Abnormal P-waves found in patients with sleep-disordered breathing are associated with triggered pro-arrhythmic activity

Abstract

Abstract Background Sleep-disordered breathing (SDB) is frequently associated with atrial arrhythmias, but diagnostic markers that predict the propensity for atrial arrhythmias are missing. Abnormal P-wave terminal force in lead V1 (PTFV1) has been associated with atrial structural/electrical remodeling and arrhythmias. Purpose Here we investigate the association of triggered pro-arrhythmic activity with abnormal PTFV1 in human right atrial appendage biopsies of patients without and with SDB. Methods 30 patients undergoing elective coronary artery bypass grafting were screened for SDB by polygraphy. An apnoea-hypopnea index (AHI) of ≥15/h defined SDB. PTFV1 was measured as product of negative P-wave amplitude and duration in lead V1 and was defined as abnormal if >4000 ms*μV. Ca/Calmodulin-dependent protein kinase II (CaMKII) activity was measured in human right atrial appendage biopsies by a specific HDAC4 pull-down assay. Premature atrial contractions (PACs) were triggered by exposure to 100 nM isoproterenol (at 3.5 mM [Ca]o) in human atrial trabeculae. PACs severity was classified by a score from 0 points (no arrhythmias) to 5 points (salve). In addition, atrial fibrosis was quantified by Masson's trichrome stain in cryo-sectioned atrial tissue. Multivariate linear regression analyses were performed accounting for age, sex, BMI, existing AF, heart failure, diabetes, and creatinine. Results Interestingly, the AHI was independently associated with the magnitude of PTFV1 (fig. A+B, B=57.47±21.03, R2=0.48, P=0.01). Importantly, patients with an abnormal PTFV1 had a significantly increased CaMKII activity (fig. C, P=0.04) and showed significantly more severe triggered PACs (fig. D, P=0.02). Moreover, the magnitude of PTFV1 correlated significantly and independently with PAC severity (fig. D, B=0.0005±0.0002, R2=0.50, P=0.03). Consistently, these arrhythmias could be significantly reduced by acute CaMKII inhibition (5 μM KN93, P<0.01), which abolished the correlation between PTFV1 and PAC severity (P=N.S.). Surprisingly, atrial fibrosis was significantly decreased in patients with an abnormal PTFV1 (fig. E, P=0.02), suggesting that abnormal PTFV1 is a marker of proarrhythmic atrial electrical remodeling of functional cardiomyocytes but not of fibrotic tissue. Conclusion The severity of sleep-disordered breathing (AHI) is independently associated with an abnormal PTFV1. Intriguingly, this abnormality is associated with an increased CaMKII activity and with CaMKII-dependent arrhythmias, suggesting PTFV1 to be a potential tool to evaluate the pro-arrhythmic risk of patients with SDB. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Part of this study was funded by Philips Respironics.