**Introduction / Hypothesis**
Major depressive disorder (MDD) is prevalent mood disorder associated with impaired quality of life and an increased risk of cardiovascular disease (CVD) and mortality. Individuals with CVD also have high rates of depression implying a bi-directional relationship between these two variables. Studies have consistently demonstrated an association between endothelial dysfunction and MDD although the link between coronary endothelial dysfunction (CED) diagnosed using invasive coronary reactivity testing and an incident diagnosis of MDD in males and females separately is unclear.

**Methods**
Patients presenting with chest pain and nonobstructive CAD (stenosis < 40%) at coronary angiography underwent an invasive assessment of CED. Macrovascular CED was characterized as a percentage change in coronary artery diameter in response to acetylcholine (%ΔCADAch) of ≤ -10% and microvascular CED was characterized as a percentage change in coronary blood flow in response to acetylcholine (%ΔCBFAch) of ≤ -50%. Patient charts were reviewed to identify those who underwent a formal clinical evaluation for MDD after the index procedure. Coronary endothelial function and the frequency of CED was compared in those with versus without MDD. Logistic regression analyses were performed to assess the association between baseline CED and incident MDD amongst all patients and after stratifying by sex.

**Results**
Between January 1992 and December 2021, 2,280 patients underwent invasive testing for CED. Five hundred and sixteen patients (22.6%) underwent a formal evaluation for MDD at a date after the index procedure and had measurements available for both %ΔCADAch and %ΔCBFAch (mean (sd) age 53.3 (12.0) years, 72.3% female). One hundred sixty (31.0%) of all individuals were diagnosed with MDD. In all patients %ΔCADAch was significantly lower in those diagnosed with MDD (-10.8% vs. -5.3%, p=0.008). This was also the case in males (-19.0% vs. -4.8%, p=0.001), but not females. In males, a higher proportion of those with macrovascular CED were diagnosed with MDD compared to those not diagnosed with MDD (58.8% vs. 38.3%, p=0.035). In multivariable analyses, macrovascular CED was associated with MDD in males (OR, 95% CI 2.99, 1.26 – 7.45, p=0.015) but not in females.

**Conclusion**
Macrovascular CED is significantly associated with incident MDD in males with chest pain and nonobstructive CAD. CED may thus be a useful marker to identify individuals at risk of depression who may benefit from more frequent screening and early preventive therapy. Further, endothelial dysfunction may represent an underlying mechanism for MDD potentially implicating the role of vascular health in the etiology and management of this condition.



**Introduction / Hypothesis**
Major depressive disorder (MDD) is prevalent mood disorder associated with impaired quality of life and an increased risk of cardiovascular disease (CVD) and mortality. Individuals with CVD also have high rates of depression implying a bi-directional relationship between these two variables. Studies have consistently demonstrated an association between endothelial dysfunction and MDD although the link between coronary endothelial dysfunction (CED) diagnosed using invasive coronary reactivity testing and an incident diagnosis of MDD in males and females separately is unclear.

**Methods**
Patients presenting with chest pain and nonobstructive CAD (stenosis < 40%) at coronary angiography underwent an invasive assessment of CED. Macrovascular CED was characterized as a percentage change in coronary artery diameter in response to acetylcholine (%ΔCADAch) of ≤ -10% and microvascular CED was characterized as a percentage change in coronary blood flow in response to acetylcholine (%ΔCBFAch) of ≤ -50%. Patient charts were reviewed to identify those who underwent a formal clinical evaluation for MDD _after_ the index procedure. Coronary endothelial function and the frequency of CED was compared in those with versus without MDD. Logistic regression analyses were performed to assess the association between baseline CED and incident MDD amongst all patients and after stratifying by sex.

**Results**
Between January 1992 and December 2021, 2,280 patients underwent invasive testing for CED. Five hundred and sixteen patients (22.6%) underwent a formal evaluation for MDD at a date _after_ the index procedure and had measurements available for both %ΔCADAch and %ΔCBFAch (mean (sd) age 53.3 (12.0) years, 72.3% female). One hundred sixty (31.0%) of all individuals were diagnosed with MDD. In all patients %ΔCADAch was significantly lower in those diagnosed with MDD (-10.8% vs. -5.3%, p=0.008). This was also the case in males (-19.0% vs. -4.8%, p=0.001), but not females. In males, a higher proportion of those with macrovascular CED were diagnosed with MDD compared to those not diagnosed with MDD (58.8% vs. 38.3%, p=0.035). In multivariable analyses, macrovascular CED was associated with MDD in males (OR, 95% CI 2.99, 1.26 – 7.45, p=0.015) but not in females.

**Conclusion**
Macrovascular CED is significantly associated with incident MDD in males with chest pain and nonobstructive CAD. CED may thus be a useful marker to identify individuals at risk of depression who may benefit from more frequent screening and early preventive therapy. Further, endothelial dysfunction may represent an underlying mechanism for MDD potentially implicating the role of vascular health in the etiology and management of this condition.



Coronary Endothelial Dysfunction Is Associated with Major Depressive Disorder In Men with Chest Pain and Non-Obstructive Coronary Artery Disease