Abstract
Background: Sleep-disordered breathing (SDB) is associated with increased oxidant generation. Oxidized Ca/calmodulin kinase II (CaMKII) can contribute to atrial arrhythmias by the stimulation of sarcoplasmic reticulum Ca release events, i.e., Ca sparks. Methods: We prospectively enrolled 39 patients undergoing cardiac surgery to screen for SDB and collected right atrial appendage biopsies. Results: SDB was diagnosed in 14 patients (36%). SDB patients had significantly increased levels of oxidized and activated CaMKII (assessed by Western blotting/specific pulldown). Moreover, SDB patients showed a significant increase in Ca spark frequency (CaSpF measured by confocal microscopy) compared with control subjects. CaSpF was 3.58 ± 0.75 (SDB) vs. 2.49 ± 0.84 (no SDB) 1/100 µm−1s−1 (p < 0.05). In linear multivariable regression models, SDB severity was independently associated with increased CaSpF (B [95%CI]: 0.05 [0.03; 0.07], p < 0.001) after adjusting for important comorbidities. Interestingly, 30 min exposure to the CaMKII inhibitor autocamtide-2 related autoinhibitory peptide normalized the increased CaSpF and eliminated the association between SDB and CaSpF (B [95%CI]: 0.01 [−0.1; 0.03], p = 0.387). Conclusions: Patients with SDB have increased CaMKII oxidation/activation and increased CaMKII-dependent CaSpF in the atrial myocardium, independent of major clinical confounders, which may be a novel target for treatment of atrial arrhythmias in SDB.
Highlights
Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting approximately4.5 million people in the European Union and 2.3 million people in North America [1,2,3].The incidence of AF is expected to increase dramatically by 2050, as the general population ages and becomes more obese [4]
The relevance of oxidized calmodulin kinase II (CaMKII) for atrial arrhythmias has been confirmed in a murine model of AF [21]
In contrast to the clear association of Sleep-disordered breathing (SDB) with CaMKII-dependent sarcoplasmic reticulum (SR) Ca leak, we found no significant correlation between magnitude of Ca spark frequency (CaSpF) and AF in the present study (Table 3)
Summary
Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting approximately4.5 million people in the European Union and 2.3 million people in North America [1,2,3].The incidence of AF is expected to increase dramatically by 2050, as the general population ages and becomes more obese [4]. Increased activity of Ca/calmodulin kinase II (CaMKII) and consequent hyperphosphorylation of the SR Ca release channel RyR2 has been identified in the right atrial myocardium of patients with AF [8,9]. Sleep-disordered breathing (SDB) is associated with increased oxidant generation. Oxidized Ca/calmodulin kinase II (CaMKII) can contribute to atrial arrhythmias by the stimulation of sarcoplasmic reticulum Ca release events, i.e., Ca sparks. Methods: We prospectively enrolled 39 patients undergoing cardiac surgery to screen for SDB and collected right atrial appendage biopsies. SDB patients had significantly increased levels of oxidized and activated CaMKII (assessed by Western blotting/specific pulldown). SDB patients showed a significant increase in Ca spark frequency (CaSpF measured by confocal microscopy) compared with control subjects. CaSpF was 3.58 ± 0.75 (SDB) vs. 2.49 ± 0.84
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