Arne van Hunnik

Left ventricular endocardial pacing improves resynchronization therapy in canine left bundle-branch hearts.

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 >10% increase in LV resynchronization (79±31 versus 32±24 ms, P<0.05) and LVdP/dtmax (92±29 versus 63±39 ms) was significantly longer for ENDO than for EPI pacing. EPI-BiV but not ENDO-BiV pacing created a significant (40±21 ms) transmural dispersion of repolarization. Conclusions—Data from this acute animal study indicate that the use of an endocardial LV pacing electrode may increase the efficacy of resynchronization therapy as compared with conventional epicardial resynchronization therapy.

Development of a Substrate of Atrial Fibrillation During Chronic Atrioventricular Block in the Goat

Background—Atrial dilatation is an important risk factor for atrial fibrillation (AF). In the present study, we monitored the electrophysiological changes during progressive atrial dilatation in chronically instrumented goats. Methods and Results—In 8 goats, 2 screw-in leads with piezoelectric crystals were implanted transvenously in the right atrium. After 2 weeks, atrial diameter and effective refractory period were measured. AF paroxysms were induced by burst pacing to determine the baseline AF cycle length and stability of AF. After His-bundle ablation, the above measurements were repeated once a week. After 4 weeks of complete AV block, the free wall of the right atrium was mapped and the atrium was fixed in formalin for histological analysis. After His-bundle ablation, the ventricular rate decreased from 113.8±4.8 to 44.6±2.5 bpm. Right atrial diameter increased gradually by 13.5±3.9% during 4 weeks of AV block (P<0.01). The duration of induced AF paroxysms increased from 4.6 seconds to 6.4 minutes (P<0.05). Atrial effective refractory period and AF cycle length remained constant. Spontaneous paroxysms of AF were not observed. Atrial mapping during rapid pacing revealed that slow conduction (<30 cm/s) was present in 3.7±1.0% of the mapped area (control, 0.9±0.5%, P<0.05). Histological analysis showed hypertrophy without atrial fibrosis. Connexin40 and connexin43 expression was unchanged. Conclusions—Chronic AV block in the goat leads to progressive atrial dilatation, prolongation of induced AF paroxysms, and local conduction delays. The increase in AF stability was not a result of a shortening of atrial refractoriness or atrial fibrosis.

Time course and mechanisms of endo-epicardial electrical dissociation during atrial fibrillation in the goat

AIMS This study aims to determine the degree and mechanisms of endo-epicardial dissociation of electrical activity during atrial fibrillation (AF) and endo-epicardial differences in atrial electrophysiology at different stages of atrial remodelling. METHODS AND RESULTS Simultaneous high-density endo-epicardial mapping of AF was performed on left atrial free walls of goats with acute AF, after 3 weeks, and after 6 months of AF (all n = 7). Endo-epicardial activation time differences and differences in the direction of conduction vectors were calculated, endocardial and epicardial effective refractory periods (ERP) were determined, and fractionation of electrograms was quantified. Histograms of endo-epicardial activation time differences and differences in the direction of conduction vectors revealed two distinct populations, i.e. dissociated and non-dissociated activity. Dyssynchronous activity (dissociated in time) increased from 17 ± 7% during acute AF to 39 ± 17% after 3 weeks, and 68 ± 13% after 6 months of AF. Dissociation was more pronounced in thicker parts of the atrial wall (thick: 49.3 ± 21.4%, thin: 42.2 ± 19.0%, P < 0.05). At baseline, endocardial ERPs were longer when compared with epicardial ERPs (ΔERP, 21.8 ± 18 ms; P < 0.001). This difference was absent after 6 months of AF. The percentage of fractionated electrograms during rapid pacing increased from 9.4 ± 1.9% (baseline) to 18.6 ± 0.6% (6 months). CONCLUSION 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.

LV Endocardial Pacing Improves Resynchronization Therapy in Canine LBBB Hearts

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 >10% increase in LV resynchronization (79±31 versus 32±24 ms, P<0.05) and LVdP/dtmax (92±29 versus 63±39 ms) was significantly longer for ENDO than for EPI pacing. EPI-BiV but not ENDO-BiV pacing created a significant (40±21 ms) transmural dispersion of repolarization. Conclusions—Data from this acute animal study indicate that the use of an endocardial LV pacing electrode may increase the efficacy of resynchronization therapy as compared with conventional epicardial resynchronization therapy.

Endocardial Left Ventricular Pacing Improves Cardiac Resynchronization Therapy in Chronic Asynchronous Infarction and Heart Failure Models

Background— Studies in canine hearts with acute left bundle branch block (LBBB) showed that endocardial left ventricular (LV) pacing improves the efficacy of cardiac resynchronization therapy (CRT) compared with conventional epicardial LV pacing. The present study explores the efficacy of endocardial CRT in more compromised hearts and the mechanisms of such beneficial effects. Methods and Results— Measurements were performed in 22 dogs, 9 with acute LBBB, 7 with chronic LBBB combined with infarction (embolization; LBBB plus myocardial infarction, and concentric remodeling), and 6 with chronic LBBB and heart failure (rapid pacing, LBBB+HF, and eccentric remodeling). A head-to-head comparison was performed of the effects of endocardial and epicardial LV pacing at 8 sites. LV activation times were measured using ≈100 endocardial and epicardial electrodes and noncontact mapping. Pump function was assessed from right ventricular and LV pressures. Endocardial CRT resulted in better electric resynchronization than epicardial CRT in all models, although the benefit was larger in concentrically remodeled LBBB plus myocardial infarction than in eccentrically remodeled LBBB+HF hearts (19% versus 10%). In LBBB and LBBB+HF animals, endocardial conduction was ≈50% faster than epicardial conduction; in all models, transmural impulse conduction was ≈25% faster when pacing from the endocardium than from the epicardium. Hemodynamic effects were congruent with electric effects. Conclusions— Endocardial CRT improves electric synchrony of activation and LV pump function compared with conventional epicardial CRT in compromised canine LBBB hearts. This benefit can be explained by a shorter path length along the endocardium and by faster circumferential and transmural impulse conduction during endocardial LV pacing.

