Clinical trial NCT04932447: Breathing Training for Improving Cardiovascular Health in Older Adults With Sleep Apnea
Official title: Time-efficient Inspiratory Muscle Strength Training for Improving Blood Pressure and Vascular Function in Older Adults With Sleep Disordered Breathing
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Obstructive Sleep Apnea
Hypertension
Keywords: Inspiratory Muscle Strength Training
Blood Pressure
Sleep Apnea
Lead sponsor: University of Arizona
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute on Aging (NIA)
name: University of Colorado, Boulder
First posted: 2021-06-21
Enrollment: 122
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomly allocated using a 1:1 ratio to A) High-Intensity Training Group (75 % maximal inspiratory pressure) or B)Low-Intensity Training Group (15% maximal inspiratory pressure)
Primary purpose: BASIC_SCIENCE

Brief summary: This clinical research study will investigate the effects of respiratory strength training on blood pressure and cardiovascular health in adults who are 50 years of age and older and have been diagnosed with moderate or severe obstructive sleep apnea.

Detailed description: Exercise has well-documented benefits for systolic blood pressure (SBP) and cardiovascular health. Whereas current guidelines advocate \~150 min moderate intensity exercise/week, our preliminary data show \~5 min/day of inspiratory muscle strength training (IMST) for 6 weeks lowers casual (resting) SBP by \~12 mmHg.

This simple approach to lowering BP could be applied to almost any population however we are studying IMST in older adults with obstructive sleep apnea (OSA). OSA is an ideal population to target because OSA prevalence is growing and because snoring and apneas result in chronic intermittent hypoxemia that drives sympathetic nervous system (SNS) hyperactivity, endothelial dysfunction and hypertension. These substantive risks for cardiovascular disease are compounded by poor adherence to the mainstay treatment continuous positive airway pressure (\<50%), obesity, fatigue and a robust intolerance for exercise.

Our findings in healthy young adults (n=50) show IMST-related reductions in BP are mediated by decreases in systemic vascular resistance, suggesting changes in vascular tone and function. Consistent with this hypothesis, our results from a pilot clinical trial in adults with OSA (n=24) show IMST-related reductions in plasma norepinephrine levels (PNE) and muscle sympathetic nerve activity (MSNA), both markers of SNS activity. Our preliminary mechanistic assessments indicate IMST may lower circulating concentrations of other vasoconstrictor factors and increase nitric oxide (NO)-mediated endothelium-dependent dilation. And, findings in a novel endothelial cell culture model, point to increases in NO and declines in reactive oxygen species (ROS) and oxidative stress. However, it is unknown if: 1) IMST lowers casual and 24-h (ambulatory) SBP in older adults with OSA; 2) the reductions in SBP are long-lasting; 3) arterial stiffness, NO-mediated endothelial dilation and/or oxidative stress are improved; and 4) if adherence in this population is high long term.

In this randomized, double-blind clinical trial we will establish the efficacy of high-intensity IMST (75% maximum inspiratory pressure, \[PImax\]) 5 days/week for 24 weeks vs. low-intensity IMST (15%PImax) (n=61/group) for lowering SBP in adults (\>50 years) with above normal BP and OSA. We hypothesize that IMST will lower SBP via reductions in SNS activity and circulating vasoconstrictor factors, improvements in vascular function, and reductions in oxidative stress/inflammation and that reductions in SBP will be sustained 4 and 12 weeks post-intervention.

Eligibility criteria: Inclusion Criteria:

* Age 50 and older
* Ability to understand study procedures and to comply with them for the entire length of the study
* Ability to provide informed consent;
* Willing to accept random assignment to condition
* AHI ≥15
* Individuals with who are unwilling or unable to adhere to CPAP
* Individuals who are adherent to CPAP therapy (i.e., 4 hours/night on 70%/nights over 30 days in the first 3 months of initial usage)
* Individuals who are adherent to mandibular advancement device each night
* Above-normal SBP (i.e., SBP ≥120)
* BMI ≤40 kg/m2
* Weight stable in the prior 3 months (\<3.0 kg weight change) and willing to remain weight stable throughout the study
* No change in anti-hypertensive medications or other medications (prescription or dosing) in the prior 3 months and willingness to maintain current medication regimen throughout the study
* Absence of unstable clinical disease as determined by medical history, physical examination, and blood chemistries
* Total cholesterol \<240 mg/dL
* Fasting plasma glucose \<300 mg/dL

