Clinical Trial: Diurnal Variation of Plasminogen Activator Inhibitor-1

Study Status: Completed
Recruit Status: Unknown status
Study Type: Interventional

Official Title: The Effects of Night-Time Versus Morning Administration of Eplerenone on the Diurnal Variation of Plasminogen Activator Inhibitor-1

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

Detailed Summary:

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 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pacemaker) when compared to those whose circadian rhythms are entrained (controlled by a central circadian pacemaker) (unpublished data), suggesting an additional system may modulate diurnal variation of PAI-1.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 PRA and aldosterone levels peak earlier than PAI-1 levels, they may be partially responsible. Indeed,
Sponsor: Vanderbilt University

Current Primary Outcome: Evidence of improved fibrinolytic balance [ Time Frame: 14 weeks ]

Original Primary Outcome: Same as current

Current Secondary Outcome:

Original Secondary Outcome:

Information By: Vanderbilt University

Dates:
Date Received: August 9, 2007
Date Started: April 2007
Date Completion: April 2010
Last Updated: January 27, 2009
Last Verified: January 2009