Publications by authors named "Sander Verheule"

84 Publications

New-onset perioperative atrial fibrillation in cardiac surgery patients: transient trouble or persistent problem?-Authors' reply.

Europace 2021 Dec 24. Epub 2021 Dec 24.

Department of Cardiothoracic Surgery, Heart and Vascular Centre Maastricht University Medical Centre, Professor Debyelaan 25, 6229 HX Maastricht, The Netherlands.

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http://dx.doi.org/10.1093/europace/euab317DOI Listing
December 2021

Thrombin generation by calibrated automated thrombography in goat plasma: Optimization of an assay.

Res Pract Thromb Haemost 2021 Dec 21;5(8):e12620. Epub 2021 Nov 21.

Department of Biochemistry and Internal Medicine Cardiovascular Research Institute Maastricht Maastricht University Medical Center Maastricht The Netherlands.

The goat model of atrial fibrillation (AF) allows investigation of the effect of AF on coagulation. However, assays for goat plasma are not available from commercial sources. Calibrated automated thrombography (CAT) provides a global view of the coagulation profile by assessing thrombin generation (TG). We describe the customization of the CAT assay in goat platelet-poor plasma (PPP) and in factor Xa (FXa)-inhibitor-anticoagulated PPP. TG was initiated in the presence of phospholipids and either (a) PPP reagent, reagent low, or reagent high; (b) goat brain protein extraction (GBP); or (c) Russell's viper venom-factor X activator (RVV-X). Contact activation was assessed by adding corn trypsin inhibitor. Different concentrations of prothrombin complex concentrate (PCC) were used to determine the sensitivity of both the GBP and RVV-X method. To obtain FXa-inhibitor anticoagulated plasma, rivaroxaban was added to plasma. TG settings with human reagents were not suitable for goat plasma. TG triggered with GBP increased peak height and ETP values. Similarly, the RVV-X method produced comparable TG curves and was more sensitive to PCC titration. Finally, both methods were able to detect the decrease in clotting potential induced by FXa inhibition. This is the first study that reports the customization of the CAT assay for goats. The GBP and RVV-X methods were comparable in triggering TG in goat plasma. The RVV-X method seemed to better discriminate changes in TG curves due to increases in clotting potential as well as to FXa inhibition by rivaroxaban in goat plasma.
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http://dx.doi.org/10.1002/rth2.12620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8606030PMC
December 2021

Electrophysiological Consequences of Cardiac Fibrosis.

Cells 2021 11 18;10(11). Epub 2021 Nov 18.

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

For both the atria and ventricles, fibrosis is generally recognized as one of the key determinants of conduction disturbances. By definition, fibrosis refers to an increased amount of fibrous tissue. However, fibrosis is not a singular entity. Various forms can be distinguished, that differ in distribution: replacement fibrosis, endomysial and perimysial fibrosis, and perivascular, endocardial, and epicardial fibrosis. These different forms typically result from diverging pathophysiological mechanisms and can have different consequences for conduction. The impact of fibrosis on propagation depends on exactly how the patterns of electrical connections between myocytes are altered. We will therefore first consider the normal patterns of electrical connections and their regional diversity as determinants of propagation. Subsequently, we will summarize current knowledge on how different forms of fibrosis lead to a loss of electrical connectivity in order to explain their effects on propagation and mechanisms of arrhythmogenesis, including ectopy, reentry, and alternans. Finally, we will discuss a histological quantification of fibrosis. Because of the different forms of fibrosis and their diverging effects on electrical propagation, the total amount of fibrosis is a poor indicator for the effect on conduction. Ideally, an assessment of cardiac fibrosis should exclude fibrous tissue that does not affect conduction and differentiate between the various types that do; in this article, we highlight practical solutions for histological analysis that meet these requirements.
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http://dx.doi.org/10.3390/cells10113220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8625398PMC
November 2021

Coagulation Factor Xa Induces Proinflammatory Responses in Cardiac Fibroblasts via Activation of Protease-Activated Receptor-1.

Cells 2021 10 30;10(11). Epub 2021 Oct 30.

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

Coagulation factor (F) Xa induces proinflammatory responses through activation of protease-activated receptors (PARs). However, the effect of FXa on cardiac fibroblasts (CFs) and the contribution of PARs in FXa-induced cellular signalling in CF has not been fully characterised. To answer these questions, human and rat CFs were incubated with FXa (or TRAP-14, PAR-1 agonist). Gene expression of pro-fibrotic and proinflammatory markers was determined by qRT-PCR after 4 and 24 h. Gene silencing of (PAR-1) and (PAR-2) was achieved using siRNA. MCP-1 protein levels were measured by ELISA of FXa-conditioned media at 24 h. Cell proliferation was assessed after 24 h of incubation with FXa ± SCH79797 (PAR-1 antagonist). In rat CFs, FXa induced upregulation of (MCP-1; >30-fold at 4 h in atrial and ventricular CF) and (IL-6; ±7-fold at 4 h in ventricular CF). Increased MCP-1 protein levels were detected in FXa-conditioned media at 24 h. In human CF, FXa upregulated the gene expression of (>3-fold) and (>4-fold) at 4 h. Silencing of (PAR-1 gene), but not (PAR-2 gene), downregulated this effect. Selective activation of PAR-1 by TRAP-14 increased and gene expression; this was prevented by (PAR-1 gene) knockdown. Moreover, SCH79797 decreased FXa-induced proliferation after 24 h. In conclusion, our study shows that FXa induces overexpression of proinflammatory genes in human CFs via PAR-1, which was found to be the most abundant PARs isoform in this cell type.
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http://dx.doi.org/10.3390/cells10112958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616524PMC
October 2021

Considerations for the Assessment of Substrates, Genetics and Risk Factors in Patients with Atrial Fibrillation.

