Abstract 9505: Short-Term Statin Therapy Improves Murine Deep Venous Thrombosis Resolution While Reducing Thrombus Inflammation: An in vivo Multi-Targeted Imaging Study
Background: Improving DVT resolution may limit the development of the post-thrombotic syndrome (PTS). Utilizing confocal intravital fluorescence microscopy (IVFM), we investigated the in vivo effects of short-term statin therapy on thrombus burden, permeability, and inflammation in subacute murine DVT.
Methods: In 24 male C57Bl/6J mice with topical FeCl3-induced femoral DVT, atorvastatin (1.14 mg/kg/day, ≈ 80 mg/day/human subject, n=12) or PBS (n=12) was administered on days 1-4 via gavage. On day 3, macrophage-targeted nanoparticles (CLIO-AF555, ex/em 555/565 nm) and an MMP activity sensor (MMPsense680, 680/700 nm) were i.v. injected. On day 4, FITC-dextran (490/520 nm) was injected to define thrombus anatomy and to evaluate thrombus permeability. 30 minutes after FITC-dextran injection, IVFM was performed. The in vivo thrombus burden, and average thrombus macrophage, MMP activity, and permeability target-to-background ratio (TBR) in the mid-thrombus zone (z-stack of 40 um thickness) were determined from CLIO, MMPsense and FITC signals. Histopathology and fluorescence microscopy studies were performed.
Results: Atorvastatin decreased DVT area on IVFM (0.17±0.01 mm2vs. 0.20±0.03 mm2 in PBS animals, p=0.001), and by microscopy (% thrombus area, 42.2±12.6% statin vs. 71.0±12.7% PBS, p<0.001). Thrombus sections from statin-treated animals showed reduced PAI-1 immunoreactivity (14.8±4.7% positive area vs. 30.7±5.0% in PBS mice, p=0.022). Notably, statin therapy reduced thrombus inflammation compared to PBS-treated animals (macrophage TBR 1.7±0.2 vs. 3.1±0.3, p=0.001; and MMP activity TBR 1.3±0.1 vs. 1.8±0.2, p=0.021, respectively). Thrombus permeability was similar in the two groups (p=NS). Correlative fluorescence microscopy and immunohistochemistry corroborated the in vivo imaging findings.
Conclusions: Short-term statin therapy in subacute DVT reduces thrombus burden and improves DVT resolution in vivo. The observed benefits of statin treatment are linked to its anti-thrombotic properties, and occur in the setting of reduced thrombus inflammation and similar thrombus permeability. Statin therapy may offer a clinically translatable approach to improve DVT resolution and to limit PTS.
- © 2011 by American Heart Association, Inc.