Propranolol mitigates sleep apnea-related cardiac responses during CPAP withdrawal: a randomized placebo-controlled cross-over clinical study

Abstract

Background

Obstructive Sleep Apnea (OSA) causes hemodynamic and autonomic changes during sleep that may promote cardiovascular dysfunction. The extent of heart rate acceleration following respiratory events is associated with mortality in OSA patients. Beta blockers may blunt hemodynamic sequelae of OSA but their impact on heart rate, breathing, sleep and vascular function have not been systematically studied.

Methods

We performed a double-blind randomized crossover study of long-acting propranolol long-acting (LA, 80 mg) vs. placebo interceded by a 1-week washout in OSA patients. In these patients, we used a 3-night CPAP withdrawal protocol to temporarily elicit severe untreated OSA. Participants received propranolol or placebo at 6:30 PM and underwent polysomnography followed by morning blood pressure (BP), reactive hyperemia index (RHI) and augmentation index (AIX) assessments. The primary outcome was heart rate. Secondary outcomes heart rate trajectory over time, OSA severity, sleep architecture, BP, RHI and AIX. Outcomes were compared non-parametric paired tests, or mixed effects regression for heart rate trajectory.

Results

21 participants (51 ± 11 years old, 62% male, BMI 33.8 ± 6.8 kg/m²) completed the study. Propranolol decreased mean overnight heart rate by 3.6 BPM (p < 0.001). Analysis by event phase revealed that propranolol reduced heart rate during stable sleep and blunted heart rate accelerations associated with apneas, hypopneas and arousals. Propranolol also reduced sleep efficiency, stage N2 sleep percentage and morning diastolic BP was reduced by propranolol but OSA severity, systolic BP, RHI or AIX were unchanged.

Conclusion

Propranolol mitigates markers of OSA-related cardiovascular risk including disordered-breathing-related heart rate accelerations but impaired sleep quality. These findings may have therapeutic application for patients with OSA and inform the interpretation of data from patients with OSA taking BB.

Clinical Trial Registration.

NCT03049306.

Supplementary Information

The online version contains supplementary material available at 10.1007/s11325-026-03645-8.

Background

Obstructive sleep apnea (OSA) is associated with hypertension and cardiovascular disease (CVD). Seminal studies have shown that obstructive breathing events trigger surges in heart rate, blood pressure, and sympathetic activity [1]. Cohort studies indicate that greater heart rate elevations following OSA events [2], or more frequent heart rate surges during sleep, are associated with cardiovascular morbidity or mortality [3]. Treatment of OSA with continuous positive airway pressure (CPAP) can reduce blood pressure and plasma catecholamines [4], which may play an important role in the pathogenesis of OSA-related cardiovascular sequelae.

OSA-related elevations in autonomic tone may reduce vascular endothelial function and compliance, which may precede CVD. The reactive hyperemia index (RHI), a measure of endothelial function and an independent predictor of CVD, is reduced among OSA patients in some studies. Stiffening of the aorta alters peripheral arterial pressure profiles, increasing the amplitude of the secondary pressure peak that results from reflections from aortic bifurcation. The resulting enhancement of the composite wave relative to its initial value, the augmentation index (AIX), can be increased by several factors, including stiffening of the aortic walls through sympathetically modulated aortic smooth muscle contraction. In some studies, CPAP treatment of OSA lowers AIX [5]. Taken together, sympathetic discharges from OSA may impair endothelial function (reduce RHI) and increase arterial stiffness (increase AIX).

Beta-blockers (BB) might blunt autonomic responses to OSA and mitigate CVD risk. In observational studies, patients taking BB demonstrated more stable heart rate surrounding OSA events compared to BB-naïve patients [6, 7]. Whether BB use affects RHI or AIX in patients with OSA has not been systematically examined with randomized placebo-controlled studies with detailed hemodynamic measurements. Our study tests the hypothesis that propranolol mitigates nocturnal heart rate elevations and morning RHI and AIX alterations due to OSA.

