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

September 11, 2018 updated by: Washington University School of Medicine

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

54

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Washington University School of Medicine

Collaborators

National Institute on Aging (NIA)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2005

Primary Completion (Actual)

June 1, 2008

Study Completion (Actual)

June 1, 2008

Study Registration Dates

First Submitted

January 16, 2008

First Submitted That Met QC Criteria

January 16, 2008

First Posted (Estimate)

January 29, 2008

Study Record Updates

Last Update Posted (Actual)

September 12, 2018

Last Update Submitted That Met QC Criteria

September 11, 2018

Last Verified

September 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AG0086
  • 5R01AG015466-08 (U.S. NIH Grant/Contract)
  • 05-0810 (Registry Identifier: HRPO)
  • RDRC# 482F (Other Identifier: RDRC)
  • GCRC# 1002 (Other Identifier: GCRC)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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