Publications by authors named "Rolf Krause"

28 Publications

  • Page 1 of 1

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

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

A trainable clustering algorithm based on shortest paths from density peaks.

Sci Adv 2019 10 30;5(10):eaax3770. Epub 2019 Oct 30.

Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana, CH6500 Bellinzona, Switzerland.

Clustering is a technique to analyze empirical data, with a major application for biomedical research. Essentially, clustering finds groups of related points in a dataset. However, results depend on both metrics for point-to-point similarity and rules for point-to-group association. Non-appropriate metrics and rules can lead to artifacts, especially in case of multiple groups with heterogeneous structure. In this work, we propose a clustering algorithm that evaluates the properties of paths between points (rather than point-to-point similarity) and solves a global optimization problem, finding solutions not obtainable by methods relying on local choices. Moreover, our algorithm is trainable. Hence, it can be adapted and adopted for specific datasets and applications by providing examples of valid and invalid paths to train a path classifier. We demonstrate its applicability to identify heterogeneous groups in challenging synthetic datasets, segment highly nonconvex immune cells in confocal microscopy images, and classify arrhythmic heartbeats in electrocardiographic signals.
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http://dx.doi.org/10.1126/sciadv.aax3770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051829PMC
October 2019

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 influence of scar on the spatio-temporal relationship between electrical and mechanical activation in heart failure patients.

Europace 2020 05;22(5):777-786

Center for Computational Medicine in Cardiology, Università della Svizzera italiana, Via G. Buffi 13, CH-6900 Lugano, Switzerland.

Aims: The aim of this study was to determine the relationship between electrical and mechanical activation in heart failure (HF) patients and whether electromechanical coupling is affected by scar.

Methods And Results: Seventy HF patients referred for cardiac resynchronization therapy or biological therapy underwent endocardial anatomo-electromechanical mapping (AEMM) and delayed-enhancement magnetic resonance (CMR) scans. Area strain and activation times were derived from AEMM data, allowing to correlate mechanical and electrical activation in time and space with unprecedented accuracy. Special attention was paid to the effect of presence of CMR-evidenced scar. Patients were divided into a scar (n = 43) and a non-scar group (n-27). Correlation between time of electrical and mechanical activation was stronger in the non-scar compared to the scar group [R = 0.84 (0.72-0.89) vs. 0.74 (0.52-0.88), respectively; P = 0.01]. The overlap between latest electrical and mechanical activation areas was larger in the absence than in presence of scar [72% (54-81) vs. 56% (36-73), respectively; P = 0.02], with smaller distance between the centroids of the two regions [10.7 (4.9-17.4) vs. 20.3 (6.9-29.4) % of left ventricular radius, P = 0.02].

Conclusion: Scar decreases the association between electrical and mechanical activation, even when scar is remote from late activated regions.
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http://dx.doi.org/10.1093/europace/euz346DOI Listing
May 2020

Characterization of the Dynamic Behavior of Neutrophils Following Influenza Vaccination.

Front Immunol 2019 20;10:2621. Epub 2019 Nov 20.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.

Neutrophils are amongst the first cells to respond to inflammation and infection. Although they play a key role in limiting the dissemination of pathogens, the study of their dynamic behavior in immune organs remains elusive. In this work, we characterized the dynamic behavior of neutrophils in the mouse popliteal lymph node (PLN) after influenza vaccination with UV-inactivated virus. To achieve this, we used an image-based systems biology approach to detect the motility patterns of neutrophils and to associate them to distinct actions. We described a prominent and rapid recruitment of neutrophils to the PLN following vaccination, which was dependent on the secretion of the chemokine CXCL1 and the alarmin molecule IL-1α. In addition, we observed that the initial recruitment occurred mainly via high endothelial venules located in the paracortical and interfollicular regions of the PLN. The analysis of the spatial-temporal patterns of neutrophil migration demonstrated that, in the initial stage, the majority of neutrophils displayed a patrolling behavior, followed by the formation of swarms in the subcapsular sinus of the PLN, which were associated with macrophages in this compartment. Finally, we observed using multiple imaging techniques, that neutrophils phagocytize and transport influenza virus particles. These processes might have important implications in the capacity of these cells to present viral antigens.
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http://dx.doi.org/10.3389/fimmu.2019.02621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881817PMC
November 2020

9th Theo Rossi di Montelera forum on computer simulation and experimental assessment of cardiac function: from model to clinical outcome.

