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RESEARCH ARTICLE
Inspiratory muscle strength training lowers blood pressure and sympathetic
activity in older adults with OSA: a randomized controlled pilot trial
Guadalupe Elizabeth Ramos-Barrera, Claire M. DeLucia, and XE. Fiona Bailey
Department of Physiology, University of Arizona College of Medicine, Tucson, Arizona
Submitted 9 January 2020; accepted in final form 27 July 2020
Ramos-Barrera GE, DeLucia CM, Bailey EF. Inspiratory muscle
strength training lowers blood pressure and sympathetic activity in
older adults with OSA: a randomized controlled pilot trial. J Appl
Physiol 129: 449 – 458, 2020. First published July 30, 2020; doi:
10.1152/japplphysiol.00024.2020.—Previous work has shown low-
ered casual blood pressure after just 6 wk of inspiratory muscle
strength training (IMST), suggesting IMST as a potential therapeutic
in the prevention/treatment of hypertension. In this study, we assessed
the effects of IMST on cardiovascular parameters in older, overweight
adults diagnosed with moderate and severe obstructive sleep apnea
(OSA). Subjects were randomly assigned to one of two interventions
1) high-intensity IMST (n⫽15, 75% maximal inspiratory pressure),
or 2) a control intervention (n⫽10, 15% maximum inspiratory
pressure). Subjects in both groups trained at home completing 30
training breaths/day, 5 days/wk for 6 wk. Pre- and posttraining
measures included maximal inspiratory pressure, casual and ambula-
tory blood pressures, spontaneous cardiac baroreflex sensitivity, and
muscle sympathetic nerve activity. Men and women in the high-intensity
IMST group exhibited reductions in casual systolic (SBP), diastolic
(DBP), and mean arterial blood pressures (MAP) [SBP: ⫺8.82 ⫾4.98
mmHg; DBP: ⫺4.69 ⫾2.81 mmHg; and MAP: ⫺6.06 ⫾1.03 mmHg;
P⬍0.002] and nighttime SBP (pre: ⫺12.00 ⫾8.20 mmHg; P⬍0.01).
Muscle sympathetic nerve activities also were lower (⫺6.97 ⫾2.29
bursts/min
⫺1
;P⫽0.01 and ⫺9.55 ⫾2.42 bursts/100 heartbeats; P⫽
0.002) by week 6. Conversely, subjects allocated to the control group
showed no change in casual blood pressure or muscle sympathetic nerve
activity and a trend toward higher overnight blood pressures. A short
course of high-intensity IMST may offer significant respiratory and
cardiovascular benefits for older, overweight adults with OSA. For
Clinical Trial Registration, see https://www.clinicaltrials.gov (Identifier:
NCT02709941).
NEW & NOTEWORTHY Older, obese adults with moderate-severe
obstructive sleep apnea who perform 5 min/day high-intensity inspira-
tory muscle strength training (IMST) exhibit lowered casual and
nighttime systolic blood pressure and sympathetic nervous outflow. In
contrast, adults assigned to a control (low-intensity) intervention
exhibit no change in casual blood pressure or muscle sympathetic
nerve activity and a trend toward increased overnight blood pressure.
Remarkably, adherence to IMST even among sleep-deprived and
exercise-intolerant adults is high (96%).
obstructive sleep apnea; respiratory training; sympathetic activation
INTRODUCTION
Obstructive sleep apnea (OSA) is characterized by repeated
airflow obstruction (apnea) and airflow limitation (hypopnea)
that result in sleep disruption and chronic intermittent hypox-
emia (CIH). CIH has been linked to increases in reactive
oxygen species and oxidative stress that contribute to sympa-
thetic nervous system (SNS) hyperactivity (10, 35, 48, 65) and
hypertension in an estimated 30 –70% of OSA adults (1). The
standard of care for OSA worldwide is continuous positive
airway pressure (CPAP), which delivers a steady stream of
pressurized air via a (nasal/oral) mask to stent the upper airway
and stabilize breathing and blood oxygenation. Among adults
with OSA and hypertension, nightly CPAP use improves
spontaneous baroreflex sensitivity (BRS) (36, 67) and overall
sympathetic nervous system activity (27, 39). However, these
favorable outcomes are offset by uniformly low adherence, i.e.,
⬍4.4 h/night (18, 33, 38, 43), which continues to limit CPAP-
related improvements in cardiovascular health (43).
Aerobic exercise is a first-line treatment for all stages of
hypertension (74) and has well-documented benefits for blood
pressure. Indeed, 2017 guidelines issued by the American
Heart Association and American Cardiology Association ad-
vocate 150 min/week of aerobic exercise among the first-line
treatments for all stages of hypertension (74) to lower blood
pressure. Although traditional forms of aerobic exercise may
improve BRS and lower blood pressure in OSA, the salient
features of OSA including obesity [body mass index (BMI)
⬎30] (19, 61, 75), lethargy (62, 66), and/or exercise intoler-
ance (2, 6, 9, 26), often preclude sustained exertion (16, 41).
