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

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

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Abstract

Aims: 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. 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 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)373-379
Number of pages7
JournalAtherosclerosis
Volume227
Issue number2
DOIs
Publication statusPublished - 2013 Apr

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Suna, S., Sakata, Y., Nakatani, D., Okuda, K., Shimizu, M., Usami, M., Matsumoto, S., Hara, M., Ozaki, K., Mizuno, H., Minamino, T., Takashima, S., Nishino, M., Matsumura, Y., Takeda, H., Tanaka, T., Sato, H., Hori, M., & Komuro, I. (2013). Decreased mortality associated with statin treatment in patients with acute myocardial infarction and lymphotoxin-alpha C804A polymorphism. Atherosclerosis, 227(2), 373-379. https://doi.org/10.1016/j.atherosclerosis.2013.01.020