Arrhythm Electrophysiol Rev 2021 Oct;10(3):132-139

Department of Physiology, Cardiovascular Research Institute Maastricht, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.

Successful translation of research focussing on atrial arrhythmogenic mechanisms has potential to provide a mechanism-tailored classification and to support personalised treatment approaches in patients with AF. The clinical uptake and clinical implementation of new diagnostic techniques and treatment strategies require translational research approaches on various levels. Diagnostic translation involves the development of clinical diagnostic tools. Additionally, multidisciplinary teams are required for collaborative translation to describe genetic mechanisms, molecular pathways, electrophysiological characteristics and concomitant risk factors. In this article, current approaches for AF substrate characterisation, analysis of genes potentially involved in AF and strategies for AF risk factor assessment are summarised. The authors discuss challenges and obstacles to clinical translation and implementation into clinical practice.
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http://dx.doi.org/10.15420/aer.2020.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576487PMC
October 2021

Increased fibroblast accumulation in the equine heart following persistent atrial fibrillation.

Int J Cardiol Heart Vasc 2021 Aug 20;35:100842. Epub 2021 Jul 20.

Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Agrovej 8, DK-2630 Taastrup, Denmark.

Background: Fibroblasts maintain the extracellular matrix homeostasis and may couple to cardiomyocytes through gap junctions and thereby increase the susceptibility to slow conduction and cardiac arrhythmias, such as atrial fibrillation (AF). In this study, we used an equine model of persistent AF to characterize structural changes and the role of fibroblasts in the development of an arrhythmogenic substrate for AF.

Material And Methods: Eleven horses were subjected to atrial tachypacing until self-sustained AF developed and were kept in AF for six weeks. Horses in sinus rhythm (SR) served as control. In terminal open-chest experiments conduction velocity (CV) was measured. Tissue was harvested and stained from selected sites. Automated image analysis was performed to assess fibrosis, fibroblasts, capillaries and various cardiomyocyte characteristics.

Results: Horses in SR showed a rate-dependent slowing of CV, while in horses with persistent AF this rate-dependency was completely abolished (CV•basic cycle length relation ). Overall and interstitial amounts of fibrosis were unchanged, but an increased fibroblast count was found in left atrial appendage, Bachmann's bundle, intraatrial septum and pulmonary veins ( for all) in horses with persistent AF. The percentage of α-SMA expressing fibroblasts remained the same between the groups.

Conclusion: Persistent AF resulted in fibroblast accumulation in several regions, particularly in the left atrial appendage. The increased number of fibroblasts could be a mediator of altered electrophysiology during AF. Targeting the fibroblast proliferation and differentiation could potentially serve as a novel therapeutic target slowing down the structural remodeling associated with AF.
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http://dx.doi.org/10.1016/j.ijcha.2021.100842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322305PMC
August 2021

Clinical and electrophysiological predictors of device-detected new-onset atrial fibrillation during 3 years after cardiac surgery.

Europace 2021 Dec;23(12):1922-1930

Department of Physiology, Maastricht University, The Netherlands.

Aims: Postoperative atrial fibrillation (POAF) after cardiac surgery is an independent predictor of stroke and mortality late after discharge. We aimed to determine the burden and predictors of early (up to 5th postoperative day) and late (after 5th postoperative day) new-onset atrial fibrillation (AF) using implantable loop recorders (ILRs) in patients undergoing open chest cardiac surgery.

Methods And Results: Seventy-nine patients without a history of AF undergoing cardiac surgery underwent peri-operative high-resolution mapping of electrically induced AF and were followed 36 months after surgery using an ILR (Reveal XT™). Clinical and electrophysiological predictors of late POAF were assessed. POAF occurred in 46 patients (58%), with early POAF detected in 27 (34%) and late POAF in 37 patients (47%). Late POAF episodes were short-lasting (mostly between 2 min and 6 h) and showed a circadian rhythm pattern with a peak of episode initiation during daytime. In POAF patients, electrically induced AF showed more complex propagation patterns than in patients without POAF. Early POAF, right atrial (RA) volume, prolonged PR time, and advanced age were independent predictors of late POAF.

Conclusions: Late POAF occurred in 47% of patients without a history of AF. Patients who develop early POAF, with higher age, larger RA, or prolonged PR time have a higher risk of developing late POAF and may benefit from intensified rhythm follow-up after cardiac surgery.

Clinicaltrials.gov Number: NCT01530750.
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http://dx.doi.org/10.1093/europace/euab136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651165PMC
December 2021

The relation between the atrial blood supply and the complexity of acute atrial fibrillation.

