Atrial fibrillation (AF) is one of the most common cardiac arrhythmias in adults, affecting 2–4% of the global adult population and 1.6% of Chinese adults [1, 2, 3]. Due to its frequent association with advanced age and comorbid chronic conditions (such as hypertension, diabetes, and obesity), the prevalence of AF has been progressively increasing annually [4, 5]. Obstructive sleep apnea syndrome (OSAS) is also a common chronic condition, being the most prevalent sleep-related breathing disorder; it is characterized by recurrent episodes of sleep apnea leading to periodic hypoxemia and hypercapnia [6]. Globally, OSAS affects over a billion people, with some countries experiencing prevalence rates exceeding 50% [7]. AF and OSAS often share common risk factors, including hypertension, coronary artery disease, and congestive heart failure (HF) [8]. The two are closely related, with an AF prevalence of approximately 21–87% among OSAS patients [5], and OSAS being present in about 50% of AF patients [9]. Having both AF and OSAS (AF + OSAS) can worsen patients’ outcomes; with a link between AF and higher mortality rates [10], severe OSAS is significantly associated with an increased risk of all-cause mortality in patients [11]. In addition to the above, AF + OSAS imposes significant economic burdens on patients’ families and the public healthcare system. In the United States, the annual cost of treating AF and its complications exceeds $28 billion [12], and a study in Italy indicated an annual treatment cost of over €234M for patients with OSAS [13].

For many years, antiarrhythmic drugs have been the mainstay of treatment for AF. Catheter ablation (CA), since the introduction of in 1994, has provided AF patients with additional treatment options and hope. A meta-analysis has shown that CA significantly reduces cardiovascular and all-cause mortality rates in AF patients [14], but the recurrence rate after CA in patients with AF + OSAS can be as high as 80% [15]. Continuous positive airway pressure (CPAP) therapy, the primary treatment for OSAS patients, has not yet shown an impact on survival rates in OSAS patients [16]. The effectiveness of current mainstream treatment options in improving all-cause mortality rates in patients with AF + OSAS remains unclear.

As mentioned earlier, both AF and OSAS are significantly associated with increased all-cause mortality rates, with intricate and complex underlying mechanisms. Despite this, effective preventive strategies for all-cause mortality in patients with AF + OSAS have not been established so far, which has raised significant concerns. With the aging population trend increasing the incidence of AF + OSAS, this undoubtedly places a heavy burden on the public healthcare system in terms of disease and economic pressure. To our knowledge, there is currently no dedicated risk-assessment tool for all-cause mortality in patients with AF + OSAS.

As the largest healthcare institution in the region, we have access to the highest quality healthcare resources and the largest patient population. Our medical center serves patients of various races and is equipped with a comprehensive Hospital Information System (HIS). Therefore, our research focused on using routine clinical characteristics, laboratory parameters, and imaging findings readily available in the HIS to construct predictive models and scoring systems. These tools were used to assess the all-cause mortality risk in patients with AF + OSAS, with the goal of optimizing patient prognosis and quality of life. Additionally, by identifying high-risk patients, healthcare professionals can adopt more proactive monitoring and intervention measures. Understanding the mechanisms of all-cause mortality in patients with AF + OSAS and developing new approaches to enhance survival rates is a promising area for future in-depth research.

The condition of AF + OSAS, due to its complexity and multitude of factors, has resulted in high mortality rates. Given the disease burden, families also have faced significant pressures, making it a substantial public health challenge. In the present study, through Lasso regression, we selected 10 variables from the abundant patient information that included hypoxemia, CA, RBC count, Lymphocyte count, Baso count, TBA, D-dimer, FT3, NT-proBNP, and COPD. Significant variables identified in the univariate logistic regression analysis were included in the multivariable logistic regression analysis, which revealed that CA (OR = 0.21) was an independent protective factor, whereas moderate-to-severe hypoxemia (OR = 11.11), RBC 3.8 $\times$ 10¹²/L (OR = 20.70), and D-dimer $\ge$280 ng/mL (OR = 7.07) were independent risk factors. A risk-scoring system was developed in the present study to assess the overall mortality risk of patients with AF + OSAS, which defined –1–0 points as low risk, 1–2 points as moderate risk, and 3–5 points as high risk. The percentage bar chart showed that as the risk level increased, the mortality rate of patients rose, and the survival rate decreased. The results of this study demonstrated good predictive accuracy.

