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Prior MDD moderates the association between endothelin-1 and post-ACS depressive symptoms

Key clinical point: Prior major depressive disorder (MDD) moderates the association between post-acute coronary syndrome (ACS) depressive symptoms and endothelin-1 (ET-1), such that recurrent depressive symptoms are associated with elevated levels of ET-1 than new-onset symptoms.

Major finding: Depressive symptoms were more strongly associated with levels of ET-1 in patients with prior MDD than those without after adjustment for age, sex, medical covariates, and anxiety (B = 0.024; P = .012). MDD history did not moderate the associations between depressive symptoms and other biomarkers.

Study details: The findings are based on an exploratory analysis of GRACE study including 164 post-ACS patients.

Disclosures: Data on funding and conflicts of interest were not available.


“Based on a comprehensive literature review, an American Heart Association Scientific Statement (Lichtman et al, 2014) concluded that depression, after acute coronary syndrome (ACS), is an adverse prognostic risk factor with respect to all-cause and cardiac mortality, and nonfatal cardiac events.

As discussed in a recent review (Parker et al, 2020), multiple questions about depression as an adverse post-ACS prognostic risk factor remain, including: Is an adverse post-ACS prognosis limited to particular depressive subgroups? For example, timing of depression relative to the ACS event may be relevant – i.e. Depression of new onset vs depression recurrence may influence post-ACS outcomes differently. While this hypothesis has mixed evidence, if true, it implies that different pathophysiological bases underlie new vs recurrent post-ACS depression.

The original “GRACE” study of 164 volunteers reported that post-ACS depression was associated with increased endothelial dysfunction (Endothelin-1 blood levels) and inflammatory markers (IL-17 +/- TNF-alpha blood levels). Both are previously implicated as mediators of the adverse cardiovascular effects of depression. This secondary analysis examined the association of biomarkers and depression severity in the two subgroups: Unlike new onset post-ACS depression, recurrent depression moderated the association of depressive symptoms with ET-1, but not with inflammatory markers (IL-17, TNF-alpha). i.e. Patients in the recurrent depression subgroup were more likely to have high levels of endothelial dysfunction. Inflammation severity was not influenced by whether post-ACS depression was of new onset or recurrent.

Consistent with other research, this study supports the heterogenous nature of post-ACS depression, which as noted by experts including Parker et al (2020), may explain the contradictions in the literature regarding the association of depression and cardiovascular disease. While understanding evolves, a number of reasonable clinical decisions include:

1. Educating depressed patients the associated risk of coronary artery disease to encourage them to adhere to primary or secondary prevention recommendations such as exercising, reducing cholesterol tobacco abstinence and treatment adherence.

2. Screening depression with PHQ-2/PHQ-9 in the post-ACS period.

3. Encouraging post-ACS depressed patients to enter multidisciplinary rehabilitation programs that promote lifestyle change and psychological well-being.

4. In the absence of clear evidence as to whether treatment influences cardiac prognosis, optimizing quality of life is the goal of post-ACS depression treatment.

5. Evidence-based psychotherapies, such as Cognitive-Behavioral Therapy have been shown to improve post-ACS depression

6. The influence of antidepressants on prognosis has not been clarified. Tricyclic antidepressants are clearly contraindicated. The most studied antidepressant in treating post-ACS depression is sertraline, which is effective. So far, no safety concerns in the post-ACS period have emerged in underpowered studies. Other SSRIs are likely reasonable, with the exception of citalopram which widens the QTc.”

A Gita Ramamurthy, MD

Director, Psychiatry Consultation-Liaison Service


Madva EN et al. J Psychosom Res. 2020 Nov 11. doi: 10.1016/j.jpsychores.2020.110291.