Publications by authors named "Javier Saiz"

49 Publications

3D patient-specific spinal cord computational model for SCS management: potential clinical applications.

J Neural Eng 2021 Feb 8. Epub 2021 Feb 8.

Universitat Politècnica de València, Camino de Vera, s/n, Valencia, 46022, SPAIN.

Background And Objective: Although Spinal Cord Stimulation (SCS) is an established therapy for treating neuropathic chronic pain, in tonic stimulation, postural changes, electrode migration or badly-positioned electrodes can produce annoying stimulation (intercostal neuralgia) in about 35% of the patients. SCS models are used to study the effect of electrical stimulation to better manage the stimulation parameters and electrode position. The goal of this work was to develop a realistic 3D patient-specific spinal cord model from a real patient and develop a future clinical application that would help physicians to optimize paresthesia coverage in SCS therapy.

Methods: We developed two 3D patient-specific models from a high-resolution MRI of two patients undergoing SCS treatment. The model consisted of a finite element model of the spinal cord and a sensory myelinated nerve fiber model. The same simulations were performed with a generalized spinal cord model and we compared the results with the clinical data to evaluate the advantages of a patient-specific model. To identify the geometrical parameters that most influence the stimulation predictions, a sensitivity analysis was conducted. We used the patient-specific model to perform a clinical application involving the pre-implantation selection of electrode polarity and study the effect of electrode offset.

Results: The patient-specific model correlated better with clinical data than the generalized model. Electrode-dura mater distance, dorsal CSF thickness, and CSF diameter are the geometrical parameters that caused significant changes in the stimulation predictions. Electrode polarity could be planned and optimized to stimulate the patient's painful dermatomes. The addition of offset in parallel electrodes would not have been beneficial for one of the patients of this study because they reduce neural activation displacement.

Conclusions: This is the first study to relate the activation area model prediction in dorsal columns with the clinical effect on paresthesia coverage. The outcomes show that 3D patient-specific models would help physicians to choose the best stimulation parameters to optimize neural activation and SCS therapy in tonic stimulation.
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http://dx.doi.org/10.1088/1741-2552/abe44fDOI Listing
February 2021

Ranolazine as an Alternative Therapy to Flecainide for SCN5A V411M Long QT Syndrome Type 3 Patients.

Front Pharmacol 2020 17;11:580481. Epub 2020 Dec 17.

Centro de Investigación e Innovación en Bioingeniería (CI2B), Universitat Politècnica de València, Valencia, España.

The prolongation of the QT interval represents the main feature of the long QT syndrome (LQTS), a life-threatening genetic disease. The heterozygous SCN5A V411M mutation of the human sodium channel leads to a LQTS type 3 with severe proarrhythmic effects due to an increase in the late component of the sodium current (INaL). The two sodium blockers flecainide and ranolazine are equally recommended by the current 2015 ESC guidelines to treat patients with LQTS type 3 and persistently prolonged QT intervals. However, awareness of pro-arrhythmic effects of flecainide in LQTS type 3 patients arose upon the study of the SCN5A E1784K mutation. Regarding SCN5A V411M individuals, flecainide showed good results albeit in a reduced number of patients and no evidence supporting the use of ranolazine has ever been released. Therefore, we ought to compare the effect of ranolazine and flecainide in a SCN5A V411M model using an in-silico modeling and simulation approach. We collected clinical data of four patients. Then, we fitted four Markovian models of the human sodium current (INa) to experimental and clinical data. Two of them correspond to the wild type and the heterozygous SCN5A V411M scenarios, and the other two mimic the effects of flecainide and ranolazine on INa. Next, we inserted them into three isolated cell action potential (AP) models for endocardial, midmyocardial and epicardial cells and in a one-dimensional tissue model. The SCN5A V411M mutation produced a 15.9% APD90 prolongation in the isolated endocardial cell model, which corresponded to a 14.3% of the QT interval prolongation in a one-dimensional strand model, in keeping with clinical observations. Although with different underlying mechanisms, flecainide and ranolazine partially countered this prolongation at the isolated endocardial model by reducing the APD90 by 8.7 and 4.3%, and the QT interval by 7.2 and 3.2%, respectively. While flecainide specifically targeted the mutation-induced increase in peak INaL, ranolazine reduced it during the entire AP. Our simulations also suggest that ranolazine could prevent early afterdepolarizations triggered by the SCN5A V411M mutation during bradycardia, as flecainide. We conclude that ranolazine could be used to treat SCN5A V411M patients, specifically when flecainide is contraindicated.
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http://dx.doi.org/10.3389/fphar.2020.580481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845660PMC
December 2020

In vitro and in vivo cardiac toxicity of flavored electronic nicotine delivery systems.

Am J Physiol Heart Circ Physiol 2021 01 20;320(1):H133-H143. Epub 2020 Nov 20.

Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, Florida.

The usage of flavored electronic nicotine delivery systems (ENDS) is popular, specifically in the teen and young adult age-groups. The possible cardiac toxicity of the flavoring aspect of ENDS is largely unknown. Vaping, a form of electronic nicotine delivery, uses "e-liquid" to generate "e-vapor," an aerosolized mixture of nicotine and/or flavors. We report our investigation into the cardiotoxic effects of flavored e-liquids. E-vapors containing flavoring aldehydes such as vanillin and cinnamaldehyde, as indicated by mass spectrometry, were more toxic in HL-1 cardiomyocytes than fruit-flavored e-vapor. Exposure of human induced pluripotent stem cell-derived cardiomyocytes to cinnamaldehyde or vanillin-flavored e-vapor affected the beating frequency and prolonged the field potential duration of these cells more than fruit-flavored e-vapor. In addition, vanillin aldehyde-flavored e-vapor reduced the human ether-à-go-go-related gene (hERG)-encoded potassium current in transfected human embryonic kidney cells. In mice, inhalation exposure to vanillin aldehyde-flavored e-vapor for 10 wk caused increased sympathetic predominance in heart rate variability measurements. In vivo inducible ventricular tachycardia was significantly longer, and in optical mapping, the magnitude of ventricular action potential duration alternans was significantly larger in the vanillin aldehyde-flavored e-vapor-exposed mice than in controls. We conclude that the widely popular flavored ENDS are not harm free, and they have a potential for cardiac harm. More studies are needed to further assess their cardiac safety profile and long-term health effects. The use of electronic nicotine delivery systems (ENDS) is not harm free. It is not known whether ENDS negatively affect cardiac electrophysiological function. Our study in cell lines and in mice shows that ENDS can compromise cardiac electrophysiology, leading to action potential instability and inducible ventricular arrhythmias. Further investigations are necessary to assess the long-term cardiac safety profile of ENDS products in humans and to better understand how individual components of ENDS affect cardiac toxicity.
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http://dx.doi.org/10.1152/ajpheart.00283.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847071PMC
January 2021

Cardiac computational modelling.

