Suicide is a global health issue, and much effort has been dedicated to identify patients at risk of suicide and devise preventive strategies. However, no markers have been validated to predict SI, where suicide is a complex, multifactorial phenomenon involving interactions between various environmental stressors (e.g., childhood adversities and physical illness) and individual factors including hopelessness, temperament, and biological mechanisms [e.g., sensory processing, serotonergic system function, hypothalamic–pituitary–adrenergic (HPA) axis activity, inflammatory status, and genetic vulnerabilities] (1–4). Life-threatening physical illnesses, including acute coronary syndrome (ACS), are risk factors for suicide because of their psychological (e.g., hopelessness and psychiatric comorbidities) and biological (e.g., inflammation and a heightened stress response due to HPA axis activity) effects (5, 6). Previous epidemiological and clinical studies demonstrated an increased risk of suicide in ACS patients (6, 7). Suicide/suicidal behavior (SB) includes suicidal ideation (SI), suicidal attempts (SA), and death due to suicide. SI is associated with poor long-term cardiac outcomes in ACS patients (8). Therefore, it is important to investigate the pathophysiology and biological markers of suicide in ACS patients.

Previous studies reported that abnormal inflammatory responses, including changes in cytokines, contribute to SB, which includes SI and SA (9, 10). Additionally, inflammation is a well-established pathomechanism underlying ACS (11). Cytokines are key modulators of inflammation and promising biomarkers of SB in ACS patients (12). Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine produced by T cells, glial cells, and neurons. Tumor necrosis factor-alpha activates the serotonergic system of the brain by stimulating serotonin transport and decreasing extracellular serotonin (13). Accordingly, many studies have reported that an increase in the TNF-α level and expression is associated with SI, SA, and death (14–17). However, other studies have reported no such association (18, 19) or a negative association has been reported (20). For the studies of TNF-α polymorphism, TNF-α-308 G/A is associated with SA (21) and male suicide (22). However, others reported no such associations (23, 24).

Despite accumulating evidence for a high risk of suicidality in ACS patients (6, 7), and the associations between suicide and cytokine abnormalities (9, 10), no study has investigated the association between cytokine imbalance (including TNF-α) and suicidality in ACS patients. The TNF-α level is affected by TNF-α gene polymorphisms; −850T and −308A alleles result in higher TNF-α levels compared to −850C and −308G alleles (25, 26). Interventions focused on suicide prevention are needed for patients at high risk of SI within 2 weeks, and 1 year after, ACS onset, based on their TNF-α status (level and polymorphism). We hypothesized that increased inflammation within 2 weeks of ACS onset, evidenced by a higher TNF-α serum level or polymorphisms that increase TNF-α expression, may be associated with SI in ACS patients. Additionally, individual and interactive effects of TNF-α serum levels and polymorphisms on SI in ACS patients may vary according to the time elapsed since ACS. Therefore, we investigated the individual effects of the serum TNF-α level and polymorphisms (−850C/T and −308G/A), as well as their interactive effect, on SI within 2 weeks, and 1 year after, ACS onset.

The main findings of this 1-year longitudinal study of ACS patients were that SI during the acute phase of ACS was significantly associated with higher baseline sTNFα levels and the −850 C/T or T/T polymorphism, both individually and interactively. SI during the chronic phase of ACS was associated with higher sTNFα levels individually and significantly interacted with the two polymorphisms. SI is an early and mild form of SB. However, a study including participants from several countries reported that 60% of patients transition from SI to a SA during the first year after SI onset (37). Therefore, it is essential to detect SI in the early phase after onset of severe physical illness to prevent SA.

In this study, higher sTNFα levels within 2 weeks after ACS were associated with SI, both within 2 weeks and after 1 year. This suggests that an increase in TNF-α immediately after ACS plays a role in the pathophysiology of SI in ACS patients. The association between TNF-α and suicide has not been confirmed in the psychiatric or general population. Higher TNF-α levels are associated with SA [plasma, (14)], suicidal death [brain, (15, 16)], and SI in depressed patients [serum, (17)]. However, TNF-α levels are not associated with SI, SA, or death [CSF and plasma, (19); plasma, (18)], whereas decreased TNF-α levels have been associated with SI in depressed adolescents [plasma, (20)]. These inconsistent findings may be due to differences in study design, including suicide-related outcomes, study participants, and the bio-samples measured. Moreover, no longitudinal study has been performed on the association between TNF-α level and later SI, except the antidepressant response on changes in SI (17, 38). The heightened inflammatory status of the sTNFα level following ACS (11) may have contributed to susceptibility to SI in response to a stressful event such as ACS through an interaction with the serotonergic system and neuroplasticity (39, 40).

It was interesting that the interactive effect of the TNF-α polymorphisms and sTNFα level on SI differed by time elapsed after ACS was diagnosed. The TNF-α −850 C/T polymorphism was associated with SI within 2 weeks after ACS individually and interactively with a higher sTNFα level. The significant interaction means that the association between a higher sTNFα level and SI within 2 weeks after ACS was prominent in the presence of the risk allele (−850 T). This inherited vulnerability, particularly the TNF-α −850 C/T or T/T polymorphism, which is associated with a higher sTNFα level (25), may potentiate the deleterious effect of an increased sTNFα level in response to ACS (11, 41). This proinflammatory state contributed to patients who faced the life-threatening event of ACS being susceptible to SI even in the acute phase of ACS. Although there is a lack of previous studies on the association between the TNF-α −850 C/T polymorphism and suicide ranging from SI to SA, our findings provide evidence for inflammatory dysregulation underlying SB and provide insight for future studies investigating the association between TNF-α and suicide to consider the interaction between the sTNFα level and these polymorphisms.

