ORCID Profile
0000-0001-5196-5425
Current Organisation
Maastricht University
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Publisher: Oxford University Press (OUP)
Date: 07-10-2010
DOI: 10.1093/CVR/CVQ336
Abstract: 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. 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). 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.
Publisher: Elsevier BV
Date: 07-2015
DOI: 10.1016/J.HRTHM.2015.03.017
Abstract: The pathophysiological relevance of complex fractionated atrial electrograms (CFAE) in atrial fibrillation (AF) remains poorly understood. The aim of this study was to comprehensively investigate how bipolar CFAE correlates with unipolar electrogram fractionation and the underlying electrophysiological substrate of AF. Ten-second unipolar AF electrograms were recorded using a high-density electrode from the left atrium of 20 patients with AF (10 with persistent AF and 10 with paroxysmal AF) undergoing cardiac surgery. Semiautomated bipolar CFAE algorithms: complex fractionated electrogram-mean, interval confidence interval, continuous electrical activity, average complex interval, and shortest complex interval were evaluated against AF substrate complexity measures following fibrillation wave reconstruction derived from local unipolar activation time. The effect of interelectrode spacing and electrode orientation on bipolar CFAE was also examined. All 5 semiautomated bipolar CFAE algorithms showed poor correlation with each other and AF substrate complexity measures (conduction velocity, number of waves or breakthroughs per AF cycle, and electrical dissociation). Bipolar CFAE also correlated poorly with fractionation index derived from unipolar electrograms. Increased interelectrode spacing resulted in an increase in bipolar CFAE detected except for the interval confidence interval algorithm. CFAE appears unaffected by bipolar electrode orientation (vertical vs horizontal). By contrast, unipolar fractionation index correlated well with AF substrate complexity measures and can be regarded as a marker for conduction block. The lack of pathophysiological relevance of bipolar CFAE analysis may in part contribute to the ergent and limited success rates of catheter ablation strategies targeting CFAE.
Publisher: Oxford University Press (OUP)
Date: 25-04-2017
Abstract: 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. 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. 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.
Publisher: Wiley
Date: 03-05-2012
DOI: 10.1111/J.1540-8167.2012.02335.X
Abstract: Stability of CFAE. The efficacy of complex fractionated atrial electrograms (CFAE) ablation as additional substrate modification in atrial fibrillation (AF) patients has been shown to be highly variable. Recently, the validity of sequential CFAE mapping has been challenged by concerns regarding temporal stability of CFAE. Existing studies on CFAE stability are small with very different CFAE definitions. Here, we undertook a systematic literature review to address these controversial findings. A systematic search of the scientific literature was performed through to September 1, 2011. From a total of 162 manuscripts, 7 were identified to contain assessment of the temporal stability of CFAE in human AF. These studies included a total of 96 (80 persistent/16 paroxysmal AF) patients (79% male, mean 58 years old). Varying CFAE mapping techniques or definitions were utilized. CFAE stability averaged 81% between 2 high-density sequential fractionation maps over an average time interval of 19 minutes. However, CFAE stability only averaged at 75% from shorter term continuous recordings (mean 15 comparisons within 75 seconds). Although the variability in CFAE cycle length was small (12-15 ms), coefficients of variation in continuous electrical activity were high (up to 300%). The overall spatial distribution of CFAE was found to be stable. Nevertheless, sequential mapping may not capture all CFAE sites given their dynamic characteristics. CFAE are temporally variable in keeping with the erse mechanisms underlying their existence. The dynamic nature of CFAE will continue to pose a challenge for electrophysiologists in search of critical sites requiring ablation to combat AF. (J Cardiovasc Electrophysiol, Vol. 23, pp. 980-987, September 2012).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
DOI: 10.1161/CIRCEP.113.000342
Abstract: 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. 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 .01 versus acute AF) and highest (14.2±3.8%) after 6 months AF ( P .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. 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.
Publisher: Oxford University Press (OUP)
Date: 26-02-2021
Abstract: 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. 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 in idual 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. 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.
Publisher: Oxford University Press (OUP)
Date: 31-03-2016
DOI: 10.1093/CVR/CVW071
Abstract: Type 2 diabetes (T2D) is an independent risk factor for atrial fibrillation (AF) and stroke. The serine protease cathepsin A (CatA) is up-regulated in diabetes and plays an important role in the degradation of extracellular peptides. This study sought to delineate the role of CatA for the development of atrial remodelling under diabetic conditions. Zucker Diabetic Fatty rats (ZDF) were treated with vehicle (n = 20) or CatA-inhibitor (SAR 50 mg/kg n = 20), and compared with age-matched non-diabetic littermates (Ctr, n = 20). Left-atrial (LA) emptying function [magnetic resonance imaging (MRI)] and atrial electrophysiological parameters were measured before sacrifice for histological and biochemical analysis. The impact of enhanced cardiac CatA expression on atrial remodelling was determined using CatA-transgenic mice. At the age of 9.5 months, atrial tissues of ZDF rats showed increased CatA gene expression and CatA-activity, along with increased AF-susceptibility and impaired LA-emptying function. CatA-inhibition reduced CatA-activity in ZDF comparable to Ctr values and decreased LA-fibrosis formation and connexin 43 lateralization. This was associated with shorter median duration of LA-tachyarrhythmia (12.0 ± 1.7 vs. 1.2 ± 0.47 s, P < 0.01) induced by burst pacing and diminished regions of slow conduction. Cardiac MRI revealed better LA-emptying function parameters (active per cent emptying: 29 ± 1 vs. 23 ± 2%, P < 0.01) after CatA-inhibition. CatA-inhibition reduced LA bradykinin-degrading activity in ZDF. Transgenic mice overexpressing CatA demonstrated enhanced atrial fibrosis formation and increased AF-susceptibility. T2D leads to arrhythmogenic atrial remodelling in ZDF rats. CatA-inhibition reduces LA bradykinin-degrading activity in ZDF and suppresses the development of atrial structural changes and AF-promotion, implicating CatA as an important mediator for AF-substrate in T2D.
