Stochastic Cardiac Pacing Increases Ventricular Electrical Stability—A Computational Study

AbstractThe ventricular tissue is activated in a stochastic rather than in a deterministic rhythm due to the inherent heart rate variability (HRV). Low HRV is a known predictor for arrhythmia events and traditionally is attributed to autonomic nervous system tone damage. Yet, there is no model that directly assesses the antiarrhythmic effect of pacing stochasticity per se. One-dimensional (1D) and two-dimensional (2D) human ventricular tissues were modeled, and both deterministic and stochastic pacing protocols were applied. Action potential duration restitution (APDR) and conduction velocity restitution (CVR) curves were generated and analyzed, and the propensity and characteristics of action potential duration (APD) alternans were investigated. In the 1D model, pacing stochasticity was found to sustain a moderating effect on the APDR curve by reducing its slope, rendering the tissue less arrhythmogenic. Moreover, stochasticity was found to be a significant antagonist to the development of concordant APD alternans. These effects were generally amplified with increased variability in the pacing cycle intervals. In addition, in the 2D tissue configuration, stochastic pacing exerted a protective antiarrhythmic effect by reducing the spatial APD heterogeneity and converting discordant APD alternans to concordant ones. These results suggest that high cardiac pacing stochasticity is likely to reduce the risk of cardiac arrhythmias in patients

No change in the regional distribution of tidal volume during lateral posture in mechanically ventilated patients assessed by electrical impedance tomography

We assessed the distribution of regional lung ventilation during moderate and steep lateral posture using electrical impedance tomography (EIT) in mechanically ventilated patients. Seven patients were placed on a kinetic treatment table. An elastic belt containing 16 electrodes was placed around the chest and was connected to the EIT device. Patients were moved to left and right lateral positions in a stepwise (10°) mode up to 60°. EIT images [arbitrary units (AU)] were generated and scanned for assessment of relative ventilation distribution changes [tidal volume (VT)]. A calibration procedure of arbitrary units (AUs) versus ventilator-derived VT performed in all patients during three predefined positions (supine, 60°-left dependent and 60°-right-dependent) showed a significant correlation between VT in supine, left and right lateral positions with the corresponding AUs (r2 = 0·356, P<0·05). Changes in VT were calculated and compared to supine position, and specific regions of interest (ROIs) were analysed. In our study, in contrast to recent findings, a change in lateral positions did not induce a significant change in regional tidal volume distribution. In right lateral positions, a broader variation of VT with a trend towards an increase in the dependently positioned lung was observed in comparison with supine. Lateral positioning promotes the redistribution of ventilation to the ventral regions of the lung. The use of EIT technology might become a helpful tool for understanding and guiding posture therapy in mechanically ventilated patients

Body surface localization of left and right atrial high-frequency rotors in atrial fibrillation patients: A clinical-computational study

Background: Ablation is an effective therapy in atrial fibrillation (AF) patients in which an electrical driver can be identified. Objective: The aim of this study is to present and discuss a novel and strictly non-invasive approach to map and identify atrial regions responsible for AF perpetuation. Methods: Surface potential recordings of 14 patients with AF were recorded using a 67-lead recording system. Singularity points (SPs) were identified in surface phase maps after band-pass filtering at the highest dominant frequency (HDF). Mathematical models of combined atria and torso were constructed and used to investigate the ability of surface phase maps to estimate rotor activity in the atrial wall. Results: The simulations show that surface SPs originate at atrial SPs, but not all atrial SPs are reflected at the surface. Stable SPs were found in AF signals during 8.3±5.7% vs. 73.1±16.8% of the time in unfiltered vs. HDF-filtered patient data respectively (p<0.01). The average duration of each rotational pattern was also lower in unfiltered than in HDF-filtered AF signals (160±43 vs. 342±138 ms, p<0.01) resulting in 2.8±0.7 rotations per rotor. Band-pass filtering reduced the apparent meandering of surface HDF rotors by reducing the effect of the atrial electrical activity taking place at different frequencies. Torso surface SPs representing HDF rotors during AF were reflected at specific areas corresponding to the fastest atrial location. Conclusion: Phase analysis of surface potential signals after HDF-filtering during AF shows reentrant drivers localized to either the LA or RA, helping in localizing ablation targetsThis work was supported in part by the Spanish Society of Cardiology (Becas Investigacion Clinica 2009); the Universitat Politecnica de Valencia through its research initiative program; the Generalitat Valenciana grant (ACIF/2013/021); the Ministerio de Economia y Competitividad, Rod RIC; the Centro Nacional de Investigaciones Cardiovasculares (proyecto CNIC-13); the Coulter Foundation from the Biomedical Engineering Department, University of Michigan; the Gelman Award from the Cardiovascular Division, University of Michigan; the National Heart, Lung, and Blood Institute grants (P01411.039707, P01-1111187226, and R01-11L118304); and the Leducq Foundation. Dr Femandez-Aviles served on the advisory board of Medtronic and has received research funding from St Jude Medical Spain. Dr Berenfeld has received research support from Medtronic and St Jude Medical; he is a colbunder and scientific officer of Rhythm Solutions. None of the companies disclosed financed the research described in this article.Rodrigo Bort, M.; Guillem Sánchez, MS.; Climent, AM.; Pedrón Torrecilla, J.; Liberos Mascarell, A.; Millet Roig, J.; Fernandez-Aviles, F.... (2014). Body surface localization of left and right atrial high-frequency rotors in atrial fibrillation patients: A clinical-computational study. Heart Rhythm. 11(9):1584-1591. https://doi.org/10.1016/j.hrthm.2014.05.013S1584159111

Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling

[EN] Atrial fibrillation (AF) results in a remodeling of the electrical and structural characteristics of the cardiac tissue which dramatically reduces the efficacy of pharmacological and catheter-based ablation therapies. Recent experimental and clinical results have demonstrated that the complexity of the fibrillatory process significantly differs in paroxysmal versus persistent AF; however, the lack of appropriate research models of remodeled atrial tissue precludes the elucidation of the underlying AF mechanisms and the identification of appropriated therapeutic targets. Here, we summarize the different research models used to date, highlighting the lessons learned from them and pointing to the new doors that should be open for the development of innovative treatments for AF.The authors were supported by grants from the Spanish Ministry of Science and Innovation (PLE2009-0152), the Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain: PI13-01882 and PI13-00903) the Red de Investigacion Cardiovacular (RIC) from Instituto de Salud Carlos III (Ministry of Economy and Competitiveness, Spain). F Atienza served on the advisory board of Medtronic and has received research funding from St. Jude Medical Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Climent, A.; Guillem Sánchez, MS.; Atienza Fernández, F.; Fernandez-Aviles, F. (2014). Electrophysiological characteristics of permanent atrial fibrillation: insights from research models of cardiac remodeling. Expert Review of Cardiovascular Therapy. 13(1):1-3. https://doi.org/10.1586/14779072.2015.986465S1313

Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations

[EN] Heart failure (HF) is characterized by altered Ca2+ cycling, resulting in cardiac contractile dysfunction. Failing myocytes undergo electrophysiological remodeling, which is known to be the main cause of abnormal Ca2+ homeostasis. However, structural remodeling, specifically proliferating fibroblasts coupled to myocytes in the failing heart, could also contribute to Ca2+ cycling impairment. The goal of the present study was to systematically analyze the mechanisms by which myocyte-fibroblast coupling could affect Ca2+ dynamics in normal conditions and in HF. Simulations of healthy and failing human myocytes were performed using established mathematical models, and cells were either isolated or coupled to fibroblasts. Univariate and multivariate sensitivity analyses were performed to quantify effects of ion transport pathways on biomarkers computed from intracellular [Ca2+] waveforms. Variability in ion channels and pumps was imposed and populations of models were analyzed to determine effects on Ca2+ dynamics. Our results suggest that both univariate and multivariate sensitivity analyses are valuable methodologies to shed light into the ionic mechanisms underlying Ca2+ impairment in HF, although differences between the two methodologies are observed at high parameter variability. These can result from either the fact that multivariate analyses take into account ion channels or non-linear effects of ion transport pathways on Ca2+ dynamics. Coupling either healthy or failing myocytes to fibroblasts decreased Ca2+ transients due to an indirect sink effect on action potential and thus on Ca2+ related currents. Simulations that investigated restoration of normal physiology in failing myocytes showed that Ca2+ cycling can be normalized by increasing SERCA and L-type Ca2+ current activity while decreasing Na+-Ca2+ exchange and SR Ca2+ leak. Changes required to normalize action potentials in failing myocytes depended on whether myocytes were coupled to fibroblasts. In conclusion, univariate and multivariate sensitivity analyses are helpful tools to understand how Ca2+ cycling is impaired in heart failure and how this can be exacerbated by coupling of myocytes to fibroblasts. The design of pharmacological actions to restore normal activity should take into account the degree of fibrosis in the failing heart.This work was partially supported by the National Science Foundation (MCB 1615677), the American Heart Association (15GRNT25490006), the "Plan Estatal de Investigacion Cientifica y Tecnica y de Innovacion 2013-2016 from the Ministerio de Economia, Industria y Competitividad of Spain and Fondo Europeo de Desarrollo Regional (FEDER) DPI2016-75799-R (AEI/FEDER, UE)", and the "Programa de Ayudas de Investigacion y Desarrollo (PAID-01-17)" from the Universitat Politecnica de Valencia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Mora-Fenoll, MT.; Ferrero De Loma-Osorio, JM.; Gómez García, JF.; Sobie, EA.; Trenor Gomis, BA. (2018). Ca2+ Cycling Impairment in Heart Failure Is Exacerbated by Fibrosis: Insights Gained From Mechanistic Simulations. Frontiers in Physiology. 9. https://doi.org/10.3389/fphys.2018.01194S9Aguilar, M., Qi, X. Y., Huang, H., Comtois, P., & Nattel, S. (2014). Fibroblast Electrical Remodeling in Heart Failure and Potential Effects on Atrial Fibrillation. Biophysical Journal, 107(10), 2444-2455. doi:10.1016/j.bpj.2014.10.014R. ALPERT, N., HASENFUSS, G., J. LEAVITT, B., P. ITTLEMAN, F., PIESKE, B., & A. MULIERI, L. (2000). A Mechanistic Analysis of Reduced Mechanical Performance in Human Heart Failure. Japanese Heart Journal, 41(2), 103-116. doi:10.1536/jhj.41.103Bers, D. M. (2000). Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction. Circulation Research, 87(4), 275-281. doi:10.1161/01.res.87.4.275Britton, O. J., Bueno-Orovio, A., Virág, L., Varró, A., & Rodriguez, B. (2017). The Electrogenic Na+/K+ Pump Is a Key Determinant of Repolarization Abnormality Susceptibility in Human Ventricular Cardiomyocytes: A Population-Based Simulation Study. Frontiers in Physiology, 8. doi:10.3389/fphys.2017.00278Brown, T. R., Krogh-Madsen, T., & Christini, D. J. (2016). Illuminating Myocyte-Fibroblast Homotypic and Heterotypic Gap Junction Dynamics Using Dynamic Clamp. Biophysical Journal, 111(4), 785-797. doi:10.1016/j.bpj.2016.06.042Cabo, C., & Boyden, P. A. (2009). Extracellular Space Attenuates the Effect of Gap Junctional Remodeling on Wave Propagation: A Computational Study. Biophysical Journal, 96(8), 3092-3101. doi:10.1016/j.bpj.2009.01.014Cartledge, J. E., Kane, C., Dias, P., Tesfom, M., Clarke, L., Mckee, B., … Terracciano, C. M. (2015). Functional crosstalk between cardiac fibroblasts and adult cardiomyocytes by soluble mediators. Cardiovascular Research, 105(3), 260-270. doi:10.1093/cvr/cvu264Chen, J.-B., Tao, R., Sun, H.-Y., Tse, H.-F., Lau, C.-P., & Li, G.-R. (2009). Multiple Ca2+signaling pathways regulate intracellular Ca2+activity in human cardiac fibroblasts. Journal of Cellular Physiology, n/a-n/a. doi:10.1002/jcp.22010Chilton, L., Giles, W. R., & Smith, G. L. (2007). Evidence of intercellular coupling between co-cultured adult rabbit ventricular myocytes and myofibroblasts. The Journal of Physiology, 583(1), 225-236. doi:10.1113/jphysiol.2007.135038Chilton, L., Ohya, S., Freed, D., George, E., Drobic, V., Shibukawa, Y., … Giles, W. R. (2005). K+ currents regulate the resting membrane potential, proliferation, and contractile responses in ventricular fibroblasts and myofibroblasts. American Journal of Physiology-Heart and Circulatory Physiology, 288(6), H2931-H2939. doi:10.1152/ajpheart.01220.2004Cummins, M. A., Dalal, P. J., Bugana, M., Severi, S., & Sobie, E. A. (2014). Comprehensive Analyses of Ventricular Myocyte Models Identify Targets