Int J Cardiol Heart Vasc 2021 Jun 19;34:100794. Epub 2021 May 19.

Maastricht University and Cardiovascular Research Institute Maastricht (CARIM), Department of Physiology, Universiteitssingel 50, 6229 ER Maastricht, the Netherlands.

Background: Patients with a history of myocardial infarction and coronary artery disease (CAD) have a higher risk of developing AF. Conversely, patients with atrial fibrillation (AF) have a higher risk of developing myocardial infarction, suggesting a link in underlying pathophysiology. The aim of this study was to assess whether coronary angiographic parameters are associated with a substrate for AF in patients without a history of AF.

Methods: During cardiac surgery in 62 patients (coronary artery bypass grafting (CABG;n = 47), aortic valve replacement (AVR;n = 9) or CABG + AVR (n = 6)) without a history of clinical AF (age 65.4 ± 8.5 years, 26.2% female), AF was induced by burst pacing. The preoperative coronary angiogram (CAG) was assessed for the severity of CAD, and the adequacy of atrial coronary blood supply as quantified by a novel scoring system including the location and severity of right coronary artery disease in relation to the right atrial branches. Epicardial mapping of the right atrium (256 unipolar electrodes) was used to assess the complexity of induced AF.

Results: There was no association between the adequacy of right atrial coronary blood supply on preoperative CAG and AF complexity parameters. Multivariable analysis revealed that only increasing age (B0.232 (0.030;0.433),p = 0.03) and the presence of 3VD (B3.602 (0.187;7.018),p = 0.04) were independently associated with an increased maximal activation time difference.

Conclusions: The adequacy of epicardial right atrial blood supply is not associated with increased complexity of induced atrial fibrillation in patients without a history of clinical AF, while age and the extent of ventricular coronary artery disease are.
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http://dx.doi.org/10.1016/j.ijcha.2021.100794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164021PMC
June 2021

A Variant Noncoding Region Regulates and Predisposes to Atrial Arrhythmias.

Circ Res 2021 07 7;129(3):420-434. Epub 2021 Jun 7.

Department of Medical Biology (F.M.B., J.-S.U., K.v.D., A.O.V., V.M.C., B.J.B.), Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, The Netherlands.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.121.319146DOI Listing
July 2021

Effective termination of atrial fibrillation by SK channel inhibition is associated with a sudden organization of fibrillatory conduction.

Europace 2021 Nov;23(11):1847-1859

Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.

Aims: Pharmacological termination of atrial fibrillation (AF) remains a challenge due to limited efficacy and potential ventricular proarrhythmic effects of antiarrhythmic drugs. SK channels are proposed as atrial-specific targets in the treatment of AF. Here, we investigated the effects of the new SK channel inhibitor AP14145.

Methods And Results: Eight goats were implanted with pericardial electrodes for induction of AF (30 days). In an open-chest study, the atrial conduction velocity (CV) and effective refractory period (ERP) were measured during pacing. High-density mapping of both atrial free-walls was performed during AF and conduction properties were assessed. All measurements were performed at baseline and during AP14145 infusion [10 mg/kg/h (n = 1) or 20 mg/kg/h (n = 6)]. At an infusion rate of 20 mg/kg/h, AF terminated in five of six goats. AP14145 profoundly increased ERP and reduced CV during pacing. AP14145 increased spatiotemporal instability of conduction at short pacing cycle lengths. Atrial fibrillation cycle length and pathlength (AF cycle length × CV) underwent a strong dose-dependent prolongation. Conduction velocity during AF remained unchanged and conduction patterns remained complex until the last seconds before AF termination, during which a sudden and profound organization of fibrillatory conduction occurred.

Conclusion: AP14145 provided a successful therapy for termination of persistent AF in goats. During AF, AP14145 caused an ERP and AF cycle length prolongation. AP14145 slowed CV during fast pacing but did not lead to a further decrease during AF. Termination of AF was preceded by an abrupt organization of AF with a decline in the number of fibrillation waves.
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http://dx.doi.org/10.1093/europace/euab125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576281PMC
November 2021

Incidence, prevalence, and trajectories of repetitive conduction patterns in human atrial fibrillation.

Europace 2021 03;23(23 Suppl 1):i123-i132

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

Aims: Repetitive conduction patterns in atrial fibrillation (AF) may reflect anatomical structures harbouring preferential conduction paths and indicate the presence of stationary sources for AF. Recently, we demonstrated a novel technique to detect repetitive patterns in high-density contact mapping of AF. As a first step towards repetitive pattern mapping to guide AF ablation, we determined the incidence, prevalence, and trajectories of repetitive conduction patterns in epicardial contact mapping of paroxysmal and persistent AF patients.

Methods And Results: A 256-channel mapping array was used to record epicardial left and right AF electrograms in persistent AF (persAF, n = 9) and paroxysmal AF (pAF, n = 11) patients. Intervals containing repetitive conduction patterns were detected using recurrence plots. Activation movies, preferential conduction direction, and average activation sequence were used to characterize and classify conduction patterns. Repetitive patterns were identified in 33/40 recordings. Repetitive patterns were more prevalent in pAF compared with persAF [pAF: median 59%, inter-quartile range (41-72) vs. persAF: 39% (0-51), P < 0.01], larger [pAF: = 1.54 (1.15-1.96) vs. persAF: 1.16 (0.74-1.56) cm2, P < 0.001), and more stable [normalized preferentiality (0-1) pAF: 0.38 (0.25-0.50) vs. persAF: 0.23 (0-0.33), P < 0.01]. Most repetitive patterns were peripheral waves (87%), often with conduction block (69%), while breakthroughs (9%) and re-entries (2%) occurred less frequently.

