Validation and Opportunities of Electrocardiographic Imaging: From Technical chievements to Clinical Applications

[EN] Electrocardiographic imaging (ECGI) reconstructs the electrical activity of the heart from a dense array of body-surface electrocardiograms and a patient-specific heart-torso geometry. Depending on how it is formulated, ECGI allows the reconstruction of the activation and recovery sequence of the heart, the origin of premature beats or tachycardia, the anchors/hotspots of re-entrant arrhythmias and other electrophysiological quantities of interest. Importantly, these quantities are directly and non-invasively reconstructed in a digitized model of the patient's three-dimensional heart, which has led to clinical interest in ECGI's ability to personalize diagnosis and guide therapy. Despite considerable development over the last decades, validation of ECGI is challenging. Firstly, results depend considerably on implementation choices, which are necessary to deal with ECGI's ill-posed character. Secondly, it is challenging to obtain (invasive) ground truth data of high quality. In this review, we discuss the current status of ECGI validation as well as the major challenges remaining for complete adoption of ECGI in clinical practice. Specifically, showing clinical benefit is essential for the adoption of ECGI. Such benefit may lie in patient outcome improvement, workflow improvement, or cost reduction. Future studies should focus on these aspects to achieve broad adoption of ECGI, but only after the technical challenges have been solved for that specific application/pathology. We propose 'best' practices for technical validation and highlight collaborative efforts recently organized in this field. Continued interaction between engineers, basic scientists, and physicians remains essential to find a hybrid between technical achievements, pathological mechanisms insights, and clinical benefit, to evolve this powerful technique toward a useful role in clinical practice.This study received financial support from the Hein Wellens Fonds, the Cardiovascular Research and Training Institute (CVRTI), the Nora Eccles Treadwell Foundation, the National Institute of General Medical Sciences of the National Institutes of Health (P41GM103545), the National Institutes of Health (NIH HL080093), the French government as part of the Investments of the Future program managed by the National Research Agency (ANR-10-IAHU-04), from the VEGA Grant Agency in Slovakia (2/0071/16), from the Slovak Research and Development Agency (APVV-14-0875), the Fondo Europeo de Desarrollo Regional (FEDER), the Instituto de Salud Carlos III (PI17/01106) and from Conselleria d'Educacio, Investigacio, Cultura i Esport de la Generalitat Valenciana (AICO/2018/267) and NIH grant (HL125998) and National Science Foundation (ACI-1350374).Cluitmans, M.; Brooks, D.; Macleod, RS.; Dossel, O.; Guillem Sánchez, MS.; Van Dam, P.; Svehlikova, J.... (2018). Validation and Opportunities of Electrocardiographic Imaging: From Technical chievements to Clinical Applications. Frontiers in Physiology. 9. https://doi.org/10.3389/fphys.2018.01305S9Andrews, C. M., Srinivasan, N. T., Rosmini, S., Bulluck, H., Orini, M., Jenkins, S., … Rudy, Y. (2017). Electrical and Structural Substrate of Arrhythmogenic Right Ventricular Cardiomyopathy Determined Using Noninvasive Electrocardiographic Imaging and Late Gadolinium Magnetic Resonance Imaging. Circulation: Arrhythmia and Electrophysiology, 10(7). doi:10.1161/circep.116.005105Aras, K., Good, W., Tate, J., Burton, B., Brooks, D., Coll-Font, J., … MacLeod, R. (2015). Experimental Data and Geometric Analysis Repository—EDGAR. Journal of Electrocardiology, 48(6), 975-981. doi:10.1016/j.jelectrocard.2015.08.008Austen, W., Edwards, J., Frye, R., Gensini, G., Gott, V., Griffith, L., … Roe, B. (1975). A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation, 51(4), 5-40. doi:10.1161/01.cir.51.4.5Bayley, R. H., & Berry, P. M. (1962). The electrical field produced by the eccentric current dipole in the nonhomogeneous conductor. American Heart Journal, 63(6), 808-820. doi:10.1016/0002-8703(62)90065-0Bear, L. R., Huntjens, P. R., Walton, R. D., Bernus, O., Coronel, R., & Dubois, R. (2018). Cardiac electrical dyssynchrony is accurately detected by noninvasive electrocardiographic imaging. Heart Rhythm, 15(7), 1058-1069. doi:10.1016/j.hrthm.2018.02.024Bear, L. R., LeGrice, I. J., Sands, G. B., Lever, N. A., Loiselle, D. S., Paterson, D. J., … Smaill, B. H. (2018). How Accurate Is Inverse Electrocardiographic