Left Ventricular Septal and Left Ventricular Apical Pacing Chronically Maintain Cardiac Contractile Coordination, Pump Function and Efficiency

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.

Transmural conduction is the predominant mechanism of breakthrough during atrial fibrillation: evidence from simultaneous endo-epicardial high-density activation mapping.

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.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.

Myocardial Infarction Does Not Preclude Electrical and Hemodynamic Benefits of Cardiac Resynchronization Therapy in Dyssynchronous Canine Hearts

Background—Several studies suggest that patients with ischemic cardiomyopathy benefit less from cardiac resynchronization therapy. In a novel animal model of dyssynchronous ischemic cardiomyopathy, we investigated the extent to which the presence of infarction influences the short-term efficacy of cardiac resynchronization therapy. Methods and Results—Experiments were performed in canine hearts with left bundle branch block (LBBB, n=19) and chronic myocardial infarction, created by embolization of the left anterior descending or left circumflex arteries followed by LBBB (LBBB+left anterior descending infarction [LADi; n=11] and LBBB+left circumflex infarction [LCXi; n=7], respectively). Pacing leads were positioned in the right atrium and right ventricle and at 8 sites on the left ventricular (LV) free wall. LV pump function was measured using the conductance catheter technique, and synchrony of electrical activation was measured using epicardial mapping and ECG. Average and maximal improvement in electric resynchronization and LV pump function by right ventricular+LV pacing was similar in the 3 groups; however, the site of optimal electrical and mechanical benefit was LV apical in LBBB hearts, LV midlateral in LBBB+LCXi hearts and LV basal-lateral in LBBB+LADi hearts. The best site of pacing was not the site of latest electrical activation but that providing the largest shortening of the QRS complex. During single-site LV pacing the range of atrioventricular delays yielding ≥70% of maximal hemodynamic effect was approximately 50% smaller in infarcted than noninfarcted LBBB hearts (P<0.05). Conclusions—Cardiac resynchronization therapy can improve resynchronization and LV pump function to a similar degree in infarcted and noninfarcted hearts. Optimal lead positioning and timing of LV stimulation, however, require more attention in the infarcted hearts.

Fibrillatory Conduction in the Atrial Free Walls of Goats in Persistent and Permanent Atrial Fibrillation

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], n=10) or 6 months (long-term AF [LT], n=7). 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, 93±14 versus 72±10 cm/s; RA, 94±8 versus 78±8 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, 8.4±3.0 waves/AFCL; LA, 12.8±2.4 waves/AFCL; versus ST group RA, 4.3±2.2 waves/AFCL; LA, 4.5±2.5 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.

AVE0118, Blocker of the Transient Outward Current (Ito) and Ultrarapid Delayed Rectifier Current (IKur), Fully Restores Atrial Contractility After Cardioversion of Atrial Fibrillation in the Goat

Background— The loss of atrial contractile function after cardioversion of atrial fibrillation (AF) contributes to the thromboembolic risk associated with AF. The newly developed blocker of the transient outward current (Ito) and ultrarapid delayed rectifier current (IKur) AVE0118 prolongs atrial action potential duration and might therefore enhance atrial contractility. We compared the ability of AVE0118 to restore atrial contraction after cardioversion of AF with the efficacy of conventional positive inotropic compounds in the goat model of AF. Methods and Results— Eighteen goats were chronically instrumented with epicardial electrodes, a pressure transducer in the right atrium, and piezoelectric crystals to measure right atrial diameter. Atrial contractility and refractoriness and QT duration were measured before and after 1 week (3 to 8 days) of AF induced by repetitive burst pacing. The measurements were repeated after administration of digoxin (0.02 mg/kg), dobutamine (5 &mgr;g · kg−1 · min−1), the Ca2+ sensitizer EMD57033 (1 mg · kg−1 · min−1), the L-type Ca2+ channel agonist BayY5959 (0.1 mg · kg−1 · min−1), and AVE0118 (0.01 to 0.2 mg · kg−1 · min−1). The effect of AVE0118 on the configuration of atrial monophasic action potentials was determined for comparison. After 1 week of AF, atrial contractility during sinus rhythm or slow atrial pacing was reduced to <10%. Digoxin and dobutamine failed to increase atrial contractility. EMD57033 restored 41% and BayY5959 restored 48% of atrial contractility at baseline. BayY5959 significantly prolonged QT duration by 24.7%. AVE0118 enhanced atrial contraction to 156% of the baseline value. The positive inotropic effect was accompanied by a pronounced prolongation of atrial action potential duration and refractoriness, whereas QT duration remained unchanged. Conclusions— Conventional positive inotropic drugs showed limited effect on atrial contractility after cardioversion of AF or produced QT prolongation. In contrast, the Ito/IKur blocker AVE0118 fully restored atrial contraction without proarrhythmic effects on the ventricle.