Publications by authors named "Marion Kuiper"

27 Publications

  • Page 1 of 1

Inhibition of Small-Conductance Calcium-Activated Potassium Current () Leads to Differential Atrial Electrophysiological Effects in a Horse Model of Persistent Atrial Fibrillation.

Front Physiol 2021 9;12:614483. Epub 2021 Feb 9.

Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Taastrup, Denmark.

Background: Small-conductance Ca-activated K (K2) 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 K2 current-and thereby the efficacy of small-conductance Ca-activated K current () 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 inhibition being dependent on AF duration, the anti-arrhythmic properties of the 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: 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 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, inhibition by NS8593 led to divergent effects in the right and left atrium. This divergent behavior may have impeded the cardioversion success.
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http://dx.doi.org/10.3389/fphys.2021.614483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900437PMC
February 2021

Bi-atrial high-density mapping reveals inhibition of wavefront turning and reduction of complex propagation patterns as main antiarrhythmic mechanisms of vernakalant.

Europace 2021 Feb 20. Epub 2021 Feb 20.

Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, the Netherlands.

Aims: Complex propagation patterns are observed in patients and models with stable atrial fibrillation (AF). The degree of this complexity is associated with AF stability. Experimental work suggests reduced wavefront turning as an important mechanism for widening of the excitable gap. The aim of this study was to investigate how sodium channel inhibition by vernakalant affects turning behaviour and propagation patterns during AF.

Methods And Results: Two groups of 8 goats were instrumented with electrodes on the left atrium, and AF was maintained by burst pacing for 3 or 22 weeks. Measurements were performed at baseline and two dosages of vernakalant. Unipolar electrograms were mapped (249 electrodes/array) on the left and right atrium in an open-chest experiment. Local activation times and conduction vectors, flow lines, the number of fibrillation waves, and local re-entries were determined. At baseline, fibrillation patterns contained numerous individual fibrillation waves conducting in random directions. Vernakalant induced conduction slowing and cycle length prolongation and terminated AF in 13/15 goats. Local re-entries were strongly reduced. Local conduction vectors showed increased preferential directions and less beat-to-beat variability. Breakthroughs and waves were significantly reduced in number. Flow line curvature reduced and waves conducted more homogenously in one direction. Overall, complex propagation patterns were strongly reduced. No substantial differences in drug effects between right and left atria or between goats with different AF durations were observed.

Conclusions: Destabilization of AF by vernakalant is associated with a lowering of fibrillation frequency and inhibition of complex propagation patterns, wave turning, local re-entries, and breakthroughs.
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http://dx.doi.org/10.1093/europace/euab026DOI Listing
February 2021

The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats.

Front Pharmacol 2020 27;11:608410. Epub 2021 Jan 27.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands.

The acetylcholine-activated inward rectifier potassium current (I) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective I inhibitor XAF-1407, the study investigates the effect of I inhibition in goats with pacing-induced, short-term AF. Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407. XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (<10%). No ventricular proarrhythmic events were observed. XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that I represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.
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http://dx.doi.org/10.3389/fphar.2020.608410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873360PMC
January 2021

Second heart sound splitting as an indicator of interventricular mechanical dyssynchrony using a novel splitting detection algorithm.

Physiol Rep 2021 Jan;9(1):e14687

Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM, Maastricht, the Netherlands.

Second heart sound (S2) splitting results from nonsimultaneous closures between aortic (A2) and pulmonic valves (P2) and may be used to detect timing differences (dyssynchrony) in relaxation between right (RV) and left ventricle (LV). However, overlap of A2 and P2 and the change in heart sound morphologies have complicated detection of the S2 splitting interval. This study introduces a novel S-transform amplitude ridge tracking (START) algorithm for estimating S2 splitting interval and investigates the relationship between S2 splitting and interventricular relaxation dyssynchrony (IRD). First, the START algorithm was validated in a simulated model of heart sound. It showed small errors (<5 ms) in estimating splitting intervals from 10 to 70 ms, with A2/P2 amplitude ratios from 0.2 to 5, and signal-to-noise ratios from 10 to 30 dB. Subsequently, the START algorithm was evaluated in a porcine model employing a wide range of paced RV-LV delays. IRD was quantified by the time difference between invasively measured LV and RV pressure downslopes. Between LV pre-excitation to RV pre-excitation, mean S2 splitting interval decreased from 47 ms to 23 ms (p < .001), accompanied by a decrease in mean IRD from 8 ms to -18 ms (p < .001). S2 splitting interval was significantly correlated with IRD in each experiment (p < .001). In conclusion, the START algorithm can accurately assess S2 splitting and may serve as a useful tool to assess interventricular dyssynchrony.
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http://dx.doi.org/10.14814/phy2.14687DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785055PMC
January 2021