In recent years, a novel form of exercise known as inspira-
tory muscle strength training (IMST) has yielded surprising
results including improvements in blood pressure and auto-
nomic balance in patients with hypertension (23, 39) or OSA
(70) and reductions in systemic vascular resistance in healthy
young adults (17, 69). These outcomes are of interest and
importance because in each case they were attained within 6
wk and with a training requirement of just 5 min/day for 5
days/wk or 25 min/wk total training time (70).
Whereas there is evidence that IMST performed daily lowers
casual (resting) blood pressure and plasma catecholamines in
adults with OSA and elevated or stage 1 hypertension (70), it
is unclear what effect it may have on 24-h blood pressure, a
better predictor of blood pressure related end-organ damage
(25, 44). Accordingly, in the current study we obtained mea-
sures of casual and continuous, noninvasive ambulatory blood
pressure monitoring in a cohort of older (60 – 80 yr), predom-
inantly obese (i.e., BMI ⬎30) adults with moderate-severe
OSA [apnea hypopnea index (AHI) ⱖ15] pre-post 6-wk IMST.
Because OSA is a recognized cause of secondary hypertension
and sympathetic nervous system activity plays a fundamental
role in raising blood pressure in this population (11), we also
performed microneurography to quantitate sympathetic neural
Correspondence: E. F. Bailey (ebailey@arizona.edu).
J Appl Physiol 129: 449–458, 2020.
First published July 30, 2020; doi:10.1152/japplphysiol.00024.2020.
8750-7587/20 Copyright ©2020 the American Physiological Societyhttp://www.jap.org 449
Downloaded from journals.physiology.org/journal/jappl by E. Fiona Bailey (064.119.034.107) on September 6, 2020.
activity directed to vascular smooth muscle [i.e., muscle sym-
pathetic nerve activity (MSNA)]. Last, whereas in a previous
IMST study CPAP users had been excluded, the current study
permitted inclusion of participants identified as adherent to
CPAP or mandibular advancement devices (⬎4 h nightly use).
METHODS
This prospective, randomized double-blind controlled pilot clinical
trial was conducted on adults with OSA who were recruited from the
general population via advertisements placed in regional publications.
Details about how the trial was conducted, reporting enrollment,
allocation, follow-up, and analysis of subjects involved in the clinical
trial are presented in a Consolidated Standards of Reporting Trials
(CONSORT) flow chart (see Fig. 1) (21, 58). Exclusion criteria
included asthma, history of respiratory disease, neurological impair-
ment, head/neck or thoracic surgery, hypothyroidism, immune or
nervous system impairments, recent history of infection, body mass
index (BMI) ⬎40 kg/m
2
, apnea hypopnea index ⱕ15.0 events/hour
sleep, majority mixed sleep apnea (i.e., obstructive and central ap-
neas), majority central sleep apnea, anticoagulant medication, chronic
heart failure, unstable angina, myocardial infarction, smoking, hyp-
notic or immunosuppressive medication, or cognitive disorders. Ex-
clusion criteria for systolic blood pressure (SBP) was ⱖ150 and for
diastolic blood pressure (DBP) ⱖ100. The upper limit for SBP is
based on previous observations in OSA adults that show a propensity
for slight increases in BP in some subjects during the first training
week. In view of this possibility, we adopted a somewhat conservative
cutoff for purposes of the pilot trial.
In accordance with the training device manufacturer guidelines
(http://www.powerbreathe-usa.com/), subjects with presence/history
of dyspnea, ruptured eardrum or other middle ear condition, history of
rib fracture, and marked elevated left ventricular end-diastolic volume
and/or pressure also were excluded from participation. Note that
Analysis
Analyzed (n=9)
•
Analysis
Failed MSNA
Randomized (n=25)
Assessed for eligibility (n=136)
Excluded (n=111)
•Not meeting inclusion criteria (n=62)
oAHI < 15 events/hour; mixed or
central apneas (n=34)
o< 4.0 hours HSAT or overnight
AMBP monitoring (n=28)
•Declined/unavailable to participate (n=26)
•Other reasons (n=23)
•Home Sleep Apnea Testing
•Casual Blood Pressure
•Spirometry
•Plmax
•BRS
•
•
MSNA
24 HR Ambulatory BP monitoring
•Plasma catecholamines
Excluded from analysis (n=5)
•< 4.0 hours HSAT or overnight
AMBP monitoring
Analyzed (n=6)
Allocated to interventionAllocated to intervention
Control (n=10)
High Intensity IMST (n=15)
Discontinued intervention Discontinued intervention
Withdrew (n=0)
Withdrew (n=1)
•Home Sleep Apnea Testing
•Casual Blood Pressure
•Spirometry
•Plmax
•BRS
•
•
MSNA
24 HR Ambulatory BP monitoring
•Plasma catecholamines
Excluded from analysis (n=4)
•< 4.0 hours HSAT or overnight
AMBP monitoring
Failed MSNA
Fig. 1. Consolidated Standards of Reporting
Trials (CONSORT) flow chart. AHI, apnea
hypopnea index; HSAT, home sleep apnea
testing; IMST, inspiratory muscle strength
training; AMBP, ambulatory blood pressure
monitoring; BP, blood pressure; BRS, baro-
reflex sensitivity; PI
max
, maximal inspira-
tory pressure.