Mapping? Circulation: Arrhythmia and Electrophysiology, 11(5). doi:10.1161/circep.117.006108Berger, T., Fischer, G., Pfeifer, B., Modre, R., Hanser, F., Trieb, T., … Hintringer, F. (2006). Single-Beat Noninvasive Imaging of Cardiac Electrophysiology of Ventricular Pre-Excitation. Journal of the American College of Cardiology, 48(10), 2045-2052. doi:10.1016/j.jacc.2006.08.019Berger, T., Pfeifer, B., Hanser, F. F., Hintringer, F., Fischer, G., Netzer, M., … Seger, M. (2011). Single-Beat Noninvasive Imaging of Ventricular Endocardial and Epicardial Activation in Patients Undergoing CRT. PLoS ONE, 6(1), e16255. doi:10.1371/journal.pone.0016255Dubois, R., Pashaei, A., Duchateau, J., & Vigmond, E. (2016). Evaluation of Combined Noninvasive Electrocardiographic Imaging and Phase Mapping approach for Atrial Fibrillation: A Simulation Study. 2016 Computing in Cardiology Conference (CinC). doi:10.22489/cinc.2016.037-540Duchateau, J., Potse, M., & Dubois, R. (2017). Spatially Coherent Activation Maps for Electrocardiographic Imaging. IEEE Transactions on Biomedical Engineering, 64(5), 1149-1156. doi:10.1109/tbme.2016.2593003Erem, B., Brooks, D. H., van Dam, P. M., Stinstra, J. G., & MacLeod, R. S. (2011). Spatiotemporal estimation of activation times of fractionated ECGs on complex heart surfaces. 2011 Annual International Conference of the IEEE Engineering in Medicine and Biology Society. doi:10.1109/iembs.2011.6091455Erem, B., van Dam, P. M., & Brooks, D. H. (2014). Identifying Model Inaccuracies and Solution Uncertainties in Noninvasive Activation-Based Imaging of Cardiac Excitation Using Convex Relaxation. IEEE Transactions on Medical Imaging, 33(4), 902-912. doi:10.1109/tmi.2014.2297952Erkapic, D., & Neumann, T. (2015). Ablation of Premature Ventricular Complexes Exclusively Guided by Three-Dimensional Noninvasive Mapping. Cardiac Electrophysiology Clinics, 7(1), 109-115. doi:10.1016/j.ccep.2014.11.010Everett, T. H., Lai-Chow Kok, Vaughn, R. H., Moorman, R., & Haines, D. E. (2001). Frequency domain algorithm for quantifying atrial fibrillation organization to increase defibrillation efficacy. IEEE Transactions on Biomedical Engineering, 48(9), 969-978. doi:10.1109/10.942586Faes, L., & Ravelli, F. (2007). A morphology-based approach to the evaluation of atrial fibrillation organization. IEEE Engineering in Medicine and Biology Magazine, 26(4), 59-67. doi:10.1109/memb.2007.384097Fitzpatrick, A. P., Gonzales, R. P., Lesh, M. D., odin, G. W., Lee, R. J., & Scheinman, M. M. (1994). New algorithm for the localization of accessory atrioventricular connections using a baseline electrocardiogram. Journal of the American College of Cardiology, 23(1), 107-116. doi:10.1016/0735-1097(94)90508-8Geselowitz, D. B. (1989). On the theory of the electrocardiogram. Proceedings of the IEEE, 77(6), 857-876. doi:10.1109/5.29327Geselowitz, D. B. (1992). Description of cardiac sources in anisotropic cardiac muscle. Journal of Electrocardiology, 25, 65-67. doi:10.1016/0022-0736(92)90063-6Ghanem, R. N., Jia, P., Ramanathan, C., Ryu, K., Markowitz, A., & Rudy, Y. (2005). Noninvasive Electrocardiographic Imaging (ECGI): Comparison to intraoperative mapping in patients. Heart Rhythm, 2(4), 339-354. doi:10.1016/j.hrthm.2004.12.022Ghosh, S., Rhee, E. K., Avari, J. N., Woodard, P. K., & Rudy, Y. (2008). Cardiac Memory in Patients With Wolff-Parkinson-White Syndrome. Circulation, 118(9), 907-915. doi:10.1161/circulationaha.108.781658Ghosh, S., Silva, J. N. A., Canham, R. M., Bowman, T. M., Zhang, J., Rhee, E. K., … Rudy, Y. (2011). Electrophysiologic substrate and intraventricular left ventricular dyssynchrony in nonischemic heart failure patients undergoing cardiac resynchronization therapy. Heart Rhythm, 8(5), 692-699. doi:10.1016/j.hrthm.2011.01.017Grace, A., Verma, A., & Willems, S. (2017). Dipole Density Mapping of Atrial Fibrillation. European Heart Journal, 38(1), 5-9. doi:10.1093/eurheartj/ehw585Dorset, D. L. (1996). Electron crystallography. Acta Crystallographica Section B Structural Science, 52(5), 753-769. doi:10.1107/s0108768196005599Haissaguerre, M., Hocini, M., Denis, A., Shah, A. J., Komatsu, Y., Yamashita, S., … Dubois, R. (2014). Driver Domains in Persistent Atrial Fibrillation. Circulation, 130(7), 530-538. doi:10.1161/circulationaha.113.005421HAISSAGUERRE, M., HOCINI, M., SHAH, A. J., DERVAL, N., SACHER, F., JAIS, P., & DUBOIS, R. (2013). Noninvasive Panoramic Mapping of Human Atrial Fibrillation Mechanisms: A Feasibility Report. Journal of Cardiovascular Electrophysiology, 24(6), 