About this Journal Submit a Manuscript Table of Contents
ISRN Cardiology
Volume 2012 (2012), Article ID 269680, 15 pages
http://dx.doi.org/10.5402/2012/269680
Review Article

Computational Cardiology: The Heart of the Matter

Department of Biomedical Engineering and Institute for Computational Medicine, Johns Hopkins University, 3400 North Charles Street, Hackerman Hall Room 216, Baltimore, MD 21218, USA

Received 16 August 2012; Accepted 6 September 2012

Academic Editors: T. Ohe and A. Szekely

Copyright © 2012 Natalia A. Trayanova. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. D. Noble, “Modeling the heart—from genes to cells to the whole organ,” Science, vol. 295, no. 5560, pp. 1678–1682, 2002. View at Publisher · View at Google Scholar · View at Scopus
  2. N. A. Trayanova, “Whole-heart modeling : applications to cardiac electrophysiology and electromechanics,” Circulation Research, vol. 108, no. 1, pp. 113–128, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. E. Vigmond, F. Vadakkumpadan, V. Gurev et al., “Towards predictive modelling of the electrophysiology of the heart,” Experimental Physiology, vol. 94, no. 5, pp. 563–577, 2009. View at Publisher · View at Google Scholar · View at Scopus
  4. R. H. Clayton, “Vortex filament dynamics in computational models of ventricular fibrillation in the heart,” Chaos, vol. 18, no. 4, Article ID 043127, 12 pages, 2008. View at Publisher · View at Google Scholar · View at Scopus
  5. K. H. W. J. ten Tusscher, R. Hren, and A. V. Panfilov, “Organization of ventricular fibrillation in the human heart,” Circulation Research, vol. 100, no. 12, pp. e87–e101, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. A. Garfinkel, Y. H. Kim, O. Voroshilovsky et al., “Preventing ventricular fibrillation by flattening cardiac restitution,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 11, pp. 6061–6066, 2000. View at Publisher · View at Google Scholar · View at Scopus
  7. O. Bernus, B. van Eyck, H. Verschelde, and A. V. Panfilov, “Transition from ventricular fibrillation to ventricular tachycardia: a simulation study on the role of Ca2+-channel blockers in human ventricular tissue,” Physics in Medicine and Biology, vol. 47, no. 23, pp. 4167–4179, 2002. View at Publisher · View at Google Scholar · View at Scopus
  8. B. Echebarria and A. Karma, “Mechanisms for initiation of cardiac discordant alternans,” European Physical Journal, vol. 146, no. 1, pp. 217–231, 2007. View at Publisher · View at Google Scholar · View at Scopus
  9. E. M. Cherry and F. H. Fenton, “Suppression of alternans and conduction blocks despite steep APD restitution: electrotonic, memory, and conduction velocity restitution effects,” American Journal of Physiology, vol. 286, no. 6, pp. H2332–H2341, 2004. View at Publisher · View at Google Scholar · View at Scopus
  10. R. H. Keldermann, K. H. W. J. ten Tusscher, M. P. Nash et al., “A computational study of mother rotor VF in the human ventricles,” American Journal of Physiology, vol. 296, no. 2, pp. H370–H379, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. R. H. Keldermann, K. H. W. J. ten Tusscher, M. P. Nash, R. Hren, P. Taggart, and A. V. Panfilov, “Effect of heterogeneous APD restitution on VF organization in a model of the human ventricles,” American Journal of Physiology, vol. 294, no. 2, pp. H764–H774, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. K. S. McDowell, H. J. Arevalo, M. M. Maleckar, and N. A. Trayanova, “Susceptibility to arrhythmia in the infarcted heart depends on myofibroblast density,” Biophysical Journal, vol. 101, no. 6, pp. 1307–1315, 2011. View at Publisher · View at Google Scholar
  13. R. Bordas, K. Gillow, Q. Lou et al., “Rabbit-specific ventricular model of cardiac electrophysiological function including specialized conduction system,” Progress in Biophysics and Molecular Biology, vol. 107, no. 1, pp. 90–100, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. M. Deo, P. M. Boyle, A. M. Kim, and E. J. Vigmond, “Arrhythmogenesis by single ectopic beats originating in the Purkinje system,” American Journal of Physiology, vol. 299, no. 4, pp. H1002–H1011, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. X. Jie and N. A. Trayanova, “Mechanisms for initiation of reentry in acute regional ischemia phase 1B,” Heart Rhythm, vol. 7, no. 3, pp. 379–386, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. X. Jie, B. Rodríguez, J. R. de Groot, R. Coronel, and N. Trayanova, “Reentry in survived subepicardium coupled to depolarized and inexcitable midmyocardium: insights into arrhythmogenesis in ischemia phase 1B,” Heart Rhythm, vol. 5, no. 7, pp. 1036–1044, 2008. View at Publisher · View at Google Scholar · View at Scopus
  17. X. Jie, V. Gurev, and N. Trayanova, “Mechanisms of mechanically induced spontaneous arrhythmias in acute regional ischemia,” Circulation Research, vol. 106, no. 1, pp. 185–192, 2010. View at Publisher · View at Google Scholar · View at Scopus
  18. F. Vadakkumpadan, H. Arevalo, A. J. Prassl et al., “Image-based models of cardiac structure in health and disease,” Wiley Interdisciplinary Reviews, vol. 2, no. 4, pp. 489–506, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. M. J. Bishop, G. Plank, R. A. B. Burton et al., “Development of an anatomically detailed MRI-derived rabbit ventricular model and assessment of its impact on simulations of electrophysiological function,” American Journal of Physiology, vol. 298, no. 2, pp. H699–H718, 2010. View at Publisher · View at Google Scholar · View at Scopus
  20. W. G. Stevenson, P. Brugada, and B. Waldecker, “Clinical, angiographic, and electrophysiologic findings in patients with aborted sudden death as compared with patients with sustained ventricular tachycardia after myocardial infarction,” Circulation, vol. 71, no. 6, pp. 1146–1152, 1985. View at Scopus
  21. M. Pop, M. Sermesant, T. Mansi, E. Crystal, S. Ghate, J. Peyrat, et al., “Correspondence between simple 3-D MRI-based computer models and in-vivo EP measurements in swine with chronic infarctions,” IEEE Transactions on Biomedical Engineering, vol. 58, no. 12, pp. 3483–3486, 2011. View at Publisher · View at Google Scholar
  22. H. Arevalo, G. Plank, P. Helm, H. Halperin, and N. Trayanova, “Volume of peri-infarct zone determines arrhythmogenesis in infarcted heart,” Heart Rhythm, vol. 6, no. 5, pp. S232–S233, 2009.