Long-term irregular and rapid contractions of the left atrium easily lead to stroke and HF, which increases mortality. CA is the main effective treatment for AF. The present study found that CA is an independent protective factor for all-cause mortality in patients with AF + OSAS. CA can increase the duration of sinus rhythm maintenance by interrupting abnormal electrical impulses conduction and sustaining pulmonary vein isolation, thereby reducing the burden of AF and slowing the progression from paroxysmal AF to persistent AF, and decreasing cardiac workload. This significantly reduces the risk of mortality, HF, stroke, and rehospitalization in patients with AF [18, 19, 20]. Then, CA can actively improve patient anxiety levels and symptom burden, thereby enhancing the quality of life [21, 22]. Moreover, we speculate that in patients with AF + OSAS, the atrial arrhythmia may lead to impaired atrial contraction function and compromised blood circulation, further exacerbating the patient’s hypoxemia. Restoration of normal cardiac rhythm after CA ensures adequate oxygen supply by normalizing cardiac function and blood circulation, thereby improving oxygenation status and reducing all-cause mortality. Therefore, we recommend that patients with AF + OSAS undergo CA treatment promptly to restore and maintain sinus rhythm, thereby reducing the risk of related complications, and improving quality of life and prognosis.

Of note is the fact that multivariable logistic regression analysis identified moderate to severe hypoxemia and RBC 3.8 $\times$ 10¹²/L as independent risk factors for all-cause mortality in patients with AF + OSAS. In the first place, OSAS primarily manifests as recurrent episodes of sleep apnea, leading to periodic nocturnal hypoxemia and hypercapnia. RBCs, as the major carrier of oxygen in the blood, decrease because untreated OSAS-induced inflammatory stimulation of macrophages, which in turn reduces RBC levels [23] and exacerbates hypoxemia. This subsequently triggers the alternate activation of the sympathetic and vagal nervous systems, inducing inflammation, cardiac structural remodeling, interstitial fibrosis, and ion channel disturbances, resulting in prolonged action potential duration and decreased conduction velocity. These changes lead to the formation of focal activity and reentry, promoting the progression of AF [24, 25, 26]. Second, the deoxygenation caused by hypoxemia disrupts the balance of electron transfer in the electron transport chain, leading to sustained oxidative stress [27]. The intensified oxidative stress exacerbates mitochondrial dysfunction and cellular injury, triggering the activation of transcription factors and subsequently increasing the production of inflammatory mediators [28]. Third, hypoxemia can prolong the atrial refractory period, slow conduction, and increase conduction inhomogeneity, leading to atrial electrical remodeling and worsening AF. What is more, moderate to severe nocturnal hypoxemia during sleep can lead to heightened sympathetic nervous system activity, triggering vasoconstriction, elevated blood pressure, and increased heart rate [29, 30, 31], thereby increasing the patient’s demand for oxygen. However, the reduction in RBC levels caused by untreated OSAS exacerbates hypoxemia, which can lead to prolonged myocardial oxygen deficiency and potentially induce HF. Studies have shown that OSAS is independently associated with an increased all-cause mortality rate [32], and severe nocturnal hypoxemia can independently predict sudden cardiac death [33]. CPAP, as the primary treatment for OSAS, can alleviate the burden of AF after CA or cardiac resynchronization and slow down the progression of AF [34, 35]. Despite methodological limitations and small sample sizes, these studies largely supported the view that CPAP can alleviate the burden of AF and may thereby improve prognosis. Furthermore, we speculate that severe nocturnal hypoxemia may lead to systemic hypoxia, increasing the risk of other cardiovascular events, thus further worsening prognosis. Given that many patients with AF + OSAS do not exhibit daytime symptoms of excessive sleepiness, the presence of OSAS may be masked, resulting in underdiagnosis and undertreatment of OSAS. Therefore, we recommend that symptomatic AF patients undergo proactive screening for OSAS to facilitate early detection, diagnosis, and treatment with CA and CPAP, thereby enhancing long-term prognosis.

In clinical practice, elevated levels of the fibrin-degradation product D-dimer are commonly used to assess the risk of thromboembolism and serve as an independent risk factor for all-cause mortality in patients with AF + OSAS. Primarily, the disordered intra-atrial electrical activity in patients with AF results in ineffective atrial contractions, leading to blood stasis in the atria and facilitating the formation of atrial appendage thrombi. If there are disturbances in the contractile and relaxation functions of the left ventricle, this further exacerbates left atrial enlargement and congestion, thereby promoting thrombus formation. Once these thrombi dislodge, they may trigger thromboembolic events, potentially causing severe conditions such as stroke [36]. Secondarily, the coexistence of AF and OSAS can trigger nocturnal hypoxemia, which not only increases blood viscosity, leading to circulatory disturbances, but also promotes thrombus formation, thereby adversely affecting patient prognosis. Moreover, AF + OSAS can cause dysfunction of endothelial cells, disrupting the stability of the vessel wall, increasing the risk of intravascular thrombosis, and consequently raising the likelihood of developing cardiovascular and cerebrovascular diseases [37]. Previous studies have shown that plasma D-dimer levels are significantly higher in patients with AF [38], and are significantly associated with stroke and cardiovascular death in AF patients [38, 39]. OSAS is significantly associated with thrombus formation [40, 41]. Rivaroxaban can effectively reduce plasma D-dimer levels in patients [42]. Therefore, we recommend that when AF + OSAS patients exhibit elevated D-dimer levels, consideration should be given to identifying the location of the thrombus and initiating or intensifying anticoagulant therapy. Additionally, timely correction of reversible risk factors can help reduce the risk of thromboembolism in these patients. Elevation of D-dimer, a marker of coagulation-fibrinolysis system activation, may reflect the hypercoagulable state and hidden thrombotic burden in patients with AF + OSAS. It is noteworthy that anticoagulant therapy may partially mask the predictive value of D-dimer, and systemic inflammation may interact bidirectionally with D-dimer formation through procoagulant effects. Despite the adjustments made to reduce confounding bias through multivariable analysis in the present study, future prospective research combining dynamic D-dimer monitoring and analysis of inflammatory markers is essential to clarify its independent predictive role.