Conclusion: High-density epicardial contact mapping in AF patients reveals frequent repetitive conduction patterns. In persistent AF patients, repetitive patterns were less frequent, smaller, and more variable than in paroxysmal AF patients. Future research should elucidate whether these patterns can help in finding AF ablation targets.
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http://dx.doi.org/10.1093/europace/euaa403DOI Listing
March 2021

Synergistic antiarrhythmic effect of inward rectifier current inhibition and pulmonary vein isolation in a 3D computer model for atrial fibrillation.

Europace 2021 03;23(23 Suppl 1):i161-i168

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

Aims: Recent clinical studies showed that antiarrhythmic drug (AAD) treatment and pulmonary vein isolation (PVI) synergistically reduce atrial fibrillation (AF) recurrences after initially successful ablation. Among newly developed atrial-selective AADs, inhibitors of the G-protein-gated acetylcholine-activated inward rectifier current (IKACh) were shown to effectively suppress AF in an experimental model but have not yet been evaluated clinically. We tested in silico whether inhibition of inward rectifier current or its combination with PVI reduces AF inducibility.

Methods And Results: We simulated the effect of inward rectifier current blockade (IK blockade), PVI, and their combination on AF inducibility in a detailed three-dimensional model of the human atria with different degrees of fibrosis. IK blockade was simulated with a 30% reduction of its conductivity. Atrial fibrillation was initiated using incremental pacing applied at 20 different locations, in both atria. IK blockade effectively prevented AF induction in simulations without fibrosis as did PVI in simulations without fibrosis and with moderate fibrosis. Both interventions lost their efficacy in severe fibrosis. The combination of IK blockade and PVI prevented AF in simulations without fibrosis, with moderate fibrosis, and even with severe fibrosis. The combined therapy strongly decreased the number of fibrillation waves, due to a synergistic reduction of wavefront generation rate while the wavefront lifespan remained unchanged.

Conclusion: Newly developed blockers of atrial-specific inward rectifier currents, such as IKAch, might prevent AF occurrences and when combined with PVI effectively supress AF recurrences in human.
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http://dx.doi.org/10.1093/europace/euaa413DOI Listing
March 2021

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 07;23(7):1114-1123

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286852PMC
July 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

Inducibility, but not stability, of atrial fibrillation is increased by NOX2 overexpression in mice.

Cardiovasc Res 2021 09;117(11):2354-2364

Division of Cardiovascular Medicine, University of Oxford, L6, West Wing, Oxford OX3 9DU, UK.

Aims: Gp91-containing NADPH oxidases (NOX2) are a significant source of myocardial superoxide production. An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, a direct causal role for NOX2 in AF has not been demonstrated. Accordingly, we investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favourable substrate for AF and further assessed the effects of atorvastatin, an inhibitor of NOX2, on atrial superoxide production and AF susceptibility.

Methods And Results: NOX2-Tg mice showed a 2- to 2.5-fold higher atrial protein content of NOX2 compared with wild-type (WT) controls, which was associated with a significant (twofold) increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in left and right atrial tissue homogenates (P = 0.004 and P = 0.019, respectively). AF susceptibility assessed in vivo by transoesophageal atrial burst stimulation was modestly increased in NOX2-Tg compared with WT (probability of AF induction: 88% vs. 69%, respectively; P = 0.037), in the absence of significant alterations in AF duration, surface ECG parameters, and LV mass or function. Mechanistic studies did not support a role for NOX2 in promoting electrical or structural remodelling, as high-resolution optical mapping of atrial tissues showed no differences in action potential duration and conduction velocity between genotypes. In addition, we did not observe any genotype difference in markers of fibrosis and inflammation, including atrial collagen content and Col1a1, Il-1β, Il-6, and Mcp-1 mRNA. Similarly, NOX2 overexpression did not have consistent effects on RyR2 Ca2+ leak nor did it affect PKA or CaMKII-mediated RyR2 phosphorylation. Finally, treatment with atorvastatin significantly inhibited atrial superoxide production in NOX2-Tg but had no effect on AF induction in either genotype.

Conclusion: Together, these data indicate that while atrial NOX2 overexpression may contribute to atrial arrhythmogenesis, NOX2-derived superoxide production does not affect the electrical and structural properties of the atrial myocardium.
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http://dx.doi.org/10.1093/cvr/cvab019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479801PMC
September 2021

Left Atrial Appendage Electrical Isolation Reduces Atrial Fibrillation Recurrences: A Simulation Study.

Circ Arrhythm Electrophysiol 2021 01 24;14(1):e009230. Epub 2020 Dec 24.

Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland (A.G., S.P., G.C., R.K., A.A.).

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http://dx.doi.org/10.1161/CIRCEP.120.009230DOI Listing
January 2021

Electrophysiological effects of ranolazine in a goat model of lone atrial fibrillation.