  23. H. Arevalo, H. Estner, C. Park, H. Halperin, and N. Trayanova, “In-vivo MRI-based models of infarct- related ventricular tachycardia successfully predict optimal ablation site,” Heart Rhythm, vol. 9, no. 5, p. S181, 2012.
  24. H. Ashikaga, H. Arevalo, F. Vadakkumpadan, R. Blake, R. Berger, H. Calkins, et al., “MRI-based patient-specific virtual electrophysiology laboratory for scar-related ventricular tachycardia,” Circulation, vol. 124, p. A541, 2011.
  25. J. Ng, J. T. Jacobson, J. K. Ng, D. Gordon, D. C. Lee, J. C. Carr, et al., “Virtual electrophysiological study in a 3-dimensional cardiac magnetic resonance imaging model of porcine myocardial infarction,” Journal of the American College of Cardiology, vol. 60, no. 5, pp. 423–430, 2012. View at Publisher · View at Google Scholar
  26. J. Relan, P. Chinchapatnam, M. Sermesant, K. Rhode, M. Ginks, H. Delingette, et al., “Coupled personalization of cardiac electrophysiology models for prediction of ischaemic ventricular tachycardia,” Interface Focus, vol. 1, no. 3, pp. 396–407, 2011. View at Publisher · View at Google Scholar
  27. F. Vadakkumpadan, H. Arevalo, C. Ceritoglu, M. Miller, and N. Trayanova, “Image-based estimation of ventricular fiber orientations for personalized modeling of cardiac electrophysiology,” IEEE Transactions on Medical Imaging, vol. 31, no. 5, pp. 1051–1060, 2012. View at Publisher · View at Google Scholar
  28. J. D. Bayer, R. C. Blake, G. Plank, and N. A. Trayanova, “A novel rule-based algorithm for assigning myocardial fiber orientation to computational heart models,” Annals of Biomedical Engineering, vol. 40, no. 10, pp. 2243–2254, 2012.
  29. R. L. Winslow, N. Trayanova, D. Geman, and MI. Miller, “Computational medicine: translating models to clinical care,” Science Translational Medicine, vol. 4, no. 158, p. 158rv11, 2012. View at Publisher · View at Google Scholar
  30. N. Virag, V. Jacquemet, C. S. Henriquez et al., “Study of atrial arrhythmias in a computer model based on magnetic resonance images of human atria,” Chaos, vol. 12, no. 3, pp. 754–763, 2002. View at Publisher · View at Google Scholar · View at Scopus
  31. E. S. Di Martino, C. Bellini, and D. S. Schwartzman, “In vivo porcine left atrial wall stress: computational model,” Journal of Biomechanics, vol. 44, no. 15, pp. 2589–2594, 2011. View at Publisher · View at Google Scholar
  32. G. Seemann, C. Höper, F. B. Sachse, O. Dössel, A. V. Holden, and H. Zhang, “Heterogeneous three-dimensional anatomical and electrophysiological model of human atria,” Philosophical Transactions of the Royal Society A, vol. 364, no. 1843, pp. 1465–1481, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. J. Freudenberg, T. Schiemann, U. Tiede, and K. H. Höhne, “Simulation of cardiac excitation patterns in a three-dimensional anatomical heart atlas,” Computers in Biology and Medicine, vol. 30, no. 4, pp. 191–205, 2000. View at Publisher · View at Google Scholar · View at Scopus
  34. V. M. Spitzer and D. G. Whitlock, “The visible human dataset: the anatomical platform for human simulation,” The Anatomical Record, vol. 253, no. 2, pp. 49–57, 1998.