Stationary Atrial Fibrillation Properties in the Goat Do Not Entail Stable or Recurrent Conduction Patterns.

Front Physiol 2018 27;9:947. Epub 2018 Jul 27.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Netherlands.

Electro-anatomical mapping of the atria is used to identify the substrate of atrial fibrillation (AF). Targeting this substrate by ablation in addition to pulmonary vein ablation did not consistently improve outcome in clinical trials. Generally, the assessment of the substrate is based on short recordings (≤10 s, often even shorter). Thus, targeting the AF substrate assumes spatiotemporal stationarity but little is known about the variability of electrophysiological properties of AF over time. Atrial fibrillation (AF) was maintained for 3-4 weeks after pericardial electrode implantation in 12 goats. Within a single AF episode 10 consecutive minutes were mapped on the left atrial free wall using a 249-electrode array (2.25 mm inter-electrode spacing). AF cycle length, fractionation index (FI), lateral dissociation, conduction velocity, breakthroughs, and preferentiality of conduction (Pref) were assessed per electrode and AF property maps were constructed. The Pearson correlation coefficient (PCC) between the 10 AF-property maps was calculated to quantify the degree spatiotemporal stationarity of AF properties. Furthermore, the number of waves and presence of re-entrant circuits were analyzed in the first 60-s file. Comparing conduction patterns over time identified recurrent patterns of AF with the use of recurrence plots. The averages of AF property maps were highly stable throughout the ten 60-s-recordings. Spatiotemporal stationarity was high for all 6 property maps, PCC ranged from 0.66 ± 0.11 for Pref to 0.98 ± 0.01 for FI. High stationarity was lost when AF was interrupted for about 1 h. However, the time delay between the recorded files within one episode did not affect PCC. Yet, multiple waves (7.7 ± 2.3) were present simultaneously within the recording area and during 9.2 ± 11% of the analyzed period a re-entrant circuit was observed. Recurrent patterns occurred rarely and were observed in only 3 out of 12 goats. During non-self-terminating AF in the goat, AF properties were stationary. Since this could not be attributed to stable recurrent conduction patterns during AF, it is suggested that AF properties are determined by anatomical and structural properties of the atria even when the conduction patterns are very variable.
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http://dx.doi.org/10.3389/fphys.2018.00947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072874PMC
July 2018

Local microRNA-133a downregulation is associated with hypertrophy in the dyssynchronous heart.

ESC Heart Fail 2017 Aug 3;4(3):241-251. Epub 2017 Apr 3.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands.

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.
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http://dx.doi.org/10.1002/ehf2.12154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5542733PMC
August 2017

The inward rectifier current inhibitor PA-6 terminates atrial fibrillation and does not cause ventricular arrhythmias in goat and dog models.

Br J Pharmacol 2017 08 28;174(15):2576-2590. Epub 2017 Jun 28.

Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Background And Purpose: The density of the inward rectifier current (I ) 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 I 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 ·10 min ) 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 I , but not I , 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.
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http://dx.doi.org/10.1111/bph.13869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513871PMC
August 2017

Prediction of optimal cardiac resynchronization by vectors extracted from electrograms in dyssynchronous canine hearts.

J Cardiovasc Electrophysiol 2017 Aug 27;28(8):944-951. Epub 2017 Jun 27.

Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands.

