P-wave and PQ-segment duration as novel tools for prediction of ivabradine-related atrial fibrillation. Data from an in vivo rat model

Abstract Background Clinical data suggested that ivabradine treatment may increase propensity to atrial fibrillation (AF). However, the exact mechanisms by which ivabradine promotes new-onset AF remain unclear. Furthermore, not all ivabradine-treated patients will develop AF. Identifying predictive markers for AF onset in ivabradine-treated patients would be a highly valuable clinical tool. Purpose The aim of the present study was to identify ECG parameters associated with the occurrence of ivabradine-related AF in rats. Methods Adult healthy male Wistar rats were randomized into 2 groups: Control (n = 7) and IVA (n = 7). All rats were implanted with radiotelemetry ECG devices at the beginning of the study, and 48-h ECG recordings were performed at 4 and 5 weeks of ivabradine or vehicle administration. Rats in the IVA group received ivabradine (10 mg/kg/day) in the drinking water for 5 consecutive weeks; Control rats received vehicle. ECG parameters (P wave, PQ segment, QRS complex, ST segment, T wave, and QT interval durations) were measured at 4 weeks. The occurrence, number, and duration of spontaneous AF episodes/48-h were evaluated at 5 weeks. Results As expected, rats in the IVA group had significantly lower heart rates than those in the Control group (254 [192-275] bpm vs. 357 [315-369] bpm; p< 0.0001). ECG analysis revealed longer durations of the P wave (21.9 [21.3-22.2] ms vs. 12.0 [11.5-12.7] ms; p< 0.0001) and the PQ segment (32.4 [30.6-32.8] ms vs. 28.9 [27.1-29.7] ms; p< 0.0001) in the IVA compared to the Control group. ST segment duration was significantly shorter (p< 0.0001) and T wave duration was significantly longer (p< 0.0001) in the IVA compared to the Control group. All rats in IVA group and 3 (42.80%) rats in Control group presented spontaneous AF episodes. At the end of the study, ivabradine-treated rats presented significantly higher number (2 [2-16] vs. 0 [0-2]; p= 0.02) and duration (8.25 [3.24-35.08] s vs. 0.00 [0.00-4.89] s; p= 0.02) of spontaneous AF episodes /48-h. P-wave and PQ-segment duration positively correlated with both the number (r= 0.65, 95%CI 0.17-0.88, p= 0.01; r= 0.67, 95%CI 0.21-0.89, p< 0.001, respectively) and duration (r= 0.57, 95%CI 0.04-0.85, p= 0.04; r= 0.66, 95%CI 0.18-0.88, p= 0.01, respectively) of spontaneous AF episodes . Univariate regression analysis identified P wave and PQ segment durations as independent predictors of spontaneous episodes of AF (both O.R.= 3.6, p= 0.01). In ROC analysis, a P-wave duration >11.63 ms and a PQ-segment duration >30.17 ms predicted new-onset AF occurrence with 100% and 100% sensitivity and 64.29% and 67.14% specificity, respectively. Conclusion In healthy rats, P-wave and PQ-segment duration predicted the occurrence of ivabradine-related AF episodes. Pending confirmation in clinical settings, these data suggest that these ECG parameters could emerge as easily available biomarkers for early identification of patients at high risk of ivabradine-related AF.