br Conflict of interest br Introduction Over the last

Conflict of interest
Introduction Over the last several decades, substantial research interest has been focused on characterizing the pathophysiological substrate underlying atrial fibrillation (AF) [1]. AF is a complex arrhythmia and has been shown to be temporally variable, so that AF duration and burden can vary significantly within the same patient “substrate” [2]. In general, it is widely accepted that an abnormal atrial structural substrate is more crucial for AF persistence than electrical remodeling alone [3]. However, it remains poorly understood how the same atrial “substrate” could exhibit both sustained and spontaneously terminating AF episodes. Various investigators have utilized AF electrogram characteristics, such as complex fractionated atrial electrograms (CFAE) and dominant frequency (DF), to identify critical substrate sites for catheter ablation [4,5]. To date, these approaches have demonstrated highly variable success rates, possibly due to the limitations of using sequential point-by-point mapping for the chaotic atrial activations underlying a temporally unstable arrhythmia [6–12]. Nevertheless, studies have also identified AF regularization, with a cumulative increase in AF carboxypeptidase length, prior to AF termination by the stepwise ablation approach [13], while a decreased CFAE burden/degree of fractionation and DF have been reported following pulmonary vein isolation [14]. Therefore, AF electrogram characteristics can be good markers for predicting its stability or termination.
Materials and methods We analyzed AF episodes recorded using epicardial direct contact mapping in “one-kidney, one-clip” hypertensive sheep. This induced hypertension model has been described previously [15]. In brief, nephrectomy is performed on the right kidney followed by placement of a vascular occluder over the left renal artery. Systolic blood pressure increases consistently over the ensuing weeks in a timely and reliable fashion. The hypertensive atria have been shown to develop atrial electrical and structural remodeling leading to a substrate for AF [16,17]. This study was approved by the “University of Adelaide Animal Ethics Committee” and “SA Pathology Animal Ethics Committee”, Adelaide, Australia (M2010-109, approved 01 September 2010).
Results A total of 18 male merino cross sheep (57±6kg) with induced hypertension (162±7mmHg) of 12±2 weeks’ duration were used for this study. Mean interventricular septum and left atrial size were 18±1mm and 48±8mm respectively, consistent with hypertensive heart disease. A total of 42 self-terminating (mean duration: 60±23s, range: 28–100s) and 6 longstanding sustained AF episodes (>15min; 6 sheep) were recorded. Following manual verification to ensure the correct annotation of electrograms and removal of data points with poor contact, a total of 67,733 4-s epochs from the 48 AF episodes were used for analysis.
Discussion In this study, a novel and more sophisticated measure of spatiotemporal stability (STSI) was compared to conventional sequential sampling of CFE-m and DF in an ovine hypertensive model for the detection of changes in the dynamics of AF from its onset to stabilization and termination. The principal findings are as follows (Fig. 7). First, the only parameter that mirrored the changing AF dynamics closely was the spatiotemporal stability of CFAE: the STSI of CFE-m increased with the stabilization of AF and decreased just prior to spontaneous AF termination. The same pattern was not seen with the STSI of DF or sequentially sampled mean CFE-m. Second, median DF trended lower with AF stabilization and was only significantly lower just prior to AF termination. However, the absolute change in both scenarios was physiologically non-significant, given that its magnitude was not more than 0.5Hz. Third, the STSI of both CFE-m and DF were low (approximately 0.2–0.6) during both self-terminating and sustained AF episodes, indicating poor spatiotemporal stability. Last, during the first 16s of AF initiation, sustained AF episodes demonstrated a significantly higher median DF than did those that terminated spontaneously. Taken together, the novel STSI of CFE-m is more representative of AF dynamics than the STSI of DF, or the sequential mean CFE-m or median DF.