Cardiovascular Diseases
Conditions
Brief summary
Previous work demonstrates that the red blood cells of older adults do not release a potent vasodilator (ATP) as well as the red blood cells of younger adults. The investigators are targeting a pathway within the red blood cell using fasudil hydrochloride to determine if both the release of ATP from red blood cells and blood flow responses to low oxygen (hypoxia) and exercise in older adults can be improved.
Detailed description
Participants will initiate contact with the investigators by responding to flyers placed in the community either by phone or email. The first correspondence (phone or email) will provide a brief description of the research and ask a series of screening questions to determine age, height, weight, and any medications participants may be taking as well as the current health status (diagnoses, basic health history, and physical activity level) of participants. If they qualify, a two hour screening visit is scheduled during a time when the participant will be examined by the physician. All participants will undergo informed consent in a face to face private meeting with the research coordinator. Following informed consent, participants will be evaluated by a physician and undergo a treadmill stress test to rule out cardiovascular disease. During the study, heart rate will be monitored with a 3-lead ECG and blood pressure will be monitored noninvasively with a blood pressure cuff on the finger (finometry). Venous blood will be collected at multiple time points via a catheter inserted into a forearm vein draining skeletal muscle circulation for measurement of blood gases (0.5 mL/sample) and plasma \[ATP\] (2 mL/sample), with less than 100 mL of blood being drawn in total (\ 60mL total). Blood flow at rest and in response to hypoxia and exercise will be measured non-invasively using Doppler ultrasound of the brachial artery. Hypoxia trials will be performed by having participants breathe a low oxygen gas mixture via a mouthpiece that is hooked up to gas tanks and an anesthesia monitor to decrease their oxygen saturation to \ 80% (similar to hiking a 14er) for 10 minutes. Exercise trials will last for approximately 15 minutes and will involve participants performing graded-intensity rhythmic handgrip exercise by lifting weights (corresponding to a low, moderate, and high workload) using a pulley system. The drug treatment used in this study (fasudil) is being given because it may improve red blood cell ATP release in older adults. This is a double-blinded placebo controlled study, thus participation will occur on two randomized experimental days.
Interventions
10 mg/mL vial of fasudil hydrochloride. 6 mL (60 mg) of fasudil hydrochloride are added to a 100 mL saline bag for delivery to subjects.
OTHERSaline
100 mL saline bag.
Sponsors
Colorado State University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
A person not associated with any data collection or data analysis is randomizing the treatment and preparing it in a separate room. All data is collected as visit 1 or visit 2.
Intervention model description
This is a randomized, double-blind, placebo-controlled, crossover study. Approximately 20 young and 20 older adults will be recruited for participation and randomly assigned to either a placebo (saline) infusion or a fasudil hydrochloride infusion. The dose of fasudil hydrochloride is 60 mg/ 60 min.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy * Sedentary to moderately active * 18 to 30 years old for young subjects * 60 to 80 years old for older subjects
Exclusion criteria
* Obesity (BMI ≥ 30 kg/m\^2) * Cardiovascular disease * Metabolic disease * Use of medications that can influence cardiovascular function * Blood pressure greater than or equal to 140/90 * Smoker * Use of hormone replacement therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Forearm Blood Flow Responses to Hypoxia After Administration of Intervention | Within 4 hours after administration of intervention | Forearm blood flow measured using Doppler ultrasound before and after 5 minutes of exposure to hypoxia (breathing a mix of low-oxygen gas and room air to achieve oxygen saturations of \ 80%). |
| Forearm Blood Flow Responses to Exercise After Administration of Intervention | Within 4 hours after administration of intervention | Forearm blood flow measured using Doppler ultrasound before and during continuous rhythmic handgrip exercise at a low, moderate, and high intensity workload (4 minutes at each workload for 12 minutes in total). |