No interactions were detected between the sTNFα level and individual polymorphisms on SI at 1 year after ACS, but a significant interaction was identified between the two polymorphisms and SI. During the chronic phase of ACS when adaptation to the changes after ACS has occurred, the interactive effect of the two TNF-α genetic polymorphisms rather than a single inherited polymorphism may have contributed to ACS patients experiencing SI. Although no previous studies have considered the interaction between the two TNF-α polymorphisms and underlying mechanisms, future research with larger samples is needed to ascertain these time-specific and synergistic genetic associations underlying SI in ACS patients.

This study had several strengths. It was the first longitudinal study to investigate the associations between TNF-α measured within 2 weeks and SI within 2 weeks, and at 1 year after, ACS onset. Additionally, this was the first study to investigate the individual and interactive effects of sTNFα levels and two polymorphisms (−850 C/T and −308 G/A) on SI. Moreover, many clinical and psychosocial covariates were assessed using validated instruments for psychiatric and cardiovascular evaluations. All consecutive eligible patients with recent ACS were recruited and followed up after 1 year, which reduced the error due to discordant examination intervals and increased sample homogeneity.

There were several limitations to this study. First, SI was measured using suicide-related items on a depression scale, rather than by a dedicated psychometric instrument (such as the Columbia Classification Algorithm of Suicide Assessment) (42). Although the suicide-related items of the MADRS are sensitive to changes in SI (30), future studies using scales (e.g., Columbia Classification Algorithm of Suicide Assessment) that are more specific and sensitive to SI assessment are needed to confirm our findings. Second, our findings on SI may not apply to SB in general in patients with ACS. Nevertheless, SI alone imposes a considerable healthcare burden (43) and can lead to severe SB (44). Third, the frequent co-occurrence of SI and depression needs further evaluation. In this study, 38 (80.5%) of 195 ACS patients had SI within 2 weeks of ACS onset, while 77 (88.5%) of 87 ACS patients with SI had depression at 1 year after ACS. SI is significantly associated with depression. In fact, it is one of the diagnostic criteria for depression (45). Previous studies have reported unique, shared, and interactive pathophysiological mechanisms underlying depression and suicide (46, 47). Inflammatory dysregulation has also been suggested as an underlying mechanism of depression, particularly in ACS patients during the acute phase of illness (48). In this study, the relationship between SI and TNFα levels/polymorphisms remained significant despite adjusting for depression status/treatment as a confounding factor. However, the association of SI with depression should be considered when interpreting the results of our study. Fourth, sTNFα levels were measured only once (at baseline); therefore, longitudinal associations between changes in sTNFα levels and SI could not be evaluated. Also, this study included a relatively small sample. However, polymorphism studies require large sample sizes. Moreover, we did not evaluate mental disorder history, including anxiety disorders, which may affect SI and should be considered as a potential covariate. Additionally, healthy controls were not included in this study, which precluded comparison of sTNFα levels between ACS patients and healthy controls. Future studies including healthy controls will be needed. Finally, attrition should be considered when interpreting the results. Of the participants, 84% agreed to undergo blood/genetic testing, and 73% of these patients were followed up. There was no difference between patients who did and did not undergo blood/genetic testing, but patients lost to follow-up were more likely to be older and have worse cardiac function.

In conclusion, a significant individual and interactive effect of sTNFα levels and the −850 C/T polymorphism on SI within 2 weeks after ACS onset was identified. A significant individual effect of the sTNFα level and interactive effects of the two TNF-α polymorphisms on SI at 1 year after ACS onset were observed. Our findings suggest that sTNFα levels and polymorphisms (−850 C/T and −308 G/A), individually or in combination, could be used as time-specific biomarkers of SI in ACS patients. In other words, measuring the sTNFα levels within 2 weeks after ACS and/or 850 C/T polymorphism can identify ACS patients at high risk of SI during the acute phase of the illness. Measuring the sTNFα levels or both polymorphisms (−850 C/T and –308 G/A) within 2 weeks can identify ACS patients at high risk for SI in the chronic phase of the illness who require preventive management. Detection of SI in ACS patients is crucial because SI is associated with poor long-term cardiac outcomes in ACS patients (8). Evaluation of sTNFα levels and polymorphisms in ACS patients may help clinicians to identify vulnerable patients who may benefit from focused, collaborative, and preventive strategies for SI. Our result will provide a basis for future research on the role of TNF-α in SI in ACS patients. Long-term clinical outcome studies are required on the effects of early identification of SI and preventive management in ACS patients. Further studies are warranted to evaluate the reproducibility of our results and cost-effectiveness of testing for sTNFα levels and polymorphisms.

The raw data supporting the conclusions of this article will be made available by the inquries to the corresponding author.

The studies involving human participants were reviewed and approved by The Chonnam National University Hospital Institutional Review Board. The patients/participants provided their written informed consent to participate in this study.

H-JK and J-MK conducted the data analysis and drafted the article. J-WK, J-YL, S-WK, and I-SS helped to analyze the data and to draft the article. YH, YA, and M-HJ helped to recruit the participants and perform cardiac assessment and management. All authors contributed the article and approved the submitted version.

The study was funded by a grant of the National Research Foundation of Korea Grant (NRF-2020M3E5D9080733 and NRF-2020R1A2C2003472) to J-MK.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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