To rigorously study the effects of BB on vascular function in OSA, we utilized a CPAP withdrawal paradigm. CPAP withdrawal provides a controlled model for studying the physiological effects of sleep apnea in patients already treated with CPAP. This approach avoids confounding by treatment non-adherence, limits exposure to OSA to a period, and has been widely used in prior mechanistic studies. In terms of BB choice, we chose propranolol, as it is a non-selective, lipophilic BB with sympatholytic effects across multiple organs, including the central nervous system.

Study design and methods

This was a single-center, randomized cross-over study of a single dose of propranolol (Inderal LA 80 mg) vs. placebo during 3-night CPAP withdrawal separated by a 1 to 4-week washout between sleep laboratory visits. The Propranolol for Sleep Apnea Therapy (PROSAT) clinical trial was registered with clinicaltrials.gov (NCT03049306). The study was originally designed to examine the effects of beta-blockade on metabolic outcomes throughout the night during CPAP withdrawal and included 3 arms, (1) CPAP, (2) OSA + BB, (3) OSA + placebo. Due to challenges with recruitment, including COVID-19-related interruptions, we altered the study objectives to focus on cardiovascular outcomes and on 2 arms, OSA + BB vs. OSA + placebo, after consulting with the data monitoring and safety board.

This study was approved by the Johns Hopkins Institutional Review Board (IRB00113241). Full inclusion and exclusion criteria are available in the supplement. Briefly, we recruited patients, aged 20–65 years, with treated OSA (AHI ≥ 20 events/hr) from our Sleep Disorders Center. Exclusion criteria included non-OSA sleep disorders, pregnancy, diabetes necessitating insulin therapy, hypotension, significant cardiac disorders and sympatholytic or anti-arrhythmic therapy. We also excluded patients at increased risk of motor vehicle collision from CPAP withdrawal (e.g. those with a history of dozing while driving or commercial driver licenses).

At screening, all participants underwent a history, physical exam, and EKG. Eligible participants were randomized to propranolol (Inderal LA 80 mg) or placebo in random order. They were instructed to stop using CPAP starting 2 nights preceding each visit to account for milder OSA immediately after CPAP withdrawal [8]. During CPAP withdrawal nights, patients used nasal dilator strips as a placebo. During study visits, participants received a standardized dinner at 17:30 and underwent in-laboratory polysomnography (PSG) at 22:30 with serial blood sampling, as previously published [5]. Samples were taken at 17:30, 19:00, 20:00, 21:00, 22:00, 22:30 (lights out) and Q 30 min thereafter until 6:30 AM (lights on) and stored for future metabolic analysis. Attended PSG included electroencephalography, electrooculography, oximetry, respiratory effort, and transcutaneous CO₂ and were scored according to American Academy of Sleep Medicine guidelines. Hypopneas were defined as periods of ≥ 30% reduction in flow lasting ≥ 10 s, associated with ≥ 4% oxyhemoglobin desaturation.

Participants were awakened at 06:30. At 07:00, we performed peripheral arterial tonometry using EndoPAT (Itamar Medical). While semi-recumbent, we measured participants’ baseline pulse wave amplitude, from which AIX was obtained, normalized to a heart rate of 75 beats per minute (BPM) [5]. Thereafter, a pressure cuff was inflated to occlude the brachial artery occlusion for 5 min and then released to allow reperfusion of the distal arm. RHI was the post-occlusion / pre-occlusion pulse amplitude ratio.

Statistical methods

Effect size and power estimates were informed by a pilot study comparing propranolol with placebo (n = 6). Mean sleeping heart rate (SD) was 62.2 (9.2) BPM under placebo and was reduced by 6.7 BPM with propranolol. The SD of the within-subject difference was 8.9 BPM. Under a paired t-test framework, we estimated that a sample size of 16 participants would provide 80% power to detect a 10% reduction in sleeping heart rate (6.2 BPM) at a significance level of 0.05 using a one-tailed test. A one-tailed analysis was specified a priori, as β-adrenergic blockade is expected only to reduce heart rate. Power calculations were performed using the stats::power.t.test() function in R. To account for attrition and lower effect size, we targeted a sample size of 20 participants.

