title: Decreased mortality associated with statin treatment in patients with acute myocardial infarction and lymphotoxin-alpha C804A polymorphism.
abstract: OBJECTIVE
  We previously reported the association of single nucleotide polymorphisms in the lymphotoxin alpha (LTα) gene with susceptibility to acute myocardial infarction (AMI) and increased mortality after discharge. In the present study, we investigated whether the adverse effect of LTα C804A polymorphism on mortality could be pharmacologically modified by statin treatment after AMI.
  
  
  RESULTS
  We conducted a multicenter study that included 3486 post-AMI patients between 1998 and 2008. During a median follow-up period of 1775 days, 247 deaths were recorded. The mortality rate was significantly higher in LTα 804A allele carriers compared to non-804A allele carriers (7.9% vs. 5.7%, p = 0.011). The LTα 804A allele was significantly associated with increased mortality for post-AMI patients not receiving statins (hazard ratio [HR]: 1.48, 95% confidence interval [CI]: 1.03-2.12, p = 0.034), but not for those receiving statins (HR: 1.22, 95% CI: 0.70-2.10, p = 0.486). In-vitro experimental analyses demonstrated that the LTα 804A polymorphic protein, 26Asn-LTα3, induced monocyte-endothelial interaction and endoplasmic reticulum (ER) stress in cardiomyocytes more strongly than the LTα3 804C polymorphic protein 26Thr-LTα3. However, the effects of both LTα3 proteins were decreased and became comparable by the pretreatment of cells with pravastatin.
  
  
  CONCLUSIONS
  LTα C804A polymorphism was associated with an increased risk of mortality for AMI patients, although this effect was masked in patients treated with statins. This finding is supported by the observed attenuation of 26Asn-LTα3-mediated monocyte-endothelial interaction and ER stress in cardiomyocytes treated with pravastatin. LTα C804A polymorphism may have potential as a novel therapeutic target for secondary prevention after AMI.
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Japan.
authors: Shinichiro
authors: S
authors: Suna
authors: Yasuhiko
authors: Y
authors: Sakata
authors: Daisaku
authors: D
authors: Nakatani
authors: Keiji
authors: K
authors: Okuda
authors: Masahiko
authors: M
authors: Shimizu
authors: Masaya
authors: M
authors: Usami
authors: Sen
authors: S
authors: Matsumoto
authors: Masahiko
authors: M
authors: Hara
authors: Kouichi
authors: K
authors: Ozaki
authors: Hiroya
authors: H
authors: Mizuno
authors: Tetsuo
authors: T
authors: Minamino
authors: Seiji
authors: S
authors: Takashima
authors: Masami
authors: M
authors: Nishino
authors: Yasushi
authors: Y
authors: Matsumura
authors: Hiroshi
authors: H
authors: Takeda
authors: Toshihiro
authors: T
authors: Tanaka
authors: Hiroshi
authors: H
authors: Sato
authors: Masatsugu
authors: M
authors: Hori
authors: Issei
authors: I
authors: Komuro
mesh_terms: D000208:Acute Disease; D000368:Aged; D000483:Alleles; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006579:Heterozygote; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood* / Q000401:mortality*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D017035:Pravastatin / Q000627:therapeutic use*; D016016:Proportional Hazards Models; D051381:Rats; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008233:Lymphotoxin-alpha; D019010:Vascular Cell Adhesion Molecule-1; D017035:Pravastatin