Publications by authors named "Mark Potse"

55 Publications

Fibrosis and Conduction Abnormalities as Basis for Overlap of Brugada Syndrome and Early Repolarization Syndrome.

Int J Mol Sci 2021 Feb 4;22(4). Epub 2021 Feb 4.

Department of Experimental Cardiology, Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.

Brugada syndrome and early repolarization syndrome are both classified as J-wave syndromes, with a similar mechanism of arrhythmogenesis and with the same basis for genesis of the characteristic electrocardiographic features. The Brugada syndrome is now considered a conduction disorder based on subtle structural abnormalities in the right ventricular outflow tract. Recent evidence suggests structural substrate in patients with the early repolarization syndrome as well. We propose a unifying mechanism based on these structural abnormalities explaining both arrhythmogenesis and the electrocardiographic changes. In addition, we speculate that, with increasing technical advances in imaging techniques and their spatial resolution, these syndromes will be reclassified as structural heart diseases or cardiomyopathies.
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http://dx.doi.org/10.3390/ijms22041570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913989PMC
February 2021

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

Circ Arrhythm Electrophysiol 2021 Jan 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

Characterization of T Wave Amplitude, Duration and Morphology Changes During Hemodialysis: Relationship with Serum Electrolyte Levels and Heart Rate.

IEEE Trans Biomed Eng 2020 Dec 10;PP. Epub 2020 Dec 10.

Objective: Chronic kidney disease affects more than 10% of the world population. Changes in serum ion concentrations increase the risk for ventricular arrhythmias and sudden cardiac death, particularly in end-stage renal disease (ESRD) patients. We characterized how T wave amplitude, duration and morphology descriptors change with variations in serum levels of potassium and calcium and in heart rate, both in ESRD patients and in simulated ventricular fibers.

Methods: Electrocardiogram (ECG) recordings from twenty ESRD patients undergoing hemodialysis (HD) and pseudo-ECGs (pECGs) calculated from twenty-two simulated ventricular fibers at varying transmural heterogeneity levels were processed to quantify T wave width ( T ), T wave slope-to-amplitude ratio ( T ) and four indices of T wave morphological variability based on time warping ( d, d,d and d ). Serum potassium and calcium levels and heart rate were measured along HD.

Results: d was the marker most strongly correlated with serum potassium, d with calcium and d with heart rate, after correction for covariates. Median values of partial correlation coefficients were 0.75, -0.74 and -0.90, respectively. For all analyzed T wave descriptors, high inter-patient variability was observed in the pattern of such relationships. This variability, accentuated during the first HD time points, was reproduced in the simulations and shown to be influenced by differences in transmural heterogeneity.

Conclusion: Changes in serum potassium and calcium levels and in heart rate have markable effects on T wave descriptors, particularly those quantifying morphological variability.

Significance: ECG markers have the potential to be used for monitoring serum ion concentrations in ESRD patients.
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http://dx.doi.org/10.1109/TBME.2020.3043844DOI Listing
December 2020

Reconstruction of three-dimensional biventricular activation based on the 12-lead electrocardiogram via patient-specific modelling.

Europace 2020 Nov 26. Epub 2020 Nov 26.

Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Via Giuseppe Buffi 13, CH-6904 Lugano, Switzerland.

Aims: Non-invasive imaging of electrical activation requires high-density body surface potential mapping. The nine electrodes of the 12-lead electrocardiogram (ECG) are insufficient for a reliable reconstruction with standard inverse methods. Patient-specific modelling may offer an alternative route to physiologically constraint the reconstruction. The aim of the study was to assess the feasibility of reconstructing the fully 3D electrical activation map of the ventricles from the 12-lead ECG and cardiovascular magnetic resonance (CMR).

Methods And Results: Ventricular activation was estimated by iteratively optimizing the parameters (conduction velocity and sites of earliest activation) of a patient-specific model to fit the simulated to the recorded ECG. Chest and cardiac anatomy of 11 patients (QRS duration 126-180 ms, documented scar in two) were segmented from CMR images. Scar presence was assessed by magnetic resonance (MR) contrast enhancement. Activation sequences were modelled with a physiologically based propagation model and ECGs with lead field theory. Validation was performed by comparing reconstructed activation maps with those acquired by invasive electroanatomical mapping of coronary sinus/veins (CS) and right ventricular (RV) and left ventricular (LV) endocardium. The QRS complex was correctly reproduced by the model (Pearson's correlation r = 0.923). Reconstructions accurately located the earliest and latest activated LV regions (median barycentre distance 8.2 mm, IQR 8.8 mm). Correlation of simulated with recorded activation time was very good at LV endocardium (r = 0.83) and good at CS (r = 0.68) and RV endocardium (r = 0.58).

