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Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): H2020-FTI [Fast Track to Innovation] Pilot-2016 and MicroPort CRM Background Left ventricular (LV) lead positioning is an important contributor to cardiac resynchronization therapy (CRT) response. Multiple additional LV sites could be stimulated by passing a new ultra-thin (1.2 Fr, 0.4 mm) quadripolar microlead from one LV vein into another via venous collaterals. Purpose Study the acute and chronic stability and electrical pacing performance of a novel 1.2 Fr quadripolar microlead ("Axone 4LV"). Methods Seven healthy adult dogs underwent CRT defibrillator implantation, including a right ventricular lead and the microlead. The microlead was advanced into the coronary sinus network using a dedicated microguide catheter. The animals were followed up at 1, 15, 30 and 90 days post-implant to evaluate chronic stability and electrical pacing performance. Results Successful uncomplicated implantation was achieved in all cases. Despite the small diameter of the distal veins and collaterals, placement of the pacing electrodes in two different LV veins was feasible via available collateral passages. Lead position was stable in all cases and over the entire study period. Capture threshold and pacing impedance at 90 days post-implant were 1.7 ± 0.5 V with 1323 ± 245 Ω, respectively, at 0.5 ms pulse width. The mean pacing energy to get capture was 1.1 ± 0.5 µJ and less than 2 µJ in all cases (2 µJ ≈ 1.4 V @500 Ω, 0.5 ms). No phrenic nerve stimulation was observed during pacing. Conclusions The novel 1.2 Fr quadripolar microlead demonstrated adequate stability and good electrical performance allied to low energy consumption. This quadripolar microlead may extend pacing options while increasing device longevity in CRT. Changes in pacing parameters over time Post-implant Follow-up Pacing Threshold Pacing Impedance Pacing Energy 1 day 1.4 ± 0.7 V 1294 ± 270 Ω 0.8 ± 0.7 µJ 15 days 1.9 ± 0.9 V 1336 ± 274 Ω 1.8 ± 1.8 µJ 30 days 1.8 ± 0.7 V 1187 ± 303 Ω 1.5 ± 1.2 µJ 90 days 1.7 ± 0.5 V 1323 ± 245 Ω 1.1 ± 0.5 µJ

BackgroundSmall-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the KCa2 current—and thereby the efficacy of small-conductance Ca2+-activated K+ current (IK,Ca) inhibition—might be negatively related to AF duration and the extent of AF-induced remodeling.Experimental Approach and MethodsTo address the hypothesis of the efficacy of IK,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the IK,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring.ResultsIK,Ca inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved.ConclusionsIntra-atrial heterogeneity in response to IK,Ca inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, IK,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.

Background Small-conductance Ca2+-activated K+ (KCa2) channels have been proposed as a possible atrial-selective target to pharmacologically terminate atrial fibrillation (AF) and to maintain sinus rhythm. However, it has been hypothesized that the importance of the KCa2 current—and thereby the efficacy of small-conductance Ca2+-activated K+ current (IK,Ca) inhibition—might be negatively related to AF duration and the extent of AF-induced remodeling. Experimental Approach and Methods To address the hypothesis of the efficacy of IK,Ca inhibition being dependent on AF duration, the anti-arrhythmic properties of the IK,Ca inhibitor NS8593 (5 mg/kg) and its influence on atrial conduction were studied using epicardial high-density contact mapping in horses with persistent AF. Eleven Standardbred mares with tachypacing-induced persistent AF (42 ± 5 days of AF) were studied in an open-chest experiment. Unipolar AF electrograms were recorded and isochronal high-density maps analyzed to allow for the reconstruction of wave patterns and changes in electrophysiological parameters, such as atrial conduction velocity and AF cycle length. Atrial anti-arrhythmic properties and adverse effects of NS8593 on ventricular electrophysiology were evaluated by continuous surface ECG monitoring. Results IK,Ca inhibition by NS8593 administered intravenously had divergent effects on right and left AF complexity and propagation properties in this equine model of persistent AF. Despite global prolongation of AF cycle length, a slowing of conduction in the right atrium led to increased anisotropy and electrical dissociation, thus increasing AF complexity. In contrast, there was no significant change in AF complexity in the LA, and cardioversion of AF was not achieved. Conclusions Intra-atrial heterogeneity in response to IK,Ca inhibition by NS8593 was observed. The investigated dose of NS8593 increased the AF cycle length but was not sufficient to induce cardioversion. In terms of propagation properties during AF, IK,Ca inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.

