Cardiomagnetic source imaging

Magnetocardiographic (MCG) source imaging has received increasing interest in recent years. With a high enough localization accuracy of the current sources in the heart, valuable information can be provided, e.g., for the pre-ablative evaluation of arrhythmia patients. Furthermore, preliminary studies indicate that ischemic areas, i.e. areas which are suffering from lack of oxygen, and infarcted regions could be localized from multichannel MCG recordings. In this thesis, the accuracy of cardiomagnetic source imaging results, obtained by using different current source models, was investigated. In addition, the effect of the torso model on the localization accuracy was examined. In some studies, also body surface potential mapping (BSPM) data were used for comparison purposes. A high impact was given to clinical validation, i.e. how the calculation methods would work in patients. The equivalent current dipole (ECD) source model was found to produce accurate (within 3-11 mm) localizations of focal current sources in a thorax phantom and in 15 patients with a non-magnetic stimulation catheter in the heart. The accuracy was found to depend on the signal-to-noise ratio and on the goodness of fit of the localizations. The corresponding accuracy determined from simultaneous multichannel BSPM recordings in 10 patients was 25 mm. In order to localize wider source regions in the heart, distributed source models were also investigated in the thesis. Current density estimates (CDEs) were calculated in the catheter patients and in 13 patients with coronary artery disease (CAD). Promising results were obtained by using second-order Tikhonov regularization in the calculations. CDEs were found to localize both myocardial ischemia in single-vessel CAD patients, as well as more complex chronic ischemia in three-vessel CAD patients. In addition to the ECD and CDE source models, the uniform double layer (UDL) model was used in the source imaging studies. With the UDL model, the whole depolarization of the ventricles can be represented with a single inverse solution. In the validation of the activation time maps calculated from MCG and BSPM recordings, invasively measured epicardial electrograms were used to construct the reference epicardial activation times. The overall patterns of activation in the reference data were reproduced relatively well in the calculated activation time maps. The high quality of the inverse solutions obtained in this thesis prompts the use of cardiomagnetic source imaging in several clinical applications, such as in electrophysiological studies and in the estimation of myocardial viability.reviewe

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). 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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. 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Functional Mapping of Three-Dimensional Electrical Activation in Ventricles

University of Minnesota Ph.D. dissertation. 2010. Major: Biomedical Engineering. Advisor: Bin He. 1 computer file (PDF); 139 pages.Ventricular arrhythmias account for nearly 400,000 deaths per year in the United States alone. Electrical mapping of the ventricular activation could facilitate the diagnosis and treatment of arrhythmias, e.g. guiding catheter ablation. To date, both direct mapping and non-contact mapping techniques have been routinely used in electrophysiology labs for obtaining the electrical activity on the endocardial surface. Non-invasive functional mapping methods are also developed to estimate the electrical activity on the epicardium or on both epicardium and endocardium from the body surface measurements. Though successful, the results using above methods are all limited on the surface of the heart and thus cannot directly characterize the cardiac events originating within the myocardial wall. Our group's goal is to develop a functional mapping method to estimate the three-dimensional cardiac electrical activity from either non-invasive body surface potential maps or minimally-invasive intracavitary potential maps, by solving the so-called "inverse problem". Hence the information under the surface of the heart could be revealed to better characterize the cardiac activation. In the present thesis study, the previously developed three-dimensional cardiac electrical imaging (3DCEI) approach has been further investigated. Its function is expanded for not only estimating the global activation sequence but also reconstructing the potential at any myocardial site throughout the ventricle. New algorithms under the 3DCEI scheme are also explored for more powerful mapping capability. The performance of the enhanced 3DCEI approach is rigorously evaluated in both control and diseased swine models when the clinical settings are mimicked. The promising results validate the feasibility of estimating detailed three-dimensional cardiac activation by using the 3DCEI approach, and suggest that 3DCEI has great potential of guiding the clinical management of cardiac arrhythmias in a more efficient way

Comparing Non-invasive Inverse Electrocardiography With Invasive Endocardial and Epicardial Electroanatomical Mapping During Sinus Rhythm

This study presents a novel non-invasive equivalent dipole layer (EDL) based inverse electrocardiography (iECG) technique which estimates both endocardial and epicardial ventricular activation sequences. We aimed to quantitatively compare our iECG approach with invasive electro-anatomical mapping (EAM) during sinus rhythm with the objective of enabling functional substrate imaging and sudden cardiac death risk stratification in patients with cardiomyopathy. Thirteen patients (77% males, 48 ± 20 years old) referred for endocardial and epicardial EAM underwent 67-electrode body surface potential mapping and CT imaging. The EDL-based iECG approach was improved by mimicking the effects of the His-Purkinje system on ventricular activation. EAM local activation timing (LAT) maps were compared with iECG-LAT maps using absolute differences and Pearson’s correlation coefficient, reported as mean ± standard deviation [95% confidence interval]. The correlation coefficient between iECG-LAT maps and EAM was 0.54 ± 0.19 [0.49–0.59] for epicardial activation, 0.50 ± 0.27 [0.41–0.58] for right ventricular endocardial activation and 0.44 ± 0.29 [0.32–0.56] for left ventricular endocardial activation. The absolute difference in timing between iECG maps and EAM was 17.4 ± 7.2 ms for epicardial maps, 19.5 ± 7.7 ms for right ventricular endocardial maps, 27.9 ± 8.7 ms for left ventricular endocardial maps. The absolute distance between right ventricular endocardial breakthrough sites was 30 ± 16 mm and 31 ± 17 mm for the left ventricle. The absolute distance for latest epicardial activation was median 12.8 [IQR: 2.9–29.3] mm. This first in-human quantitative comparison of iECG and invasive LAT-maps on both the endocardial and epicardial surface during sinus rhythm showed improved agreement, although with considerable absolute difference and moderate correlation coefficient. Non-invasive iECG requires further refinements to facilitate clinical implementation and risk stratification