| Change in ATP Release to Hypoxia After Administration of Intervention | Within 4 hours after administration of intervention | Venous plasma concentrations of ATP measured using a luminometer before and after 5 minutes of exposure to hypoxia (breathing a mix of low-oxygen gas and room air to achieve oxygen saturations of \ 80%). |
| Change in ATP Release to Exercise After Administration of Intervention | Within 4 hours after administration of intervention | Venous plasma concentrations of ATP measured using a luminometer before and during continuous rhythmic handgrip exercise at a low, moderate, and high intensity workload (4 minutes at each workload for 12 minutes in total). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Arterial Stiffness After Administration of Intervention | Immediately following administration of intervention | Arterial stiffness measured non-invasively using a SphygmoCor system after administration of saline (placebo) and fasudil. This is a randomized crossover design study, so participants will receive 1 treatment (saline or fasudil) on their first visit and the other treatment on their second visit. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fasudil, Then Saline Participants were randomized to receive a single 100 mL intravenous infusion of 60 mg fasudil hydrocholoride + saline in 60 minutes prior to measurements of vascular function and ATP release. After a washout period of at least 5 days, participants received a single 100 mL intravenous infusion of saline (placebo) in 60 minutes prior to measurements of vascular function and ATP release. | 13 |
| Saline, Then Fasudil Participants were randomized to receive a single 100 mL intravenous infusion of saline (placebo) in 60 minutes prior to measurements of vascular function and ATP release. After a washout period of at least 5 days, participants received a single 100 mL intravenous infusion of 60 mg fasudil hydrocholoride + saline in 60 minutes prior to measurements of vascular function and ATP release. | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Study difficulties unrelated to Tx | 4 | 1 |
Baseline characteristics
| Characteristic | Fasudil, Then Saline | Saline, Then Fasudil | Total |
|---|---|---|---|
| Age, Customized 18-30 years | 6 Participants | 6 Participants | 12 Participants |
| Age, Customized 60-80 years | 7 Participants | 7 Participants | 14 Participants |
| Body Mass Index | 24.9 kg/m^2 STANDARD_DEVIATION 4 | 23.7 kg/m^2 STANDARD_DEVIATION 1.6 | 24.3 kg/m^2 STANDARD_DEVIATION 3 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 12 Participants | 12 Participants | 24 Participants |
| Race/Ethnicity, Customized White | 13 Participants | 12 Participants | 25 Participants |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 13 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 12 | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 0 / 12 | 0 / 12 | 0 / 13 | 0 / 13 |
| serious Total, serious adverse events | 0 / 12 | 0 / 12 | 0 / 13 | 0 / 13 |
Outcome results
Primary
Change in ATP Release to Exercise After Administration of Intervention
Venous plasma concentrations of ATP measured using a luminometer before and during continuous rhythmic handgrip exercise at a low, moderate, and high intensity workload (4 minutes at each workload for 12 minutes in total).
Time frame: Within 4 hours after administration of intervention
Population: All participants who completed both interventions (crossover design) with outcome data collected
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Young Saline | Change in ATP Release to Exercise After Administration of Intervention | 45.6 nmol/L | Standard Error 16.8 |
| Young Fasudil | Change in ATP Release to Exercise After Administration of Intervention | 42.2 nmol/L | Standard Error 15.1 |
| Older Saline | Change in ATP Release to Exercise After Administration of Intervention | 28.4 nmol/L | Standard Error 7.9 |
| Older Fasudil | Change in ATP Release to Exercise After Administration of Intervention | 46.2 nmol/L | Standard Error 15.2 |
Comparison: Within group comparison of treatmentp-value: 0.89ANOVA
Comparison: Within group comparison of treatmentp-value: 0.3ANOVA
Primary
Change in ATP Release to Hypoxia After Administration of Intervention
Venous plasma concentrations of ATP measured using a luminometer before and after 5 minutes of exposure to hypoxia (breathing a mix of low-oxygen gas and room air to achieve oxygen saturations of \ 80%).