Introduction: Proper optimization of atrioventricular (AV) and interventricular (VV) intervals can improve the response to cardiac resynchronization therapy (CRT). It has been demonstrated that the area of the QRS complex (QRSarea) extracted from the vectorcardiogram can be used as a predictor of optimal CRT-device settings. We explored the possibility of extracting vectors from the electrograms (EGMs) obtained from pacing electrodes and of using these EGM-based vectors (EGMVs) to individually optimize acute hemodynamic CRT response.

Methods And Results: Biventricular pacing was performed in 13 dogs with left bundle branch block (LBBB) of which five also had myocardial infarction (MI), using 100 randomized AV- and VV-settings. Settings providing an acute increase in LV dP/dt ≥ 90% of the highest achieved value were defined as optimal. The prediction capability of QRSarea derived from the EGMV (EGMV-QRSarea) was compared with that of QRS duration. EGMV-QRSarea strongly correlated to the change in LV dP/dt (R = -0.73 ± 0.19 [LBBB] and -0.66 ± 0.14 [LBBB + MI]), while QRS duration was more poorly related to LV dP/dt changes (R = -0.33 ± 0.25 [LBBB] and -0.47 ± 0.39 [LBBB + MI]). This resulted in a better prediction of optimal CRT-device settings by EGMV-QRSarea than by QRS duration (LBBB: AUC = 0.89 [0.86-0.93] vs. 0.76 [0.69-0.83], P < 0.01; LBBB + MI: AUC = 0.91 [0.84-0.99] vs. 0.82 [0.59-1.00], P = 0.20, respectively).

Conclusion: In canine hearts with chronic LBBB with or without MI, the EGMV-QRSarea predicts acute hemodynamic CRT response and identifies optimal AV and VV settings accurately. These data support the potency of EGM-based vectors as a noninvasive, easy and patient-tailored tool to optimize CRT-device settings.
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http://dx.doi.org/10.1111/jce.13241DOI Listing
August 2017

Vernakalant does not alter early repolarization or contractility in normal and electrically remodelled atria.

Europace 2018 01;20(1):140-148

Department of Physiology, Faculty of Medicine, Maastricht University, Universiteitssingel 50, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.

Aims: Besides the inhibition of the sodium inward current, vernakalant also inhibits the ultra rapid rectifier (IKur) and transient outward current (Ito). Inhibition of these currents increases contractility in canine atrial myocytes and goat atria. We investigated the effect of vernakalant on early repolarization and contractility in normal and electrically remodelled atria.

Methods And Results: Goats were implanted a pressure catheter, piezoelectric crystals, and electrodes to obtain atrial contractility and effective refractory period (ERP). The active component in pressure distance loops was used to compute the atrial work index (AWI). Experiments were performed in normal and electrically remodelled atria at clinically relevant plasma levels of vernakalant. As a positive control, the Ito/IKur blocker AVE0118 was investigated. Monophasic action potentials were recorded in anaesthetized goats and in explanted hearts to determine changes in action potential morphology. Vernakalant did not affect atrial work loops during sinus rhythm. Likewise vernakalant did not increase atrial fractional shortening or AWI during pacing with fixed heart rate and AV-delay. In contrast, AVE0118 did increase AWI, with a positive force frequency relation. Both in normal and remodelled atria, vernakalant strongly increased ERP but did not prolong early repolarization.

Conclusion: In goat atria, vernakalant does not have an atrial positive inotropic effect and does not affect early repolarization. At high rates vernakalant may even have a negative inotropic effect.
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http://dx.doi.org/10.1093/europace/eux025DOI Listing
January 2018

A Possible Role for Pacing the Left Ventricular Septum in Cardiac Resynchronization Therapy.

JACC Clin Electrophysiol 2016 Aug 6;2(4):413-422. Epub 2016 Apr 6.

Departments of Physiology and Cardiology, Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands. Electronic address:

Objectives: The purpose of this study was to investigate whether stimulation at the left ventricular (LV) septum (LVs), alone or in combination with another site, could be an alternative way to apply cardiac resynchronization therapy (CRT) that avoids the coronary sinus and phrenic nerve stimulation and may create more physiological sequence of activation.

Background: In CRT, biventricular pacing is commonly performed from the right ventricle (RV) and the epicardium of the LV lateral wall (LVlat). In the left bundle branch block (LBBB), half of the electrical delay occurs due to impulse conduction across the septum.