Conclusion: Non-invasive assessment of biventricular 3D activation using the 12-lead ECG and MR imaging is feasible. Potential applications include patient-specific modelling and pre-/per-procedural evaluation of ventricular activation.
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http://dx.doi.org/10.1093/europace/euaa330DOI Listing
November 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

The 'Digital Twin' to enable the vision of precision cardiology.

Eur Heart J 2020 Dec;41(48):4556-4564

Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King's College London, London, UK.

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine.
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http://dx.doi.org/10.1093/eurheartj/ehaa159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774470PMC
December 2020

The Spectrum of Idiopathic Ventricular Fibrillation and J-Wave Syndromes: Novel Mapping Insights.

Card Electrophysiol Clin 2019 12;11(4):699-709

IHU LIRYC, Electrophysiology and Heart Modeling Institute, Avenue du Haut Leveque, Bordeaux 33604, Passes Cedex, France; Univ Bordeaux, CRCTB, U1045, Bordeaux, France.

Idiopathic ventricular fibrillation and J-wave syndromes are causes of sudden cardiac death (SCD) without any identified structural cardiac disease after extensive investigations. Recent data show that high-density electrophysiological mapping may ultimately offer diagnoses of subclinical diseases in most patients including those termed "unexplained" SCD. Three major conditions can underlie the occurrence of SCD: (1) localized depolarization abnormalities (due to microstructural myocardial alteration), (2) Purkinje abnormalities manifesting as triggering ectopy and inducible reentry; or (3) repolarization heterogeneities. Each condition may result from a spectrum of pathophysiologic processes with implications for individual therapy.
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http://dx.doi.org/10.1016/j.ccep.2019.08.011DOI Listing
December 2019

Impact of the Endocardium in a Parameter Optimization to Solve the Inverse Problem of Electrocardiography.

Front Physiol 2018 22;9:1946. Epub 2019 Jan 22.

IHU Liryc, Electrophysiology and Heart Modeling Institute, Pessac, France.

Electrocardiographic imaging aims at reconstructing cardiac electrical events from electrical signals measured on the body surface. The most common approach relies on the inverse solution of the Laplace equation in the torso to reconstruct epicardial potential maps from body surface potential maps. Here we apply a method based on a parameter identification problem to reconstruct both activation and repolarization times. From an ansatz of action potential, based on the Mitchell-Schaeffer ionic model, we compute body surface potential signals. The inverse problem is reduced to the identification of the parameters of the Mitchell-Schaeffer model. We investigate whether solving the inverse problem with the endocardium improves the results or not. We solved the parameter identification problem on two different meshes: one with only the epicardium, and one with both the epicardium and the endocardium. We compared the results on both the heart (activation and repolarization times) and the torso. The comparison was done on validation data of sinus rhythm and ventricular pacing. We found similar results with both meshes in 6 cases out of 7: the presence of the endocardium slightly improved the activation times. This was the most visible on a sinus beat, leading to the conclusion that inclusion of the endocardium would be useful in situations where endo-epicardial gradients in activation or repolarization times play an important role.
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http://dx.doi.org/10.3389/fphys.2018.01946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349712PMC
January 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

A left bundle branch block activation sequence and ventricular pacing influence voltage amplitudes: an in vivo and in silico study.

Europace 2018 Nov;20(suppl_3):iii77-iii86

Center for Computational Medicine in Cardiology (CCMC), Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland.

Aims: The aim of this study was to investigate the influence of the activation sequence on voltage amplitudes by evaluating regional voltage differences during a left bundle branch block (LBBB) activation sequence vs. a normal synchronous activation sequence and by evaluating pacing-induced voltage differences.

Methods And Results: Twenty-one patients and three computer models without scar were studied. Regional voltage amplitudes were evaluated in nine LBBB patients who underwent endocardial electro-anatomic mapping (EAM). Pacing-induced voltage differences were evaluated in 12 patients who underwent epicardial EAM during intrinsic rhythm and right ventricular (RV) pacing. Three computer models customized for LBBB patients were created. Changes in voltage amplitudes after an LBBB (intrinsic), a normal synchronous, an RV pacing, and a left ventricular pacing activation sequence were assessed in the computer models. Unipolar voltage amplitudes in patients were approximately 4.5 mV (4.4-4.7 mV, ∼33%) lower in the septum when compared with other segments. A normal synchronous activation sequence in the computer models normalized voltage amplitudes in the septum. Pacing-induced differences were larger in electrograms with higher voltage amplitudes during intrinsic rhythm and furthermore larger and more variable at the epicardium [mean absolute difference: 3.6-6.2 mV, 40-53% of intrinsic value; interquartile range (IQR) differences: 53-63% of intrinsic value] compared to the endocardium (mean absolute difference: 3.3-3.8 mV, 28-30% of intrinsic value; IQR differences: 37-40% of intrinsic value).