Time frame: Within 4 hours after administration of intervention
Population: All participants who completed both interventions (crossover design) with outcome data collected
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Young Saline | Change in ATP Release to Hypoxia After Administration of Intervention | 21.6 nmol/L | Standard Error 10.5 |
| Young Fasudil | Change in ATP Release to Hypoxia After Administration of Intervention | 5.3 nmol/L | Standard Error 8 |
| Older Saline | Change in ATP Release to Hypoxia After Administration of Intervention | 5.3 nmol/L | Standard Error 5.4 |
| Older Fasudil | Change in ATP Release to Hypoxia After Administration of Intervention | 17.4 nmol/L | Standard Error 13.2 |
Comparison: Within group comparison of treatmentp-value: 0.28ANOVA
Comparison: Within group comparison of treatmentp-value: 0.37ANOVA
Primary
Forearm Blood Flow Responses to Exercise After Administration of Intervention
Forearm blood flow measured using Doppler ultrasound before and during continuous rhythmic handgrip exercise at a low, moderate, and high intensity workload (4 minutes at each workload for 12 minutes in total).
Time frame: Within 4 hours after administration of intervention
Population: All participants who completed both interventions (crossover design) with outcome data collected
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Young Saline | Forearm Blood Flow Responses to Exercise After Administration of Intervention | 315.4 mL/min | Standard Error 31 |
| Young Fasudil | Forearm Blood Flow Responses to Exercise After Administration of Intervention | 283.0 mL/min | Standard Error 25.4 |
| Older Saline | Forearm Blood Flow Responses to Exercise After Administration of Intervention | 255.3 mL/min | Standard Error 19.9 |
| Older Fasudil | Forearm Blood Flow Responses to Exercise After Administration of Intervention | 304.2 mL/min | Standard Error 25.2 |
Comparison: Within group comparison of treatmentp-value: <0.05ANOVA
Comparison: Within group comparison of treatmentp-value: <0.05ANOVA
Primary
Forearm Blood Flow Responses to Hypoxia After Administration of Intervention
Forearm blood flow measured using Doppler ultrasound before and after 5 minutes of exposure to hypoxia (breathing a mix of low-oxygen gas and room air to achieve oxygen saturations of \ 80%).
Time frame: Within 4 hours after administration of intervention
Population: All participants who completed both interventions (crossover design) with outcome data collected
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Young Saline | Forearm Blood Flow Responses to Hypoxia After Administration of Intervention | 6.3 mL/min | Standard Error 1.2 |
| Young Fasudil | Forearm Blood Flow Responses to Hypoxia After Administration of Intervention | 6.2 mL/min | Standard Error 1.2 |
| Older Saline | Forearm Blood Flow Responses to Hypoxia After Administration of Intervention | 2.1 mL/min | Standard Error 0.6 |
| Older Fasudil | Forearm Blood Flow Responses to Hypoxia After Administration of Intervention | 8.4 mL/min | Standard Error 1.9 |
Comparison: Within group comparison of treatmentp-value: 0.97ANOVA
Comparison: Within group comparison of treatmentp-value: <0.05ANOVA
Secondary
Arterial Stiffness After Administration of Intervention
Arterial stiffness measured non-invasively using a SphygmoCor system after administration of saline (placebo) and fasudil. This is a randomized crossover design study, so participants will receive 1 treatment (saline or fasudil) on their first visit and the other treatment on their second visit.
Time frame: Immediately following administration of intervention
Population: All participants who completed both interventions (crossover design) with outcome data collected
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Young Saline | Arterial Stiffness After Administration of Intervention | 5.4 m/s | Standard Error 0.2 |
| Young Fasudil | Arterial Stiffness After Administration of Intervention | 5.2 m/s | Standard Error 0.2 |
| Older Saline | Arterial Stiffness After Administration of Intervention | 7.8 m/s | Standard Error 0.4 |
| Older Fasudil | Arterial Stiffness After Administration of Intervention | 7.6 m/s | Standard Error 0.4 |
Comparison: Within group comparison of treatmentp-value: 0.08ANOVA
Comparison: Within group comparison of treatmentp-value: 0.05ANOVA