High blood pressure (BP) is the major modifiable risk factor for cardiovascular diseases (CVD) and related health conditions, particularly among postmenopausal (PM) women. In adults age ≥50 years this risk is primarily driven by above-normal systolic BP (SBP ≥120 mmHg), as diastolic BP plateaus, then decreases in older adulthood. Although SBP is lower in premenopausal women vs. age-matched men, SBP reaches, then surpasses men after age 60. As such, >75% of PM women in the U.S. have above-normal SBP, which, in turn, is responsible for a 2-fold increase in risk of hypertension and corresponding increases in risk of CVD, chronic kidney disease and many other disorders. A key process linking high SBP to CVD and related conditions is vascular endothelial dysfunction, mediated by excessive reactive oxygen species (ROS)-induced oxidative stress and reductions in nitric oxide (NO) bioavailability. As the number of PM women is rapidly growing, further increases in SBP-related CV disorders are projected without effective intervention.

• Aerobic exercise (AE) is a first-line, standard-of-care therapy for lowering BP. In PM women with baseline SBP ≥120 mmHg, AE reduces casual (resting) SBP by ~3 mmHg (back to baseline ≤4 weeks post-training), whereas 24-hour SBP is typically unchanged. However, only 25-30% of PM women meet guidelines for 150 min/week of moderate-intensity AE, citing the extensive time requirement, facility access and travel disruptions as major barriers. Another, far less recognized, limitation is that AE training consistently improves endothelial function in midlife/older men, but not in estrogen-deficient PM (PMe-) women, i.e., in >95% of the 60+million PM women in the U.S. Thus, establishing new lifestyle therapies that induce and sustain reductions in SBP and increases in endothelial function in PMe- women with above-normal SBP is an important public health goal.
• High-resistance inspiratory muscle strength training (IMST) is a time-efficient (5 minutes per session) lifestyle intervention consisting of 30 inspiratory maneuvers performed against a high resistance. Preliminary data suggest 6-weeks of IMST performed 6 days/week reduces SBP by 9 mmHg in adults with above-normal SBP (i.e., greater than 120 mmHg) at baseline. Importantly, this reduction in SBP is equal to or greater than the reduction in blood pressure typically achieved with time- and effort-intensive healthy lifestyle strategies like conventional aerobic exercise. In addition, IMST improved endothelial function in the PMe- women in a small pilot study.
• To translate these promising preliminary results towards clinical practice, this randomized clinical trial is being conducted to directly compare the efficacy of a longer, clinically relevant treatment duration of IMST (3 months) against home-based, moderate-intensity (standard-of-care) AE in PMe-women. The primary outcome will be the change in casual SBP (IMST vs. AE). Changes in 24-hour SBP and endothelial function will serve as secondary outcomes. Effects on NO bioavailability, ROS/oxidative stress, and the role of "circulating factors" will provide insight into mechanisms of action. The sustained effects on SBP and endothelial function also will be assessed.
• Accordingly, a randomized, blinded, sham-controlled, parallel group design clinical trial will be conducted to assess the efficacy of 3-months of IMST (75 percent maximal inspiratory pressure) vs. brisk walking (40-60% heart rate reserve; an established healthy lifestyle strategy) for lowering SBP and improving endothelial function in PMe- women age 50 years and older with above-normal SBP. It is hypothesized that IMST will lower SBP and improve endothelial function by decreasing oxidative stress and increasing nitric oxide bioavailability. It is also expect that adherence to the intervention will be excellent (over 80 percent of all training sessions completed at the appropriate intensity).
• To test this hypothesis, 90 PMe- women age 50 years and older who have SBP >/= 120 mmHg will be recruited. Participants will undergo baseline testing for casual (resting) SBP, 24-hour ambulatory SBP and endothelial function. Innovative mechanistic probes including pharmaco-dissection with vitamin C, analysis of biopsied endothelial cells, and high-throughput metabolomics, will be performed to assess oxidative stress and nitric oxide bioavailability at baseline.
• After baseline testing, subjects will be randomized to perform either 3-months of high-resistance IMST or brisk walking. Subjects will train 6 days/week. Following 3 months of training, subjects will redo all the tests that were done during baseline testing to assess training-induced changes in SBP, physiological functions, and underlying mechanisms. Subjects will then cease training for 6 weeks before returning to the lab for follow-up testing to determine the persistent effects of IMST.

Study Overview: This is a randomized, single-blind, parallel-design, clinical trial assessing the efficacy of high-resistance inspiratory muscle strength training (IMST) to lower systolic blood pressure (SBP), improve vascular endothelial function and investigate associated mechanisms in estrogen-deficient postmenopausal (PMe-) women with above-normal SBP (i.e., >/= 120 mmHg) at baseline. IMST will be compared to moderate-intensity aerobic exercise (AE; 150 min/week brisk walking) training, a standard-of-care lifestyle intervention for lowering SBP and improving vascular endothelial function. AE lowers casual SBP by approximately 3 mmHg in PMe- women; however, data from our laboratory has shown that AE does not consistently improve vascular endothelial function in this subject group. In addition, only 25-30% of PM women adhere to AE guidelines. Data from the PMe- women who participated in our 6-week IMST pilot trial suggest that IMST lowers casual SBP by 8 mmHg and improves vascular endothelial function, measured as brachial artery flow-mediated dilation (FMDba), by more than 40% in these women. In addition, IMST is a time-efficient intervention (5 min/day) that promotes adherence due to the minimal time burden (95% adherence in our pilot study). Therefore, IMST is a promising lifestyle intervention to improve cardiovascular health in PMe- women. However, these data from a small number of PMe- women need to be confirmed in an appropriately-powered clinical trial with a guideline-based treatment duration.

