Publications by authors named "Simone Pezzuto"

12 Publications

  • Page 1 of 1

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

Europace 2021 Mar;23(Supplement_1):i161-i168

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

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

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

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

Automatic reconstruction of the left atrium activation from sparse intracardiac contact recordings by inverse estimate of fibre structure and anisotropic conduction in a patient-specific model.

Europace 2021 Mar;23(Supplement_1):i63-i70

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

Aims: Electric conduction in the atria is direction-dependent, being faster in fibre direction, and possibly heterogeneous due to structural remodelling. Intracardiac recordings of atrial activation may convey such information, but only with high-quality data. The aim of this study was to apply a patient-specific approach to enable such assessment even when data are scarce, noisy, and incomplete.

Methods And Results: Contact intracardiac recordings in the left atrium from nine patients who underwent ablation therapy were collected before pulmonary veins isolation and retrospectively included in the study. The Personalized Inverse Eikonal Model from cardiac Electro-Anatomical Maps (PIEMAP), previously developed, has been used to reconstruct the conductivity tensor from sparse recordings of the activation. Regional fibre direction and conduction velocity were estimated from the fitted conductivity tensor and extensively cross-validated by clustered and sparse data removal. Electrical conductivity was successfully reconstructed in all patients. Cross-validation with respect to the measurements was excellent in seven patients (Pearson correlation r > 0.93) and modest in two patients (r = 0.62 and r = 0.74). Bland-Altman analysis showed a neglectable bias with respect to the measurements and the limit-of-agreement at -22.2 and 23.0 ms. Conduction velocity in the fibre direction was 82 ± 25 cm/s, whereas cross-fibre velocity was 46 ± 7 cm/s. Anisotropic ratio was 1.91±0.16. No significant inter-patient variability was observed. Personalized Inverse Eikonal model from cardiac Electro-Anatomical Maps correctly predicted activation times in late regions in all patients (r = 0.88) and was robust to a sparser dataset (r = 0.95).

Conclusion: Personalized Inverse Eikonal model from cardiac Electro-Anatomical Maps offers a novel approach to extrapolate the activation in unmapped regions and to assess conduction properties of the atria. It could be seamlessly integrated into existing electro-anatomic mapping systems. Personalized Inverse Eikonal model from cardiac Electro-Anatomical Maps also enables personalization of cardiac electrophysiology models.
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http://dx.doi.org/10.1093/europace/euaa392DOI Listing
March 2021

Short P-Wave Duration is a Marker of Higher Rate of Atrial Fibrillation Recurrences after Pulmonary Vein Isolation: New Insights into the Pathophysiological Mechanisms Through Computer Simulations.

J Am Heart Assoc 2021 Jan 7;10(2):e018572. Epub 2021 Jan 7.

Division of Cardiology Cardiocentro Ticino Lugano Switzerland.

Background Short ECG P-wave duration has recently been demonstrated to be associated with higher risk of atrial fibrillation (AF). The aim of this study was to assess the rate of AF recurrence after pulmonary vein isolation in patients with a short P wave, and to mechanistically elucidate the observation by computer modeling. Methods and Results A total of 282 consecutive patients undergoing a first single-pulmonary vein isolation procedure for paroxysmal or persistent AF were included. Computational models studied the effect of adenosine and sodium conductance on action potential duration and P-wave duration (PWD). About 16% of the patients had a PWD of 110 ms or shorter (median PWD 126 ms, interquartile range, 115 ms-138 ms; range, 71 ms-180 ms). At Cox regression, PWD was significantly associated with AF recurrence (=0.012). Patients with a PWD <110 ms (hazard ratio [HR], 2.20; 95% CI, 1.24-3.88; =0.007) and patients with a PWD ≥140 (HR, 1.87, 95% CI, 1.06-3.30; =0.031) had a nearly 2-fold increase in risk with respect to the other group. In the computational model, adenosine yielded a significant reduction of action potential duration 90 (52%) and PWD (7%). An increased sodium conductance (up to 200%) was robustly accompanied by an increase in conduction velocity (26%), a reduction in action potential duration 90 (28%), and PWD (22%). Conclusions One out of 5 patients referred for pulmonary vein isolation has a short PWD which was associated with a higher rate of AF after the index procedure. Computer simulations suggest that shortening of atrial action potential duration leading to a faster atrial conduction may be the cause of this clinical observation.
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http://dx.doi.org/10.1161/JAHA.120.018572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955300PMC
January 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

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

Europace 2021 Apr;23(4):640-647

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
April 2021

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

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

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

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

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

High-order finite element methods for cardiac monodomain simulations.

Front Physiol 2015 5;6:217. Epub 2015 Aug 5.

Department of Bioengineering, University of California San Diego La Jolla, CA, USA ; Department of Medicine, University of California San Diego La Jolla, CA, USA.

Computational modeling of tissue-scale cardiac electrophysiology requires numerically converged solutions to avoid spurious artifacts. The steep gradients inherent to cardiac action potential propagation necessitate fine spatial scales and therefore a substantial computational burden. The use of high-order interpolation methods has previously been proposed for these simulations due to their theoretical convergence advantage. In this study, we compare the convergence behavior of linear Lagrange, cubic Hermite, and the newly proposed cubic Hermite-style serendipity interpolation methods for finite element simulations of the cardiac monodomain equation. The high-order methods reach converged solutions with fewer degrees of freedom and longer element edge lengths than traditional linear elements. Additionally, we propose a dimensionless number, the cell Thiele modulus, as a more useful metric for determining solution convergence than element size alone. Finally, we use the cell Thiele modulus to examine convergence criteria for obtaining clinically useful activation patterns for applications such as patient-specific modeling where the total activation time is known a priori.
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http://dx.doi.org/10.3389/fphys.2015.00217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525671PMC
August 2015