Hypertension
Conditions
Keywords
systolic blood pressure (SBP), cardiovascular (CV) disease
Brief summary
More than 80% of older adults have hypertension, with higher prevalence of high systolic blood pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death. Novel compound, nicotinamide riboside may enhance the effects of exercise therapy in hypertensive older adults.
Detailed description
More than 80% of older adults have hypertension, with a higher prevalence of high systolic blood pressure (SBP) putting them at high risk for cardiovascular (CV) disease and death. Because drug therapy that lowers SBP is associated with side effects such as hypotension, syncope, and kidney dysfunction, there is a great need for effective lifestyle SBP-lowering interventions for the older population that can replace drug therapy. While aerobic exercise is a recommended lifestyle intervention for controlling SBP and preventing CV disease naturally, in older adults it has been shown to be less effective in vascular-tissue remodeling because of arterial stiffness, resulting in less efficient SBP control. Reduced bioavailability of nicotinamide adenine dinucleotide (NAD+), a cofactor for the deacetylase sirtuin1 (SIRT1), may contribute to age-related vascular dysfunction via oxidative stress and reduced nitric oxide (NO). Exercise-induced overexpression of NAD+-dependent SIRT1 improves the bioavailability of NO. Preclinical evidence suggests that poor vascular function improvement in response to exercise in older mice is caused by insufficient NAD+ levels to stimulate SIRT1 activity. Importantly, replenishment of NAD+ levels induced vascular remodeling, improved vascular function, and reduced SBP in mice. An objective of this study, therefore, is to test a combination of aerobic exercise and nicotinamide riboside, a compound that replenishes NAD+ levels, to optimize exercise's SBP-lowering effect in hypertensive older adults. Initial human clinical trials demonstrated that nicotinamide riboside supplementation (1,000 mg/day) was safe and showed a higher potential to reduce SBP and arterial stiffness in participants with elevated SBP. As we have preclinical evidence that combining NAD+ replenishment with exercise is an ideal strategy for improving vascular function, our central hypothesis is that the intervention of aerobic-exercise training combined with nicotinamide riboside supplementation will reduce SBP in hypertensive older adults more effectively than will exercise alone. We will enroll 54 participants ≥ 55 years and older into either: (1) 1,000 mg/day of nicotinamide riboside plus 3 days/week of supervised, center-based walking exercise (n=18), or (2) the same exercise program combined with placebo (n=18), or (3) 1,000 mg/day of nicotinamide riboside alone (n=18). All participants will undergo daytime continuous SBP at baseline, 3 weeks, and 6 weeks, and arterial-stiffness measurements by pulse-wave velocity at baseline and at 6 weeks. Elevated SBP will be determined as daytime average equal to or above 130 mmHg, measured by the 24-hour blood-pressure device. To our knowledge, this study will be the first attempt to enhance exercise therapy with nicotinamide riboside in hypertensive older adults. We believe that nicotinamide riboside is the missing piece of the puzzle in improving vascular remodeling and SBP management in older adults. Preliminary evidence from this pilot study may support a full-scale Phase III clinical trial in hypertensive older adults. The ultimate goal of this line of research is to find adjuvant strategies to improve the exercise's SBP-lowering effects in older adults.
Interventions
BEHAVIORALWalking Exercise
Participants randomized to this intervention 3 days/week of supervised, center-based walking exercise.
Participants randomized to this intervention will receive 1,000 mg/day of NR.
Sponsors
National Institute on Aging (NIA)
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
55 Years to 105 Years
Healthy volunteers
No
Inclusion criteria
* Age 55 years and older * Daytime average of systolic blood pressure of ≥ 130 mmHg and \< 160 mmHg. * Sedentary lifestyle, defined as \< 150 min/wk of moderate physical activity as assessed by the CHAMPS questionnaire. * Willingness to be randomized to either treatment group * Willingness to participate in all study procedures
Exclusion criteria
* Failure to provide informed consent. * Pregnant * Change in blood pressure therapy (type or dose) within the last 3 months- Temporary Exclusion * Daytime average of systolic blood pressure ≥160 mmHg. * Regular consumption of nicotinamide riboside supplement * Current involvement in supervised rehabilitation program * Absolute contraindication(s) to exercise training according to American College of Sports Medicine guidelines \[11\] * Daytime average of systolic blood pressure below 130mm Hg or Diastolic BP ≥ 100mm Hg. * Peripheral vascular disease; peripheral neuropathy; retinopathy * Severe cardiac disease, including NYHA Class III or IV congestive heart failure, clinically significant aortic stenosis, history of cardiac arrest, use of a cardiac defibrillator, or uncontrolled angina; * Myocardial infarction or stroke within past year * Significant cognitive impairment, including known dementia diagnosis or a Mini-Mental State Examination exam score \< 24 * Progressive, degenerative neurologic disease, e.g., Parkinson's Disease, multiple sclerosis; * Severe rheumatologic or orthopedic diseases, e.g., awaiting joint replacement, active inflammatory disease; * Severe pulmonary disease, requiring steroid therapy or the use of supplemental oxygen; * Hip fracture, hip or knee replacement, or spinal surgery within past 4 months; * Other significant co-morbid conditions that would impair ability to participate in the exercise-based intervention * Simultaneous participation in another intervention trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Daytime Systolic Blood Pressure | Baseline; Week 6 | The primary outcome of this study is the change in average daytime systolic blood pressure. Systolic blood pressure was measured every 20 minutes (min) during the day (from 0700 to 2200 hours) at baseline and week 6 visits. Based on the American Heart Association guideline, we selected twenty valid daytime blood pressure recordings to calculate the average daytime value, then we calculated the mean differences between week 6 and baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Arterial Stiffness | Baseline; Week 6 | The measurement of aortic pulse-wave velocity (PWV), particularly between the carotid and femoral arteries (cfPWV), was conducted using the SphygmoCor XCEL system. Briefly, cfPWV was determined by recording pressure pulse waves at the carotid and femoral arteries using a high-fidelity micromanometer and calculating the distance between the recording sites divided by the time delay between the carotid and the femoral pulse waves. |
Countries
United States
Participant flow
Pre-assignment details
Of 147 enrolled participants, 54 met the eligible criteria and were randomized to treatment.
