Background/Objective: A reduced atrial expression of connexin (Cx) 40 and 43 has been found in patients with atrial fibrillation (AF) and is causally linked to an atrial pro-arrhythmogenic substrate. Interestingly, patients with sleep disordered breathing (SDB) are at increased risk for developing AF, but the mechanisms remain unclear. In a rat model of obstructive sleep apnea, a reduced atrial Cx 43 expression and an increased vulnerability for induction of AF was observed.

Purpose: We tested the hypothesis that patients with SDB exhibit reduced atrial connexin expression independent from preexisting atrial arrhythmic disorders and other comorbidities.

Methods and Results: We analyzed right atrial appendage biopsies from 77 patients undergoing coronary artery bypass grafting in the University Medical Hospital Regensburg. Patients were tested for SDB by polygraphy in the preoperative night, and severity of SDB was quantified using the apnea-hypopnea-index (AHI). SDB was defined as an AHI≥15 per hour. Expression of total Cx 40, Cx 40 transcript A, Cx 40 transcript B and Cx 43 mRNA was quantified using real-time qPCR. All samples were measured as triplicates and the averages were used for the comparative threshold cycle (Ct) relative quantification analysis method in relation to β-actin. Analysis of baseline patient characteristics revealed significantly higher NT-proBNP levels and lower ejection fraction in patients with SDB, otherwise no significant differences (Fig 1 A). Interestingly, patients with SDB exhibited a significantly lower relative expression of Cx 43 mRNA (Fig. 1B). Furthermore, the expression of Cx 43 was significantly negatively correlated with the severity of SDB (measured by AHI, linear regression, Fig. 1C) but also with oxygen desaturation index (ODI). The latter quantifies the number of oxygen desaturations (more than 4% compared to mean O₂ saturation) per hour and is a marker of the hypoxia/reoxygenation burden. To analyze comorbidities we performed univariate logistic regression for reduced Cx 43 expression (expression in the lowest quartile, Fig. 1D) showing that besides SDB, the presence of diabetes and insufficient glycemic control (increased HbA1c) but also heart failure with reduced ejection fraction (HFrEF) were important confounding co-morbidities. Importantly, SDB remained a relevant independent factor in a multivariate logistic regression model including age, gender, diabetes, HFrEF, and TSH levels (R² =0.432, model p-value <0.01, p-value for SDB 0.001).

Conclusion: Patients with SDB exhibit a reduced atrial Cx 43 expression that was independent from comorbidities and correlated with the number of hypoxia/reoxygenation cycles. This may provide a possible explanation for increased risk of AF in these patients.