  35. S. Kharche, C. J. Garratt, M. R. Boyett et al., “Atrial proarrhythmia due to increased inward rectifier current (IK1) arising from KCNJ2 mutation—a simulation study,” Progress in Biophysics and Molecular Biology, vol. 98, no. 2-3, pp. 186–197, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. M. E. Ridler, M. Lee, D. McQueen, C. Peskin, and E. Vigmond, “Arrhythmogenic consequences of action potential duration gradients in the atria,” Canadian Journal of Cardiology, vol. 27, no. 1, pp. 112–119, 2011. View at Publisher · View at Google Scholar · View at Scopus
  37. J. Kneller, R. Q. Zou, E. J. Vigmond, Z. G. Wang, L. J. Leon, and S. Nattel, “Cholinergic atrial fibrillation in a computer model of a two-dimensional sheet of canine atrial cells with realistic ionic properties,” Circulation Research, vol. 90, no. 9, pp. E73–E87, 2002. View at Scopus
  38. V. Jacquemet, “Pacemaker activity resulting from the coupling with nonexcitable cells,” Physical Review E, vol. 74, no. 1, part 1, Article ID 011908, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. N. Kuijpers, H. ten Eikelder, and S. Verheule, “Atrial anatomy influences onset and termination of atrial fibrillation: a computer model study,” in Proceedings of the 5th International Conference on Functional Imaging and Modeling of the Heart (FIMH '09), vol. 5528 of Lecture Notes in Computer Science, pp. 285–294, Nice, France, June 2009. View at Publisher · View at Google Scholar
  40. T. Krogh-Madsen, G. W. Abbott, and D. J. Christini, “Effects of electrical and structural remodeling on atrial fibrillation maintenance: a simulation study,” PLOS Computational Biology, vol. 8, no. 2, Article ID e1002390, 2012.
  41. E. J. Vigmond, N. A. Trayanova, and R. A. Malkin, “Excitation of a cardiac muscle fiber by extracellularly applied sinusoidal current,” Journal of Cardiovascular Electrophysiology, vol. 12, no. 10, pp. 1145–1153, 2001. View at Scopus
  42. E. J. Vigmond, V. Tsoi, S. Kuo et al., “The effect of vagally induced dispersion of action potential duration on atrial arrhythmogenesis,” Heart Rhythm, vol. 1, no. 3, pp. 334–344, 2004. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Rotter, L. Dang, V. Jacquemet, N. Virag, L. Kappenberger, and M. Haïssaguerre, “Impact of varying ablation patterns in a simulation model of persistent atrial fibrillation,” Pacing and Clinical Electrophysiology, vol. 30, no. 3, pp. 314–321, 2007. View at Publisher · View at Google Scholar · View at Scopus
  44. P. Ruchat, L. Dang, J. Schlaepfer, N. Virag, L. K. von Segesser, and L. Kappenberger, “Use of a biophysical model of atrial fibrillation in the interpretation of the outcome of surgical ablation procedures,” European Journal of Cardio-Thoracic Surgery, vol. 32, no. 1, pp. 90–95, 2007. View at Publisher · View at Google Scholar · View at Scopus
  45. P. Ruchat, L. Dang, N. Virag, J. Schlaepfer, L. K. von Segesser, and L. Kappenberger, “A biophysical model of atrial fibrillation to define the appropriate ablation pattern in modified maze,” European Journal of Cardio-Thoracic Surgery, vol. 31, no. 1, pp. 65–69, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. V. Jacquemet, A. van Oosterom, J. M. Vesin, and L. Kappenberger, “Analysis of electrocardiograms during atrial fibrillation,” IEEE Engineering in Medicine and Biology Magazine, vol. 25, no. 6, pp. 79–88, 2006. View at Publisher · View at Google Scholar
  47. E. J. Vigmond and L. J. Leon, “Electrophysiological basis of mono-phasic action potential recordings,” Medical and Biological Engineering and Computing, vol. 37, no. 3, pp. 359–365, 1999. View at Scopus
  48. E. J. Vigmond, V. Tsoi, Y. Yin, P. Pagé, and A. Vinet, “Estimating atrial action potential duration from electrograms,” IEEE Transactions on Biomedical Engineering, vol. 56, no. 5, pp. 1546–1555, 2009. View at Publisher · View at Google Scholar · View at Scopus
  49. V. Jacquemet and C. S. Henriquez, “Genesis of complex fractionated atrial electrograms in zones of slow conduction: a computer model of microfibrosis,” Heart Rhythm, vol. 6, no. 6, pp. 803–810, 2009. View at Publisher · View at Google Scholar · View at Scopus
  50. M. W. Krueger, S. Severi, K. Rhode et al., “Alterations of atrial electrophysiology related to hemodialysis session: insights from a multiscale computer model,” Journal of Electrocardiology, vol. 44, no. 2, pp. 176–183, 2011. View at Publisher · View at Google Scholar · View at Scopus
  51. K. M. Lim, S. B. Hong, J. W. Jeon, M. S. Gyung, B. H. Ko, S. K. Bae, et al., “Predicting the optimal position and direction of a ubiquitous ECG using a multi-scale model of cardiac electrophysiology,” in Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC '11), pp. 993–996, Boston, Mass, USA, September 2011. View at Publisher · View at Google Scholar
  52. R. MacLeod, J. Blauer, E. Kholmovski, R. Ranjan, N. Marrouche, N. Trayanova, et al., “Subject specific, image based analysis and modeling in patients with atrial fibrillation from MRI,” in Proceedings of the 9th IEEE International Symposium on Biomedical Imaging (ISBI '12), ISBI Meeting Proceedings, p. 1364, Barcelona, Spain, May 2012. View at Publisher · View at Google Scholar
  53. K. S. McDowell, F. Vadakkumpadan, R. C. Blake, J. Blauerb, G. Plank, R. S. MacLeod, et al., “Methodology for patient-specific modeling of atrial fibrosis as a substrate for atrial fibrillation,” Journal of Electrocardiology, vol. 45, no. 6, pp. 640–645, 2012.