Conclusion: In patients and computer models without scar, lower septal unipolar voltage amplitudes are exclusively associated with an LBBB activation sequence. Pacing substantially affects voltage amplitudes, particularly at the epicardium.
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http://dx.doi.org/10.1093/europace/euy233DOI Listing
November 2018

Beat-to-beat P-wave morphological variability in patients with paroxysmal atrial fibrillation: an in silico study.

Europace 2018 Nov;20(suppl_3):iii26-iii35

Center for Computational Medicine in Cardiology, Università della Svizzera italiana, Lugano, Switzerland.

Aims: P-wave beat-to-beat morphological variability can identify patients prone to paroxysmal atrial fibrillation (AF). To date, no computational study has been carried out to mechanistically explain such finding. The aim of this study was to provide a pathophysiological explanation, by using a computer model of the human atria, of the correlation between P-wave beat-to-beat variability and the risk of AF.

Methods And Results: A physiological variability in the earliest activation site (EAS), on a beat-to-beat basis, was introduced into a computer model of the human atria by randomizing the EAS location. A methodology for generating multi-scale, spatially-correlated regions of heterogeneous conduction was developed. P-wave variability in the presence of such regions was compared with a control case. Simulations were performed with an eikonal model, for the activation map, and with the lead field approach, for P-wave computation. The methodology was eventually compared with a reference monodomain simulation. A total of 60 P-waves were simulated for each sinus node exit location (12 in total), and for each of the 15 patterns of heterogeneous conduction automatically generated by the model. A P-wave beat-to-beat variability was observed in all cases. Variability was significantly increased in presence of heterogeneous slow conducting regions, up to two-fold the variability in the control case. P-wave variability increased non-linearly with respect to the EAS variability and total area of slow conduction. Distribution of the heterogeneous conduction was more effective in increasing the variability when it surrounded the EAS locations and the fast conducting bundles. P-waves simulated by the eikonal approach compared excellently with the monodomain-based ones.

Conclusion: P-wave variability in patients with paroxysmal AF could be explained by a variability in sinoatrial node exit location in combination with slow conducting regions.
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http://dx.doi.org/10.1093/europace/euy227DOI Listing
November 2018

Depolarization versus repolarization abnormality underlying inferolateral J-wave syndromes: New concepts in sudden cardiac death with apparently normal hearts.

Heart Rhythm 2019 05 2;16(5):781-790. Epub 2018 Nov 2.

IHU LIRYC, Electrophysiology and Heart Modeling Institute, Bordeaux, France; University of Bordeaux, U1045, Bordeaux, France.

Early repolarization indicates a distinct electrocardiographic phenotype affecting the junction between the QRS complex and the ST segment in inferolateral leads (inferolateral J-wave syndromes). It has been considered a benign electrocardiographic variant for decades, but recent clinical studies have demonstrated its arrhythmogenicity in a small subset, supported by experimental studies showing transmural dispersion of repolarization. Here we review the current knowledge and the issues of risk stratification that limit clinical management. In addition, we report on new mapping data of patients refractory to pharmacologic treatment using high-density electrogram mapping at the time of inscription of J wave. These data demonstrate that distinct substrates, delayed depolarization, and abnormal early repolarization underlie inferolateral J-wave syndromes, with significant implications. Finally, based on these data, we propose a new simplified mechanistic classification of sudden cardiac deaths without apparent structural heart disease.
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http://dx.doi.org/10.1016/j.hrthm.2018.10.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6486498PMC
May 2019

Localized Structural Alterations Underlying a Subset of Unexplained Sudden Cardiac Death.

Circ Arrhythm Electrophysiol 2018 07;11(7):e006120

IHU Liryc, Electrophysiology and Heart Modeling Institute, Fondation Bordeaux Université, France (M. Haïssaguerre, M. Hocini, G.C., J.D., F.S., S.P., H.C., M.T., A.D., R.M., N.D., P.B., P.R., S.P., T.P., N.K., G.M., X.P., C.D., L.L., R.C., P.J., D.B., E.V., M.P., R.W., O.B., R.D.).

Background: Sudden cardiac death because of ventricular fibrillation (VF) is commonly unexplained in younger victims. Detailed electrophysiological mapping in such patients has not been reported.

Methods: We evaluated 24 patients (29±13 years) who survived idiopathic VF. First, we used multielectrode body surface recordings to identify the drivers maintaining VF. Then, we analyzed electrograms in the driver regions using endocardial and epicardial catheter mapping during sinus rhythm. Established electrogram criteria were used to identify the presence of structural alterations.