450 BREATHING TRAINING FOR SLEEP APNEA-RELATED HYPERTENSION
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individuals who were regular users of continuous positive airway
pressure (CPAP) (or a related pressure therapy) or users of mandibular
advancement dental devices were eligible to participate, as were
subjects with elevated, stage 1, or stage 2 hypertension. The Univer-
sity of Arizona’s Human Subjects Protection Program approved the
study procedures, and all subjects provided written informed consent
before being enrolled. Some 200 adults responded to advertisements
placed in a local newsletter, 136/200 adults completed the online
screening questionnaire and were deemed eligible to complete the
preassessments outlined below.
Spirometry
Assessments of lung function comprising assessments of forced
expiratory volume in 1.0 s (FEV
1.0
), forced vital capacity (FVC),
forced inspiratory volume in 1.0 s (FIV
1.0
), forced inspiratory capacity
(FIVC), FEV
1.0
/FVC, FIV
1.0
/FVC, FIV
1.0
/FIVC, peak expiratory
flow (PEF), and peak inspiratory flow (PIF) (WinspiroPRO, Medical
International Research, New Berlin, WI) in accordance with the
guidelines of the American Thoracic Society (45). To determine
maximal inspiratory pressure (PI
max
), subjects generated a maximal
inspiration from residual lung volume using the POWERbreathe
training device in TEST mode. The average of the three trials defined
the individual’s PI
max
(8, 31).
Home Sleep Apnea Testing
We used home sleep apnea testing (HSAT) to reliably identify
those adults in our sample with moderate and severe OSA (50 –52).
The type 3 portable testing device (ApneaLink, ResMed, Bella Vista,
Sydney, Australia) is validated for use in adults with moderate and
severe OSA (20, 24, 46, 56) and captures blood oxygenation, nasal
airflow, and thoraco-abdominal movement and yields estimates of the
severity of sleep-disordered breathing based on monitoring time.
These results are referred to as the respiratory event index (REI).
Home sleep apnea testing also permitted exclusion of other forms of
sleep disordered breathing (e.g., obesity hypoventilation syndrome or
Cheyne Stokes Respiration) on the basis of nasal airflow disturbance,
awake resting, and overnight oximetry measurement. Sleep quality,
sleep duration, sleep efficacy, sleep latency, sleep disturbance, and
impact on daily function using the Pittsburgh Sleep Quality Index
(PSQI) (53) also were recorded.
Ambulatory Blood Pressure Monitoring
Eligible adults, who passed lung function assessments and had an
AHI ⱖ15, completed a period of 24-h ambulatory BP monitoring
(SOMNOmedics, Randersacker, Germany). Given the propensity for
sleep disturbance and arousal reactions to contribute to perturbations in
SBP, we obtained continuous measures of SBP and DBP using a Food
and Drug Administration-approved and European Society of Hyperten-
sion-validated SOMNO-touch noninvasive ambulatory blood pressure
monitor (7). The device includes a small control unit worn on the wrist to
measure pulse transit time (PTT), three-channel electrocardiogram (ECG)
leads placed on the chest, and an oxygen monitor fitted to the finger that
obviates the need for arm cuff inflations that may interfere with sleep
quality (4).
After fitting each subject, the device was calibrated via a manual
blood pressure measurement. Subjects were asked to refrain from any
strenuous physical activity while wearing the device and to report
back to the laboratory 24 h later for data download. For ambulatory
recordings exceeding 4.0-h continuous recording overnight, beat-to-
beat measures of blood pressure (BP) were averaged over the entire
recording period and compared for consistency with repeated mea-
sures over shorter, i.e., 10 min, representative intervals (42).
In-Laboratory Procedures
Subjects initially underwent an in-laboratory blood draw and on a
separate day underwent in-laboratory assessments of resting blood
pressure, resting muscle sympathetic nerve activity (MSNA), and
cardiorespiratory measures (see details below). Subjects were asked to
refrain from caffeine and alcohol for 12 h and instructed not to eat for
at least 4 h before their visit. Each of the measures was repeated at the
6-wk time point after completion of training.
Plasma catecholamines. Subjects underwent a fasting blood draw
and were instructed to refrain from eating or drinking (anything other
than water) and from taking over-the-counter pain or allergy medica-
tions for the 12 h leading up the draw. Venous blood samples were
collected between the hours of 0700 and 1000 from the antecubital
region following 30 min of supine rest in a quiet, temperature-
controlled room. Samples were placed on ice in lithium-heparin-
coated tubes (BD Vacutainer, Franklin Lakes, NJ) and immediately
centrifuged (4°C, 1,500 rpm, 15 min), and the plasma frozen was at
⫺80°C. Plasma samples were analyzed via quantitative high-perfor-
mance liquid chromatography (Associated Regional and University
Pathologists–ARUP Laboratories, Salt Lake City, UT).