  54. J. Constantino, Y. Hu, and N. A. Trayanova, “A computational approach to understanding the cardiac electromechanical activation sequence in the normal and failing heart, with translation to the clinical practice of CRT,” Progress in Biophysics and Molecular Biology, vol. 110, no. 2-3, pp. 372–379, 2012. View at Publisher · View at Google Scholar
  55. V. Gurev, T. Lee, J. Constantino, H. Arevalo, and N. A. Trayanova, “Models of cardiac electromechanics based on individual hearts imaging data: image-based electromechanical models of the heart,” Biomechanics and Modeling in Mechanobiology, vol. 10, no. 3, pp. 295–306, 2011. View at Publisher · View at Google Scholar · View at Scopus
  56. R. C. P. Kerckhoffs, A. D. McCulloch, J. H. Omens, and L. J. Mulligan, “Effect of pacing site and infarct location on regional mechanics and global hemodynamics in a model based study of heart failure,” in Proceedings of the 4th International Conference on Functional Imaging and Modeling of the Heart (FIMH '07), vol. 4466 of Lecture Notes in Computer Science, pp. 350–360, June 2007. View at Scopus
  57. R. C. P. Kerckhoffs, A. D. McCulloch, J. H. Omens, and L. J. Mulligan, “Effects of biventricular pacing and scar size in a computational model of the failing heart with left bundle branch block,” Medical Image Analysis, vol. 13, no. 2, pp. 362–369, 2009. View at Publisher · View at Google Scholar · View at Scopus
  58. S. A. Niederer, G. Plank, P. Chinchapatnam et al., “Length-dependent tension in the failing heart and the efficacy of cardiac resynchronization therapy,” Cardiovascular Research, vol. 89, no. 2, pp. 336–343, 2011. View at Publisher · View at Google Scholar · View at Scopus
  59. R. C. P. Kerckhoffs, J. Lumens, K. Vernooy et al., “Cardiac resynchronization: insight from experimental and computational models,” Progress in Biophysics and Molecular Biology, vol. 97, no. 2-3, pp. 543–561, 2008. View at Publisher · View at Google Scholar · View at Scopus
  60. S. A. Niederer, A. K. Shetty, G. Plank, J. Bostock, R. Razavi, N. P. Smith, et al., “Biophysical modeling to simulate the response to multisite left ventricular stimulation using a quadripolar pacing lead,” Pacing and Clinical Electrophysiology, vol. 35, no. 2, pp. 204–214, 2011.
  61. S. A. Niederer, A. K. Shetty, G. Plank, J. Bostock, R. Razavi, N. P. Smith, et al., “Biophysical modeling to simulate the response to multisite left ventricular stimulation using a quadripolar pacing lead,” Pacing and Clinical Electrophysiology, vol. 35, no. 2, pp. 204–214, 2012. View at Publisher · View at Google Scholar
  62. J. Aguado-Sierra, A. Krishnamurthy, C. Villongco, J. Chuang, E. Howard, M. J. Gonzales, et al., “Patient-specific modeling of dyssynchronous heart failure: a case study,” Progress in Biophysics and Molecular Biology, vol. 107, no. 1, pp. 147–155, 2011. View at Publisher · View at Google Scholar
  63. M. Sermesant, R. Chabiniok, P. Chinchapatnam, T. Mansi, F. Billet, P. Moireau, et al., “Patient-specific electromechanical models of the heart for the prediction of pacing acute effects in CRT: a preliminary clinical validation,” Medical Image Analysis, vol. 16, no. 1, pp. 201–215, 2012. View at Publisher · View at Google Scholar
  64. P. Lamata, S. Niederer, D. Nordsletten et al., “An accurate, fast and robust method to generate patient-specific cubic Hermite meshes,” Medical Image Analysis, vol. 15, no. 6, pp. 801–813, 2011. View at Publisher · View at Google Scholar · View at Scopus
  65. J. Constantino, Y. Long, T. Ashihara, and N. A. Trayanova, “Tunnel propagation following defibrillation with ICD shocks: hidden postshock activations in the left ventricular wall underlie isoelectric window,” Heart Rhythm, vol. 7, no. 7, pp. 953–961, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. J. D. Moreno, Z. I. Zhu, P. C. Yang, J. R. Bankston, M. T. Jeng, C. Kang, et al., “A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms,” Science Translational Medicine, vol. 3, no. 98, p. 98ra83, 2011. View at Publisher · View at Google Scholar
  67. C. Anderson and N. A. Trayanova, “Success and failure of biphasic shocks: results of bidomain simulations,” Mathematical Biosciences, vol. 174, no. 2, pp. 91–109, 2001. View at Publisher · View at Google Scholar · View at Scopus
