Role of Nitric Oxide in the Impact of Aging on Myocardial Remodeling

Study Overview
=================
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.

Official Title
-----------------
PET Detection of the Effects of Aging on the Human Heart. Aim#1-Impact of Aging on Myocardial Remodeling: Role of Nitric Oxide

Conditions
-----------------
Cardiovascular Diseases

Intervention / Treatment
-----------------
* Drug: L-NAME
* Drug: L-Arginine
* Drug: Phenylephrine


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: L-Name in Young<br>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. | Drug: L-NAME<br>* nitric oxide synthase inhibitor 4mg/kg infusion over 30-60 minutes prior to PET imaging<br>* Other names: N (G)-nitro-L- arginine methyl ester;|
| Active Comparator: Phenylephrine<br>25 individuals age 18-35 will be getting an infusion of phenylephrine (primarily an alpha agonist) during 3 separate PET study days | Drug: Phenylephrine<br>* alpha agonist; 10 μg/kg/min infusion during PET study<br>* Other names: (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol;|
| Active Comparator: L-arginine in Young<br>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 | Drug: L-Arginine<br>* aids in nitric oxide production<br>* Other names: 2-Amino-5-guanidinopentanoic acid;|
| Active Comparator: L-arginine in Old<br>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 | Drug: L-Arginine<br>* aids in nitric oxide production<br>* Other names: 2-Amino-5-guanidinopentanoic acid;|
| Experimental: L-NAME in Old<br>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 | Drug: L-NAME<br>* nitric oxide synthase inhibitor 4mg/kg infusion over 30-60 minutes prior to PET imaging<br>* Other names: N (G)-nitro-L- arginine methyl ester;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 1-3 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
PET, Heart metabolism, Nitric oxide, Myocardial remodeling