Rev Esp Cardiol (Engl Ed) 2021 Jan 15;74(1):65-71. Epub 2020 Aug 15.

Barcelona Supercomputing Center & ELEM Biotech, Barcelona, Spain.

Cardiovascular diseases currently have a major social and economic impact, constituting one of the leading causes of mortality and morbidity. Personalized computational models of the heart are demonstrating their usefulness both to help understand the mechanisms underlying cardiac disease, and to optimize their treatment and predict the patient's response. Within this framework, the Spanish Research Network for Cardiac Computational Modelling (VHeart-SN) has been launched. The general objective of the VHeart-SN network is the development of an integrated, modular and multiscale multiphysical computational model of the heart. This general objective is addressed through the following specific objectives: a) to integrate the different numerical methods and models taking into account the specificity of patients; b) to assist in advancing knowledge of the mechanisms associated with cardiac and vascular diseases; and c) to support the application of different personalized therapies. This article presents the current state of cardiac computational modelling and different scientific works conducted by the members of the network to gain greater understanding of the characteristics and usefulness of these models.
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http://dx.doi.org/10.1016/j.rec.2020.05.024DOI Listing
January 2021

Classifiers for the Assessment of Drug Proarrhythmicity.

J Chem Inf Model 2020 Oct 18;60(10):5172-5187. Epub 2020 Aug 18.

Centro de Investigación e Innovación en Bioingeniería (Ci2B), Universitat Politècnica de València, Camino de Vera s/n, 46022 Valencia, Spain.

Drug-induced torsade de pointes (TdP) is a life-threatening ventricular arrhythmia responsible for the withdrawal of many drugs from the market. Although currently used TdP risk-assessment methods are effective, they are expensive and prone to produce false positives. In recent years, cardiac simulations have proven to be a valuable tool for the prediction of drug effects. The objective of this work is to evaluate different biomarkers of drug-induced proarrhythmic risk and to develop an risk classifier. Cellular simulations were performed using a modified version of the O'Hara et al. ventricular action potential model and existing pharmacological data (IC and effective free therapeutic plasma concentration, EFTPC) for 109 drugs of known torsadogenic risk (51 positive). For each compound, four biomarkers were tested: (drug concentration leading to a 10% prolongation of the action potential over the EFTPC), (net charge carried by ionic currents when exposed to 10 times the EFTPC with respect to the net charge in control), (triangulation for a drug concentration of 10 times the EFTPC over triangulation in control), and (drug concentration originating early afterdepolarizations over EFTPC). Receiver operating characteristic (ROC) curves were built for each biomarker to evaluate their individual predictive quality. At the optimal cutoff point, accuracies for , , , and were 89.9, 91.7, 90.8, and 78.9% respectively. The resulting accuracy of the hERG IC test (current biomarker) was 78.9%. When combining , and into a classifier based on decision trees, the prediction improves, achieving an accuracy of 94.5%. The sensitivity analysis revealed that most of the effects on the action potential are mainly due to changes in , , and . In fact, considering that drugs affect only these four currents, TdP risk classification can be as accurate as when considering effects on the seven main currents proposed by the CiPA initiative. Finally, we built a ready-to-use tool (based on more than 450 000 simulations), which can be used to quickly assess the proarrhythmic risk of a compound. In conclusion, our tool can be useful for the preclinical assessment of TdP-risk and to reduce costs related with new drug development. The TdP risk-assessment tool and the software used in this work are available at https://riunet.upv.es/handle/10251/136919.
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http://dx.doi.org/10.1021/acs.jcim.0c00201DOI Listing
October 2020

Characteristics of patients seeking outpatient smoking cessation treatment before and after the implementation of a smoke-free law in Valencia (Spain): a cross-sectional study.

BMJ Open 2020 05 15;10(5):e035319. Epub 2020 May 15.

Department of Preventive Medicine and Public Health, Food Sciences, Toxicology and Legal Medicine, University of Valencia, Valencia, Spain

Objective: Explore potential changes in the characteristics of patients requesting smoking cessation treatment at an outpatient setting in Spain before and after Law 42/2010 was enacted.

Design: This is a cross-sectional study with convenience sampling. The information was obtained from the medical records of patients receiving smoking cessation treatment from January 2008 to December 2014.

Setting: Hospital Clinico Universitario de Valencia.

Participants: 423 patients who sought smoking cessation treatment 36 months before or 48 months after the enactment of the law.

Results: After the enactment of a comprehensive smoke-free law in Spain, the patients seeking smoking cessation treatment were older (p=0.003), had lower values of exhaled CO (p<0.0001), lower number of previous attempts to quit (p=0.027) and more history of medical problems related to smoking (p=0.002).

Conclusion: Our findings support the idea that society-nation level interventions could have an impact at the individual level, reflected by the change of patients' characteristics. It seems that the Law 42/2010 mobilised certain group of patients to seek treatment.
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http://dx.doi.org/10.1136/bmjopen-2019-035319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232619PMC
May 2020

When Does the IC Accurately Assess the Blocking Potency of a Drug?

J Chem Inf Model 2020 03 10;60(3):1779-1790. Epub 2020 Mar 10.

Centro de Investigación e Innovación en Bioingeniería (Ci2B), Universitat Politècnica de València, Camino de Vera, s/n, 46022 Valencia, Spain.

Preclinical assessment of drug-induced proarrhythmicity is typically evaluated by the potency of the drug to block the potassium human ether-à-go-go-related gene (hERG) channels, which is currently quantified by the IC. However, channel block depends on the experimental conditions. Our aim is to improve the evaluation of the blocking potency of drugs by designing experimental stimulation protocols to measure the IC that will help to decide whether the IC is representative enough. We used the state-of-the-art mathematical models of the cardiac electrophysiological activity to design three stimulation protocols that enhance the differences in the probabilities to occupy a certain conformational state of the channel and, therefore, the potential differences in the blocking effects of a compound. We simulated an extensive set of 144 in silico blockers with different kinetics and affinities to conformational states of the channel and we also experimentally validated our key predictions. Our results show that the IC protocol dependency relied on the tested compounds. Some of them showed no differences or small differences on the IC value, which suggests that the IC could be a good indicator of the blocking potency in these cases. However, others provided highly protocol dependent IC values, which could differ by even 2 orders of magnitude. Moreover, the protocols yielding the maximum IC and minimum IC depended on the drug, which complicates the definition of a "standard" protocol to minimize the influence of the stimulation protocol on the IC measurement in safety pharmacology. As a conclusion, we propose the adoption of our three-protocol IC assay to estimate the potency to block hERG in vitro. If the IC values obtained for a compound are similar, then the IC could be used as an indicator of its blocking potency, otherwise kinetics and state-dependent binding properties should be accounted.
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http://dx.doi.org/10.1021/acs.jcim.9b01085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357848PMC
March 2020

The Antimalarial Chloroquine Reduces the Burden of Persistent Atrial Fibrillation.