Exhibiting Favorable Rate Dependence. PLoS Computational Biology, 10(3), e1003543. doi:10.1371/journal.pcbi.1003543Drouin, E., Lande, G., & Charpentier, F. (1998). Amiodarone reduces transmural heterogeneity of repolarization in the human heart. Journal of the American College of Cardiology, 32(4), 1063-1067. doi:10.1016/s0735-1097(98)00330-1Fukuta, H., & Little, W. C. (2007). Contribution of Systolic and Diastolic Abnormalities to Heart Failure With a Normal and a Reduced Ejection Fraction. Progress in Cardiovascular Diseases, 49(4), 229-240. doi:10.1016/j.pcad.2006.08.009Gaudesius, G., Miragoli, M., Thomas, S. P., & Rohr, S. (2003). Coupling of Cardiac Electrical Activity Over Extended Distances by Fibroblasts of Cardiac Origin. Circulation Research, 93(5), 421-428. doi:10.1161/01.res.0000089258.40661.0cGomez, J. F., Cardona, K., Martinez, L., Saiz, J., & Trenor, B. (2014). Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 2D Simulation Study. PLoS ONE, 9(7), e103273. doi:10.1371/journal.pone.0103273Gomez, J. F., Cardona, K., Romero, L., Ferrero, J. M., & Trenor, B. (2014). Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study. PLoS ONE, 9(9), e106602. doi:10.1371/journal.pone.0106602Greisas, A., & Zlochiver, S. (2016). The Multi-Domain Fibroblast/Myocyte Coupling in the Cardiac Tissue: A Theoretical Study. Cardiovascular Engineering and Technology, 7(3), 290-304. doi:10.1007/s13239-016-0266-xJacquemet, V., & Henriquez, C. S. (2008). Loading effect of fibroblast-myocyte coupling on resting potential, impulse propagation, and repolarization: insights from a microstructure model. American Journal of Physiology-Heart and Circulatory Physiology, 294(5), H2040-H2052. doi:10.1152/ajpheart.01298.2007Li, Y., Asfour, H., & Bursac, N. (2017). Age-dependent functional crosstalk between cardiac fibroblasts and cardiomyocytes in a 3D engineered cardiac tissue. Acta Biomaterialia, 55, 120-130. doi:10.1016/j.actbio.2017.04.027Lou, Q., Janks, D. L., Holzem, K. M., Lang, D., Onal, B., Ambrosi, C. M., … Efimov, I. R. (2012). Right ventricular arrhythmogenesis in failing human heart: the role of conduction and repolarization remodeling. American Journal of Physiology-Heart and Circulatory Physiology, 303(12), H1426-H1434. doi:10.1152/ajpheart.00457.2012Lyon, A. R., MacLeod, K. T., Zhang, Y., Garcia, E., Kanda, G. K., Lab, M. J., … Gorelik, J. (2009). Loss of T-tubules and other changes to surface topography in ventricular myocytes from failing human and rat heart. Proceedings of the National Academy of Sciences, 106(16), 6854-6859. doi:10.1073/pnas.0809777106Andrew MacCannell, K., Bazzazi, H., Chilton, L., Shibukawa, Y., Clark, R. B., & Giles, W. R. (2007). A Mathematical Model of Electrotonic Interactions between Ventricular Myocytes and Fibroblasts. Biophysical Journal, 92(11), 4121-4132. doi:10.1529/biophysj.106.101410Majumder, R., Nayak, A. R., & Pandit, R. (2012). Nonequilibrium Arrhythmic States and Transitions in a Mathematical Model for Diffuse Fibrosis in Human Cardiac Tissue. PLoS ONE, 7(10), e45040. doi:10.1371/journal.pone.0045040Mayourian, J., Savizky, R. M., Sobie, E. A., & Costa, K. D. (2016). Modeling Electrophysiological Coupling and Fusion between Human Mesenchymal Stem Cells and Cardiomyocytes. PLOS Computational Biology, 12(7), e1005014. doi:10.1371/journal.pcbi.1005014Miragoli, M., Gaudesius, G., & Rohr, S. (2006). Electrotonic Modulation of Cardiac Impulse Conduction by Myofibroblasts. Circulation Research, 98(6), 801-810. doi:10.1161/01.res.0000214537.44195.a3Mora, M. T., Ferrero, J. M., Romero, L., & Trenor, B. (2017). Sensitivity analysis revealing the effect of modulating ionic mechanisms on calcium dynamics in simulated human heart failure. PLOS ONE, 12(11), e0187739. doi:10.1371/journal.pone.0187739Morotti, S., Nieves-Cintrón, M., Nystoriak, M. A., Navedo, M. F., & Grandi, E. (2017). Predominant contribution of L-type Cav1.2 channel stimulation to impaired intracellular calcium and cerebral artery vasoconstriction in diabetic hyperglycemia. Channels, 11(4), 340-346. doi:10.1080/19336950.2017.1293220Muszkiewicz, A., Britton, O. J., Gemmell, P., Passini, E., Sánchez, C., Zhou, X., … Rodriguez, B. (2016). Variability in cardiac electrophysiology: Using experimentally-calibrated populations of models to move beyond the single virtual physiological human paradigm. Progress in Biophysics and Molecular Biology, 120(1-3), 115-127. doi:10.1016/j.pbiomolbio.2015.12.002Nguyen, T. P., Xie, Y., Garfinkel, A., Qu, Z., & Weiss, J. N. (2011). Arrhythmogenic consequences of myofibroblast–myocyte coupling. Cardiovascular Research, 93(2), 242-251. doi:10.1093/cvr/cvr292Nivala, M., Song, Z., Weiss, J. N., & Qu, Z. (2015). T-tubule disruption promotes calcium alternans in failing ventricular myocytes: Mechanistic insights from computational modeling. Journal of Molecular and Cellular Cardiology, 79, 32-41. doi:10.1016/j.yjmcc.2014.10.018O’Hara, T., Virág, L., Varró, A., & Rudy, Y. (2011). Simulation of the Undiseased Human Cardiac Ventricular Action Potential: Model Formulation and Experimental Validation. PLoS Computational Biology, 7(5), e1002061. doi:10.1371/journal.pcbi.1002061Ozdemir, S., Bito, V., Holemans, P., Vinet, L., Mercadier, J.-J., Varro, A., & Sipido, K. R. (2008). Pharmacological Inhibition of Na/Ca Exchange Results in Increased Cellular Ca2+Load Attributable to the Predominance of Forward Mode Block. Circulation Research, 102(11), 1398-1405. doi:10.1161/circresaha.108.173922Péréon, Y., Demolombe, S., Baró, I., Drouin, E., Charpentier, F., & Escande, D. (2000). Differential expression of KvLQT1 isoforms across the human ventricular wall. American Journal of Physiology-Heart and Circulatory Physiology, 278(6), H1908-H1915. doi:10.1152/ajpheart.2000.278.6.h1908Piacentino, V., Weber, C. R., Chen, X., Weisser-Thomas, J., Margulies, K. B., Bers, D. M., & Houser, S. R. (2003). Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocytes. Circulation Research, 92(6), 651-658. doi:10.1161/01.res.0000062469.83985.9bRocchetti, M., Alemanni, M., Mostacciuolo, G., Barassi, P., Altomare, C., Chisci, R., … Zaza, A. (2008). Modulation of Sarcoplasmic Reticulum Function by PST2744 [Istaroxime; (E,Z)-3-((2-Aminoethoxy)imino) Androstane-6,17-dione Hydrochloride)] in a Pressure-Overload Heart Failure Model. Journal of Pharmacology and Experimental Therapeutics, 326(3), 957-965. doi:10.1124/jpet.108.138701Romero, L., Carbonell, B., Trenor, B., Rodríguez, B., Saiz, J., & Ferrero, J. M. (2011). Systematic characterization of the ionic basis of rabbit cellular electrophysiology using two ventricular models. Progress in Biophysics and Molecular Biology, 107(1), 60-73. doi:10.1016/j.pbiomolbio.2011.06.012Romero, L., Pueyo, E., Fink, M., & Rodríguez, B. (2009). Impact of ionic current variability on human ventricular cellular electrophysiology. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1436-H1445. doi:10.1152/ajpheart.00263.2009Rook, M. B., van Ginneken, A. C., de Jonge, B., el Aoumari, A., Gros, D., & Jongsma, H. J. (1992). Differences in gap junction channels between cardiac myocytes, fibroblasts, and heterologous pairs. American Journal of Physiology-Cell Physiology, 263(5), C959-C977. doi:10.1152/ajpcell.1992.263.5.c959Sachse, F. B., Moreno, A. P., Seemann, G., & Abildskov, J. A. (2009). A Model of Electrical Conduction in Cardiac Tissue Including Fibroblasts. Annals of Biomedical Engineering, 37(5), 874-889. doi:10.1007/s10439-009-9667-4Sanchez-Alonso, J. L., Bhargava, A., O’Hara, T., Glukhov, A. V., Schobesberger, S., Bhogal, N., … Gorelik, J. (2016). Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart Failure. Circulation Research, 119(8), 944-955. doi:10.1161/circresaha.116.308698Savarese, G., & Lund, L. H. (2017). Global Public Health Burden of Heart Failure. Cardiac Failure Review, 03(01), 7. doi:10.15420/cfr.2016:25:2Seidel, T., Salameh, A., & Dhein, S. (2010). A Simulation Study of Cellular Hypertrophy and Connexin Lateralization in Cardiac Tissue. Biophysical Journal, 99(9), 2821-2830. doi:10.1016/j.bpj.2010.09.010Shannon, T. R., Ginsburg, K. S., & Bers, D. M. (2000). Potentiation of Fractional Sarcoplasmic Reticulum Calcium Release by Total and Free Intra-Sarcoplasmic Reticulum Calcium Concentration. Biophysical Journal, 78(1), 334-343. doi:10.1016/s0006-3495(00)76596-9Sobie, E. A. (2009). Parameter Sensitivity Analysis in Electrophysiological Models Using Multivariable Regression. Biophysical Journal, 96(4), 1264-1274. doi:10.1016/j.bpj.2008.10.056Sridhar, S., Vandersickel, N., & Panfilov, A. V. (2017). Effect of myocyte-fibroblast coupling on the onset of pathological dynamics in a model of ventricular tissue. Scientific Reports, 7(1). doi:10.1038/srep40985Tamayo, M., Manzanares, E., Bas, M., Martín-Nunes, L., Val-Blasco, A., Jesús Larriba, M., … Delgado, C. (2017). Calcitriol (1,25-dihydroxyvitamin D3) increases L-type calcium current via protein kinase A signaling and modulates calcium cycling and contractility in isolated mouse ventricular myocytes. Heart Rhythm, 14(3), 432-439. doi:10.1016/j.hrthm.2016.12.013Trayanova, N. A., & Chang, K. C. (2016). How computer simulations of the human heart can improve anti-arrhythmia therapy. The Journal of Physiology, 594(9), 2483-2502. doi:10.1113/jp270532Trenor, B., Cardona, K., Gomez, J. F., Rajamani, S., Ferrero, J. M., Belardinelli, L., & Saiz, J. (2012). Simulation and Mechanistic Investigation of the Arrhythmogenic Role of the Late Sodium Current in Human Heart Failure. PLoS ONE, 7(3), e32659. doi:10.1371/journal.pone.0032659Walmsley, J., Rodriguez, J. F., Mirams, G. R., Burrage, K., Efimov, I. R., & Rodriguez, B. (2013). mRNA Expression Levels in Failing Human Hearts Predict Cellular Electrophysiological Remodeling: A Population-Based Simulation Study. PLoS ONE, 8(2), e56359. doi:10.1371/journal.pone.0056359Xie, Y., Garfinkel, A., Camelliti, P., Kohl, P., Weiss, J. N., & Qu, Z. (2009). Effects of fibroblast-myocyte coupling on cardiac conduction and vulnerability to reentry: A computational study. Heart Rhythm, 6(11), 1641-1649. doi:10.1016/j.hrthm.2009.08.003Xie, Y., Garfinkel, A., Weiss, J. N., & Qu, Z. (2009). Cardiac alternans induced by fibroblast-myocyte coupling: mechanistic insights from computational models. American Journal of Physiology-Heart and Circulatory Physiology, 297(2), H775-H784. doi:10.1152/ajpheart.00341.2009Zhan, H., Xia, L., Shou, G., Zang, Y., Liu, F., & Crozier, S. (2014). Fibroblast proliferation alters cardiac excitation conduction and contraction: a computational study. Journal of Zhejiang University SCIENCE B, 15(3), 225-242. doi:10.1631/jzus.b1300156Zhou, X., Bueno-Orovio, A., Orini, M., Hanson, B., Hayward, M., Taggart, P., … Rodriguez, B. (2016). In Vivo and In Silico Investigation Into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes. Circulation Research, 118(2), 266-278. doi:10.1161/circresaha.115.307836Zimik, S., & Pandit, R. (2016). Instability of spiral and scroll waves in the presence of a gradient in the fibroblast density: the effects of fibroblast–myocyte coupling. New Journal of Physics, 18(12), 123014. doi:10.1088/1367-2630/18/12/123014Zlochiver, S., Muñoz, V., Vikstrom, K. L., Taffet, S. M., Berenfeld, O., & Jalife, J. (2008). Electrotonic Myofibroblast-to-Myocyte Coupling Increases Propensity to Reentrant Arrhythmias in Two-Dimensional Cardiac Monolayers. Biophysical Journal, 95(9), 4469-4480. doi:10.1529/biophysj.108.136473Zou, J., Salarian, M., Chen, Y., Zhuo, Y., Brown, N. E., Hepler, J. R., & Yang, J. J. (2017). Direct visualization of interaction between calmodulin and connexin45. Biochemical Journal, 474(24), 4035-4051. doi:10.1042/bcj2017042