Resting blood pressure. In-laboratory measures of resting (seated)
blood pressure were obtained at intake and study close and once
weekly throughout the 6-wk intervention. Measures were taken in
accordance with American Heart Association guidelines (55) with an
automated oscillometric sphygmomanometer (SunTech CT40, Sun-
Tech Medical). Three measures, taken on alternate arms, were aver-
aged to obtain systolic (SBP) and diastolic (DBP) blood pressures and
to determine mean arterial pressure (MAP) using the equation:
(MAP ⫽DBP ⫹1/3[SBP – DBP]). Measures were obtained at the
same time of day and on the same day each week for 6 wk.
Resting spontaneous cardiac baroreflex sensitivity. While subjects
were semirecumbent and after a 20-min rest, we recorded lead II-EKG
continuously (0.3–1.0 kHz) via Ag-AgCl surface electrodes placed on
the chest (2.0 kHz) and beat-to-beat changes in systolic and diastolic
blood pressures (SBP and DBP) at 1-min intervals via automated
finger cuff pressure transducer (400 Hz) (ccNexfin; Bmeye, Amster-
dam, The Netherlands). Data were recorded online using a PowerLab
(ADInstruments, Colorado Springs, CO) interface and LabChart 8.0
software. Moment-to-moment changes in the R-R interval (RRI)
coincident with fluctuations in SBP were used to obtain estimates of
cardiac BRS (28, 29, 54) using proprietary software to identify “up”
and “down” sequences (Cardioseries V2.4, Brazil). Sequences greater
than or equal to cardiac cycles that showed in beat-to-beat increases in
SBP (ⱖ1 mmHg) and lengthening of the R-R interval (ⱖ6 ms) for
each beat in the series or with beat-to-beat decreases in systolic blood
pressure (ⱖ1 mmHg), and shortening of the R-R interval (ⱖ6 ms) for
each beat in the series were included in this analysis (54, 63).
Consecutive R-R intervals were plotted against SBP (mmHg) values
in the preceding cycle to obtain regression lines and correlation values
for each sequence. Correlation coefficients ⬎0.85 were averaged to
obtain individual subject estimates of spontaneous cardiac baroreflex
sensitivity (ms/mmHg) (54). MSNA and beat-to-beat changes in
(systolic and diastolic) blood pressure were recorded over 20 min of
undisturbed rest. Data in the final 10 min of each recording were
subject to analysis. Respiration-related motions of the chest wall (100
Hz) were recorded using respiratory belt transducers (ADInstruments,
Colorado Springs, CO) placed around the chest and abdomen. All data
were recorded continuously throughout ~20 min of undisturbed rest.
Resting muscle sympathetic nerve activity. Concurrent with ECG
recordings, sympathetic nerve traffic was recorded from the common
peroneal nerve using tungsten microelectrodes (200 m: 25– 40 mm;
impedance: 5 M⍀) (FHC, Bowdoin, ME) inserted percutaneously
immediately posterior to the fibular head. Subjects rested semirecum-
bent in the dental chair with the right knee and foot supported by
positioning pillows (VersaForm
,
Performance Health, Warrenville,
IL). Microelectrode placement was confirmed via electrical stimula-
tion (0.02 mA, 1 Hz) as described previously (40). A second micro-
electrode, inserted just below the skin surface ~1.0 cm from the first,
served as a reference electrode. Neural activity was amplified (gain
2⫻10
4
) and filtered (500 Hz–2.0 kHz) using a preamplifier (Neuro-
451BREATHING TRAINING FOR SLEEP APNEA-RELATED HYPERTENSION
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Amp Ex; ADInstruments, Colorado Springs, CO) and signals were
full wave rectified (0.1-s moving window) and stored (10-kHz sam-
pling) using a computer-based data acquisition and analysis system
(LabChart 8.0 software, ADInstruments, Colorado Springs, CO).
Electrode position in muscle fascicles was confirmed by pulse syn-
chronous bursts of activity, elicitation of afferent nerve activity by
mild muscle stretch and absence of response to startle (40).
Negative deflecting cardiac-related sympathetic action potentials
were identified using both unprocessed and root mean squared MSNA
signals and quantitated as the number of bursts per 100 heartbeats,
number of bursts per minute, and total activity (mean burst area/min)
obtained from the root mean square (RMS) processed (moving aver-
age time constant or 200 ms) signal (47, 49, 60, 68, 71, 72). The
recording period was started no earlier than 15 min after insertion of
the electrode and was continuous throughout ~20 min of undisturbed
rest.
6-wk Intervention
Twenty-five adults (17 men, 8 women) were prospectively as-
signed, via stratified block randomization to high-intensity IMST (n⫽
15) or to the control condition (n⫽10), outlined below. All subjects
were unfamiliar with IMST, and all were blinded to their assigned
training group.
Subjects in both groups trained independently at home completing
30 breaths, i.e., 5 sets of 6 breaths with a ~1- to 2-min rest between
each set, 5 days/wk for 6 wk on the POWERbreathe device (K3
Series, Warwickshire, UK). Training was performed at the same time
each day, and data from each day’s training were stored on the device
and uploaded in the laboratory at the end of each training week.
