Diagnosing Natriuretic Peptide Deficiency

The cardiac natriuretic peptide (NP) system may protect against the development of
cardiometabolic risk. The classical actions of the natriuretic peptides include natriuresis,
vasodilation, and inhibition of the renin-angiotensin-aldosterone system (RAAS), which
support a key role for these hormones in blood pressure regulation. There is accumulating
biological evidence that the NPs have a wide range of favorable metabolic effects as well,
including reduced fat accumulation, activation of brown fat, and improved glucose tolerance.
These results suggest that the NPs may help protect against cardiometabolic risk.

Despite a propensity for hypertension and hypervolemia, obese individuals have reduced NP
levels.1,2 Low NP levels may reflect a "deficiency" in obese persons, as opposed to an
appropriate response to cardiovascular stimuli. Such a deficiency could have a deleterious
impact on cardiometabolic risk, creating a "vicious cycle" by which obese individuals have
increased susceptibility to further fat accumulation and glucose intolerance via impaired NP
production.

As stated above, NP hormones may protect against cardiometabolic risk. Large epidemiologic
studies have shown that resting NP levels are lower in certain groups of individuals.
However, it is difficult to say for certain whether these low resting levels of NPs reflect a
true "deficiency," as a low NP level may be biologically appropriate in certain situations
(e.g. if an individual is volume depleted). At this time, there is no test to diagnose "NP
deficiency."

Studies in animals suggest that glucocorticoids potently stimulate NP production. There are
limited studies in humans showing that glucocorticoids stimulate NP production; however, the
NP response specifically to dexamethasone, the glucocorticoid which has been shown in animal
data to potently stimulate NP production, has not been defined in humans.

Moreover, the range of normal responses to glucocorticoids in healthy individuals is not
well-defined. Understanding this range of normal responses is an important first step in
developing a diagnostic tool to detect NP deficiency. The investigators propose a pilot study
to characterize the NP response (range of NP levels, time course of response) to
dexamethasone in healthy controls. This data will be used to develop power calculations and
inform cutoff ranges for future studies aimed at developing a diagnostic test for "NP
deficiency." Developing a test to diagnose NP deficiency could have potentially important
clinical implications in understanding cardiometabolic risk.

Inclusion criteria:

- Men and women ages 18-50 years

- BMI 18.5 to <25 kg/m^2

Exclusion Criteria:

- Significant use of systemically-absorbed glucocorticoids currently or for an extended
period of time during the prior 6 months

- Current use of antihypertensive medications

- Current use of metformin, or any antidiabetic medications (which could affect glucose
and insulin levels)

- Current use of medications known to affect dexamethasone metabolism, including
phenytoin, rifampin, carbamazepine, troglitazone, and barbiturates

- Active, clinically significant infection at time of visit

- History of adrenal insufficiency or Cushing's syndrome

- Prior or current cardiovascular disease, renal disease, or liver disease

- Diabetes mellitus, pre-diabetes, impaired fasting glucose, or impaired glucose
tolerance

- Atrial fibrillation

- Bleeding disorder or anemia

- Elevated LFTs > 2 times upper limit of normal

- eGFR < 60 ml/min

- HbA1c > 5.7

- Abnormal sodium or potassium level

- Positive pregnancy test, women of child-bearing age not practicing birth control,
women who are breastfeeding