Results: VF occurred spontaneously in 3 patients and was induced in 16, whereas VF was noninducible in 5. VF mapping demonstrated reentrant and focal activities (87% versus 13%, respectively) in all. The activities were dominant in one ventricle in 9 patients, whereas they had biventricular distribution in others. During sinus rhythm areas of abnormal electrograms were identified in 15/24 patients (62.5%) revealing localized structural alterations: in the right ventricle in 11, the left ventricle in 1, and both in 3. They covered a limited surface (13±6 cm) representing 5±3% of the total surface and were recorded predominantly on the epicardium. Seventy-six percent of these areas were colocated with VF drivers (<0.001). In the 9 patients without structural alteration, we observed a high incidence of Purkinje triggers (7/9 versus 4/15, =0.033). Catheter ablation resulted in arrhythmia-free outcome in 15/18 patients at 17±11 months follow-up.

Conclusions: This study shows that localized structural alterations underlie a significant subset of previously unexplained sudden cardiac death. In the other subset, Purkinje electrical pathology seems as a dominant mechanism.
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http://dx.doi.org/10.1161/CIRCEP.117.006120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661047PMC
July 2018

Scalable and Accurate ECG Simulation for Reaction-Diffusion Models of the Human Heart.

Authors:
Mark Potse

Front Physiol 2018 20;9:370. Epub 2018 Apr 20.

CARMEN Research Team, Inria Bordeaux Sud-Ouest, Talence, France.

Realistic electrocardiogram (ECG) simulation with numerical models is important for research linking cellular and molecular physiology to clinically observable signals, and crucial for patient tailoring of numerical heart models. However, ECG simulation with a realistic torso model is computationally much harder than simulation of cardiac activity itself, so that many studies with sophisticated heart models have resorted to crude approximations of the ECG. This paper shows how the classical concept of electrocardiographic lead fields can be used for an ECG simulation method that matches the realism of modern heart models. The accuracy and resource requirements were compared to those of a full-torso solution for the potential and scaling was tested up to 14,336 cores with a heart model consisting of 11 million nodes. Reference ECGs were computed on a 3.3 billion-node heart-torso mesh at 0.2 mm resolution. The results show that the lead-field method is more efficient than a full-torso solution when the number of simulated samples is larger than the number of computed ECG leads. While the initial computation of the lead fields remains a hard and poorly scalable problem, the ECG computation itself scales almost perfectly and, even for several hundreds of ECG leads, takes much less time than the underlying simulation of cardiac activity.
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http://dx.doi.org/10.3389/fphys.2018.00370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920200PMC
April 2018

Evaluation of a Rapid Anisotropic Model for ECG Simulation.

Front Physiol 2017 2;8:265. Epub 2017 May 2.

Center for Computational Medicine in CardiologyLugano, Switzerland.

State-of-the-art cardiac electrophysiology models that are able to deliver physiologically motivated activation maps and electrocardiograms (ECGs) can only be solved on high-performance computing architectures. This makes it nearly impossible to adopt such models in clinical practice. ECG imaging tools typically rely on simplified models, but these neglect the anisotropic electric conductivity of the tissue in the forward problem. Moreover, their results are often confined to the heart-torso interface. We propose a forward model that fully accounts for the anisotropic tissue conductivity and produces the standard 12-lead ECG in a few seconds. The activation sequence is approximated with an eikonal model in the 3d myocardium, while the ECG is computed with the lead-field approach. Both solvers were implemented on graphics processing units and massively parallelized. We studied the numerical convergence and scalability of the approach. We also compared the method to the bidomain model in terms of ECGs and activation maps, using a simplified but physiologically motivated geometry and 6 patient-specific anatomies. The proposed methods provided a good approximation of activation maps and ECGs computed with a bidomain model, in only a few seconds. Both solvers scaled very well to high-end hardware. These methods are suitable for use in ECG imaging methods, and may soon become fast enough for use in interactive simulation tools.
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http://dx.doi.org/10.3389/fphys.2017.00265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411438PMC
May 2017

The relation between local repolarization and T-wave morphology in heart failure patients.

Int J Cardiol 2017 Aug 22;241:270-276. Epub 2017 Feb 22.

Maastricht University, Maastricht, The Netherlands. Electronic address:

Background: Both duration and morphology of the T-wave are regarded important parameters describing repolarization of the ventricles. Conventionally, T-wave concordance is explained by an inverse relation between the time of depolarization (TD) and repolarization (TR). Little is known about T-wave morphology and TD-TR relations in patients with heart failure.

Methods: Electro-anatomic maps were obtained in the left (LV) and right ventricle (RV) and in the coronary sinus (CS) in patients with heart failure with narrow (nQRS, n=8) and wide QRS complex with (LBBB, n=15) and without left bundle branch block (non-LBBB, n=7). TD and TR were determined from the thus acquired electrograms.

