Rationale: Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias. Increased CaMKII (Ca/calmodulin-dependent protein kinase II) activity has been previously implicated in atrial arrhythmogenesis. Objective: We hypothesized that CaMKII-dependent dysregulation of Na current (I Na ) may contribute to atrial proarrhythmic activity in patients with SDB. Methods and Results: We prospectively enrolled 113 patients undergoing elective coronary artery bypass grafting for cross-sectional study and collected right atrial appendage biopsies. The presence of SDB (defined as apnea-hypopnea index ≥15/h) was assessed with a portable SDB monitor the night before surgery. Compared with 56 patients without SDB, patients with SDB (57) showed a significantly increased level of activated CaMKII. Patch clamp was used to measure I Na . There was a significantly enhanced late I Na , but reduced peak I Na due to enhanced steady-state inactivation in atrial myocytes of patients with SDB consistent with significantly increased CaMKII-dependent cardiac Na channel phosphorylation (Na V 1.5, at serine 571, Western blotting). These gating changes could be fully reversed by acute CaMKII inhibition (AIP [autocamtide-2 related inhibitory peptide]). As a consequence, we observed significantly more cellular afterdepolarizations and more severe premature atrial contractions in atrial trabeculae of patients with SDB, which could be blocked by either AIP or KN93 (N-[2-[[[(E)-3-(4-chlorophenyl)prop-2-enyl]-methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxybenzenesulfonamide). In multivariable linear regression models incorporating age, sex, body mass index, existing atrial fibrillation, existing heart failure, diabetes mellitus, and creatinine levels, apnea-hypopnea index was independently associated with increased CaMKII activity, enhanced late I Na and correlated with premature atrial contraction severity. Conclusions: In atrial myocardium of patients with SDB, increased CaMKII-dependent phosphorylation of Na V 1.5 results in dysregulation of I Na with proarrhythmic activity that was independent from preexisting comorbidities. Inhibition of CaMKII may be useful for prevention or treatment of arrhythmias in SDB. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02877745. Visual Overview: An online visual overview is available for this article.
Aims 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. Methods and results 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. Conclusions 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.
OBJECTIVE: The study aim was to investigate the use of a novel device, the Vscan Air™, for rapidly and effectively performing ultrasound in student teaching during the COVID-19 pandemic. MATERIAL AND METHODS: As part of the ultrasound practical course with integrated hands-on activity required by the regular medical curriculum, 100 medical students were instructed in the use of the Vscan Air™, including duplex mode. They then evaluated the quality of the ultrasound images obtained by the Vscan Air™ from previously selected organs. RESULTS: 100 students were interviewed (female n = 68, male n = 32; age >18 years n = 100). The rated image quality never fell below a mean of 3 for the examined organs and portal vein flow (liver 4,58; spleen 3,99; kidneys 4,29; aorta 4,16; Douglas/rectovesical space 4,14; portal vein 4,43; pancreas 3,53; Focused Assessment with Sonography for Trauma 4,38). Scores below 3 were found sporadically in ultrasounds of the spleen (n = 4), kidneys (n = 3), Douglas/rectovesical space (n = 2), and pancreas (n = 15). The liver was rated the lowest for 59 ratings. The portal vein was evaluated in 68 cases. The hepatic artery and hepatic veins could be also visualized in all 68 examinations. The aorta was evaluated in 62 cases. CONCLUSION: The Vscan Air™ technology offered adequate image quality and provided a new, fast and patient-oriented technique to support continuous ultrasound examinations and education of students, especially during a pandemic. Particularly noteworthy is the uncomplicated compliance with the required high level of hygiene.
