Role of Nitric Oxide in the Impact of Aging on Myocardial Remodeling
Condition: Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases
Study type: Interventional

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.
    

Intervention name(s): L-NAME; L-Arginine; Phenylephrine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): nitric oxide synthase inhibitor 4mg/kg infusion over 30-60 minutes prior to PET imaging; aids in nitric oxide production; alpha agonist; 10 μg/kg/min infusion during PET study
Other intervention name(s): N (G)-nitro-L- arginine methyl ester; 2-Amino-5-guanidinopentanoic acid; (R)-3-[-1-hydroxy-2-(methylamino)ethyl]phenol
Intervention MeSH terms: Phenylephrine; Oxymetazoline; NG-Nitroarginine Methyl Ester
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: PET; Heart metabolism; Nitric oxide; Myocardial remodeling