Europace 2018 11;20(suppl_3):iii1-iii2

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

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http://dx.doi.org/10.1093/europace/euy256DOI Listing
November 2018

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

Leukocyte Tracking Database, a collection of immune cell tracks from intravital 2-photon microscopy videos.

Sci Data 2018 07 17;5:180129. Epub 2018 Jul 17.

Institute for Research in Biomedicine (IRB), Università della Svizzera italiana. Via Vincenzo Vela 6, 6500 Bellinzona, Switzerland.

Recent advances in intravital video microscopy have allowed the visualization of leukocyte behavior in vivo, revealing unprecedented spatiotemporal dynamics of immune cell interaction. However, state-of-the-art software and methods for automatically measuring cell migration exhibit limitations in tracking the position of leukocytes over time. Challenges arise both from the complex migration patterns of these cells and from the experimental artifacts introduced during image acquisition. Additionally, the development of novel tracking tools is hampered by the lack of a sound ground truth for algorithm validation and benchmarking. Therefore, the objective of this work was to create a database, namely LTDB, with a significant number of manually tracked leukocytes. Broad experimental conditions, sites of imaging, types of immune cells and challenging case studies were included to foster the development of robust computer vision techniques for imaging-based immunological research. Lastly, LTDB represents a step towards the unravelling of biological mechanisms by video data mining in systems biology.
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http://dx.doi.org/10.1038/sdata.2018.129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6049032PMC
July 2018

Integrated Assessment of Left Ventricular Electrical Activation and Myocardial Strain Mapping in Heart Failure Patients: A Holistic Diagnostic Approach for Endocardial Cardiac Resynchronization Therapy, Ablation of Ventricular Tachycardia, and Biological Therapy.

JACC Clin Electrophysiol 2018 01 6;4(1):138-146. Epub 2017 Nov 6.

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

Objectives: This study sought to test the accuracy of strain measurements based on anatomo-electromechanical mapping (AEMM) measurements compared with magnetic resonance imaging (MRI) tagging, to evaluate the diagnostic value of AEMM-based strain measurements in the assessment of myocardial viability, and the additional value of AEMM over peak-to-peak local voltages.

Background: The in vivo identification of viable tissue, evaluation of mechanical contraction, and simultaneous left ventricular activation is currently achieved using multiple complementary techniques.

Methods: In 33 patients, AEMM maps (NOGA XP, Biologic Delivery Systems, Division of Biosense Webster, a Johnson & Johnson Company, Irwindale, California) and MRI images (Siemens 3T, Siemens Healthcare, Erlangen, Germany) were obtained within 1 month. MRI tagging was used to determine circumferential strain (E) and delayed enhancement to obtain local scar extent (%). Custom software was used to measure E and local area strain (LAS) from the motion field of the AEMM catheter tip.

Results: Intertechnique agreement for E was good (R = 0.80), with nonsignificant bias (0.01 strain units) and narrow limits of agreement (-0.03 to 0.06). Scar segments showed lower absolute strain amplitudes compared with nonscar segments: E (median [first to third quartile]: nonscar -0.10 [-0.15 to -0.06] vs. scar -0.04 [-0.06 to -0.02]) and LAS (-0.20 [-0.27 to -0.14] vs. -0.09 [-0.14 to -0.06]). AEMM strains accurately discriminated between scar and nonscar segments, in particular LAS (area under the curve: 0.84, accuracy = 0.76), which was superior to peak-to-peak voltages (nonscar 9.5 [6.5 to 13.3] mV vs. scar 5.6 [3.4 to 8.3] mV; area under the curve: 0.75). Combination of LAS and peak-to-peak voltages resulted in 86% accuracy.

Conclusions: An integrated AEMM approach can accurately determine local deformation and correlates with the scar extent. This approach has potential immediate application in the diagnosis, delivery of intracardiac therapies, and their intraprocedural evaluation.
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http://dx.doi.org/10.1016/j.jacep.2017.08.011DOI Listing
January 2018

Evaluation of the use of unipolar voltage amplitudes for detection of myocardial scar assessed by cardiac magnetic resonance imaging in heart failure patients.

PLoS One 2017 5;12(7):e0180637. Epub 2017 Jul 5.

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

Background: Validation of voltage-based scar delineation has been limited to small populations using mainly endocardial measurements. The aim of this study is to compare unipolar voltage amplitudes (UnipV) with scar on delayed enhancement cardiac magnetic resonance imaging (DE-CMR).