Results: In nQRS and non-LBBB patients, TD-TR relations had a slope between 0 and +1, indicating that repolarization followed the sequence of depolarization. In LBBB patients, repolarization occurred significantly earlier in the RV than in the LV, fitting with the idea that the discordant T-waves in LBBB are secondary to the abnormal depolarization sequence. However, the slopes of the TD-TR relations in the LV and CS were not significantly different from zero, indicating no major spatial gradient in LV repolarization, despite a considerable gradient in depolarization. Remarkable was also the large (~100ms) transseptal gradient in repolarization. Values of the slopes of the TD-TR relation overlapped between the three patient groups, despite a difference in T-wave morphology between LBBB (all discordant) and nQRS patients (all flat/biphasic).

Conclusions: Discordant T-waves in LBBB patients are explained by interventricular dispersion in repolarization. T-wave morphology is determined by more factors than the TD-TR relation alone.
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http://dx.doi.org/10.1016/j.ijcard.2017.02.056DOI Listing
August 2017

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

Reduced Sodium Current in the Lateral Ventricular Wall Induces Inferolateral J-Waves.

Front Physiol 2016 26;7:365. Epub 2016 Aug 26.

Department of Clinical and Experimental Cardiology, Academic Medical CenterAmsterdam, Netherlands; Electrophysiology and Heart Modeling Institute LIRYC, Université de BordeauxBordeaux, France.

Background: J-waves in inferolateral leads are associated with a higher risk for idiopathic ventricular fibrillation. We aimed to test potential mechanisms (depolarization or repolarization dependent) responsible for inferolateral J-waves. We hypothesized that inferolateral J-waves can be caused by regional delayed activation of myocardium that is activated late during normal conditions.

Methods: Computer simulations were performed to evaluate how J-point elevation is influenced by reducing sodium current conductivity (GNa), increasing transient outward current conductivity (Gto), or cellular uncoupling in three predefined ventricular regions (lateral, anterior, or septal). Two pig hearts were Langendorff-perfused with selective perfusion with a sodium channel blocker of lateral or anterior/septal regions. Volume-conducted pseudo-electrocardiograms (ECG) were recorded to detect the presence of J-waves. Epicardial unipolar electrograms were simultaneously recorded to obtain activation times (AT).

Results: Simulation data showed that conduction slowing, caused by reduced sodium current, in lateral, but not in other regions induced inferolateral J-waves. An increase in transient outward potassium current or cellular uncoupling in the lateral zone elicited slight J-point elevations which did not meet J-wave criteria. Additional conduction slowing in the entire heart attenuated J-waves and J-point elevations on the ECG, because of masking by the QRS. Experimental data confirmed that conduction slowing attributed to sodium channel blockade in the left lateral but not in the anterior/septal ventricular region induced inferolateral J-waves. J-waves coincided with the delayed activation.

Conclusion: Reduced sodium current in the left lateral ventricular myocardium can cause inferolateral J-waves on the ECG.
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http://dx.doi.org/10.3389/fphys.2016.00365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5000556PMC
September 2016

Spatially Coherent Activation Maps for Electrocardiographic Imaging.

IEEE Trans Biomed Eng 2017 05 19;64(5):1149-1156. Epub 2016 Jul 19.

Objective: Cardiac mapping is an important diagnostic step in cardiac electrophysiology. One of its purposes is to generate a map of the depolarization sequence. This map is constructed in clinical routine either by directly analyzing cardiac electrograms (EGMs) recorded invasively or an estimate of these EGMs obtained by a noninvasive technique. Activation maps based on noninvasively estimated EGMs often show artefactual jumps in activation times. To overcome this problem, we present a new method to construct the activation maps from reconstructed unipolar EGMs.

Methods: On top of the standard estimation of local activation time from unipolar intrinsic deflections, we propose to mutually compare the EGMs in order to estimate the delays in activation for neighboring recording locations. We then describe a workflow to construct a spatially coherent activation map from local activation times and delay estimates in order to create more accurate maps. The method is optimized using simulated data and evaluated on clinical data from 12 different activation sequences.

Results: We found that the standard methodology created lines of artificially strong activation time gradient. The proposed workflow enhanced these maps significantly.

Conclusion: Estimating delays between neighbors is an interesting option for activation map computation in electrocardiographic imaging.
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http://dx.doi.org/10.1109/TBME.2016.2593003DOI Listing
May 2017

P-wave complexity in normal subjects and computer models.

J Electrocardiol 2016 Jul-Aug;49(4):545-53. Epub 2016 May 12.

Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.

Background: P waves reported in electrocardiology literature uniformly appear smooth. Computer simulation and signal analysis studies have shown much more complex shapes.

Objective: We systematically investigated P-wave complexity in normal volunteers using high-fidelity electrocardiographic techniques without filtering.