Methods: Experiments were performed in 13 dogs with LBBB, 7 of them with chronic myocardial infarction (LBBB + MI). Pacing leads were positioned in the right atrium, RV, LVs, and at the LVlat epicardium. LV pump function was measured using conductance catheter and synchrony of electrical activation of the ventricles using epicardial mapping and from surface electrocardiogram. In 12 CRT patients, LV pump function was measured during temporary RV + LVs pacing and compared to RV + LVlat and RV + LVlat endo pacing.

Results: In the animals, electrical and hemodynamic benefits of LVs and RV + LVs pacing were comparable to those during conventional biventricular pacing and were comparable in LBBB and LBBB + MI hearts. Dispersion of repolarization was reduced by LVs stimulation, but not by LVlat pacing. In patients, hemodynamic benefits of RV + LVs, RV + LVlat and RV + LVlat endo pacing were similar.

Conclusions: The use of the LVs as LV pacing site in CRT improves synchronization and acute hemodynamics comparably to conventional biventricular pacing in dyssynchronous canines and in patients. In addition, LVs stimulation may reduce dispersion of repolarization compared to epicardial pacing.
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http://dx.doi.org/10.1016/j.jacep.2016.01.010DOI Listing
August 2016

Hypercoagulability causes atrial fibrosis and promotes atrial fibrillation.

Eur Heart J 2017 01 12;38(1):38-50. Epub 2016 Apr 12.

Department of Physiology, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands

Aims: Atrial fibrillation (AF) produces a hypercoagulable state. Stimulation of protease-activated receptors by coagulation factors provokes pro-fibrotic, pro-hypertrophic, and pro-inflammatory responses in a variety of tissues. We studied the effects of thrombin on atrial fibroblasts and tested the hypothesis that hypercoagulability contributes to the development of a substrate for AF.

Methods And Results: In isolated rat atrial fibroblasts, thrombin enhanced the phosphorylation of the pro-fibrotic signalling molecules Akt and Erk and increased the expression of transforming growth factor β1 (2.7-fold) and the pro-inflammatory factor monocyte chemoattractant protein-1 (6.1-fold). Thrombin also increased the incorporation of H-proline, suggesting enhanced collagen synthesis by fibroblasts (2.5-fold). All effects could be attenuated by the thrombin inhibitor dabigatran. In transgenic mice with a pro-coagulant phenotype (TM), the inducibility of AF episodes lasting >1 s was higher (7 out of 12 vs. 1 out of 10 in wild type) and duration of AF episodes was longer compared with wild type mice (maximum episode duration 42.8 ± 68.4 vs. 0.23 ± 0.39 s). In six goats with persistent AF treated with nadroparin, targeting Factor Xa-mediated thrombin generation, the complexity of the AF substrate was less pronounced than in control animals (LA maximal activation time differences 23.3 ± 3.1 ms in control vs. 15.7 ± 2.1 ms in nadroparin, P < 0.05). In the treated animals, AF-induced α-smooth muscle actin expression was lower and endomysial fibrosis was less pronounced.

Conclusion: 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.
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http://dx.doi.org/10.1093/eurheartj/ehw119DOI Listing
January 2017

Antiarrhythmic effect of vernakalant in electrically remodeled goat atria is caused by slowing of conduction and prolongation of postrepolarization refractoriness.

Heart Rhythm 2016 Apr 8;13(4):964-72. Epub 2015 Dec 8.

Department of Physiology, Faculty of Medicine, Maastricht University, Maastricht, The Netherlands. Electronic address:

Background: Vernakalant inhibits several potassium currents and causes a rate- and voltage-dependent inhibition of the sodium current.

Objective: The aim of this study was to evaluate the antiarrhythmic mechanism of vernakalant in normal and electrically remodeled atria.

Methods: Fourteen goats were instrumented with electrodes on both atria. Drug effects on refractory period (ERP), conduction velocity (CV), and atrial fibrillation cycle length (AFCL) were determined in normal goats (control) and after 2 (2dAF) or 11 (11dAF) days of pacing-induced atrial fibrillation (AF) in awake goats. To evaluate the contribution of changes in conduction and ERP, the same experiments were performed with flecainide and AVE0118. In a subset of goats, monophasic action potentials were recorded during anesthesia.