711-717. doi:10.1111/jce.12075Han, C., Pogwizd, S. M., Killingsworth, C. R., & He, B. (2011). Noninvasive imaging of three-dimensional cardiac activation sequence during pacing and ventricular tachycardia. Heart Rhythm, 8(8), 1266-1272. doi:10.1016/j.hrthm.2011.03.014Bin He, Guanglin Li, & Xin Zhang. (2003). Noninvasive imaging of cardiac transmembrane potentials within three-dimensional myocardium by means of a realistic geometry anisotropic heart model. IEEE Transactions on Biomedical Engineering, 50(10), 1190-1202. doi:10.1109/tbme.2003.817637Bin He, & Dongsheng Wu. (2001). Imaging and visualization of 3-D cardiac electric activity. IEEE Transactions on Information Technology in Biomedicine, 5(3), 181-186. doi:10.1109/4233.945288Horáček, B. M., Sapp, J. L., Penney, C. J., Warren, J. W., & Wang, J. J. (2011). Comparison of epicardial potential maps derived from the 12-lead electrocardiograms with scintigraphic images during controlled myocardial ischemia. Journal of Electrocardiology, 44(6), 707-712. doi:10.1016/j.jelectrocard.2011.08.009Horáček, B. M., Wang, L., Dawoud, F., Xu, J., & Sapp, J. L. (2015). Noninvasive electrocardiographic imaging of chronic myocardial infarct scar. Journal of Electrocardiology, 48(6), 952-958. doi:10.1016/j.jelectrocard.2015.08.035Jamil-Copley, S., Vergara, P., Carbucicchio, C., Linton, N., Koa-Wing, M., Luther, V., … Kanagaratnam, P. (2015). Application of Ripple Mapping to Visualize Slow Conduction Channels Within the Infarct-Related Left Ventricular Scar. Circulation: Arrhythmia and Electrophysiology, 8(1), 76-86. doi:10.1161/circep.114.001827Janssen, A. M., Potyagaylo, D., Dössel, O., & Oostendorp, T. F. (2017). Assessment of the equivalent dipole layer source model in the reconstruction of cardiac activation times on the basis of BSPMs produced by an anisotropic model of the heart. Medical & Biological Engineering & Computing, 56(6), 1013-1025. doi:10.1007/s11517-017-1715-xKnecht, S., Sohal, M., Deisenhofer, I., Albenque, J.-P., Arentz, T., Neumann, T., … Rostock, T. (2017). Multicentre evaluation of non-invasive biatrial mapping for persistent atrial fibrillation ablation: the AFACART study. EP Europace, 19(8), 1302-1309. doi:10.1093/europace/euw168Kuck, K.-H., Schaumann, A., Eckardt, L., Willems, S., Ventura, R., Delacrétaz, E., … Hansen, P. S. (2010). Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): a multicentre randomised controlled trial. The Lancet, 375(9708), 31-40. doi:10.1016/s0140-6736(09)61755-4Identification of Rotors during Human Atrial Fibrillation Using Contact Mapping and Phase Singularity Detection: Technical Considerations. (2017). IEEE Transactions on Biomedical Engineering, 64(2), 310-318. doi:10.1109/tbme.2016.2554660Leong, K. M. W., Ng, F. S., Yao, C., Roney, C., Taraborrelli, P., Linton, N. W. F., … Varnava, A. M. (2017). ST-Elevation Magnitude Correlates With Right Ventricular Outflow Tract Conduction Delay in Type I Brugada ECG. Circulation: Arrhythmia and Electrophysiology, 10(10). doi:10.1161/circep.117.005107Chenguang Liu, Eggen, M. D., Swingen, C. M., Iaizzo, P. A., & Bin He. (2012). Noninvasive Mapping of Transmural Potentials During Activation in Swine Hearts From Body Surface Electrocardiograms. IEEE Transactions on Medical Imaging, 31(9), 1777-1785. doi:10.1109/tmi.2012.2202914MacLeod, R. S., Ni, Q., Punske, B., Ershler, P. R., Yilmaz, B., & Taccardi, B. (2000). Effects of heart position on the body-surface electrocardiogram. Journal of Electrocardiology, 33, 229-237. doi:10.1054/jelc.2000.20357Metzner, A., Wissner, E., Tsyganov, A., Kalinin, V., Schlüter, M., Lemes, C., … Kuck, K.-H. (2017). Noninvasive phase mapping of persistent atrial fibrillation in humans: Comparison with invasive catheter mapping. Annals of Noninvasive Electrocardiology, 23(4), e12527. doi:10.1111/anec.12527Modre, R., Tilg, B., Fischer, G., Hanser, F., Messnarz, B., Seger, M., … Roithinger, F. X. (2003). Atrial Noninvasive Activation Mapping of Paced Rhythm Data. Journal of Cardiovascular Electrophysiology, 14(7), 712-719. doi:10.1046/j.1540-8167.2003.02558.xNarayan, S. M., Krummen, D. E., Shivkumar, K., Clopton, P., Rappel, W.