Background Heart failure with preserved ejection fraction (HFpEF) is a major health problem associated with substantial morbidity and mortality. However, the underlying pathophysiological mechanisms are poorly understood, and effective treatment strategies are scarce. Importantly, SGLT2i, which have been suggested to improve cellular Na and Ca homeostasis in HFrEF, have recently been shown to also improve clinical outcomes in patients with HFpEF. Interestingly, post-hoc analyses of clinical data suggest an involvement of anti-arrhythmic effects of SGLT2i. Purpose We tested, if isolated human atrial cardiomyocytes from patients with HFpEF exhibit an increased Na influx that is responsive to treatment with the SGLT2i empagliflozin (Empa) and if Empa has anti-arrhythmic properties in human atrial trabeculae. Methods Atrial biopsies were obtained from 101 patients undergoing elective cardiac surgery. Na influx was measured as increase in [Na]i during Na/K-ATPase inhibition in isolated cardiomyocytes loaded with the Na-sensitive fluorescence dye Asante Natrium Green–2 AM (ANG-2). Western Blot and HDAC4 pulldown assay were used to investigate NaV1.5 expression/phosphorylation as well as CaMKII expression/autophosphorylation and activity. Anti-arrhythmic effects of Empa were evaluated as the reduction in premature atrial complexes (PACs), which were induced in electrically field-stimulated (1Hz) human atrial trabeculae by superfusion with isoproterenol (100 nM) and high Ca (3.5 mM). Results Compared to patients without heart failure (NF), Na influx was almost doubled in HFpEF patients (NF vs HFpEF: 0.21±0.02 vs 0.38±0.04 mmol/L/min (N=7 vs 18); p=0.005) (Fig. 1D, E). CaMKII expression, CaMKII autophosphorylation, CaMKII activity, and CaMKII-dependent NaV1.5 phosphorylation were significantly increased in atrial biopsies of HFpEF patients, whereas NaV1.5 protein abundance remained unchanged (Fig. 1A–C). Consistent with these results, the increased Na influx was significantly reduced by treatment with the specific CaMKII inhibitor autocamtide-2 related inhibitory peptide (AIP) and the late INa inhibitor tetrodotoxin (TTX) (Fig. 1D, E). Importantly, Empa also abolished the increased Na influx in HFpEF cardiomyocytes (Fig. 1D, E). Multivariate linear regression analysis, adjusting for clinical co-variates, revealed HFpEF to be an independent predictor of cardiomyocyte Na handling. In line with Empa-mediated inhibition of Na influx, the frequency of PACs in human atrial trabeculae was significantly reduced by Empa (Fig. 1F, G). Conclusion This is the first study to demonstrate increased Na influx in human cardiomyocytes from HFpEF patients potentially by an increased CaMKII-dependent NaV1.5 phosphorylation. Excitingly, treatment with Empa decreases this Na influx in HFpEF cardiomyocytes and reduces isoproterenol-induced arrhythmic activity in human atrial trabeculae, which could contribute to the cardioprotective effects of this drug in patients with HFpEF. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Else Kröner-Fresenius-Stiftung,Deutsche Forschungsgemeinschaft
Background Patients with sleep-disordered breathing (SDB) develop arrhythmias and contractile dysfunction, but the mechanisms are poorly understood, possibly due to the lack of mouse models that mimic airway obstruction in spontaneously sleeping mice. Interestingly, New Zealand obese mice have been shown to develop airway obstruction with inspiratory flow limitation resulting in apneas, but these mice also develop diabetes. Purpose We developed a novel mouse model of increased airway obstruction in spontaneously sleeping lean mice and investigated the impact on sleep-related apneas and contractile function. Methods and results Male C57BL6 mice at 8–12 weeks of age were subjected to polytetrafluoroethylene (PTFE) injection (100 μl) into the tongue. This resulted in an increased tongue volume and reduced pharyngeal luminal diameter. Conscious mice behave normal and there was no difference in body weight between PTFE injected mice and untreated littermates (control). Whole body plethysmography was used to monitor spontaneous breathing for 8h in a quiet environment. Interestingly, compared to control, mice with PTFE injection showed a significantly increased frequency of apneas (lasting >1s, fig. A, * indicated P<0.05, t-test). Echocardiographic analysis revealed that ejection fraction was significantly reduced in PTFE-treated mice 8 weeks after surgery (vs. control, fig. B). In accordance, the developed force of isolated papillary muscles from hearts of PTFE mice was significantly reduced compared to control (fig. C). Ca/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the development of heart failure. Intriguingly, compared to control, CaMKII expression was significantly increased in ventricular heart homogenates of PTFE-treated mice (fig. D). Moreover, the magnitude of CaMKII overexpression correlated significantly with the frequency of apneas (fig. E). Papillary muscle post-pause contractions can be used as measure of diastolic sarcoplasmic reticulum (SR) Ca leak, which is known to be enhanced by CaMKII. Compared to control, post-pause contraction amplitude was significantly smaller in PTFE-treated mice, indicating an increased SR Ca leak (fig. F). Figure 1 Conclusion PTFE injection in mice results in an increased frequency of spontaneous apneas. PTFE-treated mice develop mild contractile dysfunction, which is accompanied by CaMKII overexpression. This novel mouse model offers great opportunities for investigation of sleep-related breathing disorders. Acknowledgement/Funding This study was supported by the Medical Faculty of the University of Regensburg (ReForM programme).
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