Results: Vernakalant dose-dependently prolonged ERP and decreased CV in CTL experiments. Both effects were maintained after 2dAF and 11dAF. After 11dAF, conduction slowed down by 8.2 ± 1.5 cm/s and AFCL increased by 55 ± 3 ms, leading to AF termination in 5 out of 9 goats. Monophasic action potential measurements revealed that ERP prolongation was due to enhanced postrepolarization refractoriness. During pacing, vernakalant had comparable effects on CV as flecainide, while effect on ERP was comparable to AVE0118. During AF, all compounds had comparable effects on median AFCL and ERP despite differences in their effects on CV during pacing.

Conclusion: The antiarrhythmic effect of vernakalant in the goat, at clinically relevant plasma concentrations, is based on both conduction slowing and ERP prolongation due to postrepolarization refractoriness. These electrophysiological effects were not affected by long-term electrical remodeling of the atria.
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http://dx.doi.org/10.1016/j.hrthm.2015.12.009DOI Listing
April 2016

Dynamic regulation of atrial coronary blood flow in healthy adult pigs.

Heart Rhythm 2015 May 13;12(5):991-1000. Epub 2015 Jan 13.

Department of Physiology, Faculty of Medicine, Maastricht University, The Netherlands. Electronic address:

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.
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http://dx.doi.org/10.1016/j.hrthm.2015.01.016DOI Listing
May 2015

Electrophysiological and haemodynamic effects of vernakalant and flecainide in dyssynchronous canine hearts.

Europace 2014 Aug 30;16(8):1249-56. Epub 2014 Jan 30.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, Limburg, The Netherlands.

Aims: About one-third of patients with mild dyssynchronous heart failure suffer from atrial fibrillation (AF). Drugs that convert AF to sinus rhythm may further slowdown ventricular conduction. We aimed to investigate the electrophysiological and haemodynamic effects of vernakalant and flecainide in a canine model of chronic left bundle branch block (LBBB).

Methods And Results: Left bundle branch block was induced in 12 canines. Four months later, vernakalant or flecainide was administered using a regime, designed to achieve clinically used plasma concentrations of the drugs, n = 6 for each drug. Epicardial electrical contact mapping showed that both drugs uniformly prolonged myocardial conduction time. Vernakalant increased QRS width significantly less than flecainide (17 ± 13 vs. 34 ± 15%, respectively). Nevertheless, both drugs equally decreased LVdP/dtmax by ∼15%, LVdP/dtmin by ∼10%, and left ventricular systolic blood pressure by ∼5% (P = n.s. between drugs).

Conclusions: Vernakalant prolongs ventricular conduction less than flecainide, but both drugs had a similar, moderate negative effect on ventricular contractility and relaxation. Part of these reductions seems to be related to the increase in dyssynchrony.
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http://dx.doi.org/10.1093/europace/eut429DOI Listing
August 2014

Atrial supply-demand balance in healthy adult pigs: coronary blood flow, oxygen extraction, and lactate production during acute atrial fibrillation.

Cardiovasc Res 2014 Jan 18;101(1):9-19. Epub 2013 Oct 18.

Department of Physiology, Faculty of Medicine, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.

Aims: Little is known about how atrial oxygen supply responds to increased demand, and under which conditions it falls short (supply-demand mismatch). Here, we have investigated the vasodilator response, oxygen extraction, and lactate production of the left atrium (LA) and left ventricle (LV) in response to atrial pacing and atrial fibrillation (AF).

