Jae-Min Kim1, Robert Stewart2, Ju-Wan Kim3, Hee-Ju Kang3, Ju-Yeon Lee3, Seon-Young Kim3, Sung-Wan Kim3, Il-Seon Shin3, Young Joon Hong4, Youngkeun Ahn4, Myung Ho Jeong4, Jin-Sang Yoon3. 1. Department of Psychiatry, Chonnam National University Medical School, Gwangju, Republic of Korea. Electronic address: jmkim@chonnam.ac.kr. 2. King's College London, Institute of Psychiatry, Psychology and Neuroscience, London, England; South London and Maudsley NHS Foundation Trust, London, England. 3. Department of Psychiatry, Chonnam National University Medical School, Gwangju, Republic of Korea. 4. Department of Cardiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Abstract
AIMS: Brain-derived neurotrophic factor (BDNF) plays important roles in angiogenesis, inflammation, and neuronal plasticity. BDNF methylation has been extensively investigated in depression, but not in cardiac diseases. We asked whether BDNF methylation status is associated with a major adverse cardiac event (MACE), inflammation, and the association with depression comorbidity and its treatment in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: A cross-sectional baseline study and nested 24 week double-blind escitalopram placebo-controlled trial (ClinicalTrial.gov identifier NCT00419471) were performed from 2006 to 2012, with 5-12 year follow-up for MACE. Patients with recent ACS (969 total) were divided into four groups according to depression comorbidity at baseline and treatment allocation: 591, absent depression; 127, depression on escitalopram; 128, depression onplacebo; 123, depression on care as usual (CAU). BDNF methylation was measured in leucocyte DNA, and multiple demographic and clinical characteristics including interleukin 6 were evaluated as covariates at baseline. The primary outcome, time to first MACE (a composite of all-cause mortality, myocardial infarction and percutaneous coronary intervention), was investigated using Cox regression models after adjustment for covariates. Interleukin 6 level was significantly higher in patients with higher BDNF methylation values. Higher BDNF methylation was associated with increased MACE independent of confounding factors [HR (95% CI) = 1.45 (1.17-1.78)]. This association was significant in patients without depression [HR (95% CI) = 1.39 (1.01-1.90)] and depressive patients on placebo [HR (95% CI) = 1.72 (1.02-3.02)] or CAU [HR (95% CI) = 1.53 (1.01-2.61)], but not in those treated with escitalopram [HR (95% CI) = 1.00 (0.51-1.95)]. CONCLUSION:BDNF methylation was significantly associated with prognosis of ACS. Escitalopram may mitigate the deleterious effect of higher BDNF methylation in depressive patients with ACS. Further research is needed to elucidate the mechanistics and to assess the generalisability of these findings.
RCT Entities:
AIMS: Brain-derived neurotrophic factor (BDNF) plays important roles in angiogenesis, inflammation, and neuronal plasticity. BDNF methylation has been extensively investigated in depression, but not in cardiac diseases. We asked whether BDNF methylation status is associated with a major adverse cardiac event (MACE), inflammation, and the association with depression comorbidity and its treatment in patients with acute coronary syndrome (ACS). METHODS AND RESULTS: A cross-sectional baseline study and nested 24 week double-blind escitalopram placebo-controlled trial (ClinicalTrial.gov identifier NCT00419471) were performed from 2006 to 2012, with 5-12 year follow-up for MACE. Patients with recent ACS (969 total) were divided into four groups according to depression comorbidity at baseline and treatment allocation: 591, absent depression; 127, depression on escitalopram; 128, depression on placebo; 123, depression on care as usual (CAU). BDNF methylation was measured in leucocyte DNA, and multiple demographic and clinical characteristics including interleukin 6 were evaluated as covariates at baseline. The primary outcome, time to first MACE (a composite of all-cause mortality, myocardial infarction and percutaneous coronary intervention), was investigated using Cox regression models after adjustment for covariates. Interleukin 6 level was significantly higher in patients with higher BDNF methylation values. Higher BDNF methylation was associated with increased MACE independent of confounding factors [HR (95% CI) = 1.45 (1.17-1.78)]. This association was significant in patients without depression [HR (95% CI) = 1.39 (1.01-1.90)] and depressivepatients on placebo [HR (95% CI) = 1.72 (1.02-3.02)] or CAU [HR (95% CI) = 1.53 (1.01-2.61)], but not in those treated with escitalopram [HR (95% CI) = 1.00 (0.51-1.95)]. CONCLUSION:BDNF methylation was significantly associated with prognosis of ACS. Escitalopram may mitigate the deleterious effect of higher BDNF methylation in depressivepatients with ACS. Further research is needed to elucidate the mechanistics and to assess the generalisability of these findings.
Authors: Benedetta Izzi; Alfonsina Tirozzi; Chiara Cerletti; Maria Benedetta Donati; Giovanni de Gaetano; Marc F Hoylaerts; Licia Iacoviello; Alessandro Gialluisi Journal: Int J Mol Sci Date: 2020-11-21 Impact factor: 5.923