Diurnal Variation of Plasminogen Activator Inhibitor-1
Condition: Metabolic Syndrome X
MeSH terms: Metabolic Syndrome
Study type: Interventional
Phase: Phase 4

Summary: 
      To determine if nighttime administration of an aldosterone antagonist would effectively lower
      peak plasma Plasminogen Activator Inhibitor-1 (PAI-1) levels more effectively than morning
      administration.
    

Detailed description: 
      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      by a central circadian pacemaker) (unpublished data), suggesting an additional system may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.
    

Intervention name(s): Eplerenone (Morning); Eplerenone (Night-time)
Intervention type(s): Drug; Drug
Intervention description(s): Eplerenone - 50mg, by mouth, daily, in the morning x 2 weeks followed by 4 weeks at 100mg.
100mg, by mouth, daily, in the morning x 4 weeks then patients cross over to 100mg, by mouth, daily, in the evening x another 4 weeks.; Eplerenone - 50mg, by mouth, daily in the evening x 2 weeks followed by 4 weeks at 100mg
Other intervention name(s): Inspra; Inspra
Intervention MeSH terms: Eplerenone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: Metabolic syndrome; Aldosterone inhibitor; Diurnal drug regimen; PAI-1 levels