• Subject Enrollment and Screening: Potential participants will be made aware of the proposed study through described recruitment efforts (see Recruitment and Retention Plan section). Interested participants will contact a staff research assistant via phone or email (contact information supplied with recruitment materials) and will be administered a general screening form online through the Research Electronic Data Capture (REDCap) system to determine eligibility. REDCap is a secure web-based application designed to support data capture for research studies.
• After hearing a study description and having questions answered by the staff research assistant, those eligible and interested in participating in the study will provide written and verbal informed consent, and undergo in-person screening at the University of Colorado (CU) Boulder Clinical Translational Research Center (CTRC). Informed consent will only be obtained by members of the research team who have been observed and approved by the CTRC Research Subject Advocate (see Protection of Human Subjects). We plan to consent and screen 120 subjects in order to meet our enrollment targets (to account for an approximately 33% rate of exclusion based on inclusion/exclusion criteria).
• In-person screening will include: review of medical history; physical exam; resting heart rate; resting blood pressure; blood draw for metabolic profile, lipid profile, complete blood count, and thyroid stimulating hormone; measurement of ankle-brachial index; and 12-lead ECG at rest and during graded exercise testing (see Eligibility Criteria section for detailed inclusion/exclusion criteria).
• Resting blood pressure will be measured on a second occasion within one week of the initial screening to establish baseline blood pressure status. SBP measured on the two separate days will be averaged and must be >/= 120 mmHg for enrollment into the study.
• Assessment of Study Outcomes: All subjects will undergo testing for all primary, secondary, and other outcome measures, as well as assessment of subject characteristics known to effect SBP and vascular endothelial function, before and after 3 months of IMST/AE training. Additionally, casual SBP, 24-hour SBP and FMDba will be measured again 6 weeks after the cessation of training to establish the long-lasting effects of IMST. All testing will take place in the CU Boulder CTRC.
• Testing day 1: All day 1 measurements will be made after a 12-hour fast from food and caffeine (water allowed) and 24 hours after abstaining from alcohol and exercise.
• Casual BP;
• I.V. placement and blood sampling;
• Venous endothelial cell collection;
• FMDba (vascular endothelial function);
• FMDba after supra-therapeutic vitamin C infusion (ROS-mediated suppression of vascular endothelial function);
• Brachial artery dilation to sublingual nitroglycerin (endothelium-independent dilation; control measure).
• Following day 1 testing, subjects will be outfitted with an ambulatory BP monitor pre-programmed to automatically measure BP once every 20 minutes. Subjects will be provided with written and verbal instructions for proper monitor operation and will wear the monitor for 24 hours before returning it to the investigators. A study team member will evaluate ambulatory BP data for completeness immediately upon return of the monitor; if an unsatisfactory number of BP measurements (<67% of expected) were made to properly characterize 24-hour SBP, the subject will be re-outfitted with the ambulatory monitor, re-instructed on its use, and wear it for an additional 24-hour period.
• Testing day 2: All day 2 measurements will be made approximately 2 hours after eating a small meal or snack and 24 hours after abstaining from alcohol and exercise.
• Three-day diet records to ensure that daily fluid and caloric intake remain stable;
• The Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire will be completed and physical activity assessed by accelerometer (Actigraph, three-day records) to document stability of physical activity level outside of the physical activity prescribed in the intervention;
• Sleep stability assessed with the Epworth Sleepiness Scale;
• Maximal oxygen consumption using indirect calorimetry during incremental treadmill exercise (Balke protocol) will be measured to document aerobic fitness; and
• Body composition assessed by dual energy x-ray absorptiometry (DEXA) and anthropometry to measure body composition; body mass also will be determined during check-in visits.
• The Research Strategy and Outcome Measures sections provide more detailed descriptions of these procedures. Similar protocols and procedures are well established in the Integrative Physiology of Aging Laboratory and the CU Boulder CTRC.
• Participant Randomization: After completing baseline testing, subjects will be randomized to either IMST or AE. A randomized block design will be used to balance groups for age (midlife: \

Inclusion Criteria:

• Postmenopausal women (>12 months of amenorrhea)
• Estrogen deficient (no hormone therapies within the previous 12 months)
• Age 50 years and older
• Ability to provide informed consent
• Willing to accept random assignment to condition
• Resting systolic blood pressure of 120 mmHg or greater
• Body mass index <40 kg/m2
• Weight stable in the prior 3 months (<2 kg weight change) and willing to remain weight stable throughout study
• No change in blood pressure medications or other medications (prescription or dosing) in the prior 3 months and willing to maintain current medication regimen
• Free from clinical disease with the exception of hypertension

Exclusion Criteria:

• Younger than age 50 years
• Early menopause (menopause before age 45 years)
• Having had a hysterectomy
• History of uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >120 mmHg)
• Current smoker
• Alcohol dependence or abuse
• Abnormal blood pressure response to exercise (drop in systolic blood pressure below resting levels or systolic blood pressure >260 mmHg or diastolic blood pressure >115 mmHg)
• Regular vigorous aerobic/endurance exercise (>4 bouts/week, >30 min/bout at a workload >6 METS)