Balance between sodium and calcium currents underlying chronic atrial fibrillation termination: An in silico intersubject variability study

BACKGROUND Atrial remodeling as a result of long-standing persistent atrial fibrillation (AF) induces substrate modifications that lead to different perpetuation mechanisms than in paroxysmal AF and a reduction in the efficacy of antiarrhythmic treatments. OBJECTIVE The purpose of this study was to identify the ionic current modifications that could destabilize reentries during chronic AF and serve to personalize antiarrhythmic strategies. METHODS A population of 173 mathematical models of remodeled human atrial tissue with realistic intersubject variability was developed based on action potential recordings of 149 patients diagnosed with AF. The relationship of each ionic current with AF maintenance and the dynamics of functional reentries (rotor meandering, dominant frequency) were evaluated by means of 3-dimensional simulations. RESULTS Self-sustained reentries were maintained in 126 (73%) of the simulations. AF perpetuation was associated with higher expressions of I-Na and I-caL (P < .01), with no significant differences in the remaining currents. I-caL blockade promoted AF extinction in 30% of these 126 models. The mechanism of AF termination was related with collisions between rotors because of an increase in rotor meandering (1.71 +/- 2.01cm(2)) and presented an increased efficacy in models with a depressed INa (P < .01). CONCLUSION Mathematical simulations based on a population of models representing intersubject variability allow the identification of ionic mechanisms underlying rotor dynamics and the definition of new personalized pharmacologic strategies. Our results suggest that the underlying mechanism of the diverging success of I-caL block as an antiarrhythmic strategy is dependent on the basal availability of sodium and calcium ion channel conductivities.Supported by the Spanish Ministry of Education (FPU2010); the Wellcome Trust Fellowship 100246/Z/12/Z; Universitat Politecnica de Valencia; the Spanish Health Research Fund (PI13/00903); the Spanish Society of Cardiology; the Spanish Ministry of Science; Generalitat Valenciana Grants (ACIF/2013/021); and Innovation (Red RIC, PLE2009-0152). Drs. Rodriguez and Climent are equally contributing senior authors.Liberos Mascarell, A.; Bueno-Orovio, A.; Rodrigo Bort, M.; Ravens, U.; Hernández-Romero, I.; Fernández-Avilés, F.; Guillem Sánchez, MS.... (2016). Balance between sodium and calcium currents underlying chronic atrial fibrillation termination: An in silico intersubject variability study. Heart Rhythm. 13(12):2358-2365. https://doi.org/10.1016/j.hrthm.2016.08.028S23582365131