Methods And Results: Series A (n = 9 Dutch landrace pigs) was instrumented to measure LA and LV vascular conductance in branches of the circumflex artery. Coronary conductance reserve (CCR) was calculated as the ratio between conductance during adenosine infusion and baseline. Series B (n = 7) was instrumented with sampling catheters in LA and LV veins for determination of blood gases and lactate levels. LA CCR (1.76 ± 0.14) was significantly lower than LV CCR (3.16 ± 0.27, P = 0.002). However, basal oxygen extraction was lower in LA (27 ± 3%) than that in the LV (58 ± 6%, P = 0.0006), indicating a larger extraction reserve in the LA than that in the LV (4.68 ± 0.84 vs. 1.88 ± 0.26, P = 0.01). Atrial pacing caused an increase in LA conductance (Series A) and oxygen extraction (Series B). AF increased LA vascular conductance to 177 ± 14% at 1 min, 168 ± 14 at 5 min, and 164 ± 31% at 10 min of AF (P < 0.05 vs. baseline). Atrial oxygen extraction also increased from 26 ± 3% at baseline to 63 ± 5% (P < 0.01) at 5 min and 60 ± 11% (P < 0.01) at 10 min of AF. Arterio-venous lactate difference increased significantly (P = 0.02) during AF.

Conclusions: In healthy pigs, the LA has a lower CCR, but a higher extraction reserve compared with the LV. Although both reserves were recruited during AF, atrial lactate production increased significantly.
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http://dx.doi.org/10.1093/cvr/cvt239DOI Listing
January 2014

Acute electrical and hemodynamic effects of multisite left ventricular pacing for cardiac resynchronization therapy in the dyssynchronous canine heart.

Heart Rhythm 2014 Jan 9;11(1):119-25. Epub 2013 Oct 9.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.

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/dtmax ).

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 < .001 for overall comparison) and -14.2% ± 19.5% (P < .02 for overall comparison) in the septuple-LV pacing configuration, respectively. Single-LV pacing provided a mean increase of 10.7% ± 7.7% in LVdP/dtmax. LVdP/dtmax incrementally increased by the addition of pacing electrodes to 16.4% ± 8.7% (P < .001 for overall comparison). High response to single-LV pacing could not be improved further during multi-LV pacing.

Conclusions: Compared with single-LV pacing, multi-LV pacing can considerably reduce both LVTAT and DRep in dogs with LBBB, but the improvement in contractility is limited to conditions where single-LV pacing provides suboptimal improvement. Further studies are warranted to determine whether these acute effects translate in antiarrhythmic properties and better long-term outcomes.
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http://dx.doi.org/10.1016/j.hrthm.2013.10.018DOI Listing
January 2014

Electrophysiological and hemodynamic effects of vernakalant and flecainide during cardiac resynchronization in dyssynchronous canine hearts.

J Cardiovasc Pharmacol 2014 Jan;63(1):25-32

Departments of *Physiology; and †Cardiothoracic Surgery, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands; and ‡Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland.

Introduction: Patients with heart failure and left bundle branch block (LBBB) are frequently treated with biventricular pacing (BiVP). Approximately one-third of them suffer from atrial fibrillation. Pharmacological conversion of atrial fibrillation is performed with drugs that slow ventricular conduction, but the effects of these drugs on the benefit of BiVP are poorly understood.

Methods: Experiments were performed in dogs with chronic LBBB, investigating the effects of Vernakalant and Flecainide (n = 6 each) on hemodynamics and electrophysiology during epicardial (EPI) and endocardial BiVP. The degree of dyssynchrony and conduction slowing was quantified using QRS width and EPI electrical mapping.

Results: Compared with LBBB, EPI and endocardial BiVP reduced QRS duration by 7% ± 9% (P < 0.05 compared with LBBB) and 20% ± 13% (P < 0.05 compared with LBBB, P < 0.05 between modes), respectively. During BiVP, the administration of Vernakalant and Flecainide increased QRS duration by 20% ± 14% (P < 0.05 compared with predrug BiVP) and 34% ± 10% (P < 0.05 compared with predrug BiVP, P < 0.05 between drugs). left ventricular (LV) dP/dtmax decreased by 16% ± 8% (P < 0.05 compared with predrug BiVP) during Vernakalant and by 14% ± 15% (P < 0.05 compared with predrug BiVP) during Flecainide. The drugs did not affect the relative changes in QRS width and LV dP/dtmax induced by BiVP.