  68. H. Arevalo, B. Rodriguez, and N. Trayanova, “Arrhythmogenesis in the heart: multiscale modeling of the effects of defibrillation shocks and the role of electrophysiological heterogeneity,” Chaos, vol. 17, no. 1, Article ID 015103, 13 pages, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. T. Ashihara and N. A. Trayanova, “Asymmetry in membrane responses to electric shocks: insights from bidomain simulations,” Biophysical Journal, vol. 87, no. 4, pp. 2271–2282, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. D. W. Bourn, R. A. Gray, and N. A. Trayanova, “Characterization of the relationship between preshock state and virtual electrode polarization-induced propagated graded responses resulting in arrhythmia induction,” Heart Rhythm, vol. 3, no. 5, pp. 583–595, 2006. View at Publisher · View at Google Scholar · View at Scopus
  71. E. Entcheva, N. A. Trayanova, and F. J. Claydon, “Patterns of and mechanisms for shock-induced polarization in the heart: a bidomain analysis,” IEEE Transactions on Biomedical Engineering, vol. 46, no. 3, pp. 260–270, 1999. View at Publisher · View at Google Scholar · View at Scopus
  72. A. E. Lindblom, B. J. Roth, and N. A. Trayanova, “Role of virtual electrodes in arrhythmogenesis: pinwheel experiment revisited,” Journal of Cardiovascular Electrophysiology, vol. 11, no. 3, pp. 274–285, 2000. View at Scopus
  73. B. Rodríguez, J. C. Eason, and N. Trayanova, “Differences between left and right ventricular anatomy determine the types of reentrant circuits induced by an external electric shock. A rabbit heart simulation study,” Progress in Biophysics and Molecular Biology, vol. 90, no. 1–3, pp. 399–413, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. B. Rodríguez, L. Li, J. C. Eason, I. R. Efimov, and N. A. Trayanova, “Differences between left and right ventricular chamber geometry affect cardiac vulnerability to electric shocks,” Circulation Research, vol. 97, no. 2, pp. 168–175, 2005. View at Publisher · View at Google Scholar · View at Scopus
  75. N. Trayanova, K. Skouibine, and P. Moore, “Virtual electrode effects in defibrillation,” Progress in Biophysics and Molecular Biology, vol. 69, no. 2-3, pp. 387–403, 1998. View at Publisher · View at Google Scholar · View at Scopus
  76. N. Trayanova, J. Constantino, T. Ashihara, and G. Plank, “Modeling defibrillation of the heart: approaches and insights,” IEEE Reviews in Biomedical Engineering, vol. 4, pp. 89–102, 2011. View at Publisher · View at Google Scholar
  77. T. Ashihara, J. Constantino, and N. A. Trayanova, “Tunnel propagation of postshock activations as a hypothesis for fibrillation induction and isoelectric window,” Circulation Research, vol. 102, no. 6, pp. 737–745, 2008. View at Publisher · View at Google Scholar · View at Scopus
  78. B. Rodríguez, B. Tice, R. Blake, D. Gavaghan, and N. Trayanova, “Vulnerability to electric shocks in the regionally-ischemic ventricles,” in Proceedings of the 28th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBS '06), vol. 1, pp. 2280–2283, New York, NY, USA, September 2006. View at Publisher · View at Google Scholar · View at Scopus
  79. B. Rodríguez, B. M. Tice, J. C. Eason, F. Aguel, J. M. Ferrero Jr., and N. Trayanova, “Effect of acute global ischemia on the upper limit of vulnerability: a simulation study,” American Journal of Physiology, vol. 286, no. 6, pp. H2078–H2088, 2004. View at Publisher · View at Google Scholar · View at Scopus
  80. L. J. Rantner, H. J. Arevalo, J. L. Constantino, I. R. Efimov, G. Plank, and N. A. Trayanova, “Three-dimensional mechanisms of increased vulnerability to electric shocks in myocardial infarction: altered virtual electrode polarizations and conduction delay in the peri-infarct zone,” The Journal of Physiology, vol. 590, part 18, pp. 4537–4551, 2012.
  81. N. Trayanova, V. Gurev, J. Constantino, and Y. Hu, “Mathematical models of ventricular mechano-electric coupling and arrhythmia,” in Cardiac Mechano-Electric Feedback and Arrhythmias, P. Kohl, F. Sachs, and M. R. Franz, Eds., pp. 258–268, 2011.
  82. H. Tandri, S. H. Weinberg, K. C. Chang, R. Zhu, N. A. Trayanova, L. Tung, et al., “Reversible cardiac conduction block and defibrillation with high-frequency electric field,” Science Translational Medicine, vol. 3, no. 102, p. 102ra96, 2011.