Exclusion Criteria:

* Age \<50
* AHI \<15
* Individuals with central or mixed sleep disordered breathing
* Severe hypoxemia (\<80% for \>10% of recording time) during sleep
* ESS \>15
* SBP ≥160 or DBP ≥120
* Current smoker
* Chronic overt and poorly controlled medical condition (e.g., diabetes, chronic kidney disease, cancer, congestive heart failure)
* Cheyne-Stokes Respiration
* Alcohol or illegal drug dependence or abuse
* Uncontrolled thyroid disease or change in thyroid medication within previous 3 months
* Regular/vigorous aerobic exercise (\> 4 bouts/week, \>30 min/bout at high workload \>6 METS)

Primary outcomes:
measure: Change from baseline casual Systolic Blood Pressure at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
Secondary outcomes:
measure: Change from baseline 24-hour Ambulatory Systolic Blood Pressure at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from baseline Plasma Norepinephrine at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
Other outcomes:
measure: Change from baseline Nitric Oxide-mediated Endothelial Dependent Dilation (EDD) and suppression of EDD by oxidative stress at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from baseline Carotid-Femoral Pulse Wave Velocity at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from baseline vasoconstrictor factors at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from baseline influence of circulating factors on endothelial Nitric Oxide and Reactive Oxygen Species at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from Baseline Muscle Sympathetic Nerve Activity at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from Baseline Casual Diastolic Blood Pressure (DBP) at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from Baseline 24-hour Ambulatory Diastolic Blood Pressure at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from Baseline Six-Minute Walk Distance at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from Baseline NIH Toolbox - Cognitive Domain at 23 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 23, Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from Baseline Maximal Inspiratory Pressure at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from Baseline Resting Heart Rate at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from Baseline Home Sleep Apnea Testing at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
measure: Change from Baseline Grip Strength at 24 weeks, 28 weeks, and 36 weeks
timeFrame: Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST
Locations:
city: Tucson
country: United States
facility: Arizona Respiratory and Neurophysiology Laboratory
state: Arizona
Study officials:
affiliation: University of Arizona
name: Elizabeth F Bailey, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: DeLucia CM, DeBonis DR, Schwyhart SM, Bailey EF. Acute cardiovascular responses to a single bout of high intensity inspiratory muscle strength training in healthy young adults. J Appl Physiol (1985). 2021 Apr 1;130(4):1114-1121. doi: 10.1152/japplphysiol.01015.2020. Epub 2021 Feb 18.
citation: 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 (1985). 2020 Sep 1;129(3):449-458. doi: 10.1152/japplphysiol.00024.2020. Epub 2020 Jul 30.
citation: DeLucia CM, De Asis RM, Bailey EF. Daily inspiratory muscle training lowers blood pressure and vascular resistance in healthy men and women. Exp Physiol. 2018 Feb 1;103(2):201-211. doi: 10.1113/EP086641. Epub 2018 Jan 15.
citation: Vranish JR, Bailey EF. Inspiratory Muscle Training Improves Sleep and Mitigates Cardiovascular Dysfunction in Obstructive Sleep Apnea. Sleep. 2016 Jun 1;39(6):1179-85. doi: 10.5665/sleep.5826.
citation: Vranish JR, Bailey EF. Daily respiratory training with large intrathoracic pressures, but not large lung volumes, lowers blood pressure in normotensive adults. Respir Physiol Neurobiol. 2015 Sep 15;216:63-9. doi: 10.1016/j.resp.2015.06.002. Epub 2015 Jun 22.
citation: Tavoian D, Ramos-Barrera LE, Craighead DH, Seals DR, Bedrick EJ, Alpert JS, Mashaqi S, Bailey EF. Six Months of Inspiratory Muscle Training to Lower Blood Pressure and Improve Endothelial Function in Middle-Aged and Older Adults With Above-Normal Blood Pressure and Obstructive Sleep Apnea: Protocol for the CHART Clinical Trial. Front Cardiovasc Med. 2021 Nov 24;8:760203. doi: 10.3389/fcvm.2021.760203. eCollection 2021.