In canine hearts with long-term isolated LBBB, BVP largely reverses global and regional functional and structural abnormalities induced by LBBB.

During AF, pronounced dissociation of electrical activity occurs between the epicardial layer and the endocardial bundle network. The increase in dissociation is due to owing to progressive uncoupling between the epicardial layer and the endocardial bundles and correlates with increasing stability and complexity of the AF substrate.

Background— The transition from persistent to permanent atrial fibrillation (AF) is associated with increased complexity of fibrillatory conduction. We have investigated the spatial distribution of fibrillation waves and structural alterations in the atrial free walls in a goat model of AF. Methods and Results— AF was maintained for 3 weeks (short term [ST], persistent AF) or 6 months (long term [LT], permanent AF). Fibrillation patterns were assessed with epicardial mapping. The origin of fibrillation waves and sites of conduction abnormalities were more homogeneously distributed in LT than in ST goats. Histologically, the total area fraction occupied by fibrous tissue and the degree of perimysial fibrosis (separation between myocyte bundles) were not significantly different between groups. However, endomysial fibrosis (distance between myocytes within bundles) was significantly larger in LT goats, particularly in the outer millimeter of the atria. By contrast, myocyte diameters were larger in LT goats throughout the atrial walls. High-resolution optical mapping showed that epicardial wavefront expansion was slower and more anisotropic in LT than in ST goats. Finally, a mathematical model of a simplified atrial architecture confirmed the potential impact of epicardial endomysial fibrosis on AF complexity. Conclusions— Altered propagation after 6 months of AF is consistent with homogeneous structural remodeling in the outer millimeter of the atria. Loss of continuity of the epicardial layer because of endomysial fibrosis may reduce its synchronizing effect, thereby increasing the complexity of fibrillatory conduction pathways. The exact distribution of fibrosis may be more important for the occurrence of conduction disturbances than the overall quantity.

The hypercoagulable state during AF causes pro-fibrotic and pro-inflammatory responses in adult atrial fibroblasts. Hypercoagulability promotes the development of a substrate for AF in transgenic mice and in goats with persistent AF. In AF goats, nadroparin attenuates atrial fibrosis and the complexity of the AF substrate. Inhibition of coagulation may not only prevent strokes but also inhibit the development of a substrate for AF.

Background-Conventional right ventricular (RV) apex pacing can lead to adverse clinical outcome associated with asynchronous activation and reduced left ventricular (LV) pump function. We investigated to what extent alternate RV (septum) and LV (septum, apex) pacing sites improve LV electric activation, mechanics, hemodynamic performance, and efficiency over 4 months of pacing. Methods and Results-After AV nodal ablation, mongrel dogs were randomized to receive 16 weeks of VDD pacing at the RV apex, RV septum, LV apex, or LV septum (transventricular septal approach). Electric activation maps (combined epicardial contact and endocardial noncontact) showed that RV apical and RV septal pacing induced significantly greater electric desynchronization than LV apical and LV septal pacing. RV apex and RV septal pacing also significantly increased mechanical dyssynchrony, discoordination (MRI tagging) and blood flow redistribution (microspheres) and reduced LV contractility, relaxation, and myocardial efficiency (stroke work/myocardial oxygen consumption). In contrast, LV apical and LV septal pacing did not significantly alter these parameters as compared with the values during intrinsic conduction. At 16 weeks, acute intrasubject comparison showed that single-site LV apical and LV septal pacing generally resulted in similar or better contractility, relaxation, and efficiency as compared with acute biventricular pacing. Conclusions-Acute and chronic LV apical and LV septal pacing maintain regional cardiac mechanics, contractility, relaxation, and efficiency near native levels, whereas RV apical or RV septal pacing diminish these variables. Acute LV apical and LV septal pacing tend to maintain or improve contractility and efficiency compared with biventricular pacing. (Circ Arrhythmia Electrophysiol. 2009;2:571-579.)Key Words: pacing Ⅲ hemodynamics Ⅲ mapping Ⅲ mechanics Ⅲ oxygen C ompared with normal ventricular activation, conventional right ventricular (RV) apex pacing is associated with asynchronous left ventricular (LV) activation, abnormal contraction, and reduced pump function (for review, see reference 1). 1 These adverse effects have been associated with an increased risk of developing heart failure (for review, see reference 1). 1 Also contributing to this adverse outcome is a reduction in myocardial efficiency during ventricular pacing, which increases total myocardial oxygen demand. Consequently, paced hearts can be expected to be more susceptible to ischemia when coronary reserve is limited, 2 as during coronary artery disease and/or overload of the heart. Clinical Perspective on p 579Several studies have sought alternative pacing sites to improve hemodynamic performance. Because pacing leads are usually implanted transvenously, alternate sites within the RV have been studied most intensively, but results of the various studies are mixed. 3,4 Experimental and clinical studies indicate that LV pacing sites often render better hemodynamic performance than RV pacing sites. [5][6][7] In a previous acute canine stu...

