Decreased mortality associated with statin treatment in patients with acute myocardial infarction and lymphotoxin-alpha C804A polymorphism

作者：Suna Shinichiro; Sakata Yasuhiko^*; Nakatani Daisaku; Okuda Keiji; Shimizu Masahiko; Usami Masaya; Matsumoto Sen; Hara Masahiko; Ozaki Kouichi; Mizuno Hiroya; Minamino Tetsuo; Takashima Seiji; Nishino Masami; Matsumura Yasushi; Takeda Hiroshi; Tanaka Toshihiro; Sato Hiroshi; Hori Masatsugu; Komuro Issei

来源：Atherosclerosis, 2013, 227(2): 373-379.

DOI：10.1016/j.atherosclerosis.2013.01.020

• Lymphotoxin alpha
• Myocardial infarction
• Single nucleotide polymorphism
• Statin

Aims: We previously reported the association of single nucleotide polymorphisms in the lymphotoxin alpha (LT alpha) gene with susceptibility to acute myocardial infarction (AMI) and increased mortality after discharge. In the present study, we investigated whether the adverse effect of LT alpha C804A polymorphism on mortality could be pharmacologically modified by statin treatment after AMI.
Methods and 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 LT alpha 804A allele carriers compared to non-804A allele carriers (7.9% vs. 5.7%, p 0.011). The LT alpha 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 LT alpha 804A polymorphic protein, 26Asn-LT alpha(3), induced monocyte-endothelial interaction and endoplasmic reticulum (ER) stress in cardiomyocytes more strongly than the LT alpha(3) 804C polymorphic protein 26Thr-LT alpha(3). However, the effects of both LT alpha(3) proteins were decreased and became comparable by the pretreatment of cells with pravastatin.
Conclusion: LT alpha 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-LT alpha(3)-mediated monocyte-endothelial interaction and ER stress in cardiomyocytes treated with pravastatin. LT alpha C804A polymorphism may have potential as a novel therapeutic target for secondary prevention after AMI.

• 出版日期2013-4