Methods: We recorded 5-min multichannel ECGs in 16 healthy volunteers. Noise and interference were reduced by averaging over 300 beats per recording. In addition, normal P waves were simulated with a realistic model of the human atria.

Results: Measured P waves had an average of 4.1 peaks (range 1-10) that were reproducible between recordings. Simulated P waves demonstrated similar complexity, which was related to structural discontinuities in the computer model of the atria.

Conclusion: The true shape of the P wave is very irregular and is best seen in ECGs averaged over many beats.
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http://dx.doi.org/10.1016/j.jelectrocard.2016.05.005DOI Listing
November 2017

Segmentation of the left ventricular endocardium from magnetic resonance images by using different statistical shape models.

J Electrocardiol 2016 May-Jun;49(3):383-91. Epub 2016 Mar 9.

Dipartimento di Elettronica, Informazione e Bioingegneria, Politecnico di Milano, Italy.

We evaluate in this paper different strategies for the construction of a statistical shape model (SSM) of the left ventricle (LV) to be used for segmentation in cardiac magnetic resonance (CMR) images. From a large database of LV surfaces obtained throughout the cardiac cycle from 3D echocardiographic (3DE) LV images, different LV shape models were built by varying the considered phase in the cardiac cycle and the registration procedure employed for surface alignment. Principal component analysis was computed to describe the statistical variability of the SSMs, which were then deformed by applying an active shape model (ASM) approach to segment the LV endocardium in CMR images of 45 patients. Segmentation performance was evaluated by comparing LV volumes derived by ASM segmentation with different SSMs and those obtained by manual tracing, considered as a reference. A high correlation (r(2)>0.92) was found in all cases, with better results when using the SSM models comprising more than one frame of the cardiac cycle.
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http://dx.doi.org/10.1016/j.jelectrocard.2016.03.017DOI Listing
November 2017

Computer Modelling for Better Diagnosis and Therapy of Patients by Cardiac Resynchronisation Therapy.

Arrhythm Electrophysiol Rev 2015 May 10;4(1):62-7. Epub 2015 Mar 10.

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

Mathematical or computer models have become increasingly popular in biomedical science. Although they are a simplification of reality, computer models are able to link a multitude of processes to each other. In the fields of cardiac physiology and cardiology, models can be used to describe the combined activity of all ion channels (electrical models) or contraction-related processes (mechanical models) in potentially millions of cardiac cells. Electromechanical models go one step further by coupling electrical and mechanical processes and incorporating mechano-electrical feedback. The field of cardiac computer modelling is making rapid progress due to advances in research and the ever-increasing calculation power of computers. Computer models have helped to provide better understanding of disease mechanisms and treatment. The ultimate goal will be to create patient-specific models using diagnostic measurements from the individual patient. This paper gives a brief overview of computer models in the field of cardiology and mentions some scientific achievements and clinical applications, especially in relation to cardiac resynchronisation therapy (CRT).
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http://dx.doi.org/10.15420/aer.2015.4.1.62DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4711552PMC
May 2015

The Early Repolarization Pattern: A Consensus Paper.

J Am Coll Cardiol 2015 Jul;66(4):470-7

Lankenau Institute for Medical Research, Wynnewood, Pennsylvania.

The term early repolarization has been in use for more than 50 years. This electrocardiographic pattern was considered benign until 2008, when it was linked to sudden cardiac arrest due to idiopathic ventricular fibrillation. Much confusion over the definition of early repolarization followed. Thus, the objective of this paper was to prepare an agreed definition to facilitate future research in this area. The different definitions of the early repolarization pattern were reviewed to delineate the electrocardiographic measures to be used when defining this pattern. An agreed definition has been established, which requires the peak of an end-QRS notch and/or the onset of an end-QRS slur as a measure, denoted Jp, to be determined when an interpretation of early repolarization is being considered. One condition for early repolarization to be present is Jp ≥0.1 mV, while ST-segment elevation is not a required criterion.
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http://dx.doi.org/10.1016/j.jacc.2015.05.033DOI Listing
July 2015

An in-silico analysis of the effect of heart position and orientation on the ECG morphology and vectorcardiogram parameters in patients with heart failure and intraventricular conduction defects.

J Electrocardiol 2015 Jul-Aug;48(4):617-25. Epub 2015 May 8.

Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera italiana, Lugano, Switzerland; Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland.

Aim: The aim of this study was to investigate the influence of geometrical factors on the ECG morphology and vectorcardiogram (VCG) parameters.

Methods: Patient-tailored models based on five heart-failure patients with intraventricular conduction defects (IVCDs) were created. The heart was shifted up to 6 cm to the left, right, up, and down and rotated ±30° around the anteroposterior axis. Precordial electrodes were shifted 3 cm down.