Front Pharmacol 2019 27;10:1392. Epub 2019 Nov 27.

Molecular Pharmacology and Physiology Department, University of South Florida Morsani College of Medicine, Tampa, FL, United States.

In clinical practice, reducing the burden of persistent atrial fibrillation by pharmacological means is challenging. We explored if blocking the background and the acetylcholine-activated inward rectifier potassium currents (I and I) could be antiarrhythmic in persistent atrial fibrillation. We thus tested the hypothesis that blocking I and I with chloroquine decreases the burden of persistent atrial fibrillation. We used patch clamp to determine the IC of I and I block by chloroquine and molecular modeling to simulate the interaction between chloroquine and Kir2.1 and Kir3.1, the molecular correlates of I and I. We then tested, as a proof of concept, if oral chloroquine administration to a patient with persistent atrial fibrillation can decrease the arrhythmia burden. We also simulated the effects of chloroquine in a 3D model of human atria with persistent atrial fibrillation. In patch clamp the IC of I block by chloroquine was similar to that of I. A 14-day regimen of oral chloroquine significantly decreased the burden of persistent atrial fibrillation in a patient. Mathematical simulations of persistent atrial fibrillation in a 3D model of human atria suggested that chloroquine prolonged the action potential duration, leading to failure of reentrant excitation, and the subsequent termination of the arrhythmia. The combined block of I and I can be a targeted therapeutic strategy for persistent atrial fibrillation.
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http://dx.doi.org/10.3389/fphar.2019.01392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6890839PMC
November 2019

Differential Modulation of and Channels in High-Fat Diet-Induced Obese Guinea Pig Atria.

Front Physiol 2019 25;10:1212. Epub 2019 Sep 25.

Cardiac Electrophysiology and Metabolism Research Group, VA New York Harbor Healthcare System, Brooklyn, NY, United States.

Obesity mechanisms that make atrial tissue vulnerable to arrhythmia are poorly understood. Voltage-dependent potassium ( , , and ) and L-type calcium currents ( ) are electrically relevant and represent key substrates for modulation in obesity. We investigated whether electrical remodeling produced by high-fat diet (HFD) alone or in concert with acute atrial stimulation were different. Electrophysiology was used to assess atrial electrical function after short-term HFD-feeding in guinea pigs. HFD atria displayed spontaneous beats, increased ( ) and decreased densities. Only with pacing did a reduction in and increased phenotype emerge, leading to a further shortening of action potential duration. Computer modeling studies further indicate that the measured changes in potassium and calcium current densities contribute prominently to shortened atrial action potential duration in human heart. Our data are the first to show that multiple mechanisms (shortened action potential duration, early afterdepolarizations and increased incidence of spontaneous beats) may underlie initiation of supraventricular arrhythmias in obese guinea pig hearts. These results offer different mechanistic insights with implications for obese patients harboring supraventricular arrhythmias.
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http://dx.doi.org/10.3389/fphys.2019.01212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6773813PMC
September 2019

Heterogeneous Effects of Fibroblast-Myocyte Coupling in Different Regions of the Human Atria Under Conditions of Atrial Fibrillation.

Front Physiol 2019 4;10:847. Epub 2019 Jul 4.

Centre for Research and Innovation in Bioengineering, Universitat Politècnica de València, Valencia, Spain.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is characterized by alteration of the action potential (AP) propagation. Under persistent AF, myocytes undergo electrophysiological and structural remodeling, which involves fibroblast proliferation and differentiation, modifying the substrate for AP propagation. The aim of this study was to analyze the effects on the AP of fibroblast-myocyte coupling during AF and its propagation in different regions of the atria. Isolated myocytes were coupled to different numbers of fibroblasts using the established AP models and tissue simulations were performed by randomly distributing fibroblasts. Fibroblast formulations were updated to match recent experimental data. Major ion current conductances of the myocyte model were modified to simulate AP heterogeneity in four different atrial regions (right atrium posterior wall, crista terminalis, left atrium posterior wall, and pulmonary vein) according to experimental and computational studies. The results of the coupled myocyte-fibroblast simulations suggest that a more depolarized membrane potential and higher fibroblast membrane capacitance have a greater impact on AP duration and myocyte maximum depolarization velocity. The number of coupled fibroblasts and the stimulation frequency are determining factors in altering myocyte AP. Strand simulations show that conduction velocity tends to homogenize in all regions, while the left atrium is more likely to be affected by fibroblast and AP propagation block is more likely to occur. The pulmonary vein is the most affected region, even at low fibroblast densities. In 2D sheets with randomly placed fibroblasts, wavebreaks are observed in the low density (10%) central fibrotic zone and when fibroblast density increases (40%) propagation in the fibrotic region is practically blocked. At densities of 10 and 20% the width of the vulnerable window increases with respect to control but is decreased at 40%. Myocyte-fibroblast coupling characteristics heterogeneously affect AP propagation and features in the different atrial zones, and myocytes from the left atria are more sensitive to fibroblast coupling.
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http://dx.doi.org/10.3389/fphys.2019.00847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6620707PMC
July 2019

Plasticizer Interaction With the Heart: Chemicals Used in Plastic Medical Devices Can Interfere With Cardiac Electrophysiology.

Circ Arrhythm Electrophysiol 2019 07 28;12(7):e007294. Epub 2019 Jun 28.

Sheikh Zayed Institute for Pediatric Surgical Innovation (R.J., D. McCullough, L.S., D. McInerney, J.H., N.G.P.), Children's National Health System, Washington DC.

Background: Phthalates are used as plasticizers in the manufacturing of flexible, plastic medical products. Patients can be subjected to high phthalate exposure through contact with plastic medical devices. We aimed to investigate the cardiac safety and biocompatibility of mono-2-ethylhexyl phthalate (MEHP), a phthalate with documented exposure in intensive care patients.

Methods: Optical mapping of transmembrane voltage and pacing studies were performed on isolated, Langendorff-perfused rat hearts to assess cardiac electrophysiology after MEHP exposure compared with controls. MEHP dose was chosen based on reported blood concentrations after an exchange transfusion procedure.

Results: Thirty-minute exposure to MEHP increased the atrioventricular node (147 versus 107 ms) and ventricular (117 versus 77.5 ms) effective refractory periods, compared with controls. Optical mapping revealed prolonged action potential duration at slower pacing cycle lengths, akin to reverse use dependence. The plateau phase of the action potential duration restitution curve steepened and became monophasic in MEHP-exposed hearts (0.18 versus 0.06 slope). Action potential duration lengthening occurred during late-phase repolarization resulting in triangulation (70.3 versus 56.6 ms). MEHP exposure also slowed epicardial conduction velocity (35 versus 60 cm/s), which may be partly explained by inhibition of Na1.5 (874 and 231 µmol/L half-maximal inhibitory concentration, fast and late sodium current).