The scoring system developed in the present study suggested that in clinical practice, for patients with AF, enhanced screening for OSAS using polysomnography (PSG) should be conducted. If both conditions exist, routine blood counts and D-dimer tests should be performed. Additionally, the development of embedded plugins in electronic medical records can automatically score relevant results and stratify patients based on their scores, while providing alerts to supervising physicians. Furthermore, tailored management strategies should be implemented based on patients’ different risk stratifications: for low-risk patients, outpatient management with remote treatment compliance monitoring every six months; for moderate-risk patients, multidisciplinary team assessments should be initiated—for example, those patients may require multidisciplinary team (MDT) evaluations to identify and address potential underlying causes of OSAS, along with cardiology consultations for CA surgery. High-risk patients should have shorter follow-up intervals and increased outpatient-visit frequency through communication channels like phone calls, texts, and video conferencing. Equipping patients’ homes with devices such as pulse oximeters and smartwatches to monitor basic vital signs, and enhancing education for patients’ families on disease awareness and fundamental management strategies, is advised.

The conclusions drawn from this retrospective study are multidimensional. First, the study identified key factors influencing all-cause mortality in patients with AF + OSAS, encompassing both protective and risk factors. Second, the study developed a model for predicting the risk of all-cause mortality in patients with AF + OSAS, demonstrating good predictive performance. Finally, the scoring system developed based on this predictive model provided an effective tool for assessing and predicting AF recurrence, offering valuable guidance and reference for future clinical management.

Patients with AF + OSAS face a higher risk of mortality. The complex pathophysiological mechanisms of this condition have garnered significant attention. With the aging population, the incidence rates of OSAS + AF continue to rise, undoubtedly placing a heavy burden on the public health system. To our knowledge, there is currently a lack of specific tools for assessing the overall risk of mortality in patients with AF + OSAS. Therefore, this study developed a clinical predictive model suitable for this patient population. However, the study still has its limitations. First, although data from AF + OSAS patients who received treatment between 2012 and 2024 were collected retrospectively in this study, the sample size was relatively small, with a low number of deceased patients, leading to the Effective Predictor Variable being lower than the traditionally recommended value. This may affect the stability of the results. Despite rigorous variable selection, cross-validation, and independent validation, the model demonstrated good discriminative and calibration performance; however, this remains a limitation of the study. Second, although the hospital was the one with the highest number of patients in the region and thus considered representative, the predictive model was only internally validated in a single center. These limitations highlight the need for future research efforts to conduct multicenter prospective real-world clinical studies to validate these findings and provide assistance to a broader range of patients and healthcare professionals.

In patients with AF + OSAS, CA (OR = 0.21) is an independent protective factor for all-cause mortality, whereas moderate to severe hypoxemia (OR = 11.11), RBC 3.8 $\times$ 10¹²/L (OR = 20.70), and D-dimer $\ge$280 ng/mL (OR = 7.07) are independent risk factors. When these factors are combined in a scoring system, they demonstrate good predictive performance.

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

XTZ and BPT conceptualized the study. XTZ, MW, and YML contributed to the study methodology. MW and PJX were responsible for the software aspects. PJX performed data validation, while formal analysis was conducted by XTZ and YML. BPT provided the necessary resources for the study. XTZ and MW curated the data. XTZ drafted the initial manuscript and subsequently reviewed and edited it with the assistance of MW and YML. XTZ and YML were involved in data visualization. XTZ and BPT supervised the study. XTZ managed the project administration, and funding was acquired by BPT. All authors contributed to the conception and editorial changes in the manuscript. All authors have read and approved the final manuscript. All authors fully participated in this work and agreed to take responsibility for all aspects of the work.

The study was carried out in accordance with the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University with the ethics review number K202409-07. Due to the retrospective nature of this study and data collection solely through the HIS, the application for exempting informed consent signing has been granted by the Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University.

This work was supported by the Key R&D Program of Xinjiang Uygur Autonomous Region (2022B03023) and Youth Scientific Research Voyage (2023YFY-QKMS-09).

The authors declare no conflict of interest.