Background and Purpose Inward rectifier current (IK1) density increases in atrial fibrillation (AF), shortening effective refractory period and thus promotes atrial reentry. Pentamidine-Analogue 6 (PA-6) is a selective and potent IK1 inhibitor. We tested PA-6 for anti-AF efficacy and potential proarrhythmia, in established large animal models. Experimental Approach PA-6 was applied i.v. in anaesthetized goats with rapid pacing induced AF and anaesthetized chronic AV block dogs. Electrophysiological and pharmacological parameters were determined. Key Results PA-6 (2.5 mg.kg-1.10min-1) induced cardioversion to sinus rhythm (SR) in 5/6 goats. PA-6 prolonged AF cycle length (LA:139.0±23.2 vs. 152.1±22.1ms, p

Aims Left bundle branch block (LBBB) creates considerable regional differences in mechanical load within the left ventricle (LV). We investigated expression of selected microRNAs (miRs) in relation to regional hypertrophy and fibrosis in LBBB hearts and their reversibility upon cardiac resynchronization therapy (CRT). Methods and results Eighteen dogs were followed for 4 months after induction of LBBB, 10 of which received CRT after 2 months. Five additional dogs served as control. LV geometric changes were determined by echocardiography and myocardial strain by magnetic resonance imaging tagging. Expression levels of miRs, their target genes: connective tissue growth factor (CTGF), serum response factor (SRF), nuclear factor of activated T cells (NFATc4), and cardiomyocyte diameter and collagen deposition were measured in the septum and LV free wall (LVfw). In LBBB hearts, LVfw and septal systolic circumferential strain were 200% and 50% of control, respectively. This coincided with local hypertrophy in the LVfw. MiR-133a expression was reduced by 33% in the LVfw, which corresponded with a selective increase of CTGF expression in the LVfw (279% of control). By contrast, no change was observed in SRF and NFATc4 expression was decreased in LBBB hearts. CRT normalized strain patterns and reversed miR-133a and CTGF expression towards normal, expression of other miRs, related to remodelling, such as miR-199b and miR-155f, were not affected. Conclusions In the clinically relevant large animal model of LBBB, a close inverse relation exists between local hypertrophy and miR-133a. Reduced miR-133a correlated with increased CTGF levels but not with SRF and NFATc4.

Introduction. Electrical mapping of the atria is used to assess the substrate of atrial fibrillation (AF). Targeted ablation of the AF substrate assumes spatiotemporal stationarity. In this study we analyzed long AF recordings of AF using high-density contact mapping. Methods. In 12 goats with stable AF 10 successive 60s files were recorded, within a single AF episode. AF cycle length, fractionation index (FI), lateral dissociation, conduction velocity, breakthroughs and preferentiality of conduction (Pref) were assessed to construct AF-property maps. The Pearson correlation coefficient (PCC) between AF-property maps of consecutive recordings was calculated. Recurrence plots and recurrence quantification analysis were used to identify recurrent patterns. Results Spatiotemporal stationarity for the 6 properties were high, PCC ranged from 0.66±0.11 for Pref to 0.98±0.01 for FI. The PCC is not affected by the time delay between files. Yet, highly dynamic patterns were found. Recurrence plots revealed few (1.6±0.7) recurrent patterns in individual animals. Conclusions AF properties were stationary in stable AF. This cannot be attributed to stable recurrent conduction patterns. during This suggests that spatial properties of the atrium determine AF properties.

BACKGROUND Multisite left ventricular (multi-LV) epicardial pacing has been proposed as an alternative to conventional single-site LV (single-LV) pacing to increase the efficacy of cardiac resynchronization therapy. OBJECTIVE To compare the effects of multi-LV versus single-LV pacing in dogs with left bundle branch block (LBBB). METHODS Studies were performed in 9 anaesthetized dogs with chronic LBBB using 7 LV epicardial electrodes. Each electrode was tested alone and in combination with 1, 2, 3, and 6 other electrodes, the sequence of which was chosen on the basis of practical real-time electrical mapping to determine the site of the latest activation. LV total activation time (LVTAT) and dispersion of repolarization (DRep) were measured by using approximately 100 electrodes around the ventricles. LV contractility was assessed as the maximum derivative of left ventricular pressure (LVdP/dt(max)). RESULTS Single-LV pacing provided, on average, a -4.0% +/- 9.3% change in LVTAT and 0.2% +/- 13.7% change in DRep. Multi-LV pacing markedly decreased both LVTAT and DRep in a stepwise fashion to reach -41.3% +/- 5% (P

