(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Aortic-Aneurysm--Abdominal

Despite the importance of the renin-angiotensin (Ang) system in abdominal aortic aneurysm (AAA) pathogenesis, strategies targeting this system to prevent clinical aneurysm progression remain controversial and unproven. We compared the relative efficacy of two Ang II type 1 receptor blockers, telmisartan and irbesartan, in limiting experimental AAAs in distinct mouse models of aneurysm disease.. AAAs were induced using either 1) Ang II subcutaneous infusion (1000 ng/kg/min) for 28 days in male ApoE(-/-) mice, or 2) transient intra-aortic porcine pancreatic elastase infusion in male C57BL/6 mice. One week prior to AAA creation, mice started to daily receive irbesartan (50 mg/kg), telmisartan (10 mg/kg), fluvastatin (40 mg/kg), bosentan (100 mg/kg), doxycycline (100 mg/kg) or vehicle alone. Efficacy was determined via serial in vivo aortic diameter measurements, histopathology and gene expression analysis at sacrifice. Aortic aneurysms developed in 67% of Ang II-infused ApoE(-/-) mice fed with standard chow and water alone (n = 15), and 40% died of rupture. Strikingly, no telmisartan-treated mouse developed an AAA (n = 14). Both telmisartan and irbesartan limited aneurysm enlargement, medial elastolysis, smooth muscle attenuation, macrophage infiltration, adventitial neocapillary formation, and the expression of proteinases and proinflammatory mediators. Doxycycline, fluvastatin and bosentan did not influence aneurysm progression. Telmisartan was also highly effective in intra-aortic porcine pancreatic elastase infusion-induced AAAs, a second AAA model that did not require exogenous Ang II infusion.. Telmisartan suppresses experimental aneurysms in a model-independent manner and may prove valuable in limiting clinical disease progression.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Benzimidazoles; Benzoates; Biphenyl Compounds; Bosentan; Doxycycline; Fatty Acids, Monounsaturated; Fluvastatin; Indoles; Irbesartan; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Sulfonamides; Telmisartan; Tetrazoles

Topics: Angioplasty; Aortic Aneurysm, Abdominal; Blood Vessel Prosthesis Implantation; C-Reactive Protein; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Patient Selection; Vascular Surgical Procedures

To evaluate the effect of statins on aneurysm growth in a group of consecutive patients under surveillance for infrarenal aortic aneurysms (AAA).. All patients (59 statin users, 91 non-users) under surveillance between January 2002 and August 2005 with a follow-up for aneurysm growth of at least 12 months and a minimum of three diameter evaluations were retrospectively included in the analysis. Multiple regression analysis, weighted with the number of observations, was performed to test the influence of statins on AAA growth rate.. During a median period of 3.1 (1.1-13.1) years the overall mean aneurysm growth rate was 2.95+/-2.8 mm/year. Statin users had a 1.16 mm/year lower AAA growth rate compared to non-users (95% CI 0.33-1.99 mm/year). Increased age was associated with a slower growth (-0.09 mm/year per year, p = 0.003). Female gender (+1.82 mm/year, p = 0.008) and aneurysm diameter (+0.06 mm/year per mm, p = 0.049) were associated with increased AAA growth. The use of non-steroidal anti-inflammatory drugs, chronic lung disease, or other cardiovascular risk factors were not independently associated with AAA growth.. Statins appear to be associated with attenuation of AAA growth, irrespective of other known factors influencing aneurysm growth.

Topics: Aged; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Atorvastatin; Fatty Acids, Monounsaturated; Female; Fluvastatin; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Male; Netherlands; Population Surveillance; Pyrroles; Retrospective Studies; Simvastatin; Time Factors; Ultrasonography