Lessons Learned from Multi-scale Modeling of the Failing Heart

[EN] Heart failure constitutes a major public health problem worldwide. Affected patients experience a number of changes in the electrical function of the heart that predispose to potentially lethal cardiac arrhythmias. Due to the multitude of electrophysiological changes that may occur during heart failure, the scientific literature is complex and sometimes ambiguous, perhaps because these findings are highly dependent on the etiology, the stage of heart failure, and the experimental model used to study these changes. Nevertheless, a number of common features of failing hearts have been documented. Prolongation of the action potential (AP) involving ion channel remodeling and alterations in calcium handling have been established as the hallmark characteristics of myocytes isolated from failing hearts. Intercellular uncoupling and fibrosis are identified as major arrhythmogenic factors. Multi-scale computational simulations are a powerful tool that complements experimental and clinical research. The development of biophysically detailed computer models of single myocytes and cardiac tissues has contributed greatly to our understanding of processes underlying excitation and repolarization in the heart. The electrical, structural, and metabolic remodeling that arises in cardiac tissues during heart failure has been addressed from different computational perspectives to further understand the arrhythmogenic substrate. This review summarizes the contributions from computational modeling and simulation to predict the underlying mechanisms of heart failure phenotypes and their implications for arrhythmogenesis, ranging from the cellular level to whole-heart simulations. The main aspects of heart failure are presented in several related sections. An overview of the main electrophysiological and structural changes that have been observed experimentally in failing hearts is followed by the description and discussion of the simulation work in this field at the cellular level, and then in 2D and 3D cardiac structures. The implications for arrhythmogenesis in heart failure are also discussed including therapeutic measures, such as drug effects and cardiac resynchronization therapy. Finally, the future challenges in heart failure modeling and simulation will be discussed.This work was partially supported by (i) the "VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica" from the Ministerio de Economia y Competitividad of Spain and the European Commission (European Regional Development Funds ERDF-FEDER) (grant number TIN2012-37546-C03-01), and by (ii) Programa Prometeo de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana (grant number PROMETEO/2012/030).Gómez García, JF.; Cardona-Urrego, KE.; Trénor Gomis, BA. (2015). Lessons Learned from Multi-scale Modeling of the Failing Heart. Journal of Molecular and Cellular Cardiology. 89:146-159. https://doi.org/10.1016/j.yjmcc.2015.10.016S1461598

Minimizing discordances in automated classification of fractionated electrograms in human persistent atrial fibrillation

Ablation of persistent atrial fibrillation (persAF) targeting complex fractionated atrial electrograms (CFAEs) detected by automated algorithms has produced conflicting outcomes in previous electrophysiological studies. We hypothesize that the differences in these algorithms could lead to discordant CFAE classifications by the available mapping systems, giving rise to potential disparities in CFAE-guided ablation. This study reports the results of a head-to-head comparison of CFAE detection performed by NavX (St. Jude Medical) versus CARTO (Biosense Webster) on the same bipolar electrogram data (797 electrograms) from 18 persAF patients. We propose revised thresholds for both primary and complementary indices to minimize the differences in CFAE classification performed by either system. Using the default thresholds [NavX: CFEMean ≤ 120 ms; CARTO: ICL ≥ 7], NavX classified 70 % of the electrograms as CFAEs, while CARTO detected 36 % (Cohen’s kappa κ ≈ 0.3, P < 0.0001). Using revised thresholds found using receiver operating characteristic curves [NavX: CFE-Mean ≤ 84 ms, CFE-SD ≤ 47 ms; CARTO: ICL ≥ 4, ACI ≤ 82 ms, SCI ≤ 58 ms], NavX classified 45 %, while CARTO detected 42 % (κ ≈ 0.5, P < 0.0001). Our results show that CFAE target identification is dependent on the system and thresholds used by the electrophysiological study. The thresholds found in this work counterbalance the differences in automated CFAE classification performed by each system. This could facilitate comparisons of CFAE ablation outcomes guided by either NavX or CARTO in future works

Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study

Background: Heart failure is a final common pathway or descriptor for various cardiac pathologies. It is associated with sudden cardiac death, which is frequently caused by ventricular arrhythmias. Electrophysiological remodeling, intercellular uncoupling, fibrosis and autonomic imbalance have been identified as major arrhythmogenic factors in heart failure etiology and progression. Objective: In this study we investigate in silico the role of electrophysiological and structural heart failure remodeling on the modulation of key elements of the arrhythmogenic substrate, i.e., electrophysiological gradients and abnormal impulse propagation. Methods: Two different mathematical models of the human ventricular action potential were used to formulate models of the failing ventricular myocyte. This provided the basis for simulations of the electrical activity within a transmural ventricular strand. Our main goal was to elucidate the roles of electrophysiological and structural remodeling in setting the stage for malignant life-threatening arrhythmias. Results: Simulation results illustrate how the presence of M cells and heterogeneous electrophysiological remodeling in the human failing ventricle modulate the dispersion of action potential duration and repolarization time. Specifically, selective heterogeneous remodeling of expression levels for the Na+ /Ca2+ exchanger and SERCA pump decrease these heterogeneities. In contrast, fibroblast proliferation and cellular uncoupling both strongly increase repolarization heterogeneities. Conduction velocity and the safety factor for conduction are also reduced by the progressive structural remodeling during heart failure. Conclusion: An extensive literature now establishes that in human ventricle, as heart failure progresses, gradients for repolarization are changed significantly by protein specific electrophysiological remodeling (either homogeneous or heterogeneous). Our simulations illustrate and provide new insights into this. Furthermore, enhanced fibrosis in failing hearts, as well as reduced intercellular coupling, combine to increase electrophysiological gradients and reduce electrical propagation. In combination these changes set the stage for arrhythmias.This work was partially supported by (i) the "VI Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica" from the Ministerio de Economia y Competitividad of Spain (grant number TIN2012-37546-C03-01) and the European Commission (European Regional Development Funds - ERDF - FEDER), (ii) the Direccion General de Politica Cientifica de la Generalitat Valenciana (grant number GV/2013/119), and (iii) Programa Prometeo (PROMETEO/2012/030) de la Conselleria d'Educacio Formacio I Ocupacio, Generalitat Valenciana. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Gómez García, JF.; Cardona, K.; Romero Pérez, L.; Ferrero De Loma-Osorio, JM.; Trénor Gomis, BA. (2014). Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 1D Simulation Study. PLoS ONE. 9(9). https://doi.org/10.1371/journal.pone.0106602S9