Methods: Heart failure patients who underwent DE-CMR and electro-anatomic mapping were included. Thirty-three endocardial mapped patients and 27 epicardial mapped patients were investigated. UnipV were computed peak-to-peak. Electrograms were matched with scar extent of the corresponding DE-CMR segment using a 16-segment/slice model. Non-scar was defined as 0% scar, while scar was defined as 1-100% scar extent.

Results: UnipVs were moderately lower in scar than in non-scar (endocardial 7.1 [4.6-10.6] vs. 10.3 [7.4-14.2] mV; epicardial 6.7 [3.6-10.5] vs. 7.8 [4.2-12.3] mV; both p<0.001). The correlation between UnipV and scar extent was moderate for endocardial (R = -0.33, p<0.001), and poor for epicardial measurements (R = -0.07, p<0.001). Endocardial UnipV predicted segments with >25%, >50% and >75% scar extent with AUCs of 0.72, 0.73 and 0.76, respectively, while epicardial UnipV were poor scar predictors, independent of scar burden (AUC = 0.47-0.56). UnipV in non-scar varied widely between patients (p<0.001) and were lower in scar compared to non-scar in only 9/22 (41%) endocardial mapped patients and 4/19 (21%) epicardial mapped patients with scar.

Conclusion: UnipV are slightly lower in scar compared to non-scar. However, significant UnipV differences between and within patients and large overlap between non-scar and scar limits the reliability of accurate scar assessment, especially in epicardial measurements and in segments with less than 75% scar extent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180637PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498065PMC
October 2017

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

Single or Multiple Access Channels to the CYP450s Active Site? An Answer from Free Energy Simulations of the Human Aromatase Enzyme.

J Phys Chem Lett 2017 May 24;8(9):2036-2042. Epub 2017 Apr 24.

Institute for Research in Biomedicine (IRB), Università della Svizzera Italiana (USI) , Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland.

Cytochromes P450 (CYP450s), in particular, CYP19A1 and CYP17A1, are key clinical targets of breast and prostate anticancer therapies, critical players in drug metabolism, and their overexpression in tumors is associated with drug resistance. In these enzymes, ligand (substrates, drugs) metabolism occurs in deeply buried active sites accessible only via several grueling channels, whose exact biological role remains unclear. Gaining direct insights on the mechanism by which ligands travel in and out is becoming increasingly important given that channels are involved in the modulation of binding/dissociation kinetics and the specificity of ligands toward a CYP450. This has profound implications for enzymatic efficiency and drug efficacy/toxicity. Here, by applying free energy methods, for a cumulative simulation time of 20 μs, we provide detailed atomistic characterization and free energy profiles of the entry/exit routes preferentially followed by a substrate (androstenedione) and a last-generation inhibitor (letrozole) to/from the catalytic site of CYP19A1 (the human aromatase (HA) enzyme), a key clinical target against breast cancer, studied here as prototypical CYP450. Despite the remarkably different size/shape/hydrophobicity of the ligands, two channels appear accessible to their entrance, while only one exit route appears to be preferential. Our study shows that the preferential paths may be conserved among different CYP450s. Moreover, our results highlight that, at least in the case of HA, ligand channeling is associated with large enzyme structural rearrangements. A wise choice of the computational method and very long simulations are, thus, required to obtain fully converged quantitative free energy profiles, which might be used to design novel biocatalysts or next-generation cytochrome inhibitors with an in silico tuned K.
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http://dx.doi.org/10.1021/acs.jpclett.7b00697DOI Listing
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

Impact of mechanical deformation on pseudo-ECG: a simulation study.

Europace 2016 Dec;18(suppl 4):iv77-iv84

Center for Computational Medicine in Cardiology, Institute of Computational Science, Università della Svizzera Italiana, Via Giuseppe Buffi 13, Lugano CH-6900, Switzerland.

Aims: Electrophysiological simulations may help to investigate causes and possible treatments of ventricular conduction disturbances. Most electrophysiological models do not take into account that the heart moves during the cardiac cycle. We used an electro-mechanical model to study the effect of mechanical deformation on the results of electrophysiological simulations.

Methods And Results: Pseudo-electrocardiogram (ECG) were generated from the propagation of electrical signals in tissue slabs undergoing active mechanical deformation. We used the mono-domain equation for electrophysiology with the Bueno-Orovio ionic model and a fully incompressible Guccione-Costa hyperelastic law for the mechanics with the Nash-Panfilov model for the active force. We compared a purely electrophysiological approach (PE) with mono-directional (MD) and bi-directional (BD) electromechanical coupling strategies. The numerical experiments showed that BD and PE simulations led to different S- and T-waves. Mono-directional simulations generally approximated the BD ones, unless fibres were oriented along one short axis of the slab. When present, notching in the QRS-complex was larger in MD than in BD simulations.