-J., & Miller, J. M. (2012). Treatment of Atrial Fibrillation by the Ablation of Localized Sources. Journal of the American College of Cardiology, 60(7), 628-636. doi:10.1016/j.jacc.2012.05.022NG, J., KADISH, A. H., & GOLDBERGER, J. J. (2007). Technical Considerations for Dominant Frequency Analysis. Journal of Cardiovascular Electrophysiology, 18(7), 757-764. doi:10.1111/j.1540-8167.2007.00810.xOosterhoff, P., Meijborg, V. M. F., van Dam, P. M., van Dessel, P. F. H. M., Belterman, C. N. W., Streekstra, G. J., … Oostendorp, T. F. (2016). Experimental Validation of Noninvasive Epicardial and Endocardial Activation Imaging. Circulation: Arrhythmia and Electrophysiology, 9(8). doi:10.1161/circep.116.004104Oster, H. S., Taccardi, B., Lux, R. L., Ershler, P. R., & Rudy, Y. (1997). Noninvasive Electrocardiographic Imaging. Circulation, 96(3), 1012-1024. doi:10.1161/01.cir.96.3.1012Oster, H. S., Taccardi, B., Lux, R. L., Ershler, P. R., & Rudy, Y. (1998). Electrocardiographic Imaging. Circulation, 97(15), 1496-1507. doi:10.1161/01.cir.97.15.1496PEDRÓN-TORRECILLA, J., RODRIGO, M., CLIMENT, A. M., LIBEROS, A., PÉREZ-DAVID, E., BERMEJO, J., … GUILLEM, M. S. (2016). Noninvasive Estimation of Epicardial Dominant High-Frequency Regions During Atrial Fibrillation. Journal of Cardiovascular Electrophysiology, 27(4), 435-442. doi:10.1111/jce.12931Ploux, S., Lumens, J., Whinnett, Z., Montaudon, M., Strom, M., Ramanathan, C., … Bordachar, P. (2013). Noninvasive Electrocardiographic Mapping to Improve Patient Selection for Cardiac Resynchronization Therapy. Journal of the American College of Cardiology, 61(24), 2435-2443. doi:10.1016/j.jacc.2013.01.093Potyagaylo, D., Segel, M., Schulze, W. H. W., & Dössel, O. (2013). Noninvasive Localization of Ectopic Foci: A New Optimization Approach for Simultaneous Reconstruction of Transmembrane Voltages and Epicardial Potentials. Lecture Notes in Computer Science, 166-173. doi:10.1007/978-3-642-38899-6_20Punshchykova, O., Švehlíková, J., Tyšler, M., Grünes, R., Sedova, K., Osmančík, P., … Kneppo, P. (2016). Influence of Torso Model Complexity on the Noninvasive Localization of Ectopic Ventricular Activity. Measurement Science Review, 16(2), 96-102. doi:10.1515/msr-2016-0013RAMANATHAN, C., & RUDY, Y. (2001). Electrocardiographic Imaging: II. Effect of Torso Inhomogeneities on Noninvasive Reconstruction of Epicardial Potentials, Electrograms, and Isochrones. Journal of Cardiovascular Electrophysiology, 12(2), 241-252. doi:10.1046/j.1540-8167.2001.00241.xReddy, V. Y., Reynolds, M. R., Neuzil, P., Richardson, A. W., Taborsky, M., Jongnarangsin, K., … Josephson, M. E. (2007). Prophylactic Catheter Ablation for the Prevention of Defibrillator Therapy. New England Journal of Medicine, 357(26), 2657-2665. doi:10.1056/nejmoa065457Rodrigo, M., Climent, A. M., Liberos, A., Fernández-Avilés, F., Berenfeld, O., Atienza, F., & Guillem, M. S. (2017). Technical Considerations on Phase Mapping for Identification of Atrial Reentrant Activity in Direct- and Inverse-Computed Electrograms. Circulation: Arrhythmia and Electrophysiology, 10(9). doi:10.1161/circep.117.005008ROTEN, L., PEDERSEN, M., PASCALE, P., SHAH, A., ELIAUTOU, S., SCHERR, D., … HAÏSSAGUERRE, M. (2012). Noninvasive Electrocardiographic Mapping for Prediction of Tachycardia Mechanism and Origin of Atrial Tachycardia Following Bilateral Pulmonary Transplantation. Journal of Cardiovascular Electrophysiology, 23(5), 553-555. doi:10.1111/j.1540-8167.2011.02250.xRudy, Y. (2013). Noninvasive Electrocardiographic Imaging of Arrhythmogenic Substrates in Humans. Circulation Research, 112(5), 863-874. doi:10.1161/circresaha.112.279315Ghosh, S., Avari, J. N., Rhee, E. K., Woodard, P. K., & Rudy, Y. (2008). Noninvasive electrocardiographic imaging (ECGI) of epicardial activation before and after catheter ablation of the accessory pathway in a patient with Ebstein anomaly. Heart Rhythm, 5(6), 857-860. doi:10.1016/j.hrthm.2008.03.011Rudy, Y., Plonsey, R., & Liebman, J. (1979). The effects of variations in conductivity and geometrical parameters on the electrocardiogram, using an eccentric spheres model. Circulation Research, 44(1), 104-111. doi:10.1161/01.res.44.1.104SALINET, J. L., TUAN, J. H., SANDILANDS, A. J., STAFFORD, P. J., SCHLINDWEIN, F. S., & NG, G. A. (2013). Distinctive Patterns of Dominant Frequency Trajectory Behavior in Drug-Refractory Persistent Atrial Fibrillation: Preliminary Characterization of Spatiotemporal Instability. Journal of Cardiovascular Electrophysiology, 25(4), 371-379. doi:10.1111/jce.12331Dalu, Y. (1978). Relating the multipole moments of the heart to activated parts of the epicardium and endocardium. Annals of Biomedical Engineering, 6(4), 492-505. doi:10.1007/bf02584552Sánchez, C., Bueno-Orovio, A., Pueyo, E., & Rodríguez, B. (2017). Atrial Fibrillation Dynamics and Ionic Block Effects in Six Heterogeneous Human 3D Virtual Atria with Distinct Repolarization Dynamics. Frontiers in Bioengineering and Biotechnology, 5. doi:10.3389/fbioe.2017.00029Sanders, P., Berenfeld, O., Hocini, M., Jaïs, P., Vaidyanathan, R., Hsu, L.