Heart Rhythm 2021 04 21;18(4):615-622. Epub 2020 Nov 21.

Department of Cardiothoracic Surgery, Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, Germany. Electronic address:

Background: There is still an unmet need for pharmacologic treatment of atrial fibrillation (AF) with few effects on ventricular electrophysiology. Ranolazine is an antiarrhythmic drug reported to have strong atrial selectivity.

Objective: The purpose of this study was to investigate the electrophysiological effects of ranolazine in atria with AF-induced electrical remodeling in a model of lone AF in awake goats.

Methods: Electrode patches were implanted on the atrial epicardium of 8 Dutch milk goats. Experiments were performed at baseline and after 2 and 14 days of electrically maintained AF. Several electrophysiological parameters and AF episode duration were measured during infusion of vehicle and different doses of ranolazine (target plasma levels 4, 8, and 16 μM, respectively).

Results: The highest dose of ranolazine significantly prolonged atrial effective refractory period and decreased atrial conduction velocity at baseline and after 2 days of AF. After 2 weeks of AF, ranolazine prolonged the p5 and p50 of AF cycle length distribution in a dose-dependent manner but was not effective in restoring sinus rhythm. No adverse ventricular arrhythmic events (eg, premature ventricular beats or signs of hemodynamic instability) were observed during infusion of ranolazine at any point in the study.

Conclusion: The lowest investigated dose of ranolazine, which is expected to block both late I and atrial peak I, had no effect on the investigated electrophysiological parameters. The highest dose affected both atrial and ventricular electrophysiological parameters at different stages of AF-induced remodeling but was not efficacious in cardioverting AF to sinus rhythm in a goat model of lone AF.
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http://dx.doi.org/10.1016/j.hrthm.2020.11.021DOI Listing
April 2021

A Novel Tool for the Identification and Characterization of Repetitive Patterns in High-Density Contact Mapping of Atrial Fibrillation.

Front Physiol 2020 15;11:570118. Epub 2020 Oct 15.

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

Introduction: Electrical contact mapping provides a detailed view of conduction patterns in the atria during atrial fibrillation (AF). Identification of repetitive wave front propagation mechanisms potentially initiating or sustaining AF might provide more insights into temporal and spatial distribution of candidate AF mechanism and identify targets for catheter ablation. We developed a novel tool based on recurrence plots to automatically identify and characterize repetitive conduction patterns in high-density contact mapping of AF.

Materials And Methods: Recurrence plots were constructed by first transforming atrial electrograms recorded by a multi-electrode array to activation-phase signals and then quantifying the degree of similarity between snapshots of the activation-phase in the electrode array. An AF cycle length dependent distance threshold was applied to discriminate between repetitive and non-repetitive snapshots. Intervals containing repetitive conduction patterns were detected in a recurrence plot as regions with a high recurrence rate. Intervals that contained similar repetitive patterns were then grouped into clusters. To demonstrate the ability to detect and quantify the incidence, duration and size of repetitive patterns, the tool was applied to left and right atrial recordings in a goat model of different duration of persistent AF [3 weeks AF (3 wkAF, = 8) and 22 weeks AF (22 wkAF, = 8)], using a 249-electrode mapping array (2.4 mm inter-electrode distance).

Results: Recurrence plots identified frequent recurrences of activation patterns in all recordings and indicated a strong correlation between recurrence plot threshold and AF cycle length. Prolonged AF duration was associated with shorter repetitive pattern duration [mean maximum duration 3 wkAF: 74 cycles, 95% confidence interval (54-94) vs. 22 wkAF: 41 cycles (21-62), = 0.03], and smaller recurrent regions within repetitive patterns [3 wkAF 1.7 cm (1.0-2.3) vs. 22 wkAF 0.5 cm (0.0-1.2), = 0.02]. Both breakthrough patterns and re-entry were identified as repetitive conduction patterns.

Conclusion: Recurrence plots provide a novel way to delineate high-density contact mapping of AF. Dominant repetitive conduction patterns were identified in a goat model of sustained AF. Application of the developed methodology using the new generation of multi-electrode catheters could identify additional targets for catheter ablation of AF.
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http://dx.doi.org/10.3389/fphys.2020.570118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593698PMC
October 2020

Epicardial Fibrosis Explains Increased Endo-Epicardial Dissociation and Epicardial Breakthroughs in Human Atrial Fibrillation.

Front Physiol 2020 21;11:68. Epub 2020 Feb 21.

Department of Physiology, Maastricht University, Maastricht, Netherlands.

Background: Atrial fibrillation (AF) is accompanied by progressive epicardial fibrosis, dissociation of electrical activity between the epicardial layer and the endocardial bundle network, and transmural conduction (breakthroughs). However, causal relationships between these phenomena have not been demonstrated yet. Our goal was to test the hypothesis that epicardial fibrosis suffices to increase endo-epicardial dissociation (EED) and breakthroughs (BT) during AF.

Methods: We simulated the effect of fibrosis in the epicardial layer on EED and BT in a detailed, high-resolution, three-dimensional model of the human atria with realistic electrophysiology. The model results were compared with simultaneous endo-epicardial mapping in human atria. The model geometry, specifically built for this study, was based on MR images and histo-anatomical studies. Clinical data were obtained in four patients with longstanding persistent AF (persAF) and three patients without a history of AF.

