Disrupted circadian rhythm in sleep disordered breathing promotes atrial fibrillation in human myocardium

Abstract Objective Patients with severe coronary artery disease are at increased risk for multiple comorbidities and associated disorders, including sleep disordered breathing (SDB) and atrial fibrillation (AF). The role of myocardial circadian rhythm gene regulation for AF initiation and progression in these patients is still elusive, but recent research implicates disturbance of circadian rhythm gene expression in the progression of different diseases. Purpose We evaluated the myocardial expression of relevant genes involved in the circadian rhythm (BMAL1, CLOCK, NR1D1, NR1D2) in patients with severe coronary artery disease warranting bypass surgery. Methods Clinical data including a pre- and postoperative standard 12-lead ECG as well as a pre-operative test for SDB using polygraphy was acquired from 160 patients undergoing elective coronary artery bypass grafting. An apnea-hypopnea index (AHI) ≥ 15/h defined SDB diagnosis. Human myocardial tissue was analyzed from intraoperatively obtained right-atrial appendage biopsies acquired in the morning. CLOCK, BMAL1, NR1D1, NR1D2 mRNA expression was quantified using real-time qPCR. Results CLOCK expression (% ACTB) (median IQR) was reduced to 1.408 1.174 in SDB patients when compared to patients without SDB 1.844 1.292 (p 0.001, Mann-Whitney test, Figure A, left panel). Moreover, CLOCK expression was negatively correlated with increasing SDB severity (AHI; linear regression, r2 = 0.061, p = 0.002, Figure A, right panel). BMAL1 expression was also reduced in SDB patients to 0.216 0.207 compared to 0.459 0.411 in controls (p 0.001, Figure B, left panel) and negatively correlated with the AHI (r2 = 0.050, p = 0.004, Figure B, right panel). NR1D2 expression was similarly reduced in SDB patients, while NR1D1 expression was not significantly altered (not shown). For further analysis, we defined CLOCK expression in the lowest quartile of all patients as reduced (1.17% ACTB, Figure C). Intriguingly, patients with a reduced CLOCK expression had more prevalent AF at baseline (p = 0.017, Fisher’s exact, relative frequencies in Figure D). Moreover, newly diagnosed postoperative AF (in patients without previously known AF) was over 4-fold more frequent in patients with a reduced CLOCK expression (p 0.001, Figure E). Multivariate logistic regression analysis of 129 patients without pre-existing AF revealed a significant association of reduced myocardial CLOCK expression with a high risk of new-onset postoperative AF (OR 16.57, p0.001, Figure F), independent of other important AF risk (age, sex, hypertension, diabetes, SDB). Conclusion Disrupted myocardial expression of circadian rhythm genes may indicate a disturbed sleep/wake cycle in patients with sleep-disordered breathing. It is also associated with an increased risk of both pre-existing and new-onset postoperative atrial fibrillation in cardiovascular high-risk patients undergoing coronary artery bypass surgery.Figure 1