Abstract 14674: Cardiovascular Events Associated with Lymphotoxin Alpha and its Polymorphism After the Onset of Myocardial Infarction
Background. Lymphotoxin (LT) α is a member of the tumor necrosis factor family that plays a critical role in inflammation. We recently reported that the single nucleotide polymorphisms (SNPs) of the LTα gene are closely related to the susceptibility of acute myocardial infarction (AMI) and subsequent mortality after discharge. However, it remains unknown whether these unfavorable effects of LTα polymorphisms could be pharmacologically modified in the clinical settings.
Methods and Results. We investigated a total of 3,067 patients with AMI who were registered to the Osaka Acute Coronary Insufficiency Study and discharged alive from 2000 to 2007 (mean follow-up period: 1,319 days). All-cause mortality rate after discharge was significantly higher in carriers of 804A allele in the LTα gene, which replaces the LTα protein 26 threonine (Thr) to asparagines (Asn), than non-carriers (9.1% vs. 6.4%, P=0.044). Adjusted hazard ratio (HR) for mortality remains higher in A allele carriers than in non-carriers in patients without statins (HR 1.43, p=0.018), but were similar in those treated with statins (HR 1.18, p=0.558). Experimental analyses demonstrated that LTα-26Asn, when compared with LTα-26Thr, induced higher adhesion rate of monocytes onto endothelial cells and higher migration rates of monocytes toward the condition medium of LTα-treated human umbilical vein endothelial cells (HUVEC), suggesting that LTα-26Asn could be involved in the progression of atherosclerosis. Moreover, LTα-26Asn induced higher rate of endoplasmic reticulum (ER) stress characterized by CHOP and GRP78/94 expression in rat neonatal cardiomyocytes, suggesting that LTα-26Asn could be a cause of heart failure via degeneration of cardiomyocytes. Interestingly, these effects of LTα-26Asn on monocyte-endothelial adhesion and increased ER stress in cardiomyocytes were both attenuated by pravastatin treatment.
Conclusions. An increased risk of mortality in the C804A polymorphism of the LTα gene appeared to be modified by statin treatment, which may be explained by attenuation of monocyte-endothelial interaction and degeneration of cardiomyocytes. The C804A polymorphisms of the LTα gene could be a novel therapeutic target for the secondary prevention after AMI.
- © 2011 by American Heart Association, Inc.