Results: The AF cycle length (AFCL), conduction velocity (CV), and EED were comparable in the mapping studies and the simulations. EED increased from 24.1 ± 3.4 to 56.58 ± 6.2% ( < 0.05), and number of BTs per cycle from 0.89 ± 0.55 to 6.74 ± 2.11% ( < 0.05), in different degrees of fibrosis in the epicardial layer. In both mapping data and simulations, EED correlated with prevalence of BTs. Fibrosis also increased the number of fibrillation waves per cycle in the model.

Conclusion: A realistic 3D computer model of AF in which epicardial fibrosis was increased, in the absence of other pathological changes, showed increases in EED and epicardial BT comparable to those in longstanding persAF. Thus, epicardial fibrosis can explain both phenomena.
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http://dx.doi.org/10.3389/fphys.2020.00068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047215PMC
February 2020

Quantification of epicardial adipose tissue in patients undergoing hybrid ablation for atrial fibrillation.

Eur J Cardiothorac Surg 2019 Jul;56(1):79-86

Department of Cardiology, Maastricht University Medical Center, Maastricht, Netherlands.

Objectives: Epicardial adipose tissue volume (EAT-V) has been linked to atrial fibrillation (AF) recurrences after catheter ablation. We retrospectively studied the association between atrial EAT-V and outcome after hybrid AF ablation (epicardial surgical and endocardial catheter ablation).

Methods: On preoperative cardiac computed tomography angiography scans, the left atrium and right atrium were manually delineated using the open source ImageJ. With custom-made automated software, the number of pixels in the regions of interest on each slice was calculated. On the basis of the Hounsfield units, pixel size and slice thickness, EAT-V was computed and normalized in relation to the body surface area (BSA) and the myocardial tissue volume.

Results: Eighty-five patients were included. Left atrial and right atrial EAT-V normalized to BSA were not significantly different between paroxysmal and persistent AF [0.84 (0.51-1.50) vs 0.81 (0.57-1.18), 1.74 (1.02-2.56) vs 1.55 (1.26-2.18), all P = 0.9], neither between the acute conduction block and no acute conduction block in the epicardial box lesion [0.92 (0.55-1.39) vs 0.72 (0.55-1.24), P = 0.5, right atrium not applicable], nor between the sinus rhythm and arrhythmia recurrence after 12 months [0.88 (0.55-1.48) vs 0.63 (0.47-1.10), 1.61 (1.11-2.50) vs 1.55 (1.20-2.20), all P > 0.1]. Left atrial EAT-V normalized to myocardial tissue volume was not different between the groups.

Conclusions: This study could neither confirm that EAT-V was predictive of recurrence of supraventricular arrhythmias in patients undergoing a hybrid AF ablation, nor that EAT-V was different between patients with paroxysmal AF and persistent and long-standing persistent AF. This suggests that EAT-V might not affect the outcome in surgical ablation procedures and therefore should not influence preoperative or intraoperative decision-making.
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http://dx.doi.org/10.1093/ejcts/ezy472DOI Listing
July 2019

Effect of Na+-channel blockade on the three-dimensional substrate of atrial fibrillation in a model of endo-epicardial dissociation and transmural conduction.

Europace 2018 Nov;20(suppl_3):iii69-iii76

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

Aims: Atrial fibrillation (AF) is a progressive arrhythmia characterized by structural alterations that increase its stability. Both clinical and experimental studies showed a concomitant loss of antiarrhythmic drug efficacy in later stages of AF. The mechanisms underlying this loss of efficacy are not well understood. We hypothesized that structural remodelling may explain this reduced efficacy by making the substrate more three-dimensional. To investigate this, we simulated the effect of sodium (Na+)-channel block on AF in a model of progressive transmural uncoupling.

Methods And Results: In a computer model consisting of two cross-connected atrial layers, with realistic atrial membrane behaviour, structural remodelling was simulated by reducing the number of connections between the layers. 100% of endo-epicardial connectivity represented a healthy atrium. At various degrees of structural remodelling, we assessed the effect of 60% sodium channel block on AF stability, endo-epicardial electrical activity dissociation (EED), and fibrillatory conduction pattern complexity quantified by number of waves, phase singularities (PSs), and transmural conduction ('breakthrough', BT). Sodium channel block terminated AF in non-remodelled but not in remodelled atria. The temporal excitable gap (EG) and AF cycle length increased at all degrees of remodelling when compared with control. Despite an increase of EED and EG, sodium channel block decreased the incidence of BT because of transmural conduction block. Sodium channel block decreased the number of waves and PSs in normal atrium but not in structurally remodelled atrium.

Conclusion: This simple atrial model explains the loss of efficacy of sodium channel blockers in terminating AF in the presence of severe structural remodelling as has been observed experimentally and clinically. Atrial fibrillation termination in atria with moderate structural remodelling in the presence of sodium channel block is caused by reduction of AF complexity. With more severe structural remodelling, sodium channel block fails to promote synchronization of the two layers of the model.
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http://dx.doi.org/10.1093/europace/euy236DOI Listing
November 2018

Rotors Detected by Phase Analysis of Filtered, Epicardial Atrial Fibrillation Electrograms Colocalize With Regions of Conduction Block.

