ObjectiveNew-onset depressive symptoms commonly arise among persons without a history of major depressive disorder (MDD) in the setting of acute medical illness. Although depressive symptoms in general are associated with alterations in prognostic biomarkers following acute coronary syndrome (ACS), the nature of specifically new-onset depressive symptoms is less well-characterized. It is unclear whether such symptoms neurobiologically resemble recurrent symptoms of MDD or instead represent a distinct condition. In this exploratory analysis, we aimed to examine the effects of prior MDD history on the relationships between post-ACS depressive symptoms and cardiovascular biomarkers. MethodsOne-hundred sixty-four participants attended study visits 2 weeks and 6 months after ACS to complete self-report measures and provide biomarker samples. MDD history was identified by a psychiatrist through systematic electronic medical record review. Generalized estimating equations were performed to examine the moderating effects of MDD history on concurrent relationships between depressive symptoms and several biomarkers (endothelin-1, soluble intercellular adhesion molecule-1, high-sensitivity C-reactive protein, interleukin-6, and tumor necrosis factor-alpha). ResultsTwenty percent (n = 33) of participants had a history of MDD. Depressive symptoms were more strongly associated with levels of endothelin-1 in patients with prior MDD compared to those without (B = 0.024, 95% CI [0.005, 0.043], p = .012), adjusting for age, sex, medical factors, and anxiety. MDD history did not moderate relationships between depressive symptoms and other biomarkers. ConclusionRecurrent post-ACS depressive symptoms are more strongly associated with elevated endothelin-1 levels than new-onset symptoms. Further work is needed to clarify the mechanism and clinical implications of this relationship.