A novel mouse model of obstructive sleep apnea by bulking agent-induced tongue enlargement results in left ventricular contractile dysfunction

• Published in: PloS one 2020-12, Vol.15 (12), p.e0243844-e0243844
• Main Authors: Lebek, Simon, Hegner, Philipp, Schach, Christian, Reuthner, Kathrin, Tafelmeier, Maria, Maier, Lars Siegfried, Arzt, Michael, Wagner, Stefan
• Format: Article
• Language: English
• Subjects: Abnormalities; Airway management; Animal models; Animals; Apnea; Biology and Life Sciences; Ca2+/calmodulin-dependent protein kinase II; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Contractility; Correlation analysis; Diameters; Diastole; Disease Models, Animal; Echocardiography; Economic impact; Electrocardiography; Enlargement; Gene expression; Health aspects; Heart; Heart failure; Histone Demethylases - genetics; Histone Demethylases - metabolism; Hypoxemia; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Impact analysis; Inhalation; Injection; Injections; Internal medicine; Kinases; Laboratory animals; Lung - pathology; Male; Medicine; Medicine and Health Sciences; Mice, Inbred C57BL; Muscle contraction; Myocardial Contraction; Myocardium - pathology; Organ Size; Patients; Plethysmography; Polytetrafluoroethylene; Polytetrafluoroethylene - administration & dosage; Research and Analysis Methods; Respiration; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sleep; Sleep apnea; Sleep Apnea, Obstructive - complications; Sleep Apnea, Obstructive - diagnostic imaging; Sleep Apnea, Obstructive - physiopathology; Sleep disorders; Surgery; Systole; Tongue; Tongue - pathology; Ultrasonic imaging; Ventricle; Ventricular Dysfunction, Left - diagnostic imaging; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - physiopathology; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0243844

Obstructive sleep apnea (OSA) is a widespread disease with high global socio-economic impact. However, detailed pathomechanisms are still unclear, partly because current animal models of OSA do not simulate spontaneous airway obstruction. We tested whether polytetrafluoroethylene (PTFE) injection into the tongue induces spontaneous obstructive apneas. PTFE (100 μl) was injected into the tongue of 31 male C57BL/6 mice and 28 mice were used as control. Spontaneous apneas and inspiratory flow limitations were recorded by whole-body plethysmography and mRNA expression of the hypoxia marker KDM6A was quantified by qPCR. Left ventricular function was assessed by echocardiography and ventricular CaMKII expression was measured by Western blotting. After PTFE injection, mice showed features of OSA such as significantly increased tongue diameters that were associated with significantly and sustained increased frequencies of inspiratory flow limitations and apneas. Decreased KDM6A mRNA levels indicated chronic hypoxemia. 8 weeks after surgery, PTFE-treated mice showed a significantly reduced left ventricular ejection fraction. Moreover, the severity of diastolic dysfunction (measured as E/e') correlated significantly with the frequency of apneas. Accordingly, CaMKII expression was significantly increased in PTFE mice and correlated significantly with the frequency of apneas. We describe here the first mouse model of spontaneous inspiratory flow limitations, obstructive apneas, and hypoxia by tongue enlargement due to PTFE injection. These mice develop systolic and diastolic dysfunction and increased CaMKII expression. This mouse model offers great opportunities to investigate the effects of obstructive apneas.