Andrew Liuni1, Mary Clare Luca, Tommaso Gori, John D Parker. 1. Division of Cardiology, Mount Sinai and University Health Network Hospitals and Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
Abstract
OBJECTIVES: The purpose of this study was to determine whether single-dose rosuvastatin (40 mg) protects against ischemia and reperfusion (IR)-induced endothelial dysfunction in humans and whether this effect is cyclooxygenase (COX)-2 dependent. BACKGROUND: Animal studies have demonstrated that rosuvastatin can limit damage and improve recovery after IR. METHODS: In a double-blind, parallel design, 20 volunteers were randomized to a single dose of oral rosuvastatin (40 mg) or placebo. Twenty-four hours later, endothelium-dependent, flow-mediated dilation (FMD) of the radial artery was measured before and after IR (15 min of upper arm ischemia followed by 15 min of reperfusion). In a separate protocol, 18 volunteers received theCOX-2 inhibitor celecoxib (200 mg orally twice daily) for 5 days. On day 4, subjects were randomized to single-dose rosuvastatin (40 mg) or placebo and 24 h later underwent the same protocol as described. RESULTS:Pre-IR FMD was similar between groups (p = NS). IR significantly blunted FMD in the placebo group (FMD pre-IR: 6.4 +/- 1.4%; FMD post-IR: 1.1 +/- 3.8%, [p = 0.002]). Rosuvastatin prevented this impairment (FMD pre-IR: 7.5 +/- 3.1%; FMD post-IR: 6.2 +/- 3.9%, [p = NS] vs. rosuvastatin pre-IR, [p = 0.03] vs. placebo). Pre-treatment with celecoxib completely abolished rosuvastatin's protective effect (FMD pre-IR: 8.0 +/- 2.2%; FMD post-IR: 1.4 +/- 2.0%, [p < 0.001] compared with pre-IR, [p = NS] vs. placebo, [p = 0.002] vs. rosuvastatin alone). CONCLUSIONS:Rosuvastatin pharmacologically prevents the development of IR-induced conduit artery endothelial dysfunction. This beneficial effect of rosuvastatin is mediated by a COX-2-dependent mechanism, evidence that may also provide potential mechanistic insight into the reported cardiotoxic effects of COX-2 inhibitors. Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
RCT Entities:
OBJECTIVES: The purpose of this study was to determine whether single-dose rosuvastatin (40 mg) protects against ischemia and reperfusion (IR)-induced endothelial dysfunction in humans and whether this effect is cyclooxygenase (COX)-2 dependent. BACKGROUND: Animal studies have demonstrated that rosuvastatin can limit damage and improve recovery after IR. METHODS: In a double-blind, parallel design, 20 volunteers were randomized to a single dose of oral rosuvastatin (40 mg) or placebo. Twenty-four hours later, endothelium-dependent, flow-mediated dilation (FMD) of the radial artery was measured before and after IR (15 min of upper arm ischemia followed by 15 min of reperfusion). In a separate protocol, 18 volunteers received the COX-2 inhibitor celecoxib (200 mg orally twice daily) for 5 days. On day 4, subjects were randomized to single-dose rosuvastatin (40 mg) or placebo and 24 h later underwent the same protocol as described. RESULTS: Pre-IR FMD was similar between groups (p = NS). IR significantly blunted FMD in the placebo group (FMD pre-IR: 6.4 +/- 1.4%; FMD post-IR: 1.1 +/- 3.8%, [p = 0.002]). Rosuvastatin prevented this impairment (FMD pre-IR: 7.5 +/- 3.1%; FMD post-IR: 6.2 +/- 3.9%, [p = NS] vs. rosuvastatin pre-IR, [p = 0.03] vs. placebo). Pre-treatment with celecoxib completely abolished rosuvastatin's protective effect (FMD pre-IR: 8.0 +/- 2.2%; FMD post-IR: 1.4 +/- 2.0%, [p < 0.001] compared with pre-IR, [p = NS] vs. placebo, [p = 0.002] vs. rosuvastatin alone). CONCLUSIONS:Rosuvastatin pharmacologically prevents the development of IR-induced conduit artery endothelial dysfunction. This beneficial effect of rosuvastatin is mediated by a COX-2-dependent mechanism, evidence that may also provide potential mechanistic insight into the reported cardiotoxic effects of COX-2 inhibitors. Copyright (c) 2010 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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