Clinical trial NCT00603720: Role of Nitric Oxide in the Impact of Aging on Myocardial Remodeling
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Cardiovascular Diseases
Keywords: PET
Heart metabolism
Nitric oxide
Myocardial remodeling
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: National Institute on Aging (NIA)
First posted: 2008-01-29
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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

Primary outcomes:
measure: Effect of NO Inhibition on Myocardial Substrate Metabolism in Humans
timeFrame: 1-3 months
Secondary outcomes:
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Robert Gropler, MD
role: PRINCIPAL_INVESTIGATOR
References:
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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. doi: 10.1161/01.res.68.6.1560.
citation: 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. doi: 10.1093/oxfordjournals.aje.a116978.
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. doi: 10.1053/hj.1999.v137.95495.