A clinical evaluation of statin pleiotropy: statins selectively and dose-dependently reduce vascular inflammation.
Statins are thought to reduce vascular inflammation through lipid independent mechanisms. Evaluation of such an effect in atherosclerotic disease is complicated by simultaneous effects on lipid metabolism. Abdominal aortic aneurysms (AAA) are part of the atherosclerotic spectrum of diseases. Unlike atherosclerotic occlusive disease, AAA is not lipid driven, thus allowing direct evaluation of putative anti-inflammatory effects. The anti-inflammatory potency of increasing doses (0, 20 or 40 mg/day) simvastatin or atorvastatin was evaluated in 63 patients that were at least 6 weeks on statin therapy and who underwent open AAA repair. A comprehensive analysis using immunohistochemistry, mRNA and protein analyses was applied on aortic wall samples collected during surgery. The effect of statins on AAA growth was analyzed in a separate prospective study in incorporating 142 patients. Both statins equally effectively and dose-dependently reduced aortic wall expression of NFκB regulated mediators (i.e. IL-6 (P<0.001) and MCP-1 (P<0.001)); shifted macrophage polarization towards a M2 phenotype (P<0.0003); selectively reduced macrophage-related markers such as cathepsin K and S (P<0.009 and 0.0027 respectively), and ALOX5 (P<0.0009), and reduced vascular wall NFκB activity (40 mg/day group, P<0.016). No effect was found on other cell types. Evaluation of the clinical efficacy of statins to reduce AAA progression did not indicate an effect of statins on aneurysm growth (P<0.337). Hence, in the context of AAA the clinical relevance of statins pleiotropy appears minimal.
Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Evelien
E
van der Meij
Giel G
GG
Koning
Patrick W
PW
Vriens
Marcel F
MF
Peeters
C Arnoud
CA
Meijer
Kim E
KE
Kortekaas
Ronald L
RL
Dalman
J Hajo
JH
van Bockel
Roeland
R
Hanemaaijer
Teake
T
Kooistra
Robert
R
Kleemann
Jan H N
JH
Lindeman
D000368:Aged; D000369:Aged, 80 and over; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007962:Leukocytes / Q000166:cytology / Q000276:immunology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D018925:Chemokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B