Participants by arm
| Arm | Count |
|---|---|
| NR Plus Walking Exercise 1,000 mg/day of NR combined with three days/week of supervised, center-based walking exercise (n=18)
Walking Exercise: Participants randomized to this intervention 3 days/week of supervised, center-based walking exercise.
Nicotinamide Riboside (NR): Participants randomized to this intervention will receive 1,000 mg/day of NR. | 17 |
| Walking Exercise Plus Placebo 1,000 mg/day of Placebo combined with three days/week of supervised, center-based walking exercise (n=18)
Walking Exercise: Participants randomized to this intervention 3 days/week of supervised, center-based walking exercise. | 18 |
| NR Alone 1,000 mg/day of NR
Nicotinamide Riboside (NR): Participants randomized to this intervention will receive 1,000 mg/day of NR. | 19 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Taking NR supplement | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 | 1 |
Baseline characteristics
| Characteristic | Walking Exercise Plus Placebo | Total | NR Plus Walking Exercise | NR Alone |
|---|---|---|---|---|
| Age, Continuous | 68.3 years STANDARD_DEVIATION 7.7 | 67.3 years STANDARD_DEVIATION 7.3 | 67.5 years STANDARD_DEVIATION 7 | 66.3 years STANDARD_DEVIATION 7.2 |
| Baseline average daytime diastolic blood pressure | 75.2 mmHg STANDARD_DEVIATION 6.5 | 76.3 mmHg STANDARD_DEVIATION 8.5 | 75.5 mmHg STANDARD_DEVIATION 8.6 | 78.2 mmHg STANDARD_DEVIATION 10.2 |
| Baseline average daytime systolic blood pressure | 141 mmHg STANDARD_DEVIATION 12.1 | 139.4 mmHg STANDARD_DEVIATION 12.8 | 138.5 mmHg STANDARD_DEVIATION 11.8 | 138.8 mmHg STANDARD_DEVIATION 14.9 |
| Body Mass Index | 30.8 kg/m^2 STANDARD_DEVIATION 5.7 | 31.5 kg/m^2 STANDARD_DEVIATION 6.9 | 33.0 kg/m^2 STANDARD_DEVIATION 7.2 | 30.7 kg/m^2 STANDARD_DEVIATION 7.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 15 Participants | 5 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 36 Participants | 12 Participants | 11 Participants |
| Region of Enrollment United States | 18 Participants | 54 Participants | 17 Participants | 19 Participants |
| Sex: Female, Male Female | 10 Participants | 33 Participants | 11 Participants | 12 Participants |
| Sex: Female, Male Male | 8 Participants | 21 Participants | 6 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 18 | 0 / 19 |
| other Total, other adverse events | 9 / 17 | 12 / 18 | 7 / 19 |
| serious Total, serious adverse events | 0 / 17 | 0 / 18 | 1 / 19 |
Outcome results
Primary
Change in Daytime Systolic Blood Pressure
The primary outcome of this study is the change in average daytime systolic blood pressure. Systolic blood pressure was measured every 20 minutes (min) during the day (from 0700 to 2200 hours) at baseline and week 6 visits. Based on the American Heart Association guideline, we selected twenty valid daytime blood pressure recordings to calculate the average daytime value, then we calculated the mean differences between week 6 and baseline.
Time frame: Baseline; Week 6
Population: Considering within-group differences for interested variables; we focus on the mean differences between week 6 and the baseline.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NR Plus Walking Exercise | Change in Daytime Systolic Blood Pressure | 5.19 mmHg |
| Walking Exercise Plus Placebo | Change in Daytime Systolic Blood Pressure | -2.71 mmHg |
| NR Alone | Change in Daytime Systolic Blood Pressure | -0.48 mmHg |
Secondary
Change in Arterial Stiffness
The measurement of aortic pulse-wave velocity (PWV), particularly between the carotid and femoral arteries (cfPWV), was conducted using the SphygmoCor XCEL system. Briefly, cfPWV was determined by recording pressure pulse waves at the carotid and femoral arteries using a high-fidelity micromanometer and calculating the distance between the recording sites divided by the time delay between the carotid and the femoral pulse waves.
Time frame: Baseline; Week 6
Population: Considering within-group differences for interested variables; we focus on the mean differences between week 6 and the baseline.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| NR Plus Walking Exercise | Change in Arterial Stiffness | -0.29 m/s |
| Walking Exercise Plus Placebo | Change in Arterial Stiffness | -0.15 m/s |
| NR Alone | Change in Arterial Stiffness | -0.10 m/s |