Conclusions: This study highlights the impact of acute MEHP exposure, using a clinically relevant dose, on cardiac electrophysiology in the intact heart. Heightened clinical exposure to plasticized medical products may have cardiac safety implications-given that action potential triangulation and electrical restitution modifications are a risk factor for early after depolarizations and cardiac arrhythmias.
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http://dx.doi.org/10.1161/CIRCEP.119.007294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693678PMC
July 2019

An Open-Circuit Indirect Calorimetry Head Hood System for Measuring Methane Emission and Energy Metabolism in Small Ruminants.

Animals (Basel) 2019 Jun 21;9(6). Epub 2019 Jun 21.

Centro de Investigación e Innovación en Bioingeniería, Universitat Politècnica de Valencia, 46022 Valencia, Spain.

Methane (CH) is a natural by-product of microbial fermentation in the rumen and is a powerful greenhouse gas. An open-circuit indirect calorimetry system for continuous determination of CH and CO production and O consumption and, thereafter, heat production (HP) calculation for small ruminants was described and validated. The system consisted of a computerized control, data acquisition and recording system for gases and air flux. The average value ± standard deviation for the calibration factors in the system were 1.005 ± 0.0007 (n = 6), 1.013 ± 0.0012 (n = 6) and 0.988 ± 0.0035 (n = 6) for O, CO and CH, respectively. Calibration factors close to 1 confirmed the absence of leaks in the indirect calorimetry system. In addition, an experimental test with 8 goats at mid lactation was conducted to validate the system. The repeatability for CH and heat production measured with the open-circuit indirect calorimetry system was 79% and 61%, respectively. Daily average HP measured by indirect calorimetry (Respiration Quotient method) was close to the average HP determined from Carbon-Nitrogen balance (CN method), accounting for 685 and 667 kJ per kg metabolic body weight, respectively. Therefore, discrepancies averaged 1.92%, a rather satisfactory value considering the substantial amount of technical and analytical work involved. The close agreement found between both methods can be considered as being indicative of the absence of systematic error. Two diets with different forage were tested: 40% was either alfalfa hay (HAY) or alfalfa silage (SIL), and the proportion of concentrate was the same in both groups (60%). The experimental trial shown that HP and CH were higher in HAY than SIL diet (differences between treatments of 28 kJ of HP per kg of metabolic body weight and 7.1 L CH/day were found). The data acquisition and recording device developed improved the accuracy of the indirect calorimetry system by reducing the work involved in managing output data and refining the functionality for measuring gas exchange and energy metabolism in small ruminants.
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http://dx.doi.org/10.3390/ani9060380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6616995PMC
June 2019

Far-field contributions in multi-electrodes atrial recordings blur distinction between anatomical and functional reentries and may cause imaginary phase singularities - A computational study.

Comput Biol Med 2019 05 14;108:276-287. Epub 2019 Mar 14.

Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, USA.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia and the most important cause of embolic stroke, requiring new technologies for its better understanding and therapies. Recent approaches to map the electrical activity during AF with multi-electrode systems aim at localizing patient-specific ablation targets of reentrant patterns. However, there is a critical need to determine the accuracy of those mapping systems. We performed computer simulations as a numerical approach of systematically evaluating the influence of far-field sources on the electrical recordings and detection of rotors.

Methods: We constructed 2 computer models of atrial tissue: (i) a 2D sheet model with varying non-active cells area in its center, and (ii) a whole realistic 3D atrial model. Phase maps were built based on the Hilbert transform of the unipolar electrograms recorded by virtual 2D and 3D multi-electrode systems and rotors were tracked through phase singularities detections.

Results: Analysis of electrograms recorded away from the 2D atrial model shows that the larger the distance between an electrode and the tissue model, the stronger the far-field sources contribution to the electrogram is. Importantly, even if an electrode is positioned in contact with the tissue, the electrogram contains significant contributions from distal sources that blur the distinction between anatomical and functional reentries. Moreover, when mapping the 3D atrial model, remote activity generated false phase singularities at locations without local reentrant excitation patterns.

Conclusions: Far-field contributions to electrograms during AF reduce the accuracy of detecting and interpreting reentrant activity.
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http://dx.doi.org/10.1016/j.compbiomed.2019.02.022DOI Listing
May 2019

Computational Study of the Effect of Electrode Polarity on Neural Activation Related to Paresthesia Coverage in Spinal Cord Stimulation Therapy.

Neuromodulation 2019 Apr 26;22(3):269-279. Epub 2018 Dec 26.

Center of Research and Innovation in Bioengineering, Universitat Politècnica de València, Valencia, Spain.

Objective: Using computer simulation, we investigated the effect of electrode polarity on neural activation in spinal cord stimulation and propose a new strategy to maximize the activating area in the dorsal column (DC) and, thus, paresthesia coverage in clinical practice.

Materials And Methods: A new three-dimensional spinal cord model at the T10 vertebral level was developed to simulate neural activation induced by the electric field distribution produced by different typical four-contact electrode polarities in single- and dual-lead stimulation. Our approach consisted of the combination of a finite element model of the spinal cord developed in COMSOL Multiphysics and a nerve fiber model implemented in MATLAB. Five evaluation parameters were evaluated, namely, the recruitment ratio, the perception and discomfort thresholds, and the activating area and depth. The results were compared quantitatively.

Results: The dual-guarded cathode presents the maximum activating area and depth in single- and dual-lead stimulation. However, the lowest value of the ratio between the perception threshold in DC and the perception threshold in the dorsal root (DR) is achieved when the guarded cathode is programmed. Although the two versions of bipolar polarity (namely bipolar 1 and bipolar 2) produce higher activating area and depth than the guarded cathode, they are suitable for producing DR stimulation. Similarly, dual-lead stimulation is likely to activate DR fibers because the electrodes are closer to these fibers.

Conclusions: The results suggest that the activating area in the DC is maximized by using the dual-guarded cathode both in single- and dual-lead stimulation modes. However, DC nerve fibers are preferentially stimulated when the guarded cathode is used. According to these results, the new electrode programming strategy that we propose for clinical practice first uses the dual-guarded cathode, but, if the DR nerve fibers are activated, it then uses guarded cathode polarity.
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http://dx.doi.org/10.1111/ner.12909DOI Listing
April 2019

Atrial Fibrosis Hampers Non-invasive Localization of Atrial Ectopic Foci From Multi-Electrode Signals: A 3D Simulation Study.

Front Physiol 2018 18;9:404. Epub 2018 May 18.

Computational Multiscale Simulation Lab, Department of Computer Science, Universitat de Valencia, Valencia, Spain.

