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

Not Applicable

Completed

Conditions: Cardiovascular Diseases

Interventions: Drug: Phenylephrine
Drug: L-Arginine
Drug: L-NAME

Registration Number: NCT00603720

Lead Sponsor: Washington University School of Medicine

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 54

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Phenylephrine	Phenylephrine	25 individuals age 18-35 will be getting an infusion of phenylephrine (primarily an alpha agonist) during 3 separate PET study days
L-arginine in Young	L-Arginine	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 in Old	L-Arginine	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-Name in Young	L-NAME	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 in Old	L-NAME	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

Primary Outcome Measures

Name	Time	Method
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.

Secondary Outcome Measures