The primary outcome was mean overnight heart rate, derived from the oximeter plethysmography signal and time-averaged to 1-s resolution. We censored data before lights on, after lights off, or data containing oximetry artifact (< 0.1% of the data set). Heart rate data was averaged per night and compared between nights within subjects with a Wilcoxon signed-rank test, as heart rate distribution was not normally distributed. For longitudinal analyses of heart rate trajectory across the night (a secondary outcome), we used a linear mixed-effects model with participant ID as a random intercept and fixed effects for time, drug, and the time × drug interaction, allowing us to account for repeated measurements within participants. To explore the impact of propranolol on heart rate responses following sleep events (apneas, hypopneas, arousals, or respiratory arousals), we extracted the minimum heart rate during events, the maximal heart rate up to 10 s following events and the heart rate change surrounding each respiratory event. Two-sided p values < 0.05 were considered statistically significant. All analyses were performed using R (version 4.02) using the lme4 package for mixed effects modeling. Data are in controlled access data storage at Johns Hopkins University. The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Results

Study population

Figure 1 shows a CONSORT diagram of the study. Among 24 people consented, 23 were randomized and 21 subjects completed the study. 1 subject from each randomization arm withdrew prior to study visits. Participants’ baseline characteristics Table 1 were notable for 62% male, aged 51 ± 11 years old, and a BMI of 33.8 ± 6.8 kg/m². There were no differences in demographics by randomization order (not shown). One-third of the cohort had hypertension or hyperlipidemia, and 19% had type 2 diabetes.

Fig. 1.

CONSORT diagram of the PROSAT Study

Table 1.

Baseline clinical characteristics (n = 21)

	Mean ± SD or # (%)
Age (years)	51 ± 11
Male Sex	13 (62%)
Body mass index (kg/m2)	33.8 ± 6.8
Hypertension	10 (48%)
Hyperlipidemia	7 (33%)
Diabetes	4 (19%)
Pre-Diabetes	1 (5%)
Medications
Metformin	2 (9.5%)
Statin	4 (19%)
ACE Inhibitor	5 (24%)
Angiotensin Receptor Blocker	3 (14.3%)
Amlodipine	2 (9.5%)
Number of Antihypertensive Drugs
1 Drug	9 (43%)
2 Drugs	1 (5%)
≥ 3 Drugs	0 (0%)
Race
Asian	3 (14%)
Black	6 (29%)
Native American	1 (4.8%)
White	9 (43%)
Ethnicity
Hispanic	2 (9.5%)
Non-hispanic	19 (91.5%)

Heart-rate-related outcomes

Propranolol decreased heart rate throughout the night Fig. 2. Heart rate changes were already apparent before sleep onset and persisted throughout the night. The difference in average heart rate between propranolol and placebo was 3.9 BPM (propranolol: 64.1 ± 5.1, placebo: 60.2 ± 4.4: p < 0.001). In terms of heart rate trajectory over the course of the night, we found that heart rate decreased progressively, regardless of drug (time ß = −0.361 BPM per hour, p < 0.001). Propranolol caused an overall lower heart rate (drug ß = −0.878 BPM, p < 0.001), and a steeper decline in heart rate (time * drug ß = −0.216 BPM/hr, p < 0.001) over time. Propranolol also reduced heart rate variability assessed by the moving window standard deviation of the heart rate (p < 0.001). Propranolol reduced the proportion of the night spent at any given threshold heart rate Fig. 2, bottom panel. These effects were most pronounced at greater heart rates, i.e. propranolol reduced the proportion of the night spent with heart rate > 80 BPM from 6.7% to 1.8% and the proportion with heart rate > 70 was reduced from 26.8% to 16%. In post-hoc analyses stratified by sleep stage Fig. 3, we found that propranolol reduced heart rate and heart rate variability by similar degrees across all sleep and wake stages. Heart rate was reduced by 3.7 BPM in men (n = 13) and 4.5 BPM in women (n = 8, supplemental e-Fig. 1). Finally, we tested the hypothesis that propranolol reduced heart rate changes surrounding events including apneas and hypopneas, with and without arousals. The effects of propranolol on heart rate throughout the time course of apneas and hypopneas are shown in Fig. 4. Propranolol decreased the heart rate during and after sleep apnea events and blunted the increase in heart rate following all events, regardless of the presence of arousals Fig. 5. Propranolol did not alter the effect of arousals on post-apnea heart rate increases (p > 0.05 for interaction). In summary, propranolol lowered mean overnight heart rate during wake and sleep, and specifically heart rate changes after OSA-related events.