Conclusions: Tissue deformation has to be taken into account when estimating the S- and T-wave of the ECG in electrophysiological simulations.
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http://dx.doi.org/10.1093/europace/euw353DOI Listing
December 2016

Changes in P-wave morphology after pulmonary vein isolation: insights from computer simulations.

Europace 2016 Dec;18(suppl 4):iv23-iv34

Département de Physiologie Moléculaire et Intégrative, Institut de Génie Biomédical, Université de Montréal, Montréal, QC, Canada

Aims: Apparently conflicting clinical measurements of P-wave duration (PWD) pre- vs. post-ablation have been reported. To assist the interpretation of these clinical data, we used a computer model of the atria and torso to simulate P waves before and after pulmonary vein (PV) isolation.

Methods And Results: Twenty ablation patterns were designed (segmental or ipsilateral ablation; five distances to PV sleeves; addition of a roof line or not). Possible PV reconnections were introduced as gaps in the ablation lines. PWD and area were measured during sinus rhythm in vectorcardiogram (VCG) magnitude signals and on the 16-lead ECG before and after ablation, and after PV reconnection. After PV isolation, biatrial activation time was prolonged by 0-5 ms without and by 48±5 ms with roof line. Yet PWD was shortened in lead V3 and V4 by up to 15 ms. The effect of ablation on P-wave morphology was stronger when larger PV areas were isolated. Segmental and ipsilateral PV isolation led to concordant results. P-wave area increased in V1 and decreased in V6. Changes in PWD and area on the VCG were sensitive to the threshold used for detecting the end of the P wave. The occurrence of PV reconnection was best identified on leads V3, V4, and V9.

Conclusion: PV isolation and reconnection induced measurable changes on the 16-lead ECG that might be used to improve patient follow-up after ablation.
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http://dx.doi.org/10.1093/europace/euw348DOI Listing
December 2016

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

Verification of cardiac mechanics software: benchmark problems and solutions for testing active and passive material behaviour.

Proc Math Phys Eng Sci 2015 Dec;471(2184):20150641

Department of Biomedical Engineering, King's College London , London, UK.

Models of cardiac mechanics are increasingly used to investigate cardiac physiology. These models are characterized by a high level of complexity, including the particular anisotropic material properties of biological tissue and the actively contracting material. A large number of independent simulation codes have been developed, but a consistent way of verifying the accuracy and replicability of simulations is lacking. To aid in the verification of current and future cardiac mechanics solvers, this study provides three benchmark problems for cardiac mechanics. These benchmark problems test the ability to accurately simulate pressure-type forces that depend on the deformed objects geometry, anisotropic and spatially varying material properties similar to those seen in the left ventricle and active contractile forces. The benchmark was solved by 11 different groups to generate consensus solutions, with typical differences in higher-resolution solutions at approximately 0.5%, and consistent results between linear, quadratic and cubic finite elements as well as different approaches to simulating incompressible materials. Online tools and solutions are made available to allow these tests to be effectively used in verification of future cardiac mechanics software.
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http://dx.doi.org/10.1098/rspa.2015.0641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707707PMC
December 2015

Molecular Determinants for Unphosphorylated STAT3 Dimerization Determined by Integrative Modeling.

Biochemistry 2015 Sep 25;54(35):5489-501. Epub 2015 Aug 25.

Institute of Research in Biomedicine (IRB) and Universitá della Svizzera italiana (USI) , Via Vincenzo Vela 6, CH-6500 Bellinzona, Switzerland.

Signal transducer and activator of transcription factors (STATs) are proteins that can translocate into the nucleus, bind DNA, and activate gene transcription. STAT proteins play a crucial role in cell proliferation, apoptosis, and differentiation. The prevalent view is that STAT proteins are able to form dimers and bind DNA only upon phosphorylation of specific tyrosine residues in the transactivation domain. However, this paradigm has been questioned recently by the observation of dimers of unphosphorylated STATs (USTATs) by X-ray, Förster resonance energy transfer, and site-directed mutagenesis. A more complex picture of the dimerization process and of the role of the dimers is, thus, emerging. Here we present an integrated modeling study of STAT3, a member of the STAT family of utmost importance in cancer development and therapy, in which we combine available experimental data with several computational methodologies such as homology modeling, protein-protein docking, and molecular dynamics to build reliable atomistic models of USTAT3 dimers. The models generated with the integrative approach presented here were then validated by performing computational alanine scanning for all the residues in the protein-protein interface. These results confirmed the experimental observation of the importance of some of these residues (in particular Leu78 and Asp19) in the USTAT3 dimerization process. Given the growing importance of USTAT3 dimers in several cellular pathways, our models provide an important tool for studying the effects of pathological mutations at the molecular and/or atomistic level, and in the rational design of new inhibitors of dimerization.
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http://dx.doi.org/10.1021/bi501529xDOI Listing
September 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

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

Validation of a heterogeneous elastic-biphasic model for the numerical simulation of the PDL.