Circ Arrhythm Electrophysiol 2018 10;11(10):e005858

Department of Physiology, Maastricht University, the Netherlands (P.P., S.Z., A.v.H., S.V.).

Background: Several recent studies suggest rotors detected by phase mapping may act as main drivers of persistent atrial fibrillation. However, the electrophysiological nature of detected rotors remains unclear. We performed a direct, 1:1 comparison between phase and activation time mapping in high-density, epicardial, direct-contact mapping files of human atrial fibrillation.

Methods: Thirty-eight unipolar electrogram files of 10 s duration were recorded in patients with atrial fibrillation (n=20 patients) using a 16×16 electrode array placed on the epicardial surface of the left atrial posterior wall or the right atrial free wall. Phase maps and isochrone wave maps were constructed for all recordings. For each detected phase singularity (PS) with a lifespan of >1 cycle length, the corresponding conduction pattern was investigated in the isochrone wave maps.

Results: When using sinusoidal recomposition and Hilbert Transform, 138 PSs were detected. One hundred and four out of 138 PSs were detected within 1 electrode distance (1.5 mm) from a line of conduction block between nonrotating wavefronts detected by activation mapping. Far fewer rotating wavefronts were detected when rotating activity was identified based on wave mapping (18 out of 8219 detected waves). Fourteen out of these 18 cases were detected as PSs in phase mapping. Phase analysis of filtered electrograms produced by simulated wavefronts separated by conduction block also identified PSs on the line of conduction block.

Conclusions: PSs identified by phase analysis of filtered epicardial electrograms colocalize with conduction block lines identified by activation mapping. Detection of PSs using phase analysis has a low specificity for identifying rotating wavefronts during human atrial fibrillation using activation mapping.
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http://dx.doi.org/10.1161/CIRCEP.117.005858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553551PMC
October 2018

Loss of Side-to-Side Connections Affects the Relative Contributions of the Sodium and Calcium Current to Transverse Propagation Between Strands of Atrial Myocytes.

Front Physiol 2018 4;9:1212. Epub 2018 Sep 4.

Department of Physiology, Maastricht University, Maastricht, Netherlands.

Atrial fibrillation (AF) leads to a loss of transverse connections between myocyte strands that is associated with an increased complexity and stability of AF. We have explored the interaction between longitudinal and transverse coupling, and the relative contribution of the sodium (I) and calcium (I) current to propagation, both in healthy tissue and under diseased conditions using computer simulations. Two parallel strands of atrial myocytes were modeled (Courtemanche et al. ionic model). As a control condition, every single cell was connected both transversely and longitudinally. To simulate a loss of transverse connectivity, this number was reduced to 1 in 4, 8, 12, or 16 transversely. To study the interaction with longitudinal coupling, anisotropy ratios of 3, 9, 16, and 25:1 were used. All simulations were repeated for varying degrees of I and I block and the transverse activation delay (TAD) between the paced and non-paced strands was calculated for all cases. The TAD was highly sensitive to the transverse connectivity, increasing from 1 ms at 1 in 1, to 25 ms at 1 in 4, and 100 ms at 1 in 12 connectivity. The TAD also increased when longitudinal coupling was increased. Both decreasing transverse connectivity and increasing longitudinal coupling enhanced the synchronicity of activation of the non-paced strand and increased the propensity for transverse conduction block. Even after long TADs, the action potential upstroke in the non-paced strand was still mainly dependent on the I. Nevertheless, I in the paced strand was essential to provide depolarizing current to the non-paced strand. Loss of transverse connections increased the sensitivity to both I and I block. However, when longitudinal coupling was relatively high, transverse propagation was more sensitive to I block than to I block. Although transverse propagation depends on both I and I, their relative contribution, and sensitivity to channel blockade, depends on the distribution of transverse connections and the axial conductivity. This simple two-strand model helps to explain the nature of atrial discontinuous conduction during structural remodeling and provides an opportunity for more effective drug development.
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http://dx.doi.org/10.3389/fphys.2018.01212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131618PMC
September 2018

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

Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation.

Heart Rhythm 2018 09 23;15(9):1328-1336. Epub 2018 May 23.

Division of Cardiology, Department of Medicine, Medical University of Graz, Graz, Austria; Department of Cardiology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.

Background: Arterial hypertension (HT) contributes to progression of atrial fibrillation (AF) via unknown mechanisms.

Objective: We aimed to characterize electrical and structural changes accounting for increased AF stability in a large animal model of rapid atrial pacing (RAP)-induced AF combined with desoxycorticosterone acetate (DOCA)-induced HT.

Methods: Eighteen pigs were instrumented with right atrial endocardial pacemaker leads and custom-made pacemakers to induce AF by continuous RAP (600 beats/min). DOCA pellets were subcutaneously implanted in a subgroup of 9 animals (AF+HT group); the other 9 animals served as controls (AF group). Final experiments included electrophysiology studies, endocardial electroanatomic mapping, and high-density mapping with epicardial multielectrode arrays. In addition, 3-dimensional computational modeling was performed.