Results: Geometry modifications strongly altered ECG notching/slurring and intrinsicoid deflection time. Maximum VCG parameter changes were small for QRS duration (-6% to +10%) and QRS-T angle (-6% to +3%), but considerable for QRS amplitude (-36% to +59%), QRS area (-37% to +42%), T-wave amplitude (-41% to +36%), and T-wave area (-42% to +33%).

Conclusion: The position of the heart with respect to the electrodes is an important factor determining notching/slurring and voltage-dependent parameters and therefore must be considered for accurate diagnosis of IVCDs.
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http://dx.doi.org/10.1016/j.jelectrocard.2015.05.004DOI Listing
March 2016

In vivo electromechanical assessment of heart failure patients with prolonged QRS duration.

Heart Rhythm 2015 Jun 5;12(6):1259-67. Epub 2015 Mar 5.

Center for Computational Medicine in Cardiology, Institute of Computational Science, University of Lugano, Lugano, Switzerland; Division of Cardiology, Fondazione Cardiocentro Ticino, Lugano, Switzerland. Electronic address:

Background: Combined measurement of electrical activation and mechanical dyssynchrony in heart failure (HF) patients is scarce but may contain important mechanistic and diagnostic clues.

Objective: The purpose of this study was to characterize the electromechanical (EM) coupling in HF patients with prolonged QRS duration.

Methods: Ten patients with QRS width >120 ms underwent left ventricular (LV) electroanatomic contact mapping using the Noga® XP system (Biosense Webster). Recorded voltages during the cardiac cycle were converted to maps of depolarization time (TD). Electrode positions were tracked and converted into maps of time-to-peak shortening (TPS) using custom-made deformation analysis software. Correlation analysis was performed between the 2 maps to quantify EM coupling. Simulations with the CircAdapt cardiovascular system model were performed to mechanistically unravel the observed relation between TD and TPS.

Results: The delay between earliest LV electrical activation and peak shortening differed considerably between patients (TPSmin-TDmin = 360 ± 73 ms). On average, total mechanical dyssynchrony exceeded total electrical activation (ΔTPS = 177 ± 47 ms vs ΔTD = 93 ± 24 ms, P <.001), but a large interpatient variability was observed. The TD and TPS maps correlated strongly in all patients (median R = 0.87, P <.001). These correlations were similar for regions with unipolar voltages above and below 6mV (Mann-Whitney U test, P = .93). Computer simulations revealed that increased passive myocardial stiffness decreases ΔTPS relative to ΔTD and that lower contractility predominantly increases TPSmin-TDmin.

Conclusion: EM coupling in HF patients is maintained, but the relationship between TD and TPS differs strongly between patients. Intra-individual and inter-individual differences may be explained by local and global differences in passive and contractile myocardial properties.
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http://dx.doi.org/10.1016/j.hrthm.2015.03.006DOI Listing
June 2015

Patient-specific modelling of cardiac electrophysiology in heart-failure patients.

Europace 2014 Nov;16 Suppl 4:iv56-iv61

Center for Computational Medicine in Cardiology, Faculty of Informatics, Università della Svizzera italiana, Via Giuseppe Buffi 13, 6904 Lugano, Switzerland Division of Cardiology, Fondazione Cardiocentro Ticino, 6904 Lugano, Switzerland.

Aims: Left-ventricular (LV) conduction disturbances are common in heart-failure patients and a left bundle-branch block (LBBB) electrocardiogram (ECG) type is often seen. The precise cause of this pattern is uncertain and is probably variable between patients, ranging from proximal interruption of the left bundle branch to diffuse distal conduction disease in the working myocardium. Using realistic numerical simulation methods and patient-tailored model anatomies, we investigated different hypotheses to explain the observed activation order on the LV endocardium, electrogram morphologies, and ECG features in two patients with heart failure and LBBB ECG.

Methods And Results: Ventricular electrical activity was simulated using reaction-diffusion models with patient-specific anatomies. From the simulated action potentials, ECGs and cardiac electrograms were computed by solving the bidomain equation. Model parameters such as earliest activation sites, tissue conductivity, and densities of ionic currents were tuned to reproduce the measured signals. Electrocardiogram morphology and activation order could be matched simultaneously. Local electrograms matched well at some sites, but overall the measured waveforms had deeper S-waves than the simulated waveforms.

Conclusion: Tuning a reaction-diffusion model of the human heart to reproduce measured ECGs and electrograms is feasible and may provide insights in individual disease characteristics that cannot be obtained by other means.
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http://dx.doi.org/10.1093/europace/euu257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4217520PMC
November 2014

Critical appraisal of the mechanism underlying J waves.

J Electrocardiol 2013 Sep-Oct;46(5):390-4. Epub 2013 Jul 16.