Subjects were instructed first to exhale to residual volume and then
inhaled via the device mouthpiece to their target pressure. As previ-
ously, target pressures for the control group were set to 15% of the
PI
max
, and those for the high-intensity IMST group were set to 75%
of the PI
max
(17, 69, 70). Neither group encountered resistance to
expiration. Because IMST improves inspiratory muscle strength and
subjects in both groups typically show improvement in PI
max
test
performance, target pressures for both groups (i.e., 15% or 75%
PI
max
) were reassessed at the end of each training week.
Statistical Analysis
A per protocol, two-way repeated-measures mixed model ANOVA
was used to test the main effects of treatment (IMST vs. control) and
time point (week 1 vs. week 6). Statistical significance was set at Pⱕ
0.05. If the ANOVA revealed significance, planned post hoc within-
group and between-group comparisons were performed using paired
Table 1. Average values for age, body mass index, neck
circumference, respiratory disturbance index, Pittsburgh
Sleep Quality Index, obstructive sleep apnea therapy type,
cardiovascular risk category, blood pressure medication/s,
and level of physical activity reported by participants in the
control group and high-intensity IMST group at study intake
Parameters Intervention Group
Control (n⫽10) High-Intensity
IMST (n⫽15)
Subjects 6 men, 4 women 11 men, 4 women
Age 69.7 ⫾6.7 65.9 ⫾6.0
BMI, kg/m
2
31.3 ⫾6.5 30.7 ⫾6.2
Neck circumference, cm 41.0 ⫾3.9 41.6 ⫾5.2
RDI 26.2 ⫾13.5 22.9 ⫾11.0
PSQI 9.0 ⫾5.0 8.6 ⫾4.0
OSA therapies
Continuous positive airway pressure 3 3
Mandibular advancement device 1 0
No device 6 2
Cardiovascular risk category
Normal (systolic) BP (⬍120 mmHg) 2 4
Elevated systolic BP (120–129 mmHg) 1 4
Stage 1 hypertension (130–139 mmHg) 2 1
Stage 2 hypertension (⬎140 mmHg) 5 6
BP medications
Beta-blocker 1 3
Angiotensin receptor blocker 1 3
Calcium channel blocker 0 3
ACE inhibitor 3 0
No BP medication 5 6
Physical activity levels
Minimally active (0–2 h exercise/wk) 2 5
Moderately active (3–4 h exercise/wk) 4 7
Vigorously active no. (⬎5 h exercise/wk) 4 3
Average values ⫾SD for age, body mass index (BMI), neck circumference,
respiratory disturbance index (RDI), Pittsburgh Sleep Quality Index (PSQI),
obstructive sleep apnea (OSA) therapy type, cardiovascular risk category,
blood pressure (BP) medication/s and level of physical activity reported by
participants in the control group (n⫽10) and high-intensity inspiratory muscle
strength training (IMST) group (n⫽15) at study intake. BMI, body mass
index; ACE, angiotensin-converting enzyme.
Fig. 2. A–F: individual results for in-laboratory measures of resting blood
pressure for subjects in the high-intensity inspiratory muscle strength training
(IMST; black symbols) (n⫽14) and control (gray symbols) (n⫽10) groups.
Individual results for casual systolic (SBP; Aand B; circles), diastolic blood
pressure (DBP; Cand D), and mean arterial blood pressure (MAP; Eand F)
measured pre (week 1)- and postintervention (week 6). *Significant differences
in the main effect of time pre vs. post (P⬍0.05).
452 BREATHING TRAINING FOR SLEEP APNEA-RELATED HYPERTENSION
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and independent sample ttests, respectively, with significance ad-
justed (P⫽0.025) according to the Bonferroni correction. Investiga-
tors were blinded to participant group assignment during data analy-
sis.
RESULTS
Twenty-five adults were randomized to high-intensity IMST
or the control intervention. One subject was disqualified from
continuing the study due to nonadherence to the training
regimen. As a result, the study retention rate was 96%. There
were no between-group differences in sex, age, neck circum-
ference, BMI, systolic and diastolic BP, respiratory disturbance
index, or PSQI scores (P⬎0.1) at study intake. Details of
subject number, anthropomorphic data, and health status (i.e.,
sleep apnea severity, sleep apnea therapy, cardiovascular risk
category, medications and physical activity levels) for high-
intensity IMST and control groups are presented in Table 1.
Overall, key sleep indexes including awake and resting
oxygen desaturations, and sleep duration, were unchanged pre-
and postintervention for both groups (P⬎0.1). Maximum
inspiratory pressures (PI
max
) were greater pre-post for IMST
(82.6 ⫾12.5 to 116.5 ⫾13.6 cmH
2
O) (P⬍0.001) and control
groups (85.60 ⫾4.5 to 101.2 ⫾6.94 cmH
2
O) (P⬍0.01), but
there was no effect of either intervention on tests of pulmonary
function: FEV
1.0
; FVC; FIV
1.0
; FEV
1.0
/FVC; FIV
1.0
/FIVC;
PEF; or PIF (P⬎0.05) (data not shown).