Fig. 2.

Mean overnight heart rate (top panel) and standard deviation of heart calculated every 5 min (middle panel) among 21 study participants. Propranolol LA 80 mg or placebo was taken at 7:00 PM, lights were turned off at 10:30 PM, and lights were turned on at 06:30 AM. Wilcoxon signed rank exact test p-value: 0.001 for both outcomes. The cumulative distribution of heart rate throughout night are presented in bottom panel

Fig. 3.

Average heart rate (top row) and standard deviation of the heart rate by sleep stage among 21 participants. Heart rate and SD of the heart rate were significantly reduced in all sleep stages (p < 0.01, Wilcoxon signed rank test). N1, NREM stage 1; N2, NREM stage 2, N3, NREM stage 3, REM, rapid eye movement sleep

Fig. 4.

Evolution of heart rate during and after apneas and hypopneas. The data are stratified by event duration for clarity. Lines and shaded areas represent means ± standard error of the mean for all events

Fig. 5.

Heart rate nadir during and post-respiratory-event peak with and without arousals. heart rate was decreased during and after respiratory events (p < 0.05, Wilcoxon signed rank exact test). propranolol reduced Peak-nadir difference significantly and by similar levels regardless of presence of arousals (p < 0.05 for independent effect, p > 0.05 for interaction by ANOVA)

Sleep apnea and sleep architecture

Propranolol had no effect on OSA severity as measured by AHI, arousal index, or variables of hypoxia such as oxygen desaturation index (ODI), time of oxyhemoglobin saturation < 90% (T90%), or average or minimum oxyhemoglobin saturation Table 2. Regarding sleep architecture, propranolol reduced total sleep time from 372 ± 56 to 336 ± 62 min, a difference of 36 (95% CI: [−85, 135]) minutes decrease in sleep efficiency. Sleep distribution shifted towards lighter stages of NREM sleep Table 2.

Table 2.

Sleep architecture and sleep apnea metrics (n = 21)

Sleep Architecture	Placebo	Propranolol	p
Total Sleep Time (min)	372 ± 56	336 ± 62	0.02
Sleep Efficiency (%)	78 ± 12	70 ± 13	0.02
Stage N1 (%)	22 ± 12	28 ± 18	0.01
Stage N2 (%)	52 ± 8	45 ± 10	0.02
Stage N3 (%)	15 ± 10	16 ± 10	0.8
Stage REM (%)	10.5 ± 5.1	10.4 ± 5.7	0.9
Arousal index (events/hr)	67 ± 27	68 ± 29	0.5
Sleep Apnea
AHI (events/hr)	44 ± 29	43 ± 27	0.7
ODI3 (events/hr)	56 ± 32	53 ± 28	0.6
ODI4 (events/hr)	41 ± 30	40 ± 27	0.9
Mean Desaturation Nadir (%)	87.9 ± 4.9	88.6 ± 4.0	0.8
T90% (min)	65 ± 85	54 ± 61	0.2
Minimum O2 (%)	79 ± 8	80 ± 7	0.6

AHI Apnea–hypopnea index

ODI₃ and ODI₄: frequency per hour of sleep of oxyhemoglobin desaturations ≥ 3% and ≥ 4%, respectively.

T90%: Duration of sleep with oxyhemoglobin saturation < 90%

p values were determined by Wilcox signed rank test.

