Association of Transient Endothelial Dysfunction Induced by Mental Stress With Major Adverse Cardiovascular Events in Men and Women With Coronary Artery Disease

Abstract

Importance: Acute mental stress can result in transient endothelial dysfunction, but the prognostic relevance of this phenomenon is unknown.

Objective: To determine the association between mental stress-induced impairment in endothelium-dependent relaxation as assessed by brachial artery flow-mediated vasodilation and adverse cardiovascular outcomes among individuals with stable coronary artery disease.

Design, setting, and participants: This cohort study was conducted at a university-affiliated hospital network between June 2011 and August 2014. A cohort of individuals with stable coronary artery disease were included. Data analysis took place from November 2018 to May 2019.

Exposures: Study participants were subjected to a laboratory mental stress task (public speaking).

Main outcomes and measures: Flow-mediated vasodilation was measured before and 30 minutes after a public-speaking mental stress task. We examined the association of the rest (prestress), poststress, and δ flow-mediated vasodilation (poststress minus prestress levels) with an adjudicated composite end point of adverse events, including cardiovascular death, myocardial infarction, unstable angina leading to revascularization, and heart failure hospitalization, after adjusting for sociodemographic factors, medical history, and depression.

Results: A total of 569 patients were included (mean [SD] age, 62.6 [9.3] years; 420 men [73.8%]). Flow-mediated vasodilation decreased from a mean (SD) of 4.8% (3.7%) before mental stress to 3.9% (3.6%) after mental stress (a 23% reduction; P < .001), and 360 participants (63.3%) developed transient endothelial dysfunction (a decrease in flow-mediated vasodilation). During a median (interquartile range) follow-up period of 3.0 (2.9-3.1) years, 74 patients experienced a major adverse cardiovascular event. The presence of transient endothelial dysfunction with mental stress was associated with a 78% increase (subdistribution hazard ratio [sHR], 1.78 [95% CI, 1.15-2.76]) in the incidence of major adverse cardiovascular event. Both the δ flow-mediated vasodilation (sHR, 1.15 [95% CI, 1.03-1.27] for each 1% decline) and poststress flow-mediated vasodilation (sHR, 1.14 [95% CI, 1.04-1.24] for each 1% decline) were associated with major adverse cardiovascular event. Risk discrimination statistics demonstrated a significant model improvement after addition of either poststress flow-mediated vasodilation (change in the area under the curve, 0.05 [95% CI, 0.01-0.09]) or prestress plus δ flow-mediated vasodilation (change in the area under the curve, 0.04 [95% CI, 0.00-0.08]) compared with conventional risk factors.

Conclusions and relevance: In this study, transient endothelial dysfunction with mental stress was associated with adverse cardiovascular outcomes in patients with coronary artery disease. Endothelial responses to stress represent a possible mechanism through which psychological stress may affect outcomes in patients with coronary artery disease.

Figure 1.. Adjusted Cumulative Incidence of Major Adverse Cardiovascular Events (MACEs) According to Flow-Mediated Vasodilation (FMD) Levels

Data stratified by prestress FMD (A), poststress FMD (B), stress-induced transient endothelial dysfunction status (C), and 4 categories combining information on prestress FMD and stress-induced transient endothelial dysfunction status (D). Major adverse cardiovascular events are defined as a combination of cardiovascular death, myocardial infarction, unstable angina with revascularization, and decompensated heart failure. Subdistribution hazard ratios (sHR) represent the risk of end points for the comparison vs the reference groups while treating noncardiovascular death as competing risks. P values were generated from the cumulative-incidence function homogeneity test of Gray.

Figure 2.. Multivariate Survival Analysis of the Associations of Prestress Measurements, Poststress Measurements, and δ Flow-Mediated Vasodilation with Study End Points

δ Flow-mediated vasodilation (FMD) was defined as poststress minus prestress FMD. Subdistribution hazard ratios (HRs) represent the risk of end points per 1% decrement in FMD, while treating noncardiovascular death as competing risk. The δ FMD models were also adjusted for resting FMD. MACE indicates major adverse cardiovascular events.