Focal atrial tachycardia is commonly treated by radio frequency ablation with an acceptable long-term success. Although the location of ectopic foci tends to appear in specific hot-spots, they can be located virtually in any atrial region. Multi-electrode surface ECG systems allow acquiring dense body surface potential maps (BSPM) for non-invasive therapy planning of cardiac arrhythmia. However, the activation of the atria could be affected by fibrosis and therefore biomarkers based on BSPM need to take these effects into account. We aim to analyze the effect of fibrosis on a BSPM derived index, and its potential application to predict the location of ectopic foci in the atria. We have developed a 3D atrial model that includes 5 distributions of patchy fibrosis in the left atrium at 5 different stages. Each stage corresponds to a different amount of fibrosis that ranges from 2 to 40%. The 25 resulting 3D models were used for simulation of Focal Atrial Tachycardia (FAT), triggered from 19 different locations described in clinical studies. BSPM were obtained for all simulations, and the body surface potential integral maps (BSPiM) were calculated to describe atrial activations. A machine learning (ML) pipeline using a supervised learning model and support vector machine was developed to learn the BSPM patterns of each of the 475 activation sequences and relate them to the origin of the FAT source. Activation maps for stages with more than 15% of fibrosis were greatly affected, producing conduction blocks and delays in propagation. BSPiMs did not always cluster into non-overlapped groups since BSPiMs were highly altered by the conduction blocks. From stage 3 (15% fibrosis) the BSPiMs showed differences for ectopic beats placed around the area of the pulmonary veins. Classification results were mostly above 84% for all the configurations studied when a large enough number of electrodes were used to map the torso. However, the presence of fibrosis increases the area of the ectopic focus location and therefore decreases the utility for the electrophysiologist. The results indicate that the proposed ML pipeline is a promising methodology for non-invasive ectopic foci localization from BSPM signal even when fibrosis is present.
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http://dx.doi.org/10.3389/fphys.2018.00404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968126PMC
May 2018

In Silico QT and APD Prolongation Assay for Early Screening of Drug-Induced Proarrhythmic Risk.

J Chem Inf Model 2018 04 16;58(4):867-878. Epub 2018 Mar 16.

Centro de Investigación e Innovación en Bioingeniería (CI2B) , Universitat Politècnica de València , camino de Vera, s/n , 46022 Valencia , Spain.

Drug-induced proarrhythmicity is a major concern for regulators and pharmaceutical companies. For novel drug candidates, the standard assessment involves the evaluation of the potassium hERG channels block and the in vivo prolongation of the QT interval. However, this method is known to be too restrictive and to stop the development of potentially valuable therapeutic drugs. The aim of this work is to create an in silico tool for early detection of drug-induced proarrhythmic risk. The system is based on simulations of how different compounds affect the action potential duration (APD) of isolated endocardial, midmyocardial, and epicardial cells as well as the QT prolongation in a virtual tissue. Multiple channel-drug interactions and state-of-the-art human ventricular action potential models ( O'Hara , T. , PLos Comput. Biol. 2011 , 7 , e1002061 ) were used in our simulations. Specifically, 206.766 cellular and 7072 tissue simulations were performed by blocking the slow and the fast components of the delayed rectifier current ( I and I, respectively) and the L-type calcium current ( I) at different levels. The performance of our system was validated by classifying the proarrhythmic risk of 84 compounds, 40 of which present torsadogenic properties. On the basis of these results, we propose the use of a new index (Tx) for discriminating torsadogenic compounds, defined as the ratio of the drug concentrations producing 10% prolongation of the cellular endocardial, midmyocardial, and epicardial APDs and the QT interval, over the maximum effective free therapeutic plasma concentration (EFTPC). Our results show that the Tx index outperforms standard methods for early identification of torsadogenic compounds. Indeed, for the analyzed compounds, the Tx tests accuracy was in the range of 87-88% compared with a 73% accuracy of the hERG IC based test.
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http://dx.doi.org/10.1021/acs.jcim.7b00440DOI Listing
April 2018

Factors affecting basket catheter detection of real and phantom rotors in the atria: A computational study.

PLoS Comput Biol 2018 03 5;14(3):e1006017. Epub 2018 Mar 5.

Centro de Investigación e Innovación en Bioingeniería, Universitat Politècnica de València, Valencia, Spain.

Anatomically based procedures to ablate atrial fibrillation (AF) are often successful in terminating paroxysmal AF. However, the ability to terminate persistent AF remains disappointing. New mechanistic approaches use multiple-electrode basket catheter mapping to localize and target AF drivers in the form of rotors but significant concerns remain about their accuracy. We aimed to evaluate how electrode-endocardium distance, far-field sources and inter-electrode distance affect the accuracy of localizing rotors. Sustained rotor activation of the atria was simulated numerically and mapped using a virtual basket catheter with varying electrode densities placed at different positions within the atrial cavity. Unipolar electrograms were calculated on the entire endocardial surface and at each of the electrodes. Rotors were tracked on the interpolated basket phase maps and compared with the respective atrial voltage and endocardial phase maps, which served as references. Rotor detection by the basket maps varied between 35-94% of the simulation time, depending on the basket's position and the electrode-to-endocardial wall distance. However, two different types of phantom rotors appeared also on the basket maps. The first type was due to the far-field sources and the second type was due to interpolation between the electrodes; increasing electrode density decreased the incidence of the second but not the first type of phantom rotors. In the simulations study, basket catheter-based phase mapping detected rotors even when the basket was not in full contact with the endocardial wall, but always generated a number of phantom rotors in the presence of only a single real rotor, which would be the desired ablation target. Phantom rotors may mislead and contribute to failure in AF ablation procedures.
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http://dx.doi.org/10.1371/journal.pcbi.1006017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854439PMC
March 2018

Pro-arrhythmic effects of low plasma [K] in human ventricle: An illustrated review.

Trends Cardiovasc Med 2018 05 24;28(4):233-242. Epub 2017 Nov 24.

Faculties of Kinesiology and Medicine, University of Calgary, 2500 University Drive, Calgary T2N 1N4, Canada. Electronic address:

Potassium levels in the plasma, [K], are regulated precisely under physiological conditions. However, increases (from approx. 4.5 to 8.0mM) can occur as a consequence of, e.g., endurance exercise, ischemic insult or kidney failure. This hyperkalemic modulation of ventricular electrophysiology has been studied extensively. Hypokalemia is also common. It can occur in response to diuretic therapy, following renal dialysis, or during recovery from endurance exercise. In the human ventricle, clinical hypokalemia (e.g., [K] levels of approx. 3.0mM) can cause marked changes in both the resting potential and the action potential waveform, and these may promote arrhythmias. Here, we provide essential background information concerning the main K-sensitive ion channel mechanisms that act in concert to produce prominent short-term ventricular electrophysiological changes, and illustrate these by implementing recent mathematical models of the human ventricular action potential. Even small changes (~1mM) in [K] result in significant alterations in two different K currents, I and HERG. These changes can markedly alter in resting membrane potential and/or action potential waveform in human ventricle. Specifically, a reduction in net outward transmembrane K currents (repolarization reserve) and an increased substrate input resistance contribute to electrophysiological instability during the plateau of the action potential and may promote pro-arrhythmic early after-depolarizations (EADs). Translational settings where these insights apply include: optimal diuretic therapy, and the interpretation of data from Phase II and III trials for anti-arrhythmic drug candidates.
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http://dx.doi.org/10.1016/j.tcm.2017.11.002DOI Listing
May 2018

Legacy data sharing to improve drug safety assessment: the eTOX project.