Background and Purpose The density of the inward rectifier current (IK1) increases in atrial fibrillation (AF), shortening effective refractory period and thus promoting atrial re‐entry. The synthetic compound pentamidine analogue 6 (PA‐6) is a selective and potent IK1 inhibitor. We tested PA‐6 for anti‐AF efficacy and potential proarrhythmia, using established models in large animals. Experimental Approach PA‐6 was applied i.v. in anaesthetized goats with rapid pacing‐induced AF and anaesthetized dogs with chronic atrio‐ventricular (AV) block. Electrophysiological and pharmacological parameters were determined. Key Results PA‐6 (2.5 mg·kg−1·10 min−1) induced cardioversion to sinus rhythm (SR) in 5/6 goats and prolonged AF cycle length. AF complexity decreased significantly before cardioversion. PA‐6 accumulated in cardiac tissue with ratios between skeletal muscle : atrial muscle : ventricular muscle of approximately 1:8:21. In SR dogs, PA‐6 peak plasma levels 10 min post infusion were 5.5 ± 0.9 μM, PA‐6 did not induce significant prolongation of QTc and did not affect heart rate, PQ or QRS duration. In dogs with chronic AV block, PA‐6 did not affect QRS but lengthened QTc during the experiment, but not chronically. PA‐6 did not induce TdP arrhythmias in nine animals (0/9) in contrast to dofetilide (5/9). PA‐6 (200 nM) inhibited IK1, but not IK,ACh, in human isolated atrial cardiomyocytes. Conclusion and Implications PA‐6 restored SR in goats with persistent AF and, in dogs with chronic AV block, prolonged QT intervals, without inducing TdP arrhythmias. Our results demonstrate cardiac safety and good anti‐AF properties for PA‐6.

Background— The relative contribution of electromechanical synchronization and ventricular filling to the optimal hemodynamic effect in cardiac resynchronization therapy (CRT) during adjustment of stimulation-timings is incompletely understood. We investigated whether optimal hemodynamic effect in CRT requires collision of pacing-induced and intrinsic activation waves and optimal filling of the left ventricle (LV). Methods and Results— CRT was performed in dogs with chronic left bundle–branch block (n=8) or atrioventricular (AV) block (n=6) through atrial (A), right ventricular (RV) apex, and LV-basolateral pacing. A 100 randomized combinations of A-LV/A-RV intervals were tested. Total activation time (TAT) was calculated from >100 contact mapping electrodes. Mechanical interventricular dyssynchrony was determined as the time delay between upslopes of LV and RV pressure curves. Settings providing an increase in LVdP/dt max (maximal rate of rise of left ventricular pressure) of ≥90% of the maximum LVdP/dt max value were defined as optimal (CRT opt ). Filling was assessed by changes in LV end-diastolic volume (EDV; conductance catheter technique). In all hearts, CRT opt was observed during multiple settings, providing an average LVdP/dt max increase of ≈15%. In AV-block hearts, CRT opt exclusively depended on interventricular-interval and not on AV-interval. In left bundle–branch block hearts, CRT opt occurred at A-LV intervals that allowed fusion of LV-pacing–derived activation with right bundle–derived activation. In all animals, CRT opt occurred at settings resulting in the largest decrease in TAT and mechanical interventricular dyssynchrony, whereas LV EDV hardly changed. Conclusions— In left bundle–branch block and AV-block hearts, optimal hemodynamic effect of CRT depends on optimal interplay between pacing-induced and intrinsic activation waves and the corresponding mechanical resynchronization rather than filling.