  83. P. J. Schwartz, S. G. Priori, C. Spazzolini et al., “Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias,” Circulation, vol. 103, no. 1, pp. 89–95, 2001. View at Scopus
  84. M. Perry, F. B. Sachse, and M. C. Sanguinetti, “Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 34, pp. 13827–13832, 2007. View at Publisher · View at Google Scholar · View at Scopus
  85. H. Sale, J. Wang, T. J. O'Hara et al., “Physiological properties of hERG 1a/1b heteromeric currents and a hERG 1b-specific mutation associated with long-QT syndrome,” Circulation Research, vol. 103, no. 7, pp. e81–e95, 2008. View at Publisher · View at Google Scholar · View at Scopus
  86. P. S. Spector, M. E. Curran, M. T. Keating, and M. C. Sanguinetti, “Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel open-channel block by methanesulfonanilides,” Circulation Research, vol. 78, no. 3, pp. 499–503, 1996. View at Scopus
  87. C. E. Clancy, Z. I. Zhu, and Y. Rudy, “Pharmacogenetics and anti-arrhythmic drug therapy: a theoretical investigation,” American Journal of Physiology, vol. 292, no. 1, pp. H66–H75, 2007. View at Publisher · View at Google Scholar · View at Scopus
  88. V. V. Nesterenko, A. C. Zygmunt, S. Rajamani, L. Belardinelli, and C. Antzelevitch, “Mechanisms of atrial-selective block of Na channels by ranolazine: II. Insights from a mathematical model,” American Journal of Physiology, vol. 301, no. 4, pp. H1615–H1624, 2011. View at Publisher · View at Google Scholar
  89. C. Antzelevitch, L. Belardinelli, A. C. Zygmunt et al., “Electrophysiological effects of ranolazine, a novel antianginal agent with antiarrhythmic properties,” Circulation, vol. 110, no. 8, pp. 904–910, 2004. View at Publisher · View at Google Scholar · View at Scopus
  90. A. Burashnikov, J. M. Di Diego, A. C. Zygmunt, L. Belardinelli, and C. Antzelevitch, “Atrium-selective sodium channel block as a strategy for suppression of atrial fibrillation: differences in sodium channel inactivation between atria and ventricles and the role of ranolazine,” Circulation, vol. 116, no. 13, pp. 1449–1457, 2007. View at Publisher · View at Google Scholar · View at Scopus
  91. N. Morita, J. H. Lee, Y. Xie et al., “Suppression of re-entrant and multifocal ventricular fibrillation by the late sodium current blocker ranolazine,” Journal of the American College of Cardiology, vol. 57, no. 3, pp. 366–375, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. B. Rodriguez, K. Burrage, D. Gavaghan, V. Grau, P. Kohl, and D. Noble, “The systems biology approach to drug development: application to toxicity assessment of cardiac drugs,” Clinical Pharmacology and Therapeutics, vol. 88, no. 1, pp. 130–134, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. A. X. Sarkar and E. A. Sobie, “Regression analysis for constraining free parameters in electrophysiological models of cardiac cells,” PLoS Computational Biology, vol. 6, no. 9, Article ID e1000914, 2010. View at Publisher · View at Google Scholar · View at Scopus
  94. D. M. Roden and T. Yang, “Protecting the heart against arrhythmias: potassium current physiology and repolarization reserve,” Circulation, vol. 112, no. 10, pp. 1376–1378, 2005. View at Publisher · View at Google Scholar · View at Scopus
  95. T. O'Hara and Y. Rudy, “Quantitative comparison of cardiac ventricular myocyte electrophysiology and response to drugs in human and nonhuman species,” American Journal of Physiology, vol. 302, no. 5, pp. H1023–H1030, 2011. View at Publisher · View at Google Scholar
  96. H. Nakamura, J. Kurokawa, C. X. Bai et al., “Progesterone regulates cardiac repolarization through a nongenomic pathway: an in vitro patch-clamp and computational modeling study,” Circulation, vol. 116, no. 25, pp. 2913–2922, 2007. View at Publisher · View at Google Scholar · View at Scopus
  97. P. C. Yang, J. Kurokawa, T. Furukawa, and C. E. Clancy, “Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: a simulation study,” PLoS Computational Biology, vol. 6, no. 1, Article ID e1000658, 2010. View at Publisher · View at Google Scholar · View at Scopus
  98. A. P. Benson, M. Al-Owais, and A. V. Holden, “Quantitative prediction of the arrhythmogenic effects of de novo hERG mutations in computational models of human ventricular tissues,” European Biophysics Journal, vol. 40, no. 5, pp. 627–639, 2011. View at Publisher · View at Google Scholar · View at Scopus
  99. S. Ghosh, E. K. Rhee, J. N. Avari, P. K. Woodard, and Y. Rudy, “Cardiac memory in patients with Wolff-Parkinson-White syndrome: noninvasive imaging of activation and repolarization before and after catheter ablation,” Circulation, vol. 118, no. 9, pp. 907–915, 2008. View at Publisher · View at Google Scholar · View at Scopus
  100. P. S. Cuculich, J. Zhang, Y. Wang, K. A. Desouza, R. Vijayakumar, P. K. Woodard, et al., “The electrophysiological cardiac ventricular substrate in patients after myocardial infarction: noninvasive characterization with electrocardiographic imaging,” Journal of the American College of Cardiology, vol. 58, no. 18, pp. 1893–1902, 2011. View at Publisher · View at Google Scholar