-F., … Haïssaguerre, M. (2005). Spectral Analysis Identifies Sites of High-Frequency Activity Maintaining Atrial Fibrillation in Humans. Circulation, 112(6), 789-797. doi:10.1161/circulationaha.104.517011Sapp, J. L., Bar-Tal, M., Howes, A. J., Toma, J. E., El-Damaty, A., Warren, J. W., … Horáček, B. M. (2017). Real-Time Localization of Ventricular Tachycardia Origin From the 12-Lead Electrocardiogram. JACC: Clinical Electrophysiology, 3(7), 687-699. doi:10.1016/j.jacep.2017.02.024Sapp, J. L., Dawoud, F., Clements, J. C., & Horáček, B. M. (2012). Inverse Solution Mapping of Epicardial Potentials. Circulation: Arrhythmia and Electrophysiology, 5(5), 1001-1009. doi:10.1161/circep.111.970160Sapp, J. L., Wells, G. A., Parkash, R., Stevenson, W. G., Blier, L., Sarrazin, J.-F., … Tang, A. S. L. (2016). Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs. New England Journal of Medicine, 375(2), 111-121. doi:10.1056/nejmoa1513614Schulze, W. H. W., Chen, Z., Relan, J., Potyagaylo, D., Krueger, M. W., Karim, R., … Dössel, O. (2016). ECG imaging of ventricular tachycardia: evaluation against simultaneous non-contact mapping and CMR-derived grey zone. Medical & Biological Engineering & Computing, 55(6), 979-990. doi:10.1007/s11517-016-1566-xShah, D. C., Jaïs, P., Haïssaguerre, M., Chouairi, S., Takahashi, A., Hocini, M., … Clémenty, J. (1997). Three-dimensional Mapping of the Common Atrial Flutter Circuit in the Right Atrium. Circulation, 96(11), 3904-3912. doi:10.1161/01.cir.96.11.3904Shome, S., & Macleod, R. (s. f.). Simultaneous High-Resolution Electrical Imaging of Endocardial, Epicardial and Torso-Tank Surfaces Under Varying Cardiac Metabolic Load and Coronary Flow. Lecture Notes in Computer Science, 320-329. doi:10.1007/978-3-540-72907-5_33SIMMS, H. D., & GESELOWITZ, D. B. (1995). Computation of Heart Surface Potentials Using the Surface Source Model. Journal of Cardiovascular Electrophysiology, 6(7), 522-531. doi:10.1111/j.1540-8167.1995.tb00425.xSvehlikova, J., Teplan, M., & Tysler, M. (2018). Geometrical constraint of sources in noninvasive localization of premature ventricular contractions. Journal of Electrocardiology, 51(3), 370-377. doi:10.1016/j.jelectrocard.2018.02.013Tsyganov, A., Wissner, E., Metzner, A., Mironovich, S., Chaykovskaya, M., Kalinin, V., … Kuck, K.-H. (2018). Mapping of ventricular arrhythmias using a novel noninvasive epicardial and endocardial electrophysiology system. Journal of Electrocardiology, 51(1), 92-98. doi:10.1016/j.jelectrocard.2017.07.018Umapathy, K., Nair, K., Masse, S., Krishnan, S., Rogers, J., Nash, M. P., & Nanthakumar, K. (2010). Phase Mapping of Cardiac Fibrillation. Circulation: Arrhythmia and Electrophysiology, 3(1), 105-114. doi:10.1161/circep.110.853804Van Dam, P. M., Oostendorp, T. F., Linnenbank, A. C., & van Oosterom, A. (2009). Non-Invasive Imaging of Cardiac Activation and Recovery. Annals of Biomedical Engineering, 37(9), 1739-1756. doi:10.1007/s10439-009-9747-5Van Oosterom, A. (2001). Genesis of the T wave as based on an equivalent surface source model. Journal of Electrocardiology, 34(4), 217-227. doi:10.1054/jelc.2001.28896Van Oosterom, A. (2002). Solidifying the solid angle. Journal of Electrocardiology, 35(4), 181-192. doi:10.1054/jelc.2002.37176Van Oosterom, A. (2004). ECGSIM: an interactive tool for stu

Doctor of Philosophy

dissertationDespite a century of research and practice, the clinical accuracy of the electrocardiogram (ECG) to detect and localize myocardial ischemia remains less than satisfactory. Myocardial ischemia occurs when the heart does not receive adequate oxygen-rich blood to keep up with its metabolic requirements, and severe ischemia can lead to myocardial infarction and life-threatening arrhythmias. Early and accurate detection is an essential component of managing this condition. Ischemia is known to be a dynamic condition that reflects a changing imbalance between blood supply and metabolic demand so that it is natural that examination under physical stress conditions or exercise testing (ET) is in widespread clinical use. However, ET is characterized by poor sensitivity (68%) and specificity (77%), limiting its diagnostic usefulness and providing the motivation to address some gaps in our understanding of myocardial ischemia and its ECG signature. This dissertation is composed of three studies. The aim of the first study was to evaluate the conventionally held mechanisms for nontransmural ischemia using intramural