Morning vascular function

After awakening, propranolol continued to affect heart rate Table 3. The morning heart rate was reduced from 63 to 57 BPM (mean difference, 5.19 [−4.5, 20]). Propranolol caused a trend in reduction of systolic morning blood pressure from 131 to 125 mm Hg (mean difference, 6.1 [−11.5, 28]) and significantly reduced diastolic blood pressure from 80 to 76 mmHg (mean difference, 4.3 [−10, 17.5]). Propranolol had no effect on RHI or AIX.

Table 3.

Morning blood pressure and vascular outcomes

	Placebo	Propranolol	p
Systolic BP (mmHg)	131 ± 14	125 ± 15	0.07
Diastolic BP (mmHg)	80 ± 9	76 ± 11	0.02
Heart Rate (BPM)	63 ± 9	57 ± 9	0.002
Reactive Hyperemia Index	2.04 ± 0.55	2.11 ± 0.49	0.5
Augmentation Index (%)	14 ± 19	21 ± 29	0.3

Mean ± standard deviation.

Discussion

This randomized trial showed that an evening dose of propranolol lowers overnight average heart rate and blunts heart rate responses to OSA-related events during CPAP withdrawal, a validated method to induce OSA. As expected, CPAP withdrawal elicited severe OSA during sleep with associated perturbations of heart rate, oxygenation, and sleep architecture. Propranolol also reduced morning diastolic blood pressure and heart rate but had no effect on endothelial function (RHI) or arterial stiffness (AIX). Additionally, propranolol did not affect OSA severity but modestly worsened sleep architecture. In the following discussion, we will address these findings in the context of other studies and highlight mechanistic and practical implications.

OSA is characterized by repetitive hypoxemia, hypercapnia, negative intrathoracic pressure swings, and arousals from sleep, each of which triggers phasic sympathetic activation and catecholamine release. Seminal studies in humans and animals have shown the OSA produces cyclical heart rate swings and blood pressure elevation during sleep through a combination of intermittent hypoxia-induced chemoreflex activation and arousal-linked sympathetic activation [1]. In terms of cardiac effects, catecholamines activate β1-adrenergic receptors to increase chronotropy and inotropy, resulting in exaggerated heart rate accelerations following respiratory events. Recurrent apnea-related tachycardia and post-event heart rate overshoot may contribute to cumulative myocardial stress through repeated increases in shear forces, oxygen consumption, and mechanical workload. By reducing both baseline nocturnal heart rate and the amplitude of event-related heart rate accelerations, β-adrenergic blockade may partially restore a physiological “cardiac rest” period during sleep, analogous to the effect of effective CPAP therapy observed in prior studies. Importantly, propranolol is a nonselective β-blocker with central nervous system penetration, which may further dampen sympathetic outflow through central mechanisms, although the relative contribution of central versus peripheral β-adrenergic effects cannot be determined from the present study. Inhibiting this pathway could confer cardiovascular benefits in patients with untreated OSA.

The nocturnal heart rate profile may provide additional prognostic information compared to the AHI and serve as a complementary biomarker of CVD risk in OSA. In the Copenhagen Holter Study, nighttime heart rate was the strongest predictor (out of a 48-h signal) of all-cause mortality over a ~ 6-year observation period [9]. A blunted reduction in nocturnal heart was associated with lower survival among patients with diabetes [10] and heart failure with implanted cardioverter-defibrillators [11], both populations at high risk for OSA.

Higher heart rate following respiratory events was a risk factor for cardiovascular mortality in the Sleep Heart Health Study and the MESA cohort [2], while more frequent heart rate surges during sleep were associated with CVD in the Wisconsin Sleep Cohort Study [3]. In a post-hoc analysis of the RICCADSA study, investigators found that a reduction in apnea-related heart rate changes from 6 to 4 BPM, similar to the changes observed in our study, was associated with a 1.5 fold reduction in risk for CVD [12]. Alternatively, increased heart rate and post-apnea heart rate accelerations may be driven by impaired perfusion from atherosclerotic vascular disease. In summary, lower nighttime heart rate and blunted apnea-related heart rate variations are markers of better CV outcome in both OSA-specific cohorts and other studies.