Individual results for casual in-laboratory measures of systolic,
diastolic, and mean arterial blood pressures are shown in Fig. 2.
For the high-intensity IMST group, average (⫾SD) SBP, DBP,
and MAP all declined from week 1 to week 6 (SBP: ⫺8.82 ⫾
4.98; DBP: ⫺4.69 ⫾2.81; and MAP: ⫺6.06 ⫾1.03); P⬍
0.002). Heart rate and BRS were unchanged (Table 2). For the
control group, measures of blood pressure (SBP: ⫺2.23 ⫾6.85;
Table 2. Average values for respiratory disturbance index;
systolic, diastolic; and mean arterial pressure, heart rate;
and cardiac baroreflex sensitivity for subjects in the high-
intensity IMST group, pre- and postintervention
High-Intensity IMST
Week 1
preintervention
Week 6
postintervention
Home sleep apnea assessment (n⫽15)
Mild (RDI ⱕ15) 0 0
Moderate (RDI 15–29) 12 12
Severe (RDI ⱖ30) 3 2
Group average RDI 22.9 ⫾11.0 21.2 ⫾12.2
Cardiovascular measures (n⫽15)
Systolic blood pressure, mmHg 140.8 ⫾17.9 132.8 ⴞ14.2*
Diastolic blood pressure, mmHg 74.9 ⫾9.9 70.2 ⫾8.6
Mean arterial pressure, mmHg 95.0 ⫾11.2 89.0 ⴞ10.4*
Heart rate, beats/min 59.2 ⫾5.4 59.7 ⫾5.5
BRS, ms/mmHg 10.4 ⫾3.9 10.9 ⫾5.8
Plasma norepinephrine, 80–520 pg/mL 307.1 ⫾69.1 293.8 ⫾72.4
Plasma epinephrine, 10–200 pg/mL 28.0 ⫾13.8 26.5 ⫾12.4
Average values ⫾SD for respiratory disturbance index (RDI); systolic,
diastolic, and mean arterial pressure; heart rate; and cardiac baroreflex sensi-
tivity (BRS) for subjects in the high-intensity inspiratory muscle strength
training (IMST) group (n⫽14), pre (week 1)- and postintervention (week 6).
*Significant difference pre vs. post (P⬍0.01).
Table 3. Average values obtained from 24-h noninvasive
blood pressure monitoring and in-laboratory measures of
resting muscle sympathetic nerve activity for subjects in the
high-intensity IMST group, pre- and postintervention
High-Intensity IMST
Cardiovascular Measures (n⫽9)
Week 1
Preintervention
Week 6
Postintervention
Ambulatory (noninvasive) monitoring
24-h systolic blood pressure, mmHg 143.1 ⫾18.5 136.4 ⫾16.7
24-h diastolic blood pressure, mmHg 77.7 ⫾8.7 75.3 ⫾7.9
24-h heart rate, beats/min 66.1 ⫾2.7 67.1 ⫾6.8
Nighttime systolic blood pressure, mmHg 141.6 ⫾18.9 129.6 ⴞ15.7*
Nighttime diastolic blood pressure, mmHg 76.6 ⫾8.5 74.1 ⫾9.2
Nighttime heart rate, betas/min 57.8 ⫾3.6 59.3 ⫾4.7
Muscle sympathetic nerve activity
Burst incidence, burst/100 beats
⫺1
91.7 ⫾6.7 83.5 ⴞ9.3*
Burst frequency, burst/min
⫺1
53.7 ⫾7.0 46.7 ⴞ8.0*
Average values ⫾SD obtained from 24-h noninvasive blood pressure
monitoring and in-laboratory measures of resting muscle sympathetic nerve
activity (MSNA) for subjects in the high-intensity inspiratory muscle strength
training (IMST) group (n⫽9), pre (week 1)- and postintervention (week 6).
*Significant difference pre vs. post (P⬍0.01).
Fig. 3. A–F: individual results from in home, overnight noninvasive monitoring
of blood pressure for high-intensity inspiratory muscle strength training
(IMST; black symbols) (n⫽9) and control (gray symbols) (n⫽6) groups.
Individual results for systolic blood pressure (SBP; Aand B), diastolic blood
pressure (DBP; Cand D), and mean arterial blood pressure (MAP; Eand F)
measured pre (week 1)- and postintervention (week 6). *Significant differences
in the main effect of time pre vs. post (P⬍0.05).
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DBP: ⫺1.10 ⫾3.96; and MAP: ⫺1.48 ⫾4.60), heart rate (2.2 ⫾
2.4 beats/min), and BRS (⫺0.31 ⫾1.9 ms/mmHg) were un-
changed pre vs. post (P⬎0.1).