  101. S. Ghosh, J. N. A. Silva, R. M. Canham et al., “Electrophysiologic substrate and intraventricular left ventricular dyssynchrony in nonischemic heart failure patients undergoing cardiac resynchronization therapy,” Heart Rhythm, vol. 8, no. 5, pp. 692–699, 2011. View at Publisher · View at Google Scholar · View at Scopus
  102. Y. Wang, P. S. Cuculich, J. Zhang, K. A. Desouza, R. Vijayakumar, J. Chen, et al., “Noninvasive electroanatomic mapping of human ventricular arrhythmias with electrocardiographic imaging,” Science Translational Medicine, vol. 3, no. 98, p. 98ra84, 2011. View at Publisher · View at Google Scholar
  103. P. S. Cuculich, Y. Wang, B. D. Lindsay et al., “Noninvasive characterization of epicardial activation in humans with diverse atrial fibrillation patterns,” Circulation, vol. 122, no. 14, pp. 1364–1372, 2010. View at Publisher · View at Google Scholar · View at Scopus
  104. P. M. van Dam, T. F. Oostendorp, A. C. Linnenbank, and A. van Oosterom, “Non-invasive imaging of cardiac activation and recovery,” Annals of Biomedical Engineering, vol. 37, no. 9, pp. 1739–1756, 2009. View at Publisher · View at Google Scholar · View at Scopus
  105. T. Berger, B. Pfeifer, F. F. Hanser et al., “Single-beat noninvasive imaging of ventricular endocardial and epicardial activation in patients undergoing CRT,” PLoS ONE, vol. 6, no. 1, Article ID e16255, 2011. View at Publisher · View at Google Scholar · View at Scopus
  106. C. Han, C. Liu, S. Pogwizd, and B. He, “Noninvasive three-dimensional cardiac activation imaging on a rabbit model,” in Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC '09), pp. 3271–3273, September 2009. View at Publisher · View at Google Scholar
  107. T. Berger, G. Fischer, B. Pfeifer et al., “Single-beat noninvasive imaging of cardiac electrophysiology of ventricular pre-excitation,” Journal of the American College of Cardiology, vol. 48, no. 10, pp. 2045–2052, 2006. View at Publisher · View at Google Scholar · View at Scopus
  108. A. V. Kalinin, “Iterative algorithm for the inverse problem of electrocardiography in a medium with piecewise-constant electrical conductivity,” Computational Mathematics and Modeling, vol. 22, no. 1, pp. 30–34, 2011. View at Publisher · View at Google Scholar · View at Scopus
  109. D. Lai, C. Liu, M. D. Eggen, P. A. Iaizzo, and B. He, “Localization of endocardial ectopic activity by means of noninvasive endocardial surface current density reconstruction,” Physics in Medicine and Biology, vol. 56, no. 13, pp. 4161–4176, 2011. View at Publisher · View at Google Scholar · View at Scopus
  110. C. Han, S. M. Pogwizd, C. R. Killingsworth, and B. He, “Noninvasive imaging of three-dimensional cardiac activation sequence during pacing and ventricular tachycardia,” Heart Rhythm, vol. 8, no. 8, pp. 1266–1272, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. C. Han, S. M. Pogwizd, C. R. Killingsworth, and B. He, “Noninvasive reconstruction of the three-dimensional ventricular activation sequence during pacing and ventricular tachycardia in the canine heart,” American Journal of Physiology, vol. 302, no. 1, pp. H244–H252, 2012. View at Publisher · View at Google Scholar
  112. A. V. Kalinin, “Iterative algorithm for the inverse problem of electrocardiography in a medium with piecewise-constant electrical conductivity,” Computational Mathematics and Modeling, vol. 22, no. 1, pp. 30–34, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. L. A. Bokeriia, A. S. Revishvili, A. V. Kalinin, V. V. Kalinin, O. A. Liadzhina, and E. A. Fetisova, “Hardware-software system for noninvasive electrocardiographic examination of heart based on inverse problem of electrocardiography,” Meditsinskaia Tekhnika, no. 6, pp. 1–7, 2008. View at Scopus
  114. J. J. Goldberger, A. E. Buxton, M. Cain et al., “Risk stratification for arrhythmic sudden cardiac death: identifying the roadblocks,” Circulation, vol. 123, no. 21, pp. 2423–2430, 2011. View at Publisher · View at Google Scholar · View at Scopus
  115. D. L. Kuchar, C. W. Thorburn, and N. L. Sammel, “Prediction of serious arrhythmic events after myocardial infarction: signal-averaged electrocardiogram, Holter monitoring and radionuclide ventriculography,” Journal of the American College of Cardiology, vol. 9, no. 3, pp. 531–538, 1987. View at Scopus
  116. M. K. Das, B. Khan, S. Jacob, A. Kumar, and J. Mahenthiran, “Significance of a fragmented QRS complex versus a Q wave in patients with coronary artery disease,” Circulation, vol. 113, no. 21, pp. 2495–2501, 2006. View at Publisher · View at Google Scholar · View at Scopus
  117. D. S. Rosenbaum, L. E. Jackson, J. M. Smith, H. Garan, J. N. Ruskin, and R. J. Cohen, “Electrical alternans and vulnerability to ventricular arrhythmias,” The New England Journal of Medicine, vol. 330, no. 4, pp. 235–241, 1994. View at Publisher · View at Google Scholar · View at Scopus
  118. R. D. Berger, E. K. Kasper, K. L. Baughman, E. Marban, H. Calkins, and G. F. Tomaselli, “Beat-to-beat QT interval variability: novel evidence for repolarization lability in ischemic and nonischemic dilated cardiomyopathy,” Circulation, vol. 96, no. 5, pp. 1557–1565, 1997. View at Scopus