Our finding that propranolol lowered heart rate during sleep resembles that of observational BB studies in OSA patients. Lombardi et al. examined 228 consecutive patients who underwent PSG. After excluding patients with pacemakers or anti-arrhythmic therapy, they identified 78 BB-naïve and 88 BB-treated patients. The average heart rate in BB-naïve patients was 61.4 BPM while that of BB-treated group was 59.7 (p = 0.054) and the latter exhibited less tachycardia after respiratory events [7]. Wolf et al. examined 88 patients from a hypertension clinic who underwent PSG with an AHI > 15 and excluded those with significant cardiopulmonary disease. They compared BB-naïve patients (n = 32) to those who were treated with BB (n = 56). They found that heart rate acceleration after apneas was significantly lower in patients treated with BB (82 vs. 74 BPM) [6]. The magnitude of heart rate difference in our study is smaller, and could be due to differing BB regimens, the short-term nature of our experiment, or indication bias in the observational study (compared to BB-naïve patients, the BB-treated group had a greater prevalence of coronary artery disease (29% vs. 0%), which could contribute to the heart rate acceleration.

Interventional BB studies involving patients with OSA were primarily designed to compare the efficacy of pharmacological approaches for hypertension. Reasoning that OSA causes sympathetic activation and suppression of nitric oxide [13], Heitmann et al. hypothesized that nebivolol, a B1-selective agent with nitric oxide-upregulating properties, might be particularly effective for hypertension in OSA [14]. They randomized patients with untreated OSA to nebivolol (5 mg, n = 16) or an angiotensin receptor blocker, valsartan (80 mg, n = 15). Sleep, daytime heart rate, and daytime BP were measured before and after medication. After six weeks, both groups showed significant reductions in systolic and diastolic BP (nebivolol, −14.8 /—8.6 mmHg; valsartan −11.6 / −8.8 mmHg) and morning heart rate (nebivolol, −11.5, valsartan, −5.4 BPM) without affecting OSA severity. Weichler et al. examined metoprolol (100 mg daily) versus the angiotensin-converting enzyme inhibitor, cilazapril (2.5 mg daily) for eight days [15]. Both drugs reduced BP by a similar degree. Kraiczi et al. compared 6 weeks of atenolol, amlodipine, enalapril, hydrochlorothiazide, and losartan among 40 OSA patients who each randomly received 2 of the agents with an intervening washout period. All medications effectively lowered BP, with atenolol showing a more pronounced effect on nighttime BP [16]. In the current study, we showed that an evening dose of propranolol lowered nocturnal heart rate and next-morning diastolic BP, strengthening the findings of the aforementioned studies with the inclusion of a placebo group and more detailed PSG and heart rate analyses. The BB effect on heart rate trajectory is similar to that of CPAP when compared to our previous study of CPAP withdrawal [5]. Thus, BB treatment may partially restore the window for cardiac rest in patients with OSA.

In our study, propranolol did not alter RHI or AIX, suggesting that the drug did not affect morning vascular function or arterial stiffness. These findings could be interpreted in several ways. First, altered RHI or AIX in OSA patients may result from mechanisms other than increased beta adrenergic signaling. In other clinical contexts such as hypertension, BB did not consistently improve endothelial function [17] or arterial stiffness [18] as compared to other drugs such as angiotensin blockade. Vascular dysfunction in patients with OSA may instead be related to factors such as hypoxia [19] or visceral obesity [20]. Second, the dose or duration of BB may have been insufficient to normalize RHI or AIX. Propranolol LA is designed to provide sustained plasma concentrations over a 24-h period. Propranolol LA has an effective half-life of 10–20 h. The reductions in morning blood pressure and heart rate compared to placebo suggest continued beta-adrenergic blockade at time of measurement (12 h post-dose). We acknowledge that measures of vascular function such as the RHI and AIX may be less sensitive to β-blockade at these concentrations or may require different pharmacodynamic thresholds, or longer treatment duration. In patients with hypertension, atenolol hypertension increased flow mediated dilation, a measure of endothelial function, after one year [21]. Participants in our study had heart rates in the 50 s, suggesting that higher multiple doses may not have been tolerated. Third, lack of an effect of CPAP withdrawal on vascular function could have precluded an improvement with medication. The effects of OSA on vascular outcomes has been heterogeneous [5, 22, 23, 26]. Reversing small and varied effects with BB may require a much larger sample size.

