GJA1 Expression and Left Atrial Remodeling in the Incidence of Atrial Fibrillation in Patients with Obstructive Sleep Apnea Syndrome

Abstract

Obstructive sleep apnea syndrome (OSAS) is an important risk factor for atrial fibrillation (AF). GJA1 gene encoding connexin43, a major protein in cardiac gap junctions, plays a crucial role in the synchronized contraction of the heart and in cardiac arrhythmia. However, little is known regarding the role of GJA1 expression in the incidence of AF in patients with OSAS. All prospectively enrolled OSAS patients underwent polysomnography, electrocardiography, a 24-hour Holter test, and echocardiography. Moderate-to-severe OSAS was defined as an apnea-hypopnea index (AHI) ≥ 15. Exosomes were purified from the plasma of all OSAS patients and incubated in HL-1 cells to investigate the effect of exosomes from patients with and without AF on GJA1 expression. A total of 129 patients were recruited for this study; 26 were excluded due to an AHI < 15. Of the 103 enrolled patients, 21 had AF, and 82 did not. Multivariate analysis showed diabetes mellitus, lower sleep efficiency, lower left ventricular ejection fraction, and larger left atrial (LA) size were independent predictors of AF occurrence in OSAS patients. The area under the receiver operating characteristic curve for LA with a size ≥ 38.5 mm for predicting AF occurrence in OSAS patients was 0.795 (95% confidence interval [0.666, 0.925]); p < 0.001). GJA1 expression in HL-1 cells incubated with exosomes from OSAS patients with AF was lower than that with exosomes from patients without AF after controlling for age and sex and was negatively correlated with the AHI and oxygen desaturation index (ODI), especially during the non-rapid eye movement period (NREM) of OSAS patients with AF (all p < 0.05). LA size was an independent predictor of AF occurrence in OSAS patients. The AHI and ODI in the NREM period of OSAS patients with AF were negatively correlated with GJA1 expression in HL-1 cells, which offers a hint that GJA1 may play a crucial role in the development of AF in patients with OSAS.

The Impact of Intermittent Hypoxemia on Left Atrial Remodeling in Patients with Obstructive Sleep Apnea Syndrome

“…An overnight PSG study was performed on all individuals who were enrolled in this trial. The PSG procedures were described in detail in our previous research [30,31]. To summarize, the overnight PSG study was conducted in the sleep center of our hospital utilizing a commercial suite that has been standardized (Sandman Elite, Mallinckrodt Inc., St. Louis, MO, USA).…”

“…HL-1 cells are contractile and exhibit phenotypic characteristics similar to those of adult atrial cardiomyocytes [29]. Our previous study demonstrated that exosomes isolated from the plasma of OSAS patients with AF influenced GJA1 gene expression in HL-1 cells [30]. The purpose of this study was to determine the effect of exosomes from patients with and without significant OSAS on LA remodeling by analyzing the expression of genes in HL-1 cells treated with exosomes.…”

Molecular mechanisms of postoperative atrial fibrillation in patients with obstructive sleep apnea

“…35 Besides, in OSA patients there are several evidences of decreased atrial Cx43 expression and GJA1 expression, the gene encoding Cx43, which correlated with its severity independently of other concomitant diseases. [36][37][38] OSAWe, therefore, suggest that OSA patients may present a pro-arrhythmogenic state that favors the development of AF and this "environment" might remain in balance until a relevant factor, such as cardiac surgery, acts as the triggering "spark" leading to the development of de novo AF. Indeed, a study demonstrated in a rat model that cumulative exposure to sleep apnea-related conditions resulted in AF substrate and was associated with increased AF susceptibility.…”

“…Indeed, studies in mouse have reported that Cx40 deficiencies can lead to alterations in cardiac conduction and Cx40 expression was reduced in those 208−/− knockout mouse hearts 35 . Besides, in OSA patients there are several evidences of decreased atrial Cx43 expression and GJA1 expression, the gene encoding Cx43, which correlated with its severity independently of other concomitant diseases 36–38 …”

Ion channel dysfunction and fibrosis in atrial fibrillation: Two sides of the same coin

“…70 Mutations in the genes of matrix metalloproteinases (MMP3), that maintain a balance between connective tissue synthesis and degradation, cartilage oligomeric matrix protein (COMP), that regulate ECM turnover, 71 and Collagen-encoding genes (COL12A1/COL23A1) that regulate fibrosis 72 and gap junction channels GJA5 (encoding Connexin40) 73 and GJA1 (encoding Cx43) also cause heart fibrosis and early AF. 4,74 Genes involved in cardiogenesis are also linked with risk of AF. Mutations in NKX2 DNA tracts, that are homebox-containing transcription factors involved in cardiac development and septation, 4 and GATA4 and GATA6 genes, that work synergistically with them, are associated with AF.…”