Aims Left bundle branch block (LBBB) creates considerable regional differences in mechanical load within the left ventricle (LV). We investigated expression of selected microRNAs (miRs) in relation to regional hypertrophy and fibrosis in LBBB hearts and their reversibility upon cardiac resynchronization therapy (CRT). Methods and results Eighteen dogs were followed for 4 months after induction of LBBB, 10 of which received CRT after 2 months. Five additional dogs served as control. LV geometric changes were determined by echocardiography and myocardial strain by magnetic resonance imaging tagging. Expression levels of miRs, their target genes: connective tissue growth factor (CTGF), serum response factor (SRF), nuclear factor of activated T cells (NFATc4), and cardiomyocyte diameter and collagen deposition were measured in the septum and LV free wall (LVfw). In LBBB hearts, LVfw and septal systolic circumferential strain were 200% and 50% of control, respectively. This coincided with local hypertrophy in the LVfw. MiR‐133a expression was reduced by 33% in the LVfw, which corresponded with a selective increase of CTGF expression in the LVfw (279% of control). By contrast, no change was observed in SRF and NFATc4 expression was decreased in LBBB hearts. CRT normalized strain patterns and reversed miR‐133a and CTGF expression towards normal, expression of other miRs, related to remodelling, such as miR‐199b and miR‐155f, were not affected. Conclusions In the clinically relevant large animal model of LBBB, a close inverse relation exists between local hypertrophy and miR‐133a. Reduced miR‐133a correlated with increased CTGF levels but not with SRF and NFATc4.

Background— In cardiac resynchronization therapy (CRT), optimization of left ventricular (LV) stimulation timing is often time consuming. We hypothesized that the QRS vector in the vectorcardiogram (VCG) reflects electric interventricular dyssynchrony, and that the QRS vector amplitude (VA QRS ), halfway between that during left bundle branch block (LBBB) and LV pacing, reflects optimal resynchronization, and can be used for easy optimization of CRT. Methods and Results— In 24 canine hearts with LBBB (12 acute, 6 with heart failure, and 6 with myocardial infarction), the LV was paced over a wide range of atrioventricular (AV) delays. Surface ECGs were recorded from the limb leads, and VA QRS was calculated in the frontal plane. Mechanical interventricular dyssynchrony (MIVD) was determined as the time delay between upslopes of LV and right ventricular pressure curves, and systolic function was assessed as LV dP/dt max . VA QRS and MIVD were highly correlated ( r =0.94). The VA QRS halfway between that during LV pacing with short AV delay and intrinsic LBBB activation accurately predicted the optimal AV delay for LV pacing (1 ms; 95% CI, –5 to 8ms). Increase in LV dP/dt max at the VCG predicted AV delay was only slightly lower than the highest observed ∆LV dP/dt max (–2.7%; 95% CI, –3.6 to –1.8%). Inability to reach the halfway value of VA QRS during simultaneous biventricular pacing (53% of cases) was associated with suboptimal hemodynamic response, which could be corrected by sequential pacing. Conclusions— The VA QRS reflects electric interventricular dyssynchrony and accurately predicts optimal timing of LV stimulation in canine LBBB hearts. Therefore, VCG may be useful as a reliable and easy tool for individual optimization of CRT.

Background There are several indications for a mismatch between atrial oxygen supply and demand during atrial fibrillation (AF), but atrial coronary flow regulation has not been investigated extensively. Objective The purpose of this study was to characterize the dynamic regulation of atrial coronary flow in pigs. Methods In anesthetized open-chest pigs, Doppler flow probes were placed around left atrial (LA) and left ventricular (LV) branches of the circumflex artery. Pressures and work indices were measured simultaneously. Systolic and diastolic flow contribution, flow response kinetics, and relationship between pressures, work, and flow were investigated during sinus rhythm, atrial pacing, and acute AF. Results During atrial systole, LA flow decreased. Only 2% of total LA flow occurred during atrial systole. Pacing with 2:1 AV block and infusion of acetylcholine revealed that atrial contraction itself impeded atrial coronary flow. The response to sudden changes in heart rate was slower in LA compared to LV. Both LA and LV vascular conductance were positively correlated with work. After the cessation of acute AF, the LA showed a more pronounced phase of supranormal vascular conductance than the LV, indicating a period of atrial reactive hyperemia. Conclusion In healthy adult pigs, atrial coronary flow is impeded by atrial contraction. Although atrial coronary blood flow is positively correlated with atrial external work, it reacts more slowly to changes in rate than ventricular flow. The occurrence of a pronounced hyperemic phase after acute AF supports the notion of a significant supply–demand mismatch during AF.

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.

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.

