Diurnal Variation of Plasminogen Activator Inhibitor-1

Plasminogen activator inhibitor-1, a member of the serine protease inhibitor (serpin)
superfamily, is the principal inhibitor to tissue-type plasminogen activator and
urokinase-type plasminogen activator. Elevated plasma PAI-1 levels, an independent
cardiovascular risk factor, has been shown to be a predictor of recurrent myocardial
infarction (MI). Acute changes in plasma PAI-1 after MI is a predictor of mortality. PAI-1
levels are elevated in the individuals with hypertension, insulin resistance,
hypertriglyceridemia, obesity, and the constellation of risk-factors known as the metabolic
syndrome. PAI-1 is synthesized in the liver, vascular endothelium, vascular smooth muscle,
and visceral adipose tissue. A number of factors have been shown to regulate PAI-1, including
metabolic factors such as insulin, glucose, triglycerides; inflammatory cytokines such as
tumor necrosis factor-α, transforming growth factor-β, interleukin-1, and more notably,
components of the renin-angiotensin-aldosterone system (RAAS), namely angiotensin II and
aldosterone.

PAI-1 also has a diurnal variation with a peak plasma level occurring between 8 and 9 AM that
may help explain why the incidence of acute MI is highest in the morning and why thrombolysis
is least effective at that time. PAI-1's diurnal variation is been shown to be directly
regulated by central and peripheral circadian pacemakers in vitro, and in vivo. Our group has
observed that the diurnal variation of plasma PAI-1 levels is blunted and delayed in blind
individuals who's circadian mechanisms are free running (not controlled by a central
circadian pacemaker) when compared to those whose circadian rhythms are entrained (controlled
by a central circadian pacemaker) (unpublished data), suggesting an additional system may
modulate diurnal variation of PAI-1. As plasma renin activity (PRA) and aldosterone levels
peak earlier than PAI-1 levels, they may be partially responsible. Indeed, continuous
infusion of candesartan eliminated diurnal variation of aortic PAI-1 message expression in
Wistar-Kyoto and spontaneously hypertensive rats, while hydralazine did not.

The use of therapies to modulate plasma PAI-1 levels in human subjects have met with variable
success. Low salt diet was shown to increase plasma PAI-1 levels in normotensive subjects in
a manner that correlated with plasma aldosterone levels. Twice daily treatment with quinapril
(40mg) lowered plasma PAI-1 levels during the expected peak time. In a second study of twice
daily quinapril compared to twice daily losartan in normotensive subjects both only had a
modest effect on plasma PAI-1 levels. A third study helped to explain this finding. In a
crossover study, hypertensive subjects received daily spironolactone or hydrochlorothiazide
(HCTZ) in a randomized fashion. Plasma PAI-1 levels were increased after HCTZ treatment, but
not significantly changed from baseline with spironolactone treatment. Spironolactone
treatment, however, resulted in significantly higher aldosterone levels. The correlation
between plasma aldosterone and PAI-1 that was observed at baseline and with HCTZ treatment
was not observed in the spironolactone arm, suggesting that the endogenous relationship
between aldosterone and PAI-1 can be disrupted by mineralocorticoid receptor antagonism.

Inclusion Criteria:

- Age18-65

- Metabolic Syndrome (3 or more of the following):

1. Blood pressure 130/85 or greater

2. Central obesity (Waist - Male > 40", Female > 35")

3. Fasting glucose ≥ 110 mg/dl

4. Low HDL (Male < 40 mg/dl, Female < 50 mg/dl)

5. Elevated Triglycerides (> 150 mg/dl)

Exclusion Criteria:

- Cigarette Use

- Renal insufficiency

- Coronary Artery Disease

- Diabetes

- Blindness

- Cerebrovascular Disease

- Secondary hypertension (renal artery stenosis, pheo, etc.)

- RAAS disease (Primary Aldosteronism, etc.)

- Other chronic illness (cancer, autoimmune or liver disease)

- Pregnancy

- Anemia (Hgb < 12 mg/dl)

- Evening or Night Shift work

- Transmeridian travel in previous 6 months

- History of sleep disorders

- Hypokalemia (serum potassium < 3.5 milliequivalent (mEq/L)

- Hyperkalemia (serum potassium > 5.5 mEq/L

- Reported hypersensitivity to HCTZ or eplerenone