The aging of the population and prolongation of the lives of patients with cardiovascular disease due to improvements in therapy have resulted in an increased incidence of HF (1). Despite advances in both pharmacologic and non-pharmacologic therapies, the mortality and the rate of repeat hospitalization due to exacerbation of HF remain high (2, 3). Therefore, further treatment strategies targeting conditions with potential HF risk are needed.

Obstructive sleep apnea (OSA), one of the most prevalent sleep-disordered breathing characterized by repeated episodes of upper airway obstruction during sleep, consequent chronic intermittent hypoxia, and sleep fragmentation, has been recognized as a potential risk factor in the development of cardiovascular diseases (4–6). The Sleep Heart Health Study showed an adjusted hazard ratio for incident HF of 1.58 for men with AHI of ≥30 compared with those with AHI of <5 (7). The prevalence of OSA in HF populations is reportedly high (4, 8, 9). An observational study reported a negative prognostic impact of untreated OSA in patients with HF (10).

Based on the results of clinical studies, CPAP therapy has been demonstrated as an effective therapy for OSA and the underlying HF (10, 11) through an increase in the LVEF (12, 13). The degree of improvement in LVEF varied from 5 to 9% in these studies (12, 13). However, no study has investigated the efficacy of CPAP for OSA and underlying HF among the Japanese population. Moreover, it is unclear which factors are associated with the degree of LVEF improvement by CPAP therapy. This study aimed to investigate whether LVEF in Japanese patients with OSA and HF improved after 1 month of CPAP therapy and to clarify which factors are associated with the degree of LVEF improvement.

We analyzed 55 consecutive patients with HF and reduced LVEF. The baseline patient characteristics are shown in Table 1. The proportion of men was 94.5%. The mean age was 60.7 ± 12.2 years, and the mean BMI was 27.4 ± 5.4 kg/m (2). The mean LVEF was 37.2 ± 9.8%. The data of the sleep study on diagnosis and CPAP are shown in Table 2. The data on CPAP demonstrated considerable improvements in sleep apnea and sleep quality, which were expressed as sleep stages, percentage of slow-wave sleep, and rapid eye movement (REM) sleep. The CPAP therapy decreased AHI, as well as the arousal index from 45.3 ± 16.1 to 5.4 ± 4.1 per hour and 43.9 ± 19.6 to 15.7 ± 10.3 per hour, respectively. The LVEF improved from 37.2 ± 9.8 to 43.2 ± 11.7% after 1 month of CPAP treatment (Figure 1). Significant decreases in systolic and diastolic BP and HR (Figures 2A–C) after treatment were noted. The serum norepinephrine concentration decreased, and the ESS improved significantly after the treatment, while no significant changes were observed in BMI (Figures 3A–C).

Univariate regression analysis showed that age, BMI, atrial fibrillation, lowest SpO₂, and pressure levels of CPAP were significantly associated with improvements in LVEF (Table 3), whereas the changes in variables after CPAP therapy, including BMI, BP, HR, norepinephrine concentration, and ESS, were not associated (Table 4). After adjusting for confounding variables, the age and BMI remained significant determinants of LVEF improvement (Table 5).

In this study, 1-month CPAP treatment for OSA significantly increased LVEF improvements in Japanese patients with HF complicated by OSA. The degree of improvement in the LVEF was 6% in this population. Multivariate regression analyses showed that age and BMI were determinants of LVEF improvement.

Previous studies have shown that the degree of LVEF improvement by CPAP therapy varies from 5 to 9% (12, 13), which is consistent with our results. Kaneko et al. (12) examined the effects of CPAP on cardiac function in patients with reduced LVEF and OSA. They reported that CPAP therapy improved OSA, reduced daytime systolic BP and HR, and increased LVEF by 9%.

To date, several underlying mechanisms of how CPAP improves LVEF have been described. First, the obstructive apnea due to upper airway obstruction activates the sympathetic nervous system in patients with HF via hypoxia, hypercapnia, decreased cardiac output, and arousal from sleep (19, 20). Additionally, the acute arousal from sleep evokes sympathetic activation and BP elevation, which are carried over into the daytime (21–23). The treatment of OSA with CPAP therapy lowers sympathetic nervous overactivation, resulting in decreased BP and HR (23). The mechanisms of these effects remain uncertain but may be related to the adaptation of chemoreceptor reflexes or central processes governing autonomic outflow. Second, the respiratory efforts during obstructive apnea decrease the intrathoracic pressure, leading to increased left ventricular transmural pressure, left ventricular afterload, and cardiac metabolic demand (24, 25). Furthermore, augmentation of venous return to the right ventricle results in a leftward septal shift and reduced left ventricular preload and stroke volume (26). The CPAP therapy for exaggerated intrathoracic negative pressure may decrease left ventricular transmural pressure and left ventricular afterload, potentially counteracting or minimizing the effects of respiratory efforts during obstructive apnea on left ventricular systolic function (27–29). Meanwhile, the CPAP therapy increases intrathoracic pressure, which decreases systemic venous return, while positive pressure ventilation increases pulmonary vascular resistance and right ventricular afterload, thus, reducing the right ventricular stroke volume (30, 31), left ventricular preload, and stroke volume (32–35). These ambivalent effects of CPAP on hemodynamics may depend on an individual's specific preload and afterload states (30).

To date, the factors associated with LVEF improvement remain unknown. The novelty of our study is that we demonstrated age and BMI as determinants of LVEF improvement by CPAP. The LVEF was more likely to improve in young patients with obesity after 1 month of CPAP therapy.

Several speculations can be made regarding the mechanisms of these results. In patients with obesity, the pharyngeal fat deposition facilitates upper airway narrowing and collapses by increasing the external peripharyngeal soft tissue pressure. In addition, fat deposition to the chest wall leads to a reduction in compliance and an increase in airway resistance (36–38). An improvement in exaggerated negative intrathoracic pressure by CPAP is speculated to have a positive effect on hemodynamics more in patients with obesity, which may partly explain our finding that LVEF was more likely to improve in patients with obesity. Age is a determinant of the prognosis of HF, as shown in previous reports (3, 39–41). Advancing age is accompanied by the loss of cardiomyocytes via apoptosis and necrosis (42–44) and decreased responses to both sympathetic and parasympathetic antagonists (45). Based on these data, the elderly patients with HF might be less likely to show LVEF improvement with CPAP therapy for OSA.

Among patients with OSA and HF, the LVEF significantly improved after 1 month of CPAP therapy. The degree of LVEF improvement was significantly associated with age, BMI, atrial fibrillation, the severity of hypoxia, and the treatment pressure level of CPAP. After adjustment for baseline variables and changes in variables at 1 month, the LVEF was more likely to be improved in young patients with obesity.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.

TK contributed to conception and design of the study. RN wrote the first draft of the manuscript. TD, HT, KN, and S-iM reviewed the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.

Grant to the Intractable Respiratory Diseases and Pulmonary Hypertension Research Group, from the Ministry of Health, Labor, and Welfare, Japan Grant/Award No: 20FC1027; JSPS KAKENHI, Grant/Award No: JP17K09527, 21K08116.

RN and TK are affiliated with a department endowed by Philips Respironics, ResMed, and Fukuda Denshi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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