A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship

The most common sustained cardiac arrhythmias in humans are atrial tachyarrhythmias, mainly atrial fibrillation. Areas of complex fractionated atrial electrograms and high dominant frequency have been proposed as critical regions for maintaining atrial fibrillation; however, there is a paucity of data on the relationship between the characteristics of electrograms and the propagation pattern underlying them. In this study, a realistic 3D computer model of the human atria has been developed to investigate this relationship. The model includes a realistic geometry with fiber orientation, anisotropic conductivity and electrophysiological heterogeneity. We simulated different tachyarrhythmic episodes applying both transient and continuous ectopic activity. Electrograms and their dominant frequency and organization index values were calculated over the entire atrial surface. Our simulations show electrograms with simple potentials, with little or no cycle length variations, narrow frequency peaks and high organization index values during stable and regular activity as the observed in atrial flutter, atrial tachycardia (except in areas of conduction block) and in areas closer to ectopic activity during focal atrial fibrillation. By contrast, cycle length variations and polymorphic electrograms with single, double and fragmented potentials were observed in areas of irregular and unstable activity during atrial fibrillation episodes. Our results also show: 1) electrograms with potentials without negative deflection related to spiral or curved wavefronts that pass over the recording point and move away, 2) potentials with a much greater proportion of positive deflection than negative in areas of wave collisions, 3) double potentials related with wave fragmentations or blocking lines and 4) fragmented electrograms associated with pivot points. Our model is the first human atrial model with realistic fiber orientation used to investigate the relationship between different atrial arrhythmic propagation patterns and the electrograms observed at more than 43000 points on the atrial surface.This work was partially supported by the Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica, Ministerio de Ciencia e Innovacion of Spain (TEC2008-02090), by the Plan Avanza (Accion Estrategica de Telecomunicaciones y Sociedad de la Informacion), Ministerio de Industria Turismo y Comercio of Spain (TSI-020100-2010-469), by the Programa Prometeo 2012 of the Generalitat Valenciana and by the Programa de Apoyo a la Investigacion y Desarrollo de la Universitat Politecnica de Valencia (PAID-06-11-2002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Tobón Zuluaga, C.; Ruiz Villa, CA.; Heidenreich, E.; Romero Pérez, L.; Hornero, F.; Saiz Rodríguez, FJ. (2013). A three-dimensional human atrial model with fiber orientation. Electrograms and arrhythmic activation patterns relationship. PLoS ONE. 8(2):1-13. https://doi.org/10.1371/journal.pone.0050883S11382Ho SY, Sanchez-Quintana D, Anderson RH (1998) Can anatomy define electric pathways? In: International Workshop on Computer Simulation and Experimental Assessment of Electrical Cardiac Function, Lausanne, Switzerland. 77–86.Tobón C (2009) Evaluación de factores que provocan fibrilación auricular y de su tratamiento mediante técnicas quirúrgicas. Estudio de simulación. Master Thesis Universitat Politècnica de València.Ruiz C (2010) Estudio de la vulnerabilidad a reentradas a través de modelos matemáticos y simulación de la aurícula humana. Doctoral Thesis Universitat Politècnica de València.Tobón C (2010) Modelización y evaluación de factores que favorecen las arritmias auriculares y su tratamiento mediante técnicas quirúrgicas. Estudio de simulación. Doctoral Thesis Universitat Politècnica de València.Henriquez, C. S., & Papazoglou, A. A. (1996). Using computer models to understand the roles of tissue structure and membrane dynamics in arrhythmogenesis. Proceedings of the IEEE, 84(3), 334-354. doi:10.1109/5.486738Grimm, R. A., Chandra, S., Klein, A. L., Stewart, W. J., Black, I. W., Kidwell, G. A., & Thomas, J. D. (1996). Characterization of left atrial appendage Doppler flow in atrial fibrillation and flutter by Fourier analysis. American Heart Journal, 132(2), 286-296. doi:10.1016/s0002-8703(96)90424-xMaleckar, M. M., Greenstein, J. L., Giles, W. R., & Trayanova, N. A. (2009). K+ current changes account for the rate dependence of the action potential in the human atrial myocyte. American Journal of Physiology-Heart and Circulatory Physiology, 297(4), H1398-H1410. doi:10.1152/ajpheart.00411.200