Ambulatory blood pressure and MSNA recordings were ob-
tained in a subset of individuals, pre- and postintervention (9
high-intensity and 6 control). Group data for high-intensity IMST
are provided in Table 3 and results for individuals in both groups
are shown in Fig. 3. Despite overall declines in nighttime BP, only
results for SBP (pre: 141.56 ⫾18.93 mmHg; post: 129.55 ⫾
15.67 mmHg) attained significance (P⬍0.01). Nighttime DBP
(pre: 76.56 ⫾8.88 mmHg; post: 74.11 ⫾9.22 mmHg) and MAP
(pre: 98.67 ⫾11.19; post: 92.78 ⫾8.73 mmHg) (Fig. 3) also
Fig. 4. Representative recordings (30 s) of muscle sympathetic nerve activity (MSNA), blood pressure (BP), electrocardiogram (EKG), and chest wall motion
traces from 4 obstructive sleep apnea (OSA) adults pre (week 1)- and post (week 6)-high-intensity inspiratory muscle strength training (IMST). RMS, root mean
squares. *Sympathetic bursts included in participant’s average burst/min count.
454 BREATHING TRAINING FOR SLEEP APNEA-RELATED HYPERTENSION
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declined but did not attain statistical significance (P⬍0.10). In
the control group, average (⫾SD) nighttime SBP (pre: 135.14 ⫾
13.13; post: 144.67 ⫾19.10 mmHg), DBP (pre: 73.17 ⫾13.63;
post: 77.17 ⫾13.72 mmHg) and MAP (pre: 93.83 ⫾13.67; post:
100.33 ⫾15.67 mmHg) slightly increased postintervention (P⬎
0.05) (Fig. 3).
Results for in-laboratory measures of resting MSNA for high-
intensity IMST are provided in Table 3 and representative record-
ings in Fig. 4. Average measures of MSNA bursts per minute
(⫺6.97 ⫾2.29; P⫽0.01) and bursts per 100 heartbeats
(⫺9.55 ⫾2.42; P⫽0.002) were lower at week 6 than in week 1
following high-intensity IMST but did not change following the
control intervention (4.87 ⫾2.80 bursts/min
⫺1
;P⫽0.10 and
5.527 ⫾2.96 bursts/100 heartbeats; P⫽0.85) (Fig. 5). Neither
training protocol was associated with significant changes in plasma
norepinephrine (high-intensity IMST: pretraining 307.10 ⫾69.15 vs.
posttraining 293.82 ⫾72.37; P⫽0.64; control: pretraining 298.71 ⫾
89.43 vs. posttraining 313.29 ⫾99.04; P⫽0.67).
DISCUSSION
OSA is characterized by repeated airway obstructions that
result in intermittent hypoxemia and arousal from sleep, which
together drive increases in nighttime sympathetic nervous ac-
tivity (64). Although previous studies confirm the benefits of
CPAP and/or daily exercise on cardiovascular health (3, 5, 22,
36, 67), adherence rates for CPAP remain low (43). Further-
more, many adults with OSA are unwilling or unable to
maintain a regular exercise program (2, 6).
Compared with traditional forms of aerobic exercise, reten-
tion rates for IMST are consistently high (92–95%) exceeding
those of comparable duration lifestyle, i.e., aerobic exercise
and/or dietary interventions (30, 37). With no treatment-emer-
gent adverse events and a 96% adherence rate (number of
prescribed training sessions completed at the target pressure),
IMST appears well tolerated by the OSA population.
Strengths and Limitations
Participants were recruited via advertisements in a regional
publication. The general recruitment call yielded two groups,
well matched in regard to key parameters of sex, age, BMI,
CPAP use, and sleep apnea severity (see Table 1); however, we
acknowledge that we were unable to obtain complete data sets
from all our subject participants and that the requirement for
pre- and post-24-h blood pressure monitoring and MSNA
recordings posed a particular challenge in this population.
While subject loss does not limit the generalizability of the
lower probability outcomes (i.e., P⬍0.05), the variability
inherent in smaller samples may contribute false negative
outcomes, which may have affected outcomes for measures of
overnight BP.
Sleep and nighttime breathing including blood oxygen de-
saturation (32), nasal airflow, and thoraco-abdominal move-
ment were monitored using an in-home sleep apnea testing
(HSAT) validated for use in adults with moderate and severe
OSA (20, 46, 56). Importantly, the device assesses time spent
with blood oxygen desaturation ⬍90%, nasal airflow, and
thoraco-abdominal movement and the intraclass correlation
between results obtained with this form of home sleep apnea
testing and with overnight PSG is excellent (12).
Pre- and post-HSAT showed no evidence of intervention-
related changes in apnea frequency (respiratory disturbance
index), oxygen desaturation (⬍90%), total sleep time, and
modest improvements in subjects’ subjective assessment of
sleep quality (PSQI). The latter outcome differs from previ-
ously published findings in adults with mild-moderate OSA
(70) who reported improved sleep quality (PSQI) under the
same IMST protocol. Nevertheless, because weight, neck cir-
cumference, physical activity, medications, sleep quality, and
AHI each remained consistent throughout the study period, the
observed reductions in casual and overnight SBP and SNS
hyperactivity cannot be ascribed to change/s in the aforemen-
tioned variables.
