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

Cardiovascular Diseases Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00603720
• Other study ID #: AG0086
• Secondary ID: 5R01AG015466-080
• Status: Completed
• Phase: N/A
• Start date: September 2005
• Est. completion date: June 2008

Study information

• Verified date: September 2018
• Source: Washington University School of Medicine
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: June 2008
• Est. primary completion date: June 2008
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Cardiovascular Diseases

Intervention

Drug:
• L-NAME
nitric oxide synthase inhibitor 4mg/kg infusion over 30-60 minutes prior to PET imaging
• L-Arginine
aids in nitric oxide production
• Phenylephrine
alpha agonist; 10 µg/kg/min infusion during PET study

Locations

Country	Name	City	State
United States	Washington University School of Medicine	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Washington University School of Medicine	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

References & Publications (4)

Coughlin SS, Neaton JD, Sengupta A, Kuller LH. Predictors of mortality from idiopathic dilated cardiomyopathy in 356,222 men screened for the Multiple Risk Factor Intervention Trial. Am J Epidemiol. 1994 Jan 15;139(2):166-72. — View Citation

Haldeman GA, Croft JB, Giles WH, Rashidee A. Hospitalization of patients with heart failure: National Hospital Discharge Survey, 1985 to 1995. Am Heart J. 1999 Feb;137(2):352-60. — View Citation

Ogawa T, Spina RJ, Martin WH 3rd, Kohrt WM, Schechtman KB, Holloszy JO, Ehsani AA. Effects of aging, sex, and physical training on cardiovascular responses to exercise. Circulation. 1992 Aug;86(2):494-503. — View Citation

Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991 Jun;68(6):1560-8. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
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.	1-3 months