Nat Rev Drug Discov 2017 Dec 13;16(12):811-812. Epub 2017 Oct 13.

Lead Molecular Design S.L., 08172 Sant Cugat del Vallès, Spain.

The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through the Innovative Medicines Initiative to explore this possibility.
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http://dx.doi.org/10.1038/nrd.2017.177DOI Listing
December 2017

Cardiac action potential repolarization revisited: early repolarization shows all-or-none behaviour.

J Physiol 2017 11 9;595(21):6599-6612. Epub 2017 Oct 9.

Faculties of Kinesiology and Medicine, University of Calgary, Calgary, Alberta, Canada, T2N 1N4.

In healthy mammalian hearts the action potential (AP) waveform initiates and modulates each contraction, or heartbeat. As a result, AP height and duration are key physiological variables. In addition, rate-dependent changes in ventricular AP duration (APD), and variations in APD at a fixed heart rate are both reliable biomarkers of electrophysiological stability. Present guidelines for the likelihood that candidate drugs will increase arrhythmias rely on small changes in APD and Q-T intervals as criteria for safety pharmacology decisions. However, both of these measurements correspond to the final repolarization of the AP. Emerging clinical evidence draws attention to the early repolarization phase of the action potential (and the J-wave of the ECG) as an additional important biomarker for arrhythmogenesis. Here we provide a mechanistic background to this early repolarization syndrome by summarizing the evidence that both the initial depolarization and repolarization phases of the cardiac action potential can exhibit distinct time- and voltage-dependent thresholds, and also demonstrating that both can show regenerative all-or-none behaviour. An important consequence of this is that not all of the dynamics of action potential repolarization in human ventricle can be captured by data from single myocytes when these results are expressed as 'repolarization reserve'. For example, the complex pattern of cell-to-cell current flow that is responsible for AP conduction (propagation) within the mammalian myocardium can change APD and the Q-T interval of the electrocardiogram alter APD stability, and modulate responsiveness to pharmacological agents (such as Class III anti-arrhythmic drugs).
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http://dx.doi.org/10.1113/JP273651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663823PMC
November 2017

Non-invasive localization of atrial ectopic beats by using simulated body surface P-wave integral maps.

PLoS One 2017 13;12(7):e0181263. Epub 2017 Jul 13.

Computational Multiscale Physiology Lab (CoMMLab), Department of Computer Science, Universitat de Valencia, Valencia, Spain.

Non-invasive localization of continuous atrial ectopic beats remains a cornerstone for the treatment of atrial arrhythmias. The lack of accurate tools to guide electrophysiologists leads to an increase in the recurrence rate of ablation procedures. Existing approaches are based on the analysis of the P-waves main characteristics and the forward body surface potential maps (BSPMs) or on the inverse estimation of the electric activity of the heart from those BSPMs. These methods have not provided an efficient and systematic tool to localize ectopic triggers. In this work, we propose the use of machine learning techniques to spatially cluster and classify ectopic atrial foci into clearly differentiated atrial regions by using the body surface P-wave integral map (BSPiM) as a biomarker. Our simulated results show that ectopic foci with similar BSPiM naturally cluster into differentiated non-intersected atrial regions and that new patterns could be correctly classified with an accuracy of 97% when considering 2 clusters and 96% for 4 clusters. Our results also suggest that an increase in the number of clusters is feasible at the cost of decreasing accuracy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181263PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509320PMC
September 2017

In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome.

J Mol Cell Cardiol 2015 Oct;87:271-82

Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of I(Kr) blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in I(Kr) channel gating that would be expected to result from benign genetic variants.Weused themodel to predict themost potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed “in silico mutagenesis” by altering discrete kinetic transition rates of the Fink et al. Markov model of human I(Kr) channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of I(Kr) channels. We then screened and identified the properties of I(Kr) blockers that caused acquired long QT and therefore unmasked mutant phenotypes formild,moderate and severe variants. Mutant I(Kr) channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of I(Kr)-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and I(Kr) mutated cells. Our results show that drugs with disparate affinities to conformation states of the I(Kr) channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical formulation of the M54T MiRP1 latent mutation and simulated a provocative test. In this setting, application of dofetilide dramatically amplified the predicted QT interval duration in the M54T hMiRP1 mutation compared to wild-type.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935925PMC
http://dx.doi.org/10.1016/j.yjmcc.2015.08.015DOI Listing
October 2015

Detailed Anatomical and Electrophysiological Models of Human Atria and Torso for the Simulation of Atrial Activation.

PLoS One 2015 2;10(11):e0141573. Epub 2015 Nov 2.

Centro de Investigación e Innovación en Bioingeniería (Ci2B), Universitat Politècnica de València, Valencia, Spain.

Atrial arrhythmias, and specifically atrial fibrillation (AF), induce rapid and irregular activation patterns that appear on the torso surface as abnormal P-waves in electrocardiograms and body surface potential maps (BSPM). In recent years both P-waves and the BSPM have been used to identify the mechanisms underlying AF, such as localizing ectopic foci or high-frequency rotors. However, the relationship between the activation of the different areas of the atria and the characteristics of the BSPM and P-wave signals are still far from being completely understood. In this work we developed a multi-scale framework, which combines a highly-detailed 3D atrial model and a torso model to study the relationship between atrial activation and surface signals in sinus rhythm. Using this multi scale model, it was revealed that the best places for recording P-waves are the frontal upper right and the frontal and rear left quadrants of the torso. Our results also suggest that only nine regions (of the twenty-one structures in which the atrial surface was divided) make a significant contribution to the BSPM and determine the main P-wave characteristics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141573PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629897PMC
June 2016

Ventricular Tachycardia and Early Fibrillation in Patients With Brugada Syndrome and Ischemic Cardiomyopathy Show Predictable Frequency-Phase Properties on the Precordial ECG Consistent With the Respective Arrhythmogenic Substrate.

Circ Arrhythm Electrophysiol 2015 Oct 7;8(5):1133-43. Epub 2015 Aug 7.

