Cardiovascular Diseases
Conditions
Keywords
PET, Heart metabolism, Nitric oxide, Myocardial remodeling
Brief summary
The purpose of this study is to determine, with Positron Emission Tomography (PET), the role of nitric oxide in the age-associated effect on fatty acid and glucose delivery on myocardial substrate metabolism.
Detailed description
Aging is associated with an increased incidence and severity of various cardiovascular disorders. Previously, our laboratory has demonstrated an age-related shift in the substrates used by the heart for metabolism from primarily fatty acids to primarily glucose. Furthermore, other institutions have demonstrated that a similar shift can be induced, in animal models, with specific nitric oxide synthase inhibitors, such as L-NAME (N-Nitro-L-Arginine Methyl Ester). Our hypothesis is that a reduction in nitric oxide (NO) synthesis is responsible for the age-related shift in heart function. Accordingly, we aim to demonstrate, in young patients, an acute, transient shift in substrate use from fatty acids to glucose with L-NMMA (citrate) in association with depressed heart function. Also, we aim to demonstrate in the elderly an acute, transient shift in substrate use from glucose to fatty acids with L-arginine, in association with improved cardiac function. These results will demonstrate a portion of the mechanism for the age-related shift in substrate utilization. Each participant will undergo a screening visit which will include a Glucose Tolerance Test, an echocardiogram in conjunction with a treadmill stress test to exclude cardiac disease, and baseline blood work. Then each patient will have 3 PET study days, each lasting about 5-6 hours. During this time, the patient will have two IVs (one in each arm). They will have 4 injections of different radioactive isotopes (015 Water, C11 Acetate, C11 Glucose, and C11 Palmitate). After each injection, about 8-10 blood samples will be drawn over the course of about ½ to 1 hour of time. In between each injection, there will be about an hour break for the patient to rest and move around. During one of the breaks, the patient will have another echocardiogram. On the day 2 and 3 PET, the patient will have a 30-60 minute infusion of L-NAME. Then the PET study will commence. After the study is over the participant will have a 10-minute infusion of L-arginine to reverse the effects of L-NAME.
Interventions
DRUGL-NAME
nitric oxide synthase inhibitor 4mg/kg infusion over 30-60 minutes prior to PET imaging
DRUGL-Arginine
aids in nitric oxide production
DRUGPhenylephrine
alpha agonist; 10 μg/kg/min infusion during PET study
Sponsors
National Institute on Aging (NIA)
Washington University School of Medicine
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
* Between the ages of 18-35 or 60-75 * Normal glucose tolerance test * Normal plasma fasting lipid panel (fasting total cholesterol less than 220 mg/dL) * Normal rest/stress echocardiogram * BMI (Body Mass Index) less than 30 kg/m2
Exclusion criteria
* Coronary artery disease * High blood pressure * Current smoker * Diabetes mellitus * Cardiovascular disease (signs and symptoms of any kind) * History of stroke, peripheral vascular disease, or arrhythmia * Pregnant or breastfeeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of NO Inhibition on Myocardial Substrate Metabolism in Humans | 1-3 months | Determine in young healthy volunteers the extent to which acute inhibition of nitric oxide production will effect a shift in myocardial substrate utilization characterized as a decline in myocardial fatty acid oxidation, and perhaps myocardial fatty acid utilization, and increase in myocardial glucose uptake, and whether these changes are associated with a decline in LV function. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| L-Name in Young 20 individuals age 18-35 will be getting an infusion of L-NAME (a nitric oxide inhibitor) during 3 separate PET study days, then a 10-minute infusion of L-arginine to reverse effects of L-NAME.
L-NAME: nitric oxide synthase inhibitor 4mg/kg infusion over 30-60 minutes prior to PET imaging | 10 |
| Phenylephrine 25 individuals age 18-35 will be getting an infusion of phenylephrine (primarily an alpha agonist) during 3 separate PET study days
Phenylephrine: alpha agonist; 10 μg/kg/min infusion during PET study | 10 |
| L-arginine in Young 20 individuals age 18-35 will be getting an infusion of L-arginine 125 mcg/kg/min for 120 to 140 minutes during 3 separate PET study days
L-Arginine: aids in nitric oxide production | 12 |
| L-arginine in Old 20 individuals age 60-75 will be getting an infusion of L-arginine 125 mcg/kg/min for 120 to 140 minutes during 3 separate PET study days
L-Arginine: aids in nitric oxide production | 10 |
| L-NAME in Old 20 individuals age 60-75 will be getting an infusion of L-NAME (a nitric oxide inhibitor) during 3 separate PET study days, then a 10-minute infusion of L-arginine to reverse effects of L-NAME
L-NAME: nitric oxide synthase inhibitor 4mg/kg infusion over 30-60 minutes prior to PET imaging | 12 |
| Total | 54 |
Baseline characteristics
| Characteristic | Total | Phenylephrine | L-arginine in Young | L-arginine in Old | L-Name in Young | L-NAME in Old |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 54 Participants | 10 Participants | 12 Participants | 10 Participants | 10 Participants | 12 Participants |
| Race and Ethnicity Not Collected | 0 Participants | — | — | — | — | — |
| Region of Enrollment United States | 54 participants | 10 participants | 12 participants | 10 participants | 10 participants | 12 participants |
| Sex: Female, Male Female | 54 Participants | 10 Participants | 12 Participants | 10 Participants | 10 Participants | 12 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 12 | 0 / 10 | 0 / 12 |
| other Total, other adverse events | 0 / 10 | 0 / 10 | 0 / 12 | 0 / 10 | 0 / 12 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 12 | 0 / 10 | 0 / 12 |
Outcome results
Primary
Effect of NO Inhibition on Myocardial Substrate Metabolism in Humans
Determine in young healthy volunteers the extent to which acute inhibition of nitric oxide production will effect a shift in myocardial substrate utilization characterized as a decline in myocardial fatty acid oxidation, and perhaps myocardial fatty acid utilization, and increase in myocardial glucose uptake, and whether these changes are associated with a decline in LV function.
Time frame: 1-3 months
Population: PI left institution. Efforts were made to access the data, without success so there is no access to the data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| L-Name in Young | Effect of NO Inhibition on Myocardial Substrate Metabolism in Humans | NA percentage of substrate |
| Phenylephrine | Effect of NO Inhibition on Myocardial Substrate Metabolism in Humans | NA percentage of substrate |
| L-arginine in Young | Effect of NO Inhibition on Myocardial Substrate Metabolism in Humans | NA percentage of substrate |
| L-arginine in Old | Effect of NO Inhibition on Myocardial Substrate Metabolism in Humans | NA percentage of substrate |
| L-NAME in Old | Effect of NO Inhibition on Myocardial Substrate Metabolism in Humans | NA percentage of substrate |