Results: DOCA implantation led to secondary HT (median [interquartile range] aortic pressure 109.9 [100-137] mm Hg in AF+HT vs 82.2 [79-96] mm Hg in AF; P < .05), increased AF stability (55.6% vs 12.5% of animals with AF episodes lasting >1 hour; P < .05), concentric left ventricular hypertrophy, atrial dilatation (119 ± 31 cm in AF+HT vs 78 ± 23 cm in AF; P < .05), and fibrosis. Collagen accumulation in the AF+HT group was mainly found in non-intermyocyte areas (1.62 ± 0.38 cm in AF+HT vs 0.96 ± 0.3 cm in AF; P < .05). Left and right atrial effective refractory periods, action potential durations, endo- and epicardial conduction velocities, and measures of AF complexity were comparable between the 2 groups. A 3-dimensional computational model confirmed an increase in AF stability observed in the in vivo experiments associated with increased atrial size.

Conclusion: In this model of secondary HT, higher AF stability after 2 weeks of RAP is mainly driven by atrial dilatation.
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http://dx.doi.org/10.1016/j.hrthm.2018.05.016DOI Listing
September 2018

Cardioversion of persistent atrial fibrillation is associated with a 24-hour relapse gap: Observations from prolonged postcardioversion rhythm monitoring.

Clin Cardiol 2018 Mar 22;41(3):366-371. Epub 2018 Mar 22.

Department of Cardiology, Maastricht University Medical Centre and Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands.

Background: Many recurrences occur after electrical cardioversion (ECV) of atrial fibrillation (AF). Assessment of extent of remodeling and continuous prolonged rhythm monitoring might reveal actionable recurrence mechanisms.

Hypothesis: After ECV of AF specific patterns of arrhythmia recurrence can be distinguished.

Methods: All patients who underwent successful ECV due to persistent AF were included. Tissue velocity echocardiography during AF was performed before ECV to study atrial fibrillatory cycle length and fibrillatory velocity. After ECV, the heart rhythm of all patients was monitored 3 times daily during 4 weeks, and timing of recurrence was noted.

Results: In total, 50 patients (68% male) were included; mean age was 68 ± 9 years. Median duration of the current AF episode was 102 (range, 74-152) days. Twenty-one (42%) patients showed recurrence of persistent AF. No recurrences occurred during the first 24 hours. There were no differences in clinical characteristics between patients with or without recurrence of AF. However, patients with early recurrence of AF had significantly higher precardioversion wall-motion velocity compared with patients who remained in sinus rhythm (2.8 [1.6-3.6] vs 1.4 [0.9-3.3] cm/s; P = 0.017), whereas atrial fibrillatory cycle length did not differ.

Conclusions: In this study on 50 patients successfully cardioverted for persistent AF, there was a relapse gap of ≥24 hours. This phenomenon has not been well appreciated before and offers an AF-free window of opportunity for electrocardiographically triggered cardiac imaging or complex electrophysiological procedures. Echocardiographic tissue velocity imaging may visualize atrial remodeling relevant to AF recurrence.
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http://dx.doi.org/10.1002/clc.22877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489937PMC
March 2018

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

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

How disruption of endo-epicardial electrical connections enhances endo-epicardial conduction during atrial fibrillation.

Europace 2017 02;19(2):308-318

Department of Physiology and Maastricht Centre of Systems Biology, Maastricht University, PO Box 616, Maastricht 6200 MD, The Netherlands.

Aims: Loss of side-to-side electrical connections between atrial muscle bundles is thought to underlie conduction disturbances predisposing to atrial fibrillation (AF). Putatively, disruption of electrical connections occurs not only within the epicardial layer but also between the epicardial layer and the endocardial bundle network, thus impeding transmural conductions (‘breakthroughs’). However, both clinical and experimental studies have shown an enhancement of breakthroughs during later stages of AF. We tested the hypothesis that endo-epicardial uncoupling enhances endo-epicardial electrical dyssynchrony, breakthrough rate (BTR), and AF stability.

Methods And Results: In a novel dual-layer computer model of the human atria, 100% connectivity between the two layers served as healthy control. Atrial structural remodelling was simulated by reducing the number of connections between the layers from 96 to 6 randomly chosen locations. With progressive elimination of connections, AF stability increased. Reduction in the number of connections from 96 to 24 resulted in an increase in endo-epicardial dyssynchrony from 6.6 ± 1.9 to 24.6 ± 1.3%, with a concomitant increase in BTR. A further reduction to 12 and 6 resulted in more pronounced endo-epicardial dyssynchrony of 34.4 ± 1.15 and 40.2 ± 0.52% but with BTR reduction. This biphasic relationship between endo-epicardial coupling and BTR was found independently from whether AF was maintained by re-entry or by ectopic focal discharges.

Conclusion: Loss of endo-epicardial coupling increases AF stability. There is a biphasic relation between endo-epicardial coupling and BTR. While at high degrees of endo-epicardial connectivity, the BTR is limited by the endo-epicardial synchronicity, at low degrees of connectivity, it is limited by the number of endo-epicardial connections.
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http://dx.doi.org/10.1093/europace/euv445DOI Listing
February 2017
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