  119. J. P. Couderc, W. Zareba, S. McNitt, P. Maison-Blanche, and A. J. Moss, “Repolarization variability in the risk stratification of MADIT II patients,” Europace, vol. 9, no. 9, pp. 717–723, 2007. View at Publisher · View at Google Scholar · View at Scopus
  120. S. M. Narayan, J. D. Bayer, G. Lalani, and N. A. Trayanova, “Action potential dynamics explain arrhythmic vulnerability in human heart failure. A clinical and modeling study implicating abnormal calcium handling,” Journal of the American College of Cardiology, vol. 52, no. 22, pp. 1782–1792, 2008. View at Publisher · View at Google Scholar · View at Scopus
  121. J. D. Bayer, S. M. Narayan, G. G. Lalani, and N. A. Trayanova, “Rate-dependent action potential alternans in human heart failure implicates abnormal intracellular calcium handling,” Heart Rhythm, vol. 7, no. 8, pp. 1093–1101, 2010. View at Publisher · View at Google Scholar · View at Scopus
  122. A. N. Doshi and S. F. Idriss, “Effect of resistive barrier location on the relationship between T-wave alternans and cellular repolarization alternans: a 1-D modeling study,” Journal of Electrocardiology, vol. 43, no. 6, pp. 566–571, 2010. View at Publisher · View at Google Scholar · View at Scopus
  123. J. T. Zhao, A. P. Hill, A. Varghese et al., “Not all hERG pore domain mutations have a severe phenotype: G584S has an inactivation gating defect with mild phenotype compared to G572S, which has a dominant negative trafficking defect and a severe phenotype,” Journal of Cardiovascular Electrophysiology, vol. 20, no. 8, pp. 923–930, 2009. View at Publisher · View at Google Scholar · View at Scopus
  124. C. Jons, J. O-Uchi, A. J. Moss, M. Reumann, J. J. Rice, I. Goldenberg, et al., “Use of mutant-specific ion channel characteristics for risk stratification of long QT syndrome patients,” Science Translational Medicine, vol. 3, no. 76, p. 76ra28, 2011. View at Publisher · View at Google Scholar
  125. T. O'Hara and Y. Rudy, “Arrhythmia formation in subclinical (“silent”) long QT syndrome requires multiple insults: quantitative mechanistic study using the KCNQ1 mutation Q357R as example,” Heart Rhythm, vol. 9, no. 2, pp. 275–282, 2012. View at Publisher · View at Google Scholar
  126. X. Chen, Y. Hu, B. J. Fetics, R. D. Berger, and N. A. Trayanova, “Unstable QT interval dynamics precedes ventricular tachycardia onset in patients with acute myocardial infarction: a novel approach to detect instability in QT interval dynamics from clinical ECG,” Circulation, vol. 4, no. 6, pp. 858–866, 2011. View at Publisher · View at Google Scholar
  127. S. M. Narayan, “T-wave alternans and the susceptibility to ventricular arrhythmias,” Journal of the American College of Cardiology, vol. 47, no. 2, pp. 269–281, 2006. View at Publisher · View at Google Scholar
  128. Z. Qu, Y. Xie, A. Garfinkel, and J. N. Weiss, “T-wave alternans and arrhythmogenesis in cardiac diseases,” Frontiers in Physiology, vol. 1, p. 154, 2010. View at Publisher · View at Google Scholar
  129. D. M. Bloomfield, J. T. Bigger, R. C. Steinman et al., “Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction,” Journal of the American College of Cardiology, vol. 47, no. 2, pp. 456–463, 2006. View at Publisher · View at Google Scholar · View at Scopus
  130. S. H. Hohnloser, T. Ikeda, and R. J. Cohen, “Evidence regarding clinical use of microvolt T-wave alternans,” Heart Rhythm, vol. 6, no. 3, supplement, pp. S36–S44, 2009. View at Publisher · View at Google Scholar · View at Scopus
  131. J. N. Weiss, A. Karma, Y. Shiferaw, P. S. Chen, A. Garfinkel, and Z. Qu, “From pulsus to pulseless: the saga of cardiac alternans,” Circulation Research, vol. 98, no. 10, pp. 1244–1253, 2006. View at Publisher · View at Google Scholar · View at Scopus
  132. J. M. Pastore, S. D. Girouard, K. R. Laurita, F. G. Akar, and D. S. Rosenbaum, “Mechanism linking T-wave alternans to the genesis of cardiac fibrillation,” Circulation, vol. 99, no. 10, pp. 1385–1394, 1999. View at Scopus
  133. S. M. Narayan, M. R. Franz, G. Lalani, J. Kim, and A. Sastry, “T-wave alternans, restitution of human action potential duration, and outcome,” Journal of the American College of Cardiology, vol. 50, no. 25, pp. 2385–2392, 2007. View at Publisher · View at Google Scholar · View at Scopus
  134. J. N. Weiss, M. Nivala, A. Garfinkel, and Z. Qu, “Alternans and arrhythmias : from cell to heart,” Circulation Research, vol. 108, no. 1, pp. 98–112, 2011. View at Publisher · View at Google Scholar · View at Scopus
  135. F. M. Merchant and A. A. Armoundas, “Role of substrate and triggers in the genesis of cardiac alternans, from the myocyte to the whole heart: implications for therapy,” Circulation, vol. 125, no. 3, pp. 539–549, 2012. View at Publisher · View at Google Scholar
  136. X. Chen and N. A. Trayanova, “A novel methodology for assessing the bounded-input bounded-output instability in QT interval dynamics: application to clinical ECG with ventricular tachycardia,” IEEE Transactions on Biomedical Engineering, vol. 59, no. 8, pp. 2111–2117, 2012. View at Publisher · View at Google Scholar