Comput Methods Biomech Biomed Engin 2013 22;16(5):544-53. Epub 2012 Mar 22.

Institute of Computational Science, University of Lugano, Lugano, Switzerland.

An elastic-biphasic model for the simulation of the periodontal ligament (PDL) and the adjacent tooth is presented and investigated. The PDL is modelled as a biphasic material following the work of Ehlers and Markert (2001 ), whereas the tooth is modelled as a linear elastic body. A spatial discretisation scheme is proposed based on mixed finite elements for the spatial discretisation. Due to nonlinearity in the model, a predictor-corrector scheme is employed as a temporal discretisation scheme. In order to validate the PDL model, in vitro measurements are compared with numerical simulations. The numerical simulations are performed using geometries resulting from micro-CT scanner of the same porcine tooth, which was employed for the in vitro measurements.
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http://dx.doi.org/10.1080/10255842.2011.628660DOI Listing
February 2014

The time-dependent biomechanical behaviour of the periodontal ligament--an in vitro experimental study in minipig mandibular two-rooted premolars.

Eur J Orthod 2014 Feb 22;36(1):9-15. Epub 2011 Nov 22.

Oral Technology, University of Bonn, Germany.

The aim of the present work was to evaluate the biomechanical behaviour of the periodontal ligament (PDL) with respect to force development with different controlled loading velocities. For this purpose, an in vitro experimental study was performed on 18 minipig jaw segments. Displacements with variable increasing loading time were applied to one premolar crown of each jaw segment into the linguobuccal direction through a force sensor provided by a specialized biomechanical set-up. The predefined displacement values to be achieved were 0.1 and 0.2 mm. Each of the given displacement increments was applied on the specimens with a linear displacement increase employing the following time spans: 5, 10, 20, 30, 60, 120, 300, 450, and 600 seconds. Force values were measured during load application to register force/displacement diagrams and after the maximum displacement was reached force decay was monitored for a period of 600 seconds. Force/time curves for each tooth were plotted according to the data obtained. Diagrams of the maximum force values obtained from these plots and the force at the end of each measurement were extracted for all teeth. Forces at the point when maximum displacement was reached ranged from 0.5 to 2.5 N for the 0.1 mm activation and showed extreme variation with the specimens. The factor of volume and surface area of the individual roots were evaluated and found not to be responsible for these deviations. A comparable behaviour was recorded for the 0.2 mm deflection, however, on a higher force level. The results show that the force development at different displacement velocities is complex and dominated by the PDL biomechanical characteristics.
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http://dx.doi.org/10.1093/ejo/cjr134DOI Listing
February 2014

The effect of reduced intercellular coupling on electrocardiographic signs of left ventricular hypertrophy.

J Electrocardiol 2011 Sep-Oct;44(5):571-6. Epub 2011 Jul 14.

International Laser Center, Bratislava, Slovak Republic.

Background: The electrocardiographic (ECG) diagnosis of left ventricular hypertrophy (LVH) is based on the assumption that QRS voltage increases with left ventricular mass. However, most of patients with echocardiographically detected LVH do not have increased QRS voltage. Reduced intercellular coupling has been observed in LVH patients and animal models. The purpose of this study was to show that this uncoupling can explain relatively low QRS voltage in LVH patients.

Methods: Electrocardiograms and vectorcardiograms (VCG) were simulated with a realistic large-scale computer model of the human heart and torso that reliably represented the effects of reduced coupling on both propagation and ECG voltage.

Results: Uncoupling reduced QRS voltage in all leads except aVL, reflecting a decrease in vector amplitude as well as a leftward axis deviation that suggested left anterior fascicular block.

Conclusions: Low QRS voltage does not necessarily contradict a diagnosis of LVH but may be an indication for electrical uncoupling. The diagnostic value of this "relative voltage deficit" needs to be demonstrated in clinical studies.
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http://dx.doi.org/10.1016/j.jelectrocard.2011.06.004DOI Listing
January 2012