Conclusions: Vernakalant and Flecainide decrease contractility, slow myocardial conduction velocity, and increase activation time. The electrical and hemodynamic benefits of BiVP are not altered by the drugs.
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http://dx.doi.org/10.1097/FJC.0000000000000020DOI Listing
January 2014

Interplay of electrical wavefronts as determinant of the response to cardiac resynchronization therapy in dyssynchronous canine hearts.

Circ Arrhythm Electrophysiol 2013 Oct 18;6(5):924-31. Epub 2013 Sep 18.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.

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/dtmax (maximal rate of rise of left ventricular pressure) of ≥90% of the maximum LVdP/dtmax value were defined as optimal (CRTopt). Filling was assessed by changes in LV end-diastolic volume (EDV; conductance catheter technique). In all hearts, CRTopt was observed during multiple settings, providing an average LVdP/dtmax increase of ≈15%. In AV-block hearts, CRTopt exclusively depended on interventricular-interval and not on AV-interval. In left bundle-branch block hearts, CRTopt occurred at A-LV intervals that allowed fusion of LV-pacing-derived activation with right bundle-derived activation. In all animals, CRTopt 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.
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http://dx.doi.org/10.1161/CIRCEP.113.000753DOI Listing
October 2013

Transseptal conduction as an important determinant for cardiac resynchronization therapy, as revealed by extensive electrical mapping in the dyssynchronous canine heart.

Circ Arrhythm Electrophysiol 2013 Aug 19;6(4):682-9. Epub 2013 Jul 19.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands.

Background: Simple conceptual ideas about cardiac resynchronization therapy assume that biventricular (BiV) pacing results in collision of right and left ventricular (LV) pacing-derived wavefronts. However, this concept is contradicted by the minor reduction in QRS duration usually observed. We investigated the electric mechanisms of cardiac resynchronization therapy by performing detailed electric mapping during extensive pacing protocols in dyssynchronous canine hearts.

Methods And Results: Studies were performed in anesthetized dogs with acute left bundle-branch block (LBBB, n=10) and chronic LBBB with tachypacing-induced heart failure (LBBB+HF, n=6). Activation times (AT) were measured using LV endocardial contact and noncontact mapping and epicardial contact mapping. BiV pacing reduced QRS duration by 21±10% in LBBB but only by 5±12% in LBBB+HF hearts. Transseptal impulse conduction was significantly slower in LBBB+HF than in LBBB hearts (67±9 versus 44±16 ms, respectively), and in both groups significantly slower than transmural LV conduction (≈30 ms). In both groups QRS duration and vector and the epicardial AT vector amplitude and angle were significantly different between LV and BiV pacing, whereas the endocardial AT vector was similar. During variation of atrioventricular delay while LV pacing, and ventriculo-ventricular delay while BiV pacing, the optimal hemodynamic effect was achieved when epicardial AT and QRS vectors were minimal and endocardial AT vector indicated LV preexcitation.

Conclusions: Due to slow transseptal conduction, the LV electric activation sequence is similar in LV and BiV pacing, especially in failing hearts. Optimal hemodynamic cardiac resynchronization therapy response coincides with minimal epicardial asynchrony and QRS vector and LV preexcitation.
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http://dx.doi.org/10.1161/CIRCEP.111.000028DOI Listing
August 2013

Loss of continuity in the thin epicardial layer because of endomysial fibrosis increases the complexity of atrial fibrillatory conduction.

Circ Arrhythm Electrophysiol 2013 Feb 6;6(1):202-11. Epub 2013 Feb 6.

Department of Physiology, Maastricht University, Maastricht, the Netherlands.

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.
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http://dx.doi.org/10.1161/CIRCEP.112.975144DOI Listing
February 2013

Vectorcardiography as a tool for easy optimization of cardiac resynchronization therapy in canine left bundle branch block hearts.

Circ Arrhythm Electrophysiol 2012 Jun 24;5(3):544-52. Epub 2012 Apr 24.

Department of Physiology, Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.

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 (VAQRS), 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 VAQRS 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/dtmax. VAQRS and MIVD were highly correlated (r=0.94). The VAQRS 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 8 ms). Increase in LV dP/dtmax at the VCG predicted AV delay was only slightly lower than the highest observed LV dP/dtmax (-2.7%; 95% CI, -3.6 to -1.8%). Inability to reach the halfway value of VAQRS during simultaneous biventricular pacing (53% of cases) was associated with suboptimal hemodynamic response, which could be corrected by sequential pacing.