Nuclear calcium (Ca2+) signalling play a major role in cardiac excitation-transcription coupling. The origin of nuclear Ca2+ transient is still controversial. It has been suggested that Ca2+ diffusion from the cytosol through the nuclear pores or perinuclear and intranuclear Ca2+ release mechanisms, mostly via the inositol-3-phosphate receptors (IP3R), participate to nuclear Ca2+ transient. In rabbits subjected to rapid atrial pacing (RAP, 600bp, 5 days), a model for atrial fibrillation (AF), we recently observed that central-cellular, but not subsarcolemmal Ca2+ transient, was largely reduced. Since nuclei are often at the center of atrial myocytes, we hypothesized that nuclear Ca2+ transient is also decreased in RAP cells. Using confocal microscopy we recorded transverse line-scan images in field-stimulated sham and RAP atrial cells. Nuclear Ca2+ transient amplitude in relation to subsarcolemmal Ca2+ transient was decreased in RAP compared to sham cells (at 1Hz, DFnuclear/DFsubsarcolemmal was 0,38±0,03 in 17 RAP cells, compared to 0,81±0,06 in 16 sham cells, p

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.

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 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.

Objective: Conventional right ventricular (RV) apex pacing is associated with asynchronous activation and reduced left ventricular (LV) pump function. Previous studies have shown acute hemodynamic benefits over RV apex pacing by LV septal or LV apex pacing. We investigated whether this improvement translates into a long-term benefit and how acute LV function during single site LV pacing compares to biventricular pacing. Methods: After AV-nodal ablation, mongrel dogs were randomized to receive 16 weeks of VDD pacing at the RV apex (n = 7), LV apex (n = 7), or LV mid-septum (n = 8; trans-ventricular septal approach). LV contractility (dP/dt max /P instantaneous ) was measured during normal ventricular conduction from atrial pacing (AP) and during ventricular pacing 1–3 hours and 16 weeks after implant. At 16 weeks, contractility was also measured after an acute switch from the implant site (IS) to the non-implanted apex (both for LV septal group) and to RV apex + LV lateral (BiV) pacing. Results: While acute and chronic RV apex pacing significantly reduced contractility (Figure a ; mean ± SD, *p ). After 16 weeks of LV pacing, switching to RV apex pacing decreased contractility. Collectively, acute LV apex pacing enhanced contractility over acute BiV (p Conclusions: Chronic LV apex and LV mid-septal pacing maintain contractility near normal levels, and at a higher level than RV apex pacing. Acutely, LV apex pacing improves contractility compared to BiV pacing.

Objective: Previous studies showed hemodynamic benefits over right ventricular (RV) apex pacing by left ventricular (LV) septal or LV apex pacing. We investigated whether this benefit is also reflected in mechanical efficiency. Methods: After AV-nodal ablation, dogs received 16 weeks of VDD pacing at the RV apex (RVa; n = 8), LV apex (LVa; n = 7) or LV septum (LVs; n = 8; transventricular-septal approach). After chronic pacing, LV stroke work (SW; conductance catheter) was measured, as well as relative myocardial oxygen consumption (MVO 2 , coronary flow velocity and arterial-coronary sinus O 2 difference). Baseline efficiency (SW/MVO 2 ) was assessed during implant site (IS), RVa, LVa, and RVa + LV lateral (BiV) pacing. In order to investigate the effect of pacing site udner different conditions, measurements were performed during baseline and dobutamine infusion +/− partial aortic occlusion. The O 2 cost of generating SW, corrected for end-systolic elastance and effective arterial elastance, was calculated using the Suga model of mechano-energetics. Results: RVa pacing after chronic LV pacing reduced SW/MVO 2 (Figure a ; mean ± SD, *p2 cost (Figure b ) in combination with a 12% fall in LV dP/dt-max. However, LVa or BiV pacing after chronic RVa pacing did not significantly alter efficiency, despite a 12% increase in LV dP/dt-max. LVa pacing improved efficiency over LVs and collectively over BiV pacing (p Conclusions: Acutely, LVa pacing results in the greatest mechanical efficiency. The lack of improvement in efficiency despite increasing contractility when switching from chronic RVa pacing to LV based pacing may indicate contractile remodeling.

P3187 | BENCH Prediction of optimal electrical and functional cardiac resynchronization by vectorcardiography in dyssynchronous canine hearts M. Strik1, P. Houthuizen1, L.B. Van Middendorp1, S. Ploux1, E. Evers1, A. Van Hunnik1, M. Kuiper1, A. Auricchio2, F.W. Prinzen1. 1Maastricht University, CARIM, Department of Physiology, Maastricht, Netherlands; 2Foundation "Cardiocentro Ticino", Department of Cardiology, Lugano, Switzerland