We found that propranolol modestly impaired sleep architecture, consistent with literature suggesting that BB can affect sleep, promote awakenings, and vivid nightmares [24]. The mechanism by which BB alter sleep are not fully understood but may involve suppression of melatonin. Pineal melatonin secretion is tightly regulated by the central circadian clock via sympathetic β1-adrenergic signaling. Lipophilic BB can bind to these receptors and inhibit melatonin production [25]. In addition, BB may reduce REM sleep, which involves sympathetic activation, although we did not observe changes in REM in this study.

The potential role of propranolol in patients with OSA remains uncertain. Its hemodynamic and sympatholytic effects could confer cardiovascular protection, particularly in populations with frequent comorbid hypertension or other cardiovascular dysfunction. However, if adverse effects on sleep are substantial or persistent, the overall risk–benefit balance may be unfavorable.

We acknowledge several limitations of this study. First, the drug intervention was acute, preventing conclusions about long-term BB use in OSA patients. Further long-term studies are needed to establish the time course and persistence of these effects. Chen et al. examined the association of BB use with all-cause mortality among patients with CVD and OSA and found higher risk of death among BB users [26]. However, indication bias in this study makes causal inference difficult. Second, our study did not examine other BB classes such as those with hydrophilic or beta-selective properties. The effects on specific organs or compartments could not be inferred. Third, our study enrolled a relatively small number of patients. As a result, it was not powered to detect small effects from propranolol nor establish confidence in secondary outcomes. Our cohort also was comprised of mostly obese males, which reflects a frequently encountered clinical phenotype; however, caution is warranted in extrapolating these findings to other patient groups with OSA.

In addition, blood pressure was only modestly elevated the morning after placebo administration with only 3 participants who had SBP > 140 mmHg, suggesting that blood pressure was likely well-controlled even among hypertensive participants. A floor effect on SBP and vascular outcomes may therefore explain the lack of significance in SBP, potentially limiting our ability to detect effects on RHI and AIX. Nevertheless, the randomized double-blind, placebo-controlled design, rigorously controlled lab conditions, and comprehensive assessments of our study yielded critical mechanistic insights into the role of beta-adrenergic signaling in OSA-associated hemodynamics. Finally, the effects of propranolol on post apnea-heart rate increases could have been under-estimated, since post-apnea heart rate might not “wash out” before the start of subsequent events, particularly during periods of frequent apnea.

Propranolol reduced overall heart rate and post-OSA event heart rate surges, reduced next-morning diastolic blood pressure, and modestly impaired sleep quality without affecting OSA severity or vascular function. These findings illustrate acute cardiovascular effects of propranolol in OSA patients during sleep. Additional studies are needed to examine the long-term effects of BB on nocturnal heart rate, sleep, cardiovascular risk and neurocognitive outcomes in patients with untreated OSA.

Conclusion

In this randomized crossover study of long-acting propranolol vs. placebo during acute CPAP withdrawal, we found that propranolol blunted heart rate and diastolic blood pressure elevation induced by acute OSA exposure but also compromised sleep quality. These results clarify which of the cardiovascular effects of OSA might be mediated by β-adrenergic signaling.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

AHI

Apnea hypopnea index

AIX

Augmentation index

BB

Beta blockers

CPAP

Continuous positive airway pressure

OSA

Obstructive sleep apnea

RHI

Reactive hyperemia Index

Funding

JCJ is funded by National Institutes of Health (R01HL135483). LVP is funded by National Institutes of Health (K23HL155730). DD is funded by the National Institutes of Health (K23DK133690).

Data availability

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request, as stated in the body of manuscript (Methods, paragraph 7).

Declarations

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Johns Hopkins University School of Medicine Institutional Review Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflicts of interest

All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.