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

The Washington University

Status: Completed

Conditions: Cardiovascular Diseases

Treatments: Drug: L-Arginine; Drug: Phenylephrine; Drug: L-NAME

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00603720

05-0810 (Registry Identifier)

AG0086

5R01AG015466-08 (U.S. NIH Grant/Contract)

GCRC# 1002 (Other Identifier)

RDRC# 482F (Other Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 54 patients

Sex: All

Ages: 18 to 75 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Basic Science

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

---

54 participants in 5 patient groups

L-Name in Young

Active Comparator group

Description:

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.

Treatment:

Drug: L-NAME

Phenylephrine

Active Comparator group

Description:

25 individuals age 18-35 will be getting an infusion of phenylephrine (primarily an alpha agonist) during 3 separate PET study days

Treatment:

Drug: Phenylephrine

L-arginine in Young

Active Comparator group

Description:

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

Treatment:

Drug: L-Arginine

L-arginine in Old

Active Comparator group

Description:

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

Treatment:

Drug: L-Arginine

L-NAME in Old

Experimental group

Description:

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

Treatment:

Drug: L-NAME