Age-Related Changes in Body Composition

Advancing age is associated with an increasing prevalence, incidence, and complications of
cardiovascular diseases, particularly hypertension and atherosclerosis. The reasons why age
is associated with increased susceptibility to cardiovascular diseases are not understood but
recent literature suggests that systemic inflammation, by affecting endothelial function,
vascular stiffening, diastolic dysfunction and insulin resistance may be an important
contributing cause. Aging is also associated with substantial changes in body composition,
primarily an increase in fat mass and a decline in lean body mass. Studies in animal models
and in humans have shown that the adipose tissue is an important source of pro-inflammatory
mediators and suggested that changes in body composition may be the primary cause of the
pro-inflammatory state of aging. A number of gene expression studies in animal models show
that genes of several pro-inflammatory cytokines are over-expressed with aging, especially in
the adipose tissue. The overproduction of pro-inflammatory cytokines have important systemic
effects, including (1) endothelial dysfunction, one of the earliest features of
atherosclerosis; (2) vascular stiffening, the primary etiology for isolated systolic
hypertension in the elderly; and (3) insulin resistance, the principal metabolic abnormality
associated with cardiovascular risk. Fat infiltration in the liver also promotes chronic
inflammation both directly and by inducing apoptosis of hepatocytes with consequent
inflammatory response and deterioration of liver function.

Limited data exists suggesting that deposition of adipose tissue in specific districts but
not in others is associated with high circulating levels of pro-inflammatory markers. For
example, in humans central adiposity, including fat accumulation surrounding the heart, and
fat infiltration in the muscle, opposed to subcutaneous adiposity seems to be particularly
pro-inflammatory. However, this information comes from small studies, or studies limited to a
very narrow age-range. In addition, the assessment of regional adiposity was mostly based on
anthropometrics. Indeed, non-invasive methodology for the assessment of regional lipid
deposition profiles has become available only recently.

We propose to complement the BLSA population with a group of individuals with established CAD
because the inclusion of this group may help to determine whether, and if so the extent to
which, the expected relationships between body adiposity, inflammation, endothelial
dysfunction, arterial stiffness and insulin resistance are different in healthy individuals
compared to age-matched individuals with clinically overt vascular disease.

As a side hypothesis, we will also verify whether changes in Testosterone with age are
associated with changes in regional fat accumulation. To test this hypothesis we will measure
total, free and biovailable Testosterone in all participants.

- INCLUSION CRITERIA: (both Group A and Group B):

- Age 50-90 years

- Body mass index greater than or equal to 20 and less than or equal to 35

- Weight is less than 300 lbs

In addition, for CAD participants (Group B):

- Catheterization-documented coronary artery disease, defined as greater than or equal
to 70% stenosis in a major epicardial coronary artery, or greater than or equal to 50%
stenosis of the left main coronary artery OR

- Prior myocardial infarction defined by ischemic symptoms associated with ECG changes
and enzyme elevation.

In addition, for CAD participants in whom arterial and hepatic vein inflammatory mediators
will be obtained:

- Scheduled for clinically indicated right or left heart catheterization, no
contraindication for the procedure, and consented to the research procedure.

Exclusion criteria

- Known inflammatory disease

- Known liver disease

- Abnormal liver function tests defined by enzyme rise to greater than three times the
upper limit of normal.

- Contraindications to the performance of MRI scans

- Chronic use of anti-inflammatory agents other than low dose aspirin (81mg). Chronic
use is defined here as the inability to stop taking their anti-inflammatory agent for
at least one week before starting this study

- Pregnant or lactating

In addition, for BLSA participants:

- Known coronary artery disease by prior history, examination, or resting or stress
electrocardiogram testing.

In addition, for CAD participants undergoing arterial and hepatic vein inflammatory
mediator sampling:

- Receiving therapy with heparin, a glycoprotein IIB/IIIA inhibitor, or bivalirudin

- History of atrial fibrillation

- Presence of an inferior vena cava filter

- Deep venous thrombosis

- Active infection.