From the Arrhythmia Unit, Hospital Universitario Central de Asturias, Oviedo, Spain (D.C., J.R.); Center for Arrhythmia Research, University of Michigan, Ann Arbor (J.J., O.B.); Arrhythmia Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain (F.A., P.Á., Á.A.); Centro de Investigación e Innovación en Bioingeniería, Ci2B, Universitat Politècnica de Valencia, Valencia, Spain (J.S., L.M., A.F.); Arrhythmia Unit, Hospital Río Hortega de Valladolid and Universitario de Burgos, Valladolid-Burgos, Spain (B.H., J.G.-F.); Universitat de Valencia, Valencia, Spain (R.S.); and Department of Statistics, Hospital Universitario Central de Asturias, Oviedo, Spain (P.M.-C.).

Background: Ventricular fibrillation (VF) has been proposed to be maintained by localized high-frequency sources. We tested whether spectral-phase analysis of the precordial ECG enabled identification of periodic activation patterns generated by such sources.

Methods And Results: Precordial ECGs were recorded from 15 ischemic cardiomyopathy and 15 Brugada syndrome (type 1 ECG) patients during induced VF and analyzed in the frequency-phase domain. Despite temporal variability, induced VF episodes lasting 19.6±7.9 s displayed distinctly high power at a common frequency (shared frequency, 5.7±1.1 Hz) in all leads about half of the time. In patients with Brugada syndrome, phase analysis of shared frequency showed a V1-V6 sequence as would be expected from patients displaying a type 1 ECG pattern (P<0.001). Hilbert-based phases confirmed that the most stable sequence over the whole VF duration was V1-V6. Analysis of shared frequency in ischemic cardiomyopathy patients with anteroseptal (n=4), apical (n=3), and inferolateral (n=4) myocardial infarction displayed a sequence starting at V1-V2, V3-V4, and V5-V6, respectively, consistent with an activation origin at the scar location (P=0.005). Sequences correlated with the Hilbert-based phase analysis (P<0.001). Posterior infarction (n=4) displayed no specific sequence. On paired comparison, phase sequences during monomorphic ventricular tachycardia correlated moderately with VF (P<0.001). Moreover, there was a dominant frequency gradient from precordial leads facing the scar region to the contralateral leads (5.8±0.8 versus 5.4±1.1 Hz; P=0.004).

Conclusions: Noninvasive analysis of ventricular tachycardia and early VF in patients with Brugada syndrome and ischemic cardiomyopathy shows a predictable sequence in the frequency-phase domain, consistent with anatomic location of the arrhythmogenic substrate.
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http://dx.doi.org/10.1161/CIRCEP.114.002717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4608487PMC
October 2015

Dynamic approximate entropy electroanatomic maps detect rotors in a simulated atrial fibrillation model.

PLoS One 2014 9;9(12):e114577. Epub 2014 Dec 9.

Centro de Bioingeniería, Universidad Pontificia Bolivariana, Medellín, Colombia.

There is evidence that rotors could be drivers that maintain atrial fibrillation. Complex fractionated atrial electrograms have been located in rotor tip areas. However, the concept of electrogram fractionation, defined using time intervals, is still controversial as a tool for locating target sites for ablation. We hypothesize that the fractionation phenomenon is better described using non-linear dynamic measures, such as approximate entropy, and that this tool could be used for locating the rotor tip. The aim of this work has been to determine the relationship between approximate entropy and fractionated electrograms, and to develop a new tool for rotor mapping based on fractionation levels. Two episodes of chronic atrial fibrillation were simulated in a 3D human atrial model, in which rotors were observed. Dynamic approximate entropy maps were calculated using unipolar electrogram signals generated over the whole surface of the 3D atrial model. In addition, we optimized the approximate entropy calculation using two real multi-center databases of fractionated electrogram signals, labeled in 4 levels of fractionation. We found that the values of approximate entropy and the levels of fractionation are positively correlated. This allows the dynamic approximate entropy maps to localize the tips from stable and meandering rotors. Furthermore, we assessed the optimized approximate entropy using bipolar electrograms generated over a vicinity enclosing a rotor, achieving rotor detection. Our results suggest that high approximate entropy values are able to detect a high level of fractionation and to locate rotor tips in simulated atrial fibrillation episodes. We suggest that dynamic approximate entropy maps could become a tool for atrial fibrillation rotor mapping.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114577PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260907PMC
September 2015

Electrophysiological and structural remodeling in heart failure modulate arrhythmogenesis. 2D simulation study.

PLoS One 2014 23;9(7):e103273. Epub 2014 Jul 23.

Instituto de Investigación en Ingeniería Biomédica, UniversitatPolitècnica de València, Valencia, Spain.

Background: Heart failure is operationally defined as the inability of the heart to maintain blood flow to meet the needs of the body and it is the final common pathway of various cardiac pathologies. Electrophysiological remodeling, intercellular uncoupling and a pro-fibrotic response have been identified as major arrhythmogenic factors in heart failure.

Objective: In this study we investigate vulnerability to reentry under heart failure conditions by incorporating established electrophysiological and anatomical remodeling using computer simulations.

Methods: The electrical activity of human transmural ventricular tissue (5 cm × 5 cm) was simulated using the human ventricular action potential model Grandi et al. under control and heart failure conditions. The MacCannell et al. model was used to model fibroblast electrical activity, and their electrotonic interactions with myocytes. Selected degrees of diffuse fibrosis and variations in intercellular coupling were considered and the vulnerable window (VW) for reentry was evaluated following cross-field stimulation.

Results: No reentry was observed in normal conditions or in the presence of HF ionic remodeling. However, defined amount of fibrosis and/or cellular uncoupling were sufficient to elicit reentrant activity. Under conditions where reentry was generated, HF electrophysiological remodeling did not alter the width of the VW. However, intermediate fibrosis and cellular uncoupling significantly widened the VW. In addition, biphasic behavior was observed, as very high fibrotic content or very low tissue conductivity hampered the development of reentry. Detailed phase analysis of reentry dynamics revealed an increase of phase singularities with progressive fibrotic components.

Conclusion: Structural remodeling is a key factor in the genesis of vulnerability to reentry. A range of intermediate levels of fibrosis and intercellular uncoupling can combine to favor reentrant activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0103273PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4108391PMC
November 2015

Cardiovascular fitness in youth: association with obesity and metabolic abnormalities.

Nutr Hosp 2014 Jun 1;29(6):1290-7. Epub 2014 Jun 1.

Pediatric Department, Consorcio Hospital General Universitario, University of Valencia, Valencia, Spain..

Unlabelled: Therapies currently implemented for obesity are focused on nutritional aspects and on physical activity. In order to make physical activity a positive therapy instead of triggering disabilities it is relevant to accurately assess cardiovascular fitness.

Objective: To assess the cardiovascular fitness by measuring the peak oxygen consumption and to asses their relationship with classical cardiometabolic parameters.