Care was taken to exclude participants with prior knowledge
of or experience with inspiratory muscle strength training.
Whereas participants in both groups trained on the same
handheld pressure-threshold training device, followed the same
training regimen (i.e., 30 breaths day for 5 days/wk for 6 wk),
and attended weekly laboratory visits and reassessments, all
visits were coordinated to preclude participant overlap to
ensure participant blinding to high-intensity IMST versus con-
trol intervention formats.
As described previously, training pressures for the control
group were significantly lower than for the high-intensity
group (i.e., 15%PI
max
vs. 75%PI
max
). However, the pressure
range for the control group encompassed ⫺15.0 to ⫺20.0
cmH
2
O exceeding pressures typical of tidal (73) or deep
breathing (34). We anticipated the control intervention may
contribute some improvement in inspiratory muscle strength;
however, the magnitude of the increase in PI
max
(~5 cmH
2
O) is
consistent with previously published findings in healthy adults
Fig. 5. In-laboratory measures of resting muscle sympathetic nerve activity
(MSNA). Individual measures of MSNA bursts/min
⫺1
(Aand B) and MSNA
bursts/100 heartbeats (hb; Cand D), pre (week 1)- and post (week 6)-high-
intensity inspiratory muscle strength training (IMST) (black symbols) (n⫽9)
or control (gray symbols) (n⫽6) groups. *Significant differences in average
values pre- to postintervention (P⬍0.05).
455BREATHING TRAINING FOR SLEEP APNEA-RELATED HYPERTENSION
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(17) and consistent with “learning”-related improvements at-
tributable to repeat testing over a short time span (57, 59).
Mechanistic Insights into Improvement in Blood Pressure
The mechanisms responsible for the favorable effects of
IMST require further elucidation. As reported previously in
healthy adults, large (positive or negative) intrathoracic pres-
sures but not large lung volume excursions appear to be the
primary (respiratory) stimulus underpinning IMST-related re-
ductions in BP (69). However, we see no evidence of IMST-
related changes in baroreflex sensitivity, heart rate, or cardiac
output (17). Although cardiac output was not among the
primary or secondary end points of the current study, estimates
of cardiac output (CO) retrieved from in-laboratory continuous
monitoring of BP (ccNexfin, Bmeye, Amsterdam, The Neth-
erlands) indicate no changes in CO for either the high-intensity
(2.67 ⫾5.53%change) or control group (3.41 ⫾6.39%change)
relative to preintervention values. However, as these estimates
of cardiac output were derived from discontinuous data ob-
tained pre- and postintervention, they must be interpreted with
caution and are subject to reassessment using more traditional
(e.g., equilibration CO
2
rebreathing) approaches.
In contrast, there is evidence of IMST-related declines in
plasma catecholamines (70), peripheral resistance (17), endo-
thelial-dependent dilation (14) and sympathetic nervous out-
flow (current findings) that point to changes in vascular func-
tion (13). Specifically, a focus on peripheral artery stiffness
appears warranted given preliminary evidence of IMST-related
improvements in peripheral artery distensibility and increased
nitric oxide bioavailability in otherwise healthy older healthy
adults (15). Whether a similar vascular benefit might occur in
the context of OSA will require further study.
Summary
Our results confirm previously reported findings of IMST-
related improvements in casual blood pressure. In addition, the
current findings provide preliminary and novel support for the
potential for high-intensity IMST to reduce resting sympathetic
neurogenic activity and nighttime systolic blood pressure
among older, overweight adults with OSA with just 5 min
training/day. Given these findings we propose that high-inten-
sity IMST may be an effective intervention for lowering BP
among older adults with OSA. Whether IMST can confer
similar benefits when implemented in younger adults with
OSA and hypertension and whether the benefits aggregate over
the longer term (6 –12 mo) and diminish upon withdrawal
await further study.
ACKNOWLEDGMENTS
The authors thank Dr. Mark Borgstrom for assistance with statistical
analyses. We thank Dr. Chloe Taylor (School of Medicine, University of
Western Sydney) for providing us tools for assessment of baroreflex sensitiv-
ity. We sincerely thank Roxanne M. De Asis for assistance with subject
recruitment, screening, and data collection. We are indebted to all our subject
participants, who undertook the training with enthusiasm and gave willingly of
their time.
GRANTS
This work was supported by American Heart Association Grant in Aid
16GRNT26700007 (to E.F.B.).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
AUTHOR CONTRIBUTIONS
E.F.B. conceived and designed research; G.E.R.-B., C.M.D., and E.F.B.
performed experiments; G.E.R.-B., C.M.D., and E.F.B. analyzed data; G.E.R.-
B., C.M.D., and E.F.B. interpreted results of experiments; G.E.R.-B., C.M.D.,
and E.F.B. prepared figures; G.E.R.-B., C.M.D., and E.F.B. drafted manu-
script; G.E.R.-B., C.M.D., and E.F.B. edited and revised manuscript; G.E.R.-
B., C.M.D., and E.F.B. approved final version of manuscript.
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