Breathing Training for Improving Cardiovascular Health in Older Adults With Sleep Apnea

Study Overview
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Brief Summary
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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
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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.

Official Title
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Time-efficient Inspiratory Muscle Strength Training for Improving Blood Pressure and Vascular Function in Older Adults With Sleep Disordered Breathing

Conditions
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Obstructive Sleep Apnea, Hypertension

Intervention / Treatment
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* Behavioral: Inspiratory Muscle Strength Training


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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)
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Training Group A<br>Participants will perform their respiratory training (high-intensity, low-volume IMST) on a hand-held respiratory training device. | Behavioral: Inspiratory Muscle Strength Training<br>* 30 breaths/ day, 5 days/week for 24 weeks.<br>|
| Sham Comparator: Training Group B<br>Participants will perform their respiratory training (low-intensity, low-volume IMST) on a hand-held respiratory training device. | Behavioral: Inspiratory Muscle Strength Training<br>* 30 breaths/ day, 5 days/week for 24 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline casual Systolic Blood Pressure at 24 weeks, 28 weeks, and 36 weeks | The primary endpoint is casual (resting) systolic blood pressure (SBP) measured by both relative and absolute changes from baseline. SBP will be assessed in accordance with American College of Cardiology/American Heart Association guidelines. Measurements will be taken using an automated oscillometric sphygmomanometer and will be performed in triplicate over the brachial artery of the non-dominant arm after 5 minutes of quiet rest, with 1 minute of recovery between measures. SBP will be defined as the average of the 3 pressures. | Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline 24-hour Ambulatory Systolic Blood Pressure at 24 weeks, 28 weeks, and 36 weeks | The secondary endpoint is 24-hour ambulatory systolic blood pressure measured by both relative and absolute changes from baseline. We will obtain continuous measures of systolic and diastolic blood pressure over a 24-h period with an FDA approved and European Society of Hypertension validated Non-Invasive Ambulatory Blood Pressure monitor. Blood pressure data will be broken into daytime (16 hour) and nighttime (8 hour) segments according to participants' individual sleep-wake cycles. Mean systolic and diastolic blood pressures (mmHg) will be calculated for the daytime and nighttime periods to evaluate circadian systolic and diastolic blood pressure profiles. | Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST | 
| Change from baseline Plasma Norepinephrine at 24 weeks, 28 weeks, and 36 weeks | The secondary endpoint is Plasma Norepinephrine (PNE), a marker of sympathetic activity, measured by both relative and absolute changes from baseline. PNE will be determined from venous (antecubital area) blood samples and quantified via high performance liquid chromatography (HPLC). PNE will be measured following a fasting blood draw collected between the hours of 7:00 and 10:00 am, preceded by 30 minutes supine rest in a quiet, temperature-controlled room. | Measured at Baseline, Week 24, Week 28, and Week 36 to establish the intermediate and long-lasting effects of IMST | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood Pressure, Inspiratory Muscle Strength Training, Sleep Apnea