Author + information
- Andrew Steptoe, DSc∗ (, )
- Lydia Poole, PhD,
- Amy Ronaldson, MSc,
- Tara Kidd, PhD,
- Elizabeth Leigh, PhD and
- Marjan Jahangiri
- ↵∗Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, United Kingdom
Coronary artery bypass graft (CABG) is the treatment of choice for patients with multivessel disease and leads to reductions in long-term mortality, incidence of myocardial infarction (MI), and revascularization. Depressive symptoms occur in as many as 25% of patients after CABG and predict cardiovascular morbidity (1). The mechanisms underlying depressive symptoms are poorly understood, but one possibility is that they are stimulated through inflammatory processes. Inflammatory cytokines may contribute to depression, with both the innate and adaptive immune responses being relevant (2). Cytokine levels are markedly increased after CABG as part of the systemic inflammatory response. We therefore hypothesized that symptoms of depression measured 12 months after CABG would be predicted by the magnitude of inflammatory responses in the days immediately after surgery.
We investigated 145 patients who underwent elective CABG, measuring depressive symptoms 1 month before and 12 months after surgery. Plasma interleukin (IL)-6 and interferon gamma (IFN-γ) concentrations 1 to 3 days after surgery were measured as markers of innate and adaptive immune responses, respectively. Depressive symptoms were measured using the Beck Depression Inventory or the Patient Health Questionnaire 9-item version, and standard cutoffs were used to define significant depressive symptoms. Covariates included the European System for Cardiac Operative Risk Evaluation (EuroSCORE), a composite measure of mortality risk, and pre-surgery depressive symptoms. We used logistic regression to calculate the odds of depression in relation to medium and large inflammatory responses, with the small inflammatory response tertile as the reference group.
Significant depressive symptoms were recorded in 20% of patients 12 months after surgery and were positively associated with the magnitude of IFN-γ responses to surgery. The mean concentrations of IFN-γ were 23.84 ± 4.6, 37.81 ± 4.7, and 58.68 ± 7.5 pg/ml in the 3 tertiles. Compared with the lowest tertile, the odds of depressive symptoms in patients in the highest tertile were 4.32 (95% confidence interval: 1.21 to 17.96) after adjusting for covariates (Table 1). The association also was significant when IFN-γ was modeled as a continuous variable rather than being categorized into tertiles, with an adjusted odds ratio of 1.03 (95% confidence interval: 1.01 to 1.07, p = 0.029) per pg/ml increase in IFN-γ. No association between depressive symptoms and IL-6 after was observed.
These results are consistent with the notion that high levels of inflammation after CABG may contribute to the development of later depressive symptoms. We controlled for pre-surgical depressive symptoms and cardiological status, factors potentially contributing to depression, but the association with IFN-γ remained significant. Further statistical adjustment for other potential confounders was not possible due to the low event count. Our study was not powered to test clinical cardiological outcomes, but the results suggest that depressive symptoms and cardiac outcomes after bypass surgery share a common biological basis. It is notable that IL-6 was not related to subsequent depressive symptoms. IL-6 and IFN-γ represent different immune pathways. Expression of IFN-γ suggests the involvement of tryptophan metabolism because IFN-γ induces indoleamine 2,3-dioxygenase, which is responsible for the catabolism of tryptophan, leading to products such as kynurenine that are directly implicated in depression, while also lowering the availability of serotonin in the brain (3). Additionally, IFN-γ is involved in cardiovascular pathology (4). An earlier study of CABG patients demonstrated that greater IFN-γ concentration in the 12 h after surgery predicted clinical cardiac outcomes at 12 months (5). Increased IFN-γ therefore provides a mechanistic link between depressive symptoms and cardiac morbidity after CABG. These observations are not only relevant to the mental health of cardiac patients, but suggest that some of the adverse cardiovascular effect of depression may be due to inflammatory processes. Targeting inflammatory processes may have an impact on depressive symptoms as well as potentially reducing cardiac morbidity.
Please note: The research was supported by the British Heart Foundation (RG/10/05/28296). All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- 2015 American College of Cardiology Foundation