Present hypotheses on mechanisms underlying breakthrough events include transmural conduction from the opposing layer of the atrial wall (endo-epicardial or vice versa), transmural microreentry, or ectopic focal discharges. 2,[5][6][7][8][9][10][11][12] Electric dissociation between the endocardial bundle network and the epicardial layer (EED) during AF is a prerequisite condition for transmural conduction of fibrillation waves because only in the presence of EED electric activity in 1 layer of the atrial wall can encounter excitable tissue in the opposing layer.We recently demonstrated that in goats EED increases during the first 6 months of AF, 13 which might well explain the higher incidence of breakthrough in complex substrates for AF. However, increasing evidence for altered intracellular Ca 2+ handling in atrial myocytes of AF patients supports the hypothesis that ectopic focal discharges because of triggered activity might also occur during AF and contribute to its perpetuation. 9,12,14 © 2013 American Heart Association, Inc. Background-Endo-epicardial dissociation (EED) of electric activations resulting in transmural conduction of fibrillation waves (breakthroughs) has been postulated to contribute to the complexity of the substrate of atrial fibrillation (AF). The aim of this study was to elucidate the correlation between EED and incidence of breakthrough and to test the plausibility of transmural conduction versus ectopic focal discharges as sources of breakthrough. Methods and Results-We analyzed high-resolution simultaneous endo-epicardial in vivo mapping data recorded in left atrial free walls of goats with acute AF, 3 weeks and 6 months of AF (all n=7). Waves were analyzed for number, size, and width and categorized according to their origin outside (peripheral wave) or within the mapping area (breakthrough). Breakthrough incidence was lowest (2.1±1.0%) in acute AF, higher (11.4±6.1%) after 3 weeks (P<0.01 versus acute AF) and highest (14.2±3.8%) after 6 months AF (P<0.001 versus acute AF) and similar in the epicardium and endocardium. Most of the breakthroughs (86%; n=564) could be explained by transmural conduction, whereas only 13% (n=85) could be explained by ectopic focal discharges. Transmural microreentry did not play a role as source of breakthrough. Conclusions-This is the first study to present simultaneous endo-epicardial in vivo mapping data at sites of breakthrough events. Breakthrough incidence and degree of EED increased with increasing AF substrate complexity. In goat left atrial free walls, most of the breakthroughs can be explained by transmural conduction, whereas ectopic focal discharges play a limited role as source of breakthrough. (Circ Arrhythm Electrophysiol. 2013;6:334-341.) Circ Arrhythm Electrophysiol

Background-Over a time course of months, the stability of atrial fibrillation (AF) gradually increases and the efficacy of pharmacological cardioversion declines both in humans and in animal models. Changes in fibrillatory conduction over this period largely are unexplored. Methods and Result-Goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. AF was maintained for 3 weeks (short-term AF [ST], nϭ10) or 6 months (long-term AF [LT], nϭ7). AF could be cardioverted pharmacologically at the early time point (persistent AF), but not at the later time point (permanent AF). At follow-up, a high-resolution mapping electrode was used to record epicardial conduction patterns in the free walls of the right atrium (RA) and left atrium (LA). A new method for mapping of fibrillation waves was used to describe AF conduction patterns. Wavefronts propagated uniformly during slow pacing in both groups, although conduction velocity was significantly lower in the LT group (LA, 93Ϯ14 versus 72Ϯ10 cm/s; RA, 94Ϯ8 versus 78Ϯ8 cm/s). Median AF cycle length (AFCL) was not significantly different between the groups. However, the LT group showed highly complex activation patterns during AF, with an increased number of simultaneously propagating waves (LT group RA, 8.4Ϯ3.0 waves/AFCL; LA, 12.8Ϯ2.4 waves/AFCL; versus ST group RA, 4.3Ϯ2.2 waves/AFCL; LA, 4.5Ϯ2.5 waves/AFCL). Fibrillation waves in the LT group showed pronounced dissociation with large activation time differences. The incidence of waves newly appearing within the recording area also was increased in both atria. These alterations in conduction were accompanied by myocyte hypertrophy and increased endomysial fibrosis. Conclusions-Long-term AF in goats leads to dissociated conduction in the atrial free walls that may contribute to increased AF stability. (Circ Arrhythm Electrophysiol. 2010;3:590-599.)

Background-We investigated the benefits of the more physiological activation achieved by left ventricular (LV) endocardial pacing (ENDO) as compared with conventional epicardial (EPI) LV pacing in cardiac resynchronization therapy. Methods and Results-In 8 anesthetized dogs with experimental left bundle-branch block, pacing leads were positioned in the right atrium, right ventricle, and at 8 paired (EPI and ENDO) LV sites. Systolic LV pump function was assessed as LVdP/dtmax and stroke work and diastolic function as LVdP/dtmin. Electrical activation and dispersion of repolarization were determined from 122 epicardial and endocardial electrodes and from analysis of the surface ECG. Overall, ENDO-biventricular (BiV) pacing more than doubled the degree of electrical resynchronization and increased the benefit on LVdP/dtmax and stroke work by 90% and 50%, respectively, as compared with EPI-BiV pacing. During single-site LV pacing, the range of AV intervals with a Ͼ10% increase in LV resynchronization (79Ϯ31 versus 32Ϯ24 ms, PϽ0.05) and LVdP/dtmax (92Ϯ29 versus 63Ϯ39 ms) was significantly longer for ENDO than for EPI pacing. EPI-BiV but not ENDO-BiV pacing created a significant (40Ϯ21 ms) transmural dispersion of repolarization. Conclusions-Data