St. Antonius Hospital, Department of Cardiology, Nieuwegein, The Netherlands.

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http://dx.doi.org/10.1016/j.jelectrocard.2013.06.017DOI Listing
March 2014

Similarities and differences between electrocardiogram signs of left bundle-branch block and left-ventricular uncoupling.

Europace 2012 Nov;14 Suppl 5:v33-v39

Institute of Computational Science, Faculty of Informatics, Università della Svizzera italiana, Via Giuseppe Buffi 13, Lugano, Switzerland.

Aims: A left bundle-branch block (LBBB) electrocardiogram (ECG) type may be caused by either a block in the left branch of the ventricular conduction system or by uncoupling in the working myocardium. We used a realistic large-scale computer model to evaluate the effects of uncoupling with and without left-sided block and in combination with biventricular pacing.

Methods And Results: Action potential propagation was simulated using a reaction-diffusion model of the human ventricles. Electrocardiograms and cardiac electrograms were computed from the simulated action potentials by solving the bidomain equations. In all situations, diffuse uncoupling reduced QRS amplitude, prolonged QRS duration, and rotated the QRS axis leftward. Uncoupling by 50% increased QRS duration from 90 to 120 ms with a normal conduction system and from 140 to 190 ms when the left bundle branch was blocked. Biventricular pacing did not change QRS duration but reduced total ventricular activation time.

Conclusion: Uncoupling in the working myocardium can mimic left-sided block in the ventricular conduction system and can explain an LBBB ECG pattern with relatively low amplitude. Biventricular pacing improves ventricular activation in true LBBB with or without uncoupling but not in case of 50% uncoupling alone.
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http://dx.doi.org/10.1093/europace/eus272DOI Listing
November 2012

A computer model of endo-epicardial electrical dissociation and transmural conduction during atrial fibrillation.

Europace 2012 Nov;14 Suppl 5:v10-v16

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

Aims: Structural alterations during atrial fibrillation (AF) not only lead to electrical dissociation within the epicardial layer, but also between the epicardial layer and the endocardial bundle network. The aim of the study was to investigate the role of transmural conduction in the stability of AF episodes using a dual-layer computer model.

Methods And Results: A proof-of-principle dual-layer model was developed in which connections between the layers can be introduced or removed at any time during the simulation. Using an S1-S2 protocol, a spiral wave was initiated in one of the layers, which degenerated into a complex AF pattern after connection with the other layer at six randomly chosen sites. After 6 s, connections were either retained (dual-layer simulations) or removed (single-layer simulations). Dual-layer simulations were more complex, as indicated by the higher number of waves and phase singularities. Tracking waves through both layers revealed that the number of waves in dual-layer simulations was significantly higher than in the single-layer simulations, reflecting more opportunities for reentry and a concomitant increase in AF stability. In the dual-layer model, only 12% of the AF episodes died out within 6 s, while 59% died out in the single-layer model.

Conclusion: Atrial fibrillation patterns are more complex and AF episodes are more stable in a dual-layer model. This study indicates an important role for endo-epicardial conduction for the stabilization of AF.
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http://dx.doi.org/10.1093/europace/eus270DOI Listing
November 2012

Computer simulation of ECG manifestations of left ventricular electrical remodeling.

J Electrocardiol 2012 Nov-Dec;45(6):630-4. Epub 2012 Sep 7.

International Laser Center, Bratislava, Slovak Republic.

An increased QRS voltage is considered to be specific for the electrocardiogram (ECG) diagnosis of left ventricular hypertrophy (LVH). However, the QRS-complex patterns in patients with LVH cover a broader spectrum: increased QRS voltage, prolonged QRS duration, left axis deviation, and left anterior fascicular block- and left bundle branch block-like patterns, as well as pseudo-normal QRS patterns. The classical interpretation of the QRS patterns in LVH relates these changes to increased left ventricular mass (LVM) per se, while tending to neglect the modified active and passive electrical properties of the myocardium. However, it has been well documented that both active and passive electrical properties in LVH are altered. Using computer simulations, we have shown that an increased LVM is not the only determinant of QRS complex changes in LVH, as these changes could also be produced without changing the left ventricular mass, implying that these QRS patterns can be present in patients before their LVM exceeds the arbitrary upper normal limits. Our results link the experimental evidence on electrical remodeling with clinical interpretation of ECG changes in patients with LVH and stress the necessity of a complex interpretation of the QRS patterns considering both spatial and nonspatial determinants in terms of the spatial angle theory. We assume that hypertrophic electrical remodeling in combination with changes in left ventricular size and shape explains the variety of ECG patterns as well as the discrepancies between ECG and left ventricular mass.
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http://dx.doi.org/10.1016/j.jelectrocard.2012.07.009DOI Listing
May 2013