electrodes to measure three-dimensional potential distributions in the ventricles of animals exposed to acute ischemia. We demonstrated that contrary to accepted dogma, the electrocar- diographic response of acute myocardial ischemia originated throughout the ventricular wall, i.e., in the subendocardium, midmyocardium, or the subepicardium, under various conditions. Our goal in the second study was to evaluate whether acute myocardial ischemia follows a similar pattern of spatial and temporal evolution as seen in myocardial infarction. Our findings show that the spatial and temporal evolution of acute ischemia is characterized by multiple distinct regions that expand in all three directions, with maximal expansion in the circumferential direction, especially in the early stages of ischemic development. Furthermore, with increased stress, these regions continue to expand and eventually merge into one another, and in the extreme become transmural. The progression of myocardial infarction, by contrast, was very quickly transmural in extent and formed a cohesive block of affected tissues. The aim of the third study was to evaluate the sensitivity of epicardial electrical markers of acute ischemia relative to direct evidence of ischemia derived from intramural electro- grams. The key finding from this study is that the epicardial T-wave is a more sensitive index of acute ischemia than epicardial ST segment changes, especially in the early stages of acute ischemia development

Uncertainty visualization in forward and inverse cardiac models

pre-printQuantification and visualization of uncertainty in cardiac forward and inverse problems with complex geometries is subject to various challenges. Specific to visualization is the observation that occlusion and clutter obscure important regions of interest, making visual assessment difficult. In order to overcome these limitations in uncertainty visualization, we have developed and implemented a collection of novel approaches. To highlight the utility of these techniques, we evaluated the uncertainty associated with two examples of modeling myocardial activity. In one case we studied cardiac potentials during the repolarization phase as a function of variability in tissue conductivities of the ischemic heart (forward case). In a second case, we evaluated uncertainty in reconstructed activation times on the epicardium resulting from variation in the control parameter of Tikhonov regularization (inverse case). To overcome difficulties associated with uncertainty visualization, we implemented linked-view windows and interactive animation to the two respective cases. Through dimensionality reduction and superimposed mean and standard deviation measures over time, we were able to display key features in large ensembles of data and highlight regions of interest where larger uncertainties exist

Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies

[ES] Las arritmias cardíacas son un problema importante para los sistemas de salud en el mundo desarrollado debido a su alta incidencia y prevalencia a medida que la población envejece. La fibrilación auricular (FA) y la fibrilación ventricular (FV) se encuentran entre las arritmias más complejas observadas en la práctica clínica. Las consecuencias clínicas de tales alteraciones arrítmicas incluyen el desarrollo de eventos cardioembólicos complejos en la FA, y repercusiones dramáticas debido a procesos fibrilatorios sostenidos que amenazan la vida infringiendo daño neurológico tras paro cardíaco por FV, y que pueden provocar la muerte súbita cardíaca (MSC). Sin embargo, a pesar de los avances tecnológicos de las últimas décadas, sus mecanismos intrínsecos se comprenden de forma incompleta y, hasta la fecha, las estrategias terapéuticas carecen de una base mecanicista suficiente y poseen bajas tasas de éxito. Entre los mecanismos implicados en la inducción y perpetuación de arritmias cardíacas, como la FA, se cree que las dinámicas de las fuentes focales y reentrantes de alta frecuencia, en sus diferentes modalidades, son las fuentes primarias que mantienen la arritmia. Sin embargo, se sabe poco sobre los atractores, así como, de la dinámica espacio-temporal de tales fuentes fibrilatorias primarias, específicamente, las fuentes focales o rotacionales dominantes que mantienen la arritmia. Por ello, se ha desarrollado una plataforma computacional, para comprender los factores (activos, pasivos y estructurales) determinantes, y moduladores de dicha dinámica. Esto ha permitido establecer un marco para comprender