Vectorcardiographic evaluation of electrical dyssynchrony and its role in predicting response to cardiac resynchronization therapy

[Doctor of Medicine thesis]. Cardiac resynchronization therapy (CRT) has become an important therapeutic strategy for heart failure (HF) patients with impaired left ventricular (LV) systolic function and prolonged QRS duration. The benefit of CRT as an adjunct to pharmacological therapy is now well established, with sustained improvements in quality of life, hospitalization rates and mortality. However, even in carefully selected patients, the response to CRT is often unpredictable with a considerable number of nonresponders (30-50%). Although the reasons for this nonresponse are not entirely clear, studies have suggested that non-optimal left ventricular (LV) lead positioning, lack of electrical dyssynchrony, suboptimal device programming and myocardial scar burden play an important role. More recently, a wealth of evidence has pointed to the limitations of 12-lead electrocardiography, suggesting it may not accurately reflect the presence or complexities of electrical dyssynchrony in the failing heart. As the efficacy of CRT is primarily achieved through LV resynchronization, there has been renewed interest in the development of techniques that enable better characterization of cardiac electric activation patterns and identification of electrical dyssynchrony. This approach would appear logical, given that CRT is primarily an ‘electrical therapy’, designed to treat an underlying electrical conduction abnormality. Vectorcardiography (VCG), which was first described in 1920, offers an alternative interpretation of the 12-lead ECG. Its resurgence in the field of CRT has emerged from the recognition that VCG parameters can provide information on dyssynchrony beyond that currently provided by the 12-lead ECG. Prominent amongst these is vectorcardiographic QRS area (QRSarea), which has been shown to be superior to QRSd and QRS morphology in predicting response to CRT. The work presented herein is structured into two major sections. First, we investigate the role of QRSarea as a novel predictor of response to CRT. Using a combination of different study designs, our results demonstrate that QRSarea is a better predictor of CRT response than QRSd and QRS morphology. We also show that CRT-induced ΔQRSarea can be used to help quantify LV resynchronization and to predict long-term clinical outcomes following CRT. Importantly, we are the first to show that a concomitant reduction in both QRSarea and QRSd is associated with the best clinical outcomes after CRT, indicating that ECG and VCG can be used in conjunction to help improve patient selection for CRT. In the second part of this thesis, we focus on the development and validation of a novel, vector-based 3D electroanatomical modelling system. Using a novel computational method, ECGSync combines the surface ECG-derived vectorcardiogram with cardiac magnetic resonance imaging to estimate, by inverse solution, the 3-dimensional sequence of LV activation. Accordingly, we show that ECGSync can noninvasively map ventricular electrical activity and accurately locate the site of latest electrical activation prior to CRT implantation. Furthermore, we demonstrate that novel ECGSync-derived markers of dyssynchrony can help predict CRT response. Our findings suggest that VCG may have great potential to improve the clinical application of CRT

Non-Invasive Electrocardiographic Imaging of Ventricular Activities: Data-Driven and Model-Based Approaches

Die vorliegende Arbeit beleuchtet ausgewählte Aspekte der Vorwärtsmodellierung, so zum Beispiel die Simulation von Elektro- und Magnetokardiogrammen im Falle einer elektrisch stillen Ischämie sowie die Anpassung der elektrischen Potentiale unter Variation der Leitfähigkeiten. Besonderer Fokus liegt auf der Entwicklung neuer Regularisierungsalgorithmen sowie der Anwendung und Bewertung aktuell verwendeter Methoden in realistischen in silico bzw. klinischen Studien

Theory, modelling and applications of electrocardiographic mapping

In this thesis, the genesis and applications of electromagnetic signals from the human heart are investigated through theory, modelling, signal processing and clinical studies. One objective of the thesis was to develop and test signal processing methods that would be applicable to multichannel electro- and magnetocardiographic data. A signal processing method based on a type of neural networks called the self-organizing maps is introduced for spatiotemporal analysis of the body surface potential maps produced by the beating heart. This method is capable of utilizing both the spatial morphology of the potential distributions on the body surface as well as their temporal development. A signal processing method aimed at providing a reliable electric baseline for more traditional isointegral analysis of the body surface potential mapping (BSPM) data is also introduced. Another objective of the thesis was to show the utility of electrocardiographic mapping in clinical use. This was demonstrated by applying electro- and magnetocardiographic mapping to evaluation of the propensity to life-threatening arrhythmias in postinfarction patients. Electrocardiographic mapping was found to perform equally well compared to more traditional SA-ECG, but electrocardiographic mapping may be more robust against individual variability in anatomy. A third objective of the thesis was to build a computer model of the human heart that is capable of simulating the normal ventricular activation. The propagation model is based on a bidomain formulation of the cardiac tissue applied to realistic geometry of the ventricles. An anatomically accurate model of the human conduction system that reproduces measured activation sequence of the human heart was developed in this thesis. The body surface potentials and the magnetic fields computed from the simulated activation corresponded to recordings from normal subjects. In summary, the thesis demonstrates the utility of electrocardiographic mapping in clinical use and introduces new signal processing methods that can be applied to this use. Finally, a computer model of the human heart binds together the physiology and anatomy of the human heart and body, classical electromagnetic theory, and computer science to explain the genesis and characteristics of the electromagnetic signals from the human heart.reviewe

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