Conclusions: The VAQRS 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.
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http://dx.doi.org/10.1161/CIRCEP.111.966358DOI Listing
June 2012

Endocardial left ventricular pacing improves cardiac resynchronization therapy in chronic asynchronous infarction and heart failure models.

Circ Arrhythm Electrophysiol 2012 Feb 7;5(1):191-200. Epub 2011 Nov 7.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, Limburg, The Netherlands.

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.
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http://dx.doi.org/10.1161/CIRCEP.111.965814DOI Listing
February 2012

Fibrillatory conduction in the atrial free walls of goats in persistent and permanent atrial fibrillation.

Circ Arrhythm Electrophysiol 2010 Dec 11;3(6):590-9. Epub 2010 Oct 11.

Department of Physiology, Faculty of Medicine, Maastricht University, Maastrict, The Netherlands.

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.
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http://dx.doi.org/10.1161/CIRCEP.109.931634DOI Listing
December 2010

Myocardial infarction does not preclude electrical and hemodynamic benefits of cardiac resynchronization therapy in dyssynchronous canine hearts.

Circ Arrhythm Electrophysiol 2010 Aug 21;3(4):361-8. Epub 2010 May 21.

Departments of Physiology and Cardiothoracic Surgery, Cardiovascular Research Institute Maastricht, Maastricht, The Netherlands.

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 > or =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.
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http://dx.doi.org/10.1161/CIRCEP.109.931865DOI Listing
August 2010

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

Circ Arrhythm Electrophysiol 2009 Oct 10;2(5):580-7. Epub 2009 Aug 10.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht, 6200 MD Maastricht, The Netherlands.

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.
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http://dx.doi.org/10.1161/CIRCEP.108.846022DOI Listing
October 2009

Left ventricular septal and left ventricular apical pacing chronically maintain cardiac contractile coordination, pump function and efficiency.

Circ Arrhythm Electrophysiol 2009 Oct 25;2(5):571-9. Epub 2009 Aug 25.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, 6200 MD Maastricht, The Netherlands.

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.
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http://dx.doi.org/10.1161/CIRCEP.109.882910DOI Listing
October 2009

Cardiac resynchronization therapy cures dyssynchronopathy in canine left bundle-branch block hearts.

Eur Heart J 2007 Sep 4;28(17):2148-55. Epub 2007 Jul 4.

Department of Physiology, Cardiovascular Research Institute Maastricht, PO Box 616, 6200 MD, Maastricht, the Netherlands.

Aims: We investigated to what extent biventricular pacing (BVP) can normalize LV function and remodeling, induced by isolated left bundle branch block (LBBB).

Methods And Results: In 16 dogs LBBB was induced. Eight animals were followed for 16 weeks and in 8 animals BVP was started after 8 weeks. LV pressure, LV geometry (2Dechocardiography), systolic circumferential shortening (CSsys, MRI tagging) and myocardial blood flow (MBF, microspheres) was measured. * and # indicate P < 0.05 compared to pre-LBBB and 8 weeks of LBBB, respectively. Data is presented relative to pre-LBBB values (mean +/- SEM). BVP increased LV dP/dt|max from 78 +/- 5%* to 86 +/- 5%*# (immediately) and 89 +/- 6%# (after 8 weeks) and normalized regional differences in CSsys and MBF. After 8 weeks of BVP, LV end-diastolic volume (EDV) was reduced from 123 +/- 3%* to 109 +/- 6%# and LV lateral wall mass was reduced from 128 +/- 5%* to 113 +/- 3%*#. The acute increase in LV dP/dt|max upon BVP correlated with LV EDV and LV wall mass after 8 weeks of BVP.

Conclusion: In canine hearts with long-term isolated LBBB, BVP largely reverses global and regional functional and structural abnormalities induced by LBBB.
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http://dx.doi.org/10.1093/eurheartj/ehm207DOI Listing
September 2007