la compleja dinámica de los rotores con énfasis en sus propiedades deterministas para desarrollar herramientas basadas en los mecanismos para ayuda diagnóstica y terapéutica. Comprender los procesos fibrilatorios es clave para desarrollar marcadores y herramientas fisiológica- y clínicamente relevantes para la ayuda de diagnóstico temprano. Específicamente, las propiedades espectrales y de tiempo-frecuencia de los procesos fibrilatorios han demostrado resaltar el comportamiento determinista principal de los mecanismos intrínsecos subyacentes a las arritmias y el impacto de tales eventos arrítmicos. Esto es especialmente relevante para determinar el pronóstico temprano de los supervivientes comatosos después de un paro cardíaco debido a fibrilación ventricular (FV). Las técnicas de mapeo electrofisiológico, el mapeo eléctrico y óptico cardíaco, han demostrado ser recursos muy valiosos para dar forma a nuevas hipótesis y desarrollar nuevos enfoques mecanicistas y estrategias terapéuticas mejoradas. Esta tecnología permite además el trabajo multidisciplinar entre clínicos y bioingenieros, para el desarrollo y validación de dispositivos y metodologías para identificar biomarcadores multi-dominio que permitan rastrear con precisión la dinámica de las arritmias identificando fuentes dominantes y atractores con alta precisión para ser dianas de estrategias terapeúticas innovadoras. Es por ello que uno de los objetivos fundamentales ha sido la implantación y validación de nuevos sistemas de mapeo en distintas configuraciones que sirvan de plataforma de desarrollo de nuevas estrategias terapeúticas. Aunque el mapeo panorámico es el método principal y más completo para rastrear simultáneamente biomarcadores electrofisiológicos, su adopción por la comunidad científica es limitada principalmente debido al coste elevado de la tecnología. Aprovechando los avances tecnológicos recientes, nos hemos enfocado en desarrollar, y validar, sistemas de mapeo óptico de alta resolución para registro panorámico cardíaco, utilizando modelos clínicamente relevantes para la investigación básica y la bioingeniería.[CA] Les arítmies cardíaques són un problema important per als sistemes de salut del món desenvolupat a causa de la seva alta incidència i prevalença a mesura que la població envelleix. La fibril·lació auricular (FA) i la fibril·lació ventricular (FV), es troben entre les arítmies més complexes observades a la pràctica clínica. Les conseqüències clíniques d'aquests trastorns arítmics inclouen el desenvolupament d'esdeveniments cardioembòlics complexos en FA i repercussions dramàtiques a causa de processos fibril·latoris sostinguts que posen en perill la vida amb danys neurològics posteriors a la FV, que condueixen a una aturada cardíaca i a la mort cardíaca sobtada (SCD). Tanmateix, malgrat els avanços tecnològics de les darreres dècades, els seus mecanismes intrínsecs s'entenen de forma incompleta i, fins a la data, les estratègies terapèutiques no tenen una base mecanicista suficient i tenen baixes taxes d'èxit. La majoria dels avenços en el desenvolupament de biomarcadors òptims i noves estratègies terapèutiques en aquest camp provenen de tècniques valuoses en la investigació de mecanismes d'arítmia. Entre els mecanismes implicats en la inducció i perpetuació de les arítmies cardíaques, es creu que les fonts primàries subjacents a l'arítmia són les fonts focals reingressants d'alta freqüència dinàmica i AF, en les seves diferents modalitats. Tot i això, se sap poc sobre els atractors i la dinàmica espaciotemporal d'aquestes fonts primàries fibril·ladores, específicament les fonts rotacionals o focals dominants que mantenen l'arítmia. Per tant, s'ha desenvolupat una plataforma computacional per entendre determinants actius, passius, estructurals i moduladors d'aquestes dinàmiques. Això va permetre establir un marc per entendre la complexa dinàmica multidomini dels rotors amb ènfasi en les seves propietats deterministes per desenvolupar enfocaments mecanicistes per a l'ajuda i la teràpia diagnòstiques. La comprensió dels processos fibril·latoris és clau per desenvolupar puntuacions i eines rellevants fisiològicament i clínicament per ajudar al diagnòstic precoç. Concretament, les propietats espectrals i de temps-freqüència dels processos fibril·latoris han demostrat destacar un comportament determinista important dels mecanismes intrínsecs subjacents a les arítmies i l'impacte d'aquests esdeveniments arítmics. Mitjançant coneixements previs, processament de senyals, tècniques d'aprenentatge automàtic i