Publisher: IEEE
Date: 08-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2015
DOI: 10.1161/CIRCEP.114.002453
Abstract: Atrial fibrillation (AF) leads to structural and neural remodeling in the atrium, which enhances AF complexity and perpetuation. Renal denervation (RDN) can reduce renal and whole-body sympathetic activity. Aim of this study was to determine the effect of sympathetic nervous system modulation by RDN on atrial arrhythmogenesis. Eighteen goats were instrumented with an atrial endocardial pacemaker lead and a burst pacemaker. Percutaneous catheter-based RDN was performed in 8 goats (RDN-AF). Ten goats undergoing a sham procedure served as control (SHAM-AF). AF was induced and maintained by burst pacing for 6 weeks. High-resolution mapping was used to record epicardial conduction patterns of the right and left atrium. RDN reduced tyrosine hydroxylase-positive sympathetic nerve staining and resulted in lower transcardiac norepinephrine levels. This was associated with reduced expression of nerve growth factor-β, indicating less atrial nerve sprouting. Atrial endomysial fibrosis content was lower and myocyte diameter was smaller in RDN-AF. Median conduction velocity was higher (75±9 versus 65±10 cm/s, P =0.02), and AF cycle length was shorter in RDN-AF compared with SHAM-AF. Left atrial AF complexity (4.8±0.8 fibrillation waves/AF cycle length versus 8.5±0.8 waves/AF cycle length, P =0.001) and incidence of breakthroughs (2.0±0.3 versus 4.3±0.5 waves/AF cycle length, P =0.059) were lower in RDN-AF compared with SHAM-AF. Blood pressure was normal and not significantly different between the groups. RDN reduces atrial sympathetic nerve sprouting, structural alterations, and AF complexity in goats with persistent AF, independent of changes in blood pressure.
Publisher: Oxford University Press (OUP)
Date: 12-04-2016
Abstract: 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. 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 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.
Publisher: Future Medicine Ltd
Date: 11-2014
DOI: 10.2217/FCA.14.43
Abstract: ABSTRACT Atrial fibrillation is the most common sustained arrhythmia and is associated with significant morbidity and mortality. In addition to mechanisms such as atrial stretch and atrial remodeling, the activity of the autonomic nervous system has also been suggested to contribute to the progression from paroxysmal to persistent atrial fibrillation. Catheter-based renal denervation was introduced as a minimally invasive approach to reduce renal and whole body sympathetic activation with accompanying blood pressure reduction and left-ventricular morphological and functional improvement in drug-resistant hypertension. This review focuses on the potential effects of renal denervation on different arrhythmogenic mechanisms in the atrium and discusses potential anti-remodeling effects in atrial fibrillation patients with hypertension, heart failure and sleep apnea.
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2015
Publisher: Elsevier BV
Date: 08-2014
DOI: 10.1016/J.PBIOMOLBIO.2014.07.007
Abstract: Atrial fibrillation (AF) is an arrhythmia that occurs as a result of numerous pathophysiological processes in the atria. High rate, neurohumoral activation, aging and chronic stretch activate a variety of signaling pathways leading to electrical and structural remodeling. In particular, endomysial fibrosis within the epicardial layer, which also occurs as a result of AF itself, can disrupt electrical connections between muscle bundles. This leads to electrical dissociation not only within the epicardial layer, but also between the epicardial layer and the endocardial bundle network. Although the normal, healthy atrium has a complex 3-dimensional shape, differences in activation time between the epicardial layer and the underlying trabecular network in the atrial free walls are small, and the atrial walls essentially function as a 2-dimensional surface for propagating fibrillation waves. However, progressive structural remodeling leads to increased dissociation of epicardial and endocardial activation patterns. Epi-endocardial dissociation allows fibrillation waves to propagate between epicardium and endocardium, and become visible as 'breakthrough waves' that add to the overall complexity of fibrillatory conduction and thus to AF stability. This process greatly increases the effective surface area available to fibrillation waves and causes the atrial walls to behave as a 3-dimensional substrate. Computer models support that this behavior can increase AF stability. Under these conditions, ectopic activity originating from e.g. the pulmonary veins is likely to trigger longer episodes of AF. Experiments using simultaneous endo-epicardial mapping of AF suggest that disseminated, irregular and non-repetitive ectopic focal discharges might also occur during AF. The increasingly 3-dimensional character of AF as a result of structural remodeling lowers the responsiveness to antiarrhythmic compounds and ablation therapy, thus advocating early rhythm control strategies.
Publisher: Elsevier BV
Date: 04-2016
DOI: 10.1016/J.HRTHM.2015.12.009
Abstract: Vernakalant inhibits several potassium currents and causes a rate- and voltage-dependent inhibition of the sodium current. The aim of this study was to evaluate the antiarrhythmic mechanism of vernakalant in normal and electrically remodeled atria. 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. 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. 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.
Location: United States of America
No related grants have been discovered for Sander Verheule.