Methods: A modified Balke protocol was applied to one hundred and twenty-six Caucasians (60% males), ranging between 9 and 16 years old, who underwent an assessment of obesity. The non-obese group consisted of healthy age and sex matched subjects who were invited to participate from the general population.

Results: Significant differences in consumption of oxygen peak between non-obese and obese individuals were observed. In contrast, no significant differences existed between the categories of obesity. Furthermore in obese subjects consumption of oxygen peak was inversely correlated with parameters of cardiometabolic risk, particularly insulin and HOMA index. In addition, two predictive equations of consumption of oxygen peak, with an R2 of 0.74 and 0.84, respectively, have been developed.

Conclusion: The consumption of oxygen peak is a relevant clinical parameter that should be included in the routine clinical assessment of obese subjects. Therefore, it is crucial to make exercise tests more affordable which can be achieved by employing predictive equations.
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http://dx.doi.org/10.3305/nh.2014.29.6.7383DOI Listing
June 2014

In silico screening of the impact of hERG channel kinetic abnormalities on channel block and susceptibility to acquired long QT syndrome.

J Mol Cell Cardiol 2014 Jul 11;72:126-37. Epub 2014 Mar 11.

Department of Pharmacology, University of California, Davis, Genome Building Rm 3503, Davis, CA 95616-8636, USA. Electronic address:

Accurate diagnosis of predisposition to long QT syndrome is crucial for reducing the risk of cardiac arrhythmias. In recent years, drug-induced provocative tests have proved useful to unmask some latent mutations linked to cardiac arrhythmias. In this study we expanded this concept by developing a prototype for a computational provocative screening test to reveal genetic predisposition to acquired long-QT syndrome (aLQTS). We developed a computational approach to reveal the pharmacological properties of IKr blocking drugs that are most likely to cause aLQTS in the setting of subtle alterations in IKr channel gating that would be expected to result from benign genetic variants. We used the model to predict the most potentially lethal combinations of kinetic anomalies and drug properties. In doing so, we also implicitly predicted ideal inverse therapeutic properties of K channel openers that would be expected to remedy a specific defect. We systematically performed "in silico mutagenesis" by altering discrete kinetic transition rates of the Fink et al. Markov model of human IKr channels, corresponding to activation, inactivation, deactivation and recovery from inactivation of IKr channels. We then screened and identified the properties of IKr blockers that caused acquired long QT and therefore unmasked mutant phenotypes for mild, moderate and severe variants. Mutant IKr channels were incorporated into the O'Hara et al. human ventricular action potential (AP) model and subjected to simulated application of a wide variety of IKr-drug interactions in order to identify the characteristics that selectively exacerbate the AP duration (APD) differences between wild-type and IKr mutated cells. Our results show that drugs with disparate affinities to conformation states of the IKr channel are key to amplify variants underlying susceptibility to acquired long QT syndrome, an effect that is especially pronounced at slow frequencies. Finally, we developed a mathematical formulation of the M54T MiRP1 latent mutation and simulated a provocative test. In this setting, application of dofetilide dramatically amplified the predicted QT interval duration in the M54T hMiRP1 mutation compared to wild-type.
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http://dx.doi.org/10.1016/j.yjmcc.2014.02.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4066959PMC
July 2014

In silico ischaemia-induced reentry at the Purkinje-ventricle interface.

Europace 2014 Mar;16(3):444-51

Laboratorio de Bioingenieria, Departamento de Ingenieria Electrica y Electronica, Instituto Tecnologico de Cuautla, Cuautla, Morelos 62745, Mexico.

Aims: This computational modelling work illustrates the influence of hyperkalaemia and electrical uncoupling induced by defined ischaemia on action potential (AP) propagation and the incidence of reentry at the Purkinje-ventricle interface in mammalian hearts.

Methods And Results: Unidimensional and bidimensional models of the Purkinje-ventricle subsystem, including ischaemic conditions (defined as phase 1B) in the ventricle and an ischaemic border zone, were developed by altering several important electrophysiological parameters of the Luo-Rudy AP model of the ventricular myocyte. Purkinje electrical activity was modelled using the equations of DiFrancesco and Noble. Our study suggests that an extracellular potassium concentration [K(+)]o >14 mM and a slight decrease in intercellular coupling induced by ischaemia in ventricle can cause conduction block from Purkinje to ventricle. Under these conditions, propagation from ventricle to Purkinje is possible. Thus, unidirectional block (UDB) and reentry can result. When conditions of UDB are met, retrograde propagation with a long delay (320 ms) may re-excite Purkinje cells, and give rise to a reentrant pathway. This induced reentry may be the origin of arrhythmias observed in phase 1B ischaemia.

Conclusion: In a defined setting of ischaemia (phase 1B), a small amount of uncoupling between ventricular cells, as well as between Purkinje and ventricular tissue, may induce UDBs and reentry. Hyperkalaemia is also confirmed to be an important factor in the genesis of reentrant rhythms, since it regulates the range of coupling in which UDBs may be induced.
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http://dx.doi.org/10.1093/europace/eut386DOI Listing
March 2014

Carbon monoxide effects on human ventricle action potential assessed by mathematical simulations.

Front Physiol 2013 17;4:282. Epub 2013 Oct 17.

Instituto Interuniversitario de Investigación en Bioingeniería y Tecnología Orientada al Ser Humano, Universitat Politècnica de València Valencia, Spain.

Carbon monoxide (CO) that is produced in a number of different mammalian tissues is now known to have significant effects on the cardiovascular system. These include: (i) vasodilation, (ii) changes in heart rate and strength of contractions, and (iii) modulation of autonomic nervous system input to both the primary pacemaker and the working myocardium. Excessive CO in the environment is toxic and can initiate or mediate life threatening cardiac rhythm disturbances. Recent reports link these ventricular arrhythmias to an increase in the slowly inactivating, or "late" component of the Na(+) current in the mammalian heart. The main goal of this paper is to explore the basis of this pro-arrhythmic capability of CO by incorporating changes in CO-induced ion channel activity with intracellular signaling pathways in the mammalian heart. To do this, a quite well-documented mathematical model of the action potential and intracellular calcium transient in the human ventricular myocyte has been employed. In silico iterations based on this model provide a useful first step in illustrating the cellular electrophysiological consequences of CO that have been reported from mammalian heart experiments. Specifically, when the Grandi et al. model of the human ventricular action potential is utilized, and after the Na(+) and Ca(2+) currents in a single myocyte are modified based on the experimental literature, early after-depolarization (EAD) rhythm disturbances appear, and important elements of the underlying causes of these EADs are revealed/illustrated. Our modified mathematical model of the human ventricular action potential also provides a convenient digital platform for designing future experimental work and relating these changes in cellular cardiac electrophysiology to emerging clinical and epidemiological data on CO toxicity.
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http://dx.doi.org/10.3389/fphys.2013.00282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3797961PMC
October 2013