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

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.

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