver with submaximal negative pressure Mean heart rate, bpm 75 ± 11 73 ± 11 Minimal heart rate, bpm 72 ± 11 63 ± 13⁎ Mean O2 saturation, % 95 ± 2 95 ± 2 Minimal O2 saturation, % 94 ± 2 94 ± 2

73 ± 12 66 ± 14† 95 ± 2 94 ± 2

Mueller maneuver with maximal negative pressure Mean heart rate, bpm 75 ± 10 Minimal heart rate, bpm 72 ± 11 Mean O2 saturation, % 95 ± 2 94 ± 2 Minimal O2 saturation, %

73 ± 11 61 ± 11⁎ 95 ± 2 94 ± 2

75 ± 11 66 ± 12† 95 ± 2 95 ± 2

Spontaneous obstructive sleep apnea Mean heart rate, bpm 66 ± 11 Minimal heart rate, bpm 64 ± 10 Mean O2 saturation, % 92 ± 3 91 ± 3 Minimal O2 saturation, %

62 ± 8 55 ± 8⁎ 92 ± 3 89 ± 4⁎

68 ± 9 62 ± 9† 93 ± 3 93 ± 2†

⁎ p b 0.05 for during-apnea versus pre-apnea. † p b 0.05 for during-apnea versus post-apnea.

bradycardia at the end of simulated apnea. In addition, Hanly et al. [4] failed to reproduce the findings of Zwillich et al. [3]. In the study by Hanly et al. [4] Mueller maneuver induced bradycardia persisted in almost all OSA patients despite oxygen supplementation. Andreas et al. [5] performed Mueller maneuvers of fixed duration in 15 OSA patients and 15 healthy controls. As a result, Mueller maneuvers resulted in a significant decrease in heart rate in the majority of OSA patients, but only in few healthy controls. In addition, Andreas et al. [5] found a significant correlation between Mueller maneuver induced bradycardia in OSA patients and the apnea–hypopnea index as an established marker for OSA severity. The use of Mueller maneuver induced bradycardia as a potential simple screening test for OSA, however, was limited a sensitivity of 80% and a specificity of only 51% in the study by Andreas et al. [5]. In conclusion, our present study confirmed the hypothesis of previous smaller studies that simulated obstructive apnea by inhaling against an obstructed airway while awake known as Mueller maneuver predicts

heart rate response during sleep apnea in patients with severe OSA. In addition, our study supports the hypothesis that prolonged negative intrathoracic pressures during obstructive apnea are more important than oxygen desaturations as triggers of increased vagal tone and subsequent bradycardia. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] W. Grimm, U. Koehler, E. Fus, J. Hoffmann, V. Menz, R. Funck, J.H. Peter, B. Maisch, Outcome of patients with sleep apnea-associated severe bradyarrhythmias after continuous positive airway pressure therapy, Am. J. Cardiol. 86 (2000) 688–692. [2] R.S. Fitzgerald, J.L. Robotham, A. Anand, Baroreceptor output during normal and obstructed breathing and Mueller maneuvers, Am. J. Physiol. 240 (1981) H721–H729. [3] C. Zwillich, T. Devlin, D. White, N. Douglas, J. Weil, R. Martin, Bradycardia during sleep apnea. Characteristics and mechanism, J. Clin. Investig. 69 (1982) 1286–1292. [4] P.J. Hanly, C.F. George, T.W. Millar, M.H. Kryger, Heart rate response to breath-hold, valsalva and Mueller maneuvers in obstructive sleep apnea, Chest 95 (1989) 735–739. [5] S. Andreas, G. Hajak, B. von Breska, E. Rüther, H. Kreuzer, Changes in heart rate during obstructive sleep apnoea, Eur. Respir. J. 5 (1992) 853–857. [6] V.K. Somers, M.E. Dyken, J.L. Skinner, Autonomic and hemodynamic responses and interactions during the Mueller maneuver in humans, J. Auton. Nerv. Syst. 44 (1993) 253–259. [7] M. Orban, C.J. Bruce, G.S. Pressman, P. Leinveber, A. Romero-Corral, J. Korinek, T. Konecny, H.R. Villarraga, T. Kara, S.M. Caples, V.K. Somers, Dynamic changes of left ventricular performance and left atrial volume induced by the Mueller maneuver in healthy young adults and implications for obstructive sleep apnea, atrial fibrillation, and heart failure, Am. J. Cardiol. 102 (2008) 1557–1561. [8] G. Camen, C.F. Clarenbach, A.C. Stöwhas, V.A. Rossi, N.A. Sievi, J.R. Stradling, M. Kohler, The effects of simulated obstructive apnea and hypopnea on arrhythmic potential in healthy subjects, Eur. J. Appl. Physiol. 113 (2013) 489–496. [9] C.F. Clarenbach, G. Camen, N.A. Sievi, C. Wyss, J.R. Stradling, M. Kohler, Effect of simulated obstructive hypopnea and apnea on thoracic aortic wall transmural pressures, J. Appl. Physiol. 115 (2013) 613–617. [10] T. Konecny, A.D. Khanna, J. Novak, A.A. Jama, G.M. Zawadowski, M. Orban, G. Pressman, J. Bukartyk, T. Kara, F. Cetta Jr., B.A. Borlaug, V.K. Somers, G.S. Reeder, Interatrial pressure gradients during simulated obstructive sleep apnea: a catheter-based study, Catheter. Cardiovasc. Interv. 84 (2014) 1138–1145.

Heart rate response to simulated obstructive apnea while awake predicts bradycardia during spontaneous obstructive sleep apnea.

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