Atrial Fibrillation Drivers: Redefining the Electrophysiological Substrate

Background: We performed high-density mapping of persistent atrial fibrillation (AF) in animals and patients (1) to test that AF is due to greater than or equal 1 reentry, and (2) to characterize activation delay and reentries pre/ post pulmonary vein isolation (PVI). We determined electrophysiological characteristics that may predispose to the induction, maintenance, and reduction of AF. Methods and Results: This study includes 48 dogs and nine patients. 43 AF- and five sinus/ paced rhythm dogs (3-14 weeks rapid atrial pacing) were studied at open chest surgery with 117 epicardial electrograms (EGMs) (2.5mm dist.) in 6 bi-atrial regions. Rotational activity automatically detected with a new algorithm tracking the earliest and latest activation in all regions (5+/-2 per region) were stable over 424+/-505ms [120-4940ms]. Reentry stability was highest in the right atrial appendage (RAA) (405+/-219ms) and the posterior left atrium (PLA) (267+/-115ms) and anchored between >=3 zones of activation delay (15+/-5ms, median 13ms) defined as >10ms per 2.5mm. Cycle length (CL) and degree of focal fibrosis were highest in the PLA and left atrial free wall (LAFW) with 94+/-7ms, 96+/-5ms, and 49+/-14%, 47+/-19%. Fiber crossing density correlated with the stability of rotational activity (R=0.6, P<0.05). Activation delay was 2x higher in AF compared to sinus rhythm/paced rhythm (interval 200-500ms). Activation delay zones > 10ms were at the same locations, but increased 4x during AF vs. SR and were located at fiber crossings, fibrosis/ fat zones. Stability of rotational activity correlated with Organization Index (OI), Fraction Index (FI), Shannon's Entropy (ShEn), and CL (R>0.5, p< 0.0001). PVI in five hearts increased CL [2-14%] and reduced stability of rotational activity in nearly all regions remote to the pulmonary veins (PVs). Also in the clinical evaluation in nine patients using the HD-catheter (16 electrodes, 3mm dist.) activation delay at the reentrant trajectory was 2x higher at edges with maximal delay (20.5+/-8.1ms, median 19.6ms) vs (9.3+/-8.8ms, median 9.2ms) and 1.4 x higher during AF (13.0+/-18.7ms, median 7.2ms) compared to SR/ CS-pacing (18.0+/-11.6ms, median 17.7ms). Conclusion: Rotational activities in all bi-atrial regions anchored between small frequency-dependent activation delay zones in AF. PVI led to beneficial remodeling in bi-atrial regions remote to the PVs. These data may identify a new paradigm for persistent AF.

Ventricular activation pattern assessment during right ventricular pacing; ultra-high-frequency ECG study

Background: Right ventricular (RV) pacing causes delayed activation of remote ventricular segments. We used the UHF-ECG to describe ventricular depolarization when pacing different RV locations. Methods: In 51 consecutive patients, temporary pacing was performed at the RV apex, anterior and lateral wall, and at the RV septum with (cSp) and without direct conductive tissue engagement (mSp) (further subclassified as RVIT and RVOT for septal inflow and outflow positions). The timing of UHF-ECG electrical activations were quantified as: left ventricular lateral wall delay (LVLWd; V8 activation delay), RV lateral wall delay (RVLWd; V1 activation delay), and LV lateral wall depolarization duration (V5-8d). Results: The LVLWd was shortest for cSp (11 ms (95% CI; 5;17), followed by the RVIT (19 ms (11;26) and the RVOT (33 ms (27;40), (p<0.01 between all of them), although the QRSd for the latter two were the same (153 ms (148;158) vs. 153 ms (148; 158); p=0.99). The RVOT caused longer V5-8d (9 ms (3;14) compared to the RVIT (1 ms (−5;8), p<0.05. RV apical capture not only had a worse LVLWd (34 ms (26;43) compared to mSp (27 ms (20;34), p<0.05), but its RVLWd (17 ms (9;25) was also the longest compared to other RV pacing sites (mean values for cSp, mSp, anterior and lateral wall captures being below 6 ms), p<0.001 compared to each of them. Conclusions: UHF-ECG ventricular dyssynchrony parameters show that cSp offers the best ventricular synchrony followed by RVIT pacing, which should be preferred over RVOT and other RV myocardial pacing locations.

Mechanical-electrical interaction of the right ventricle in patients with repaired tetralogy of fallot: the next step towards resynchronization in congenital heart disease

Introduction Patients with repaired tetralogy of Fallot (rTF) and severe pulmonary regurgitation frequently progress to dilation and dysfunction of the right ventricle (RV). It has been documented in the literature that there is a correlation between the duration of the QRS in the surface electrocardiogram and the hemodynamic parameters of the RV of these patients, suggesting the presence of a mechanical-electrical interaction. Purpose To determine if there is an association between the contraction delay in certain areas of the RV measured in M-mode echocardiography and the delay in electrical activation measured in the electroanatomic map (EAM) of RV in patients with rTF. Methods Unicentric and observational study of all patients with rTF undergoing EAM, echocardiography with study of RV asynchrony and cardiac magnetic resonance imaging (MRI). Activation delay in the antero-basal area and in the RV outflow tract (RVOT) in the EAM were both analysed (Figure 1A). The shortening delay in the same areas in M-mode echocardiography was also evaluated (Figure 1B, C). MRI data regarding volume and ejection fraction was also collected. Results 64 patients were included (36.7±10.6 years, 65% men). The mean total activation time of the RV (RV-TAT) was 127.3±42.4 ms. Activation mapping showed a recurrent pattern with beginning in the interventricular septum and ending in RV antero-basal region and/or RVOT. A linear positive correlation was observed between RV-TAT and the activation delay in both regions analysed (ρ=0.60 and ρ=0.52, respectively; p&lt;0.001) and also between the electrical and mechanical delay in the anterior wall (ρ=0.41; p=0.001). On the other hand, it was observed a negative correlation between RV ejection fraction (RVEF), measured on MRI, and the RV-TAT (ρ=−0.41, p=0.002) and also between RVEF and the activation delay in the RV antero-basal region and in the RVOT (ρ=−0.32, p=0.016 and ρ=−0.36, p=0.007, respectively). Conclusions There is a mechanical-electrical interaction in the RV of patients with rTF, with a negative correlation between the activation delay and RVEF and between mechanical and electrical activation delay in specific anatomical regions (regional mechanical-electrical interaction). These results may guide future studies on resynchronization in this heart disease. Figure 1. EAM and echocardiographic measures Funding Acknowledgement Type of funding source: None

Promoters adopt distinct dynamic manifestations depending on transcription factor context

Cells respond to external signals and stresses by activating transcription factors (TF), which induce gene expression changes. Previous work suggests that signal-specific gene expression changes are partly achieved because different gene promoters exhibit varying induction dynamics in response to the same TF input signal. Here, using high-throughput quantitative single-cell measurements and a novel statistical method, we systematically analyzed transcription in individual cells to a large number of dynamic TF inputs. In particular, we quantified the scaling behavior among different transcriptional features extracted from the measured trajectories such as the gene activation delay or duration of promoter activity. Surprisingly, we found that even the same gene promoter can exhibit qualitatively distinct induction and scaling behaviors when exposed to different dynamic TF contexts. That is, promoters can adopt context-dependent “manifestations”. Our analysis suggests that the full complexity of signal processing by genetic circuits may be significantly underestimated when studied in specific contexts only.