anàlisi de dades, es va desenvolupar una puntuació de risc mecanicista a la aturada cardíaca per FV. Les tècniques de cartografia òptica cardíaca i electrofisiològica han demostrat ser recursos inestimables per donar forma a noves hipòtesis i desenvolupar nous enfocaments mecanicistes i estratègies terapèutiques. Aquesta tecnologia ha permès durant molts anys provar noves estratègies terapèutiques farmacològiques o ablatives i desenvolupar mètodes multidominis per fer un seguiment precís de la dinàmica d'arrímies que identifica fonts i atractors dominants. Tot i que el mapatge panoràmic és el mètode principal per al seguiment simultani de paràmetres electrofisiològics, la seva adopció per part de la comunitat multidisciplinària d'investigació cardiovascular està limitada principalment pel cost de la tecnologia. Aprofitant els avenços tecnològics recents, ens centrem en el desenvolupament i la validació de sistemes de mapes òptics de baix cost per a imatges panoràmiques mitjançant models clínicament rellevants per a la investigació bàsica i la bioenginyeria.[EN] Cardiac arrhythmias are a major problem for health systems in the developed world due to their high incidence and prevalence as the population ages. Atrial fibrillation (AF) and ventricular fibrillation (VF), are amongst the most complex arrhythmias seen in the clinical practice. Clinical consequences of such arrhythmic disturbances include developing complex cardio-embolic events in AF, and dramatic repercussions due to sustained life-threatening fibrillatory processes with subsequent neurological damage under VF, leading to cardiac arrest and sudden cardiac death (SCD). However, despite the technological advances in the last decades, their intrinsic mechanisms are incompletely understood, and, to date, therapeutic strategies lack of sufficient mechanistic basis and have low success rates. Most of the progress for developing optimal biomarkers and novel therapeutic strategies in this field has come from valuable techniques in the research of arrhythmia mechanisms. Amongst the mechanisms involved in the induction and perpetuation of cardiac arrhythmias such AF, dynamic high-frequency re-entrant and focal sources, in its different modalities, are thought to be the primary sources underlying the arrhythmia. However, little is known about the attractors and spatiotemporal dynamics of such fibrillatory primary sources, specifically dominant rotational or focal sources maintaining the arrhythmia. Therefore, a computational platform for understanding active, passive and structural determinants, and modulators of such dynamics was developed. This allowed stablishing a framework for understanding the complex multidomain dynamics of rotors with enphasis in their deterministic properties to develop mechanistic approaches for diagnostic aid and therapy. Understanding fibrillatory processes is key to develop physiologically and clinically relevant scores and tools for early diagnostic aid. Specifically, spectral and time-frequency properties of fibrillatory processes have shown to highlight major deterministic behaviour of intrinsic mechanisms underlying the arrhythmias and the impact of such arrhythmic events. Using prior knowledge, signal processing, machine learning techniques and data analytics, we aimed at developing a reliable mechanistic risk-score for comatose survivors of cardiac arrest due to VF. Cardiac optical mapping and electrophysiological mapping techniques have shown to be unvaluable resources to shape new hypotheses and develop novel mechanistic approaches and therapeutic strategies. This technology has allowed for many years testing new pharmacological or ablative therapeutic strategies, and developing multidomain methods to accurately track arrhymia dynamics identigying dominant sources and attractors. Even though, panoramic mapping is the primary method for simultaneously tracking electrophysiological parameters, its adoption by the multidisciplinary cardiovascular research community is limited mainly due to the cost of the technology. Taking advantage of recent technological advances, we focus on developing and validating low-cost optical mapping systems for panoramic imaging using clinically relevant models for basic research and bioengineering.Calvo Saiz, CJ. (2022). Novel Cardiac Mapping Approaches and Multimodal Techniques to Unravel Multidomain Dynamics of Complex Arrhythmias Towards a Framework for Translational Mechanistic-Based Therapeutic Strategies [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/182329TESI