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This study investigated the potential modifying effects of the level of the serum interleukin-18 (IL-18) on the association between <i>BDNF</i> methylation status and long-term cardiovascular outcomes in patients with acute coronary syndrome (ACS). Hospitalized ACS patients were recruited sequentially from 2006 to 2012. At baseline, the IL-18 level and <i>BDNF</i> methylation status were evaluated in 969 patients who were followed for major adverse cardiac events (MACEs) for 5–12 years, until 2017 or death. The time to first composite or individual MACE was compared between individuals with lower and higher average <i>BDNF</i> methylation levels (in the low- and high-IL-18 groups, respectively) using a Cox proportional hazards model. After adjusting for potential covariates, the modifying effects of IL-18 and average <i>BDNF</i> methylation levels on the initial composite and individual MACEs were examined. In the high-IL-18 group, but not in the low-IL-18 group, a higher average <i>BDNF</i> methylation level was associated with increases in composite MACEs (HR (95% CI) = 2.15 (1.42–3.26)), all-cause mortality (HR (95% CI) = 1.89 (1.11–3.22)), myocardial infarction (HR (95% CI) = 1.98 (1.07–3.67)), and percutaneous coronary intervention (HR (95% CI) = 1.81 (1.01–3.23)), independent of confounding variables. The interaction effect between the IL-18 and average <i>BDNF</i> methylation levels on composite MACEs (<i>p</i> = 0.019) and myocardial infarction (<i>p</i> = 0.027) was significant after adjusting for covariates. Analysis of <i>BDNF</i> methylation status and IL-18 levels may help identify ACS patients who are most likely to have adverse clinical outcomes.