When Stress Biology Meets Coronary Atherosclerosis: Diurnal Cortisol Patterns and Coronary Artery Disease Burden in Patients With Diabetes and Chronic Depression

Abstract

Background: Type 2 diabetes mellitus and chronic depression frequently co-occur and jointly accelerate coronary artery disease (CAD), and dysregulation of the hypothalamic–pituitary–adrenal axis has been proposed as a biological link. This study aimed to determine whether diurnal serum cortisol metrics are associated with the angiographic burden of CAD in patients with both conditions.

Methods: In this retrospective observational study with a case–control component, 100 participants were analyzed: 50 patients with type 2 diabetes and clinician-documented chronic depression (cases) and 50 healthy controls. Morning (06:00–10:00) and evening (16:00–20:00) serum cortisol was measured with the Roche Elecsys Cortisol II immunoassay, and the AM–PM difference and AM/PM ratio were derived. In cases, coronary burden was classified from catheter angiography reports as multivessel CAD (≥ 70% stenosis in two or more major epicardial arteries) and obstructive CAD (≥ 70% stenosis in any epicardial vessel or ≥ 50% in the left main). Group comparisons, exploratory multivariable logistic regression adjusted for age, sex, body mass index, hypertension, dyslipidemia and smoking, and receiver operating characteristic (ROC) analyses were performed; because of the small number of events, the adjusted and ROC analyses are reported as exploratory and hypothesis-generating.

Results: Compared with controls, cases had higher morning cortisol (17.00 ± 3.00 vs. 15.02 ± 2.63 µg/dL; mean difference 1.98 µg/dL, 95% confidence interval (CI): 0.86–3.10, P = 0.0007), higher evening cortisol (median 4.72 vs. 3.21 µg/dL, P < 0.001), and a lower AM/PM ratio (median 3.56 vs. 4.28, P = 0.0087), whereas the absolute AM–PM difference did not differ (P = 0.25). Among cases, 37 had multivessel CAD and 19 had obstructive CAD. No cortisol parameter differed according to multivessel (all P ≥ 0.29) or obstructive status (all P ≥ 0.52), and, in exploratory adjusted models, none was independently associated with either endpoint (e.g., adjusted odds ratio (aOR) for evening cortisol 0.61, 95% CI 0.33–1.11 for multivessel CAD and 0.74, 95% CI 0.41–1.33 for obstructive CAD). In exploratory ROC analyses, cortisol metrics showed poor discrimination, with areas under the curve ranging from 0.39 (95% CI 0.22–0.59) to 0.59 (95% CI 0.43–0.74); every 95% CI included 0.50. In the exploratory adjusted model, older age was inversely associated with obstructive CAD (aOR 0.91, 95% CI 0.84–0.99, P = 0.030), a finding that requires confirmation given only 19 obstructive CAD events.

Conclusions: Patients with comorbid type 2 diabetes and chronic depression show elevated cortisol with a blunted diurnal ratio, but single-day spot serum cortisol metrics are not associated with the angiographic extent or severity of CAD in this sample; the adjusted and ROC analyses were exploratory and require confirmation. Measures of cumulative cortisol exposure, such as repeated multi-day salivary sampling and hair cortisol, combined with comprehensive coronary computed tomography angiography, merit evaluation in larger prospective cohorts.