Computational Cardiac and Neural Electrophysiology

[Research Statement] [Lab] [Publications] [CV]

Research Statement

Electrophysiology is the study of how electricity is used by the body to coordinate activities between cells. In the heart, coordination between cells results in the large-scale rhythmic pumping of blood. In the brain, cellular communication results in the large-scale propagation and processing of information. These two biological processes share in common the important property of being coherent enough that they are stable, but not so coherent that they are inflexible. My research is driven by four broad questions: 1) How and why do biological processes acting at a cellular level give rise to large-scale behavior? 2) How does breaking or enhancing coherency lead to disease? 3) What are measures of coherency that may be used to diagnose disease states? and 4) How might we design cures for diseases by returning the balance between coherency and incoherency?

For many scientific questions, studying the heart and the brain in humans poses an ethical dilemma. Furthermore, for the theoretical questions I have posed, experimental studies do not always allow measurement of all the important quantities. Therefore, the primary tool in my research is the numerical simulation of mathematical models on a computer. Below are two examples of recent research that is ongoing in my lab.

The co-existence of reentrant spirals in the heart with multiple rates of rotation

During each heart beat a wave of electrical activity propagates throughout the heart and leads to the precisely timed contraction of individual muscle cells. In a healthy heart, this wavefront is initiated by a group of cells known as the pacemaker. In an unhealthy heart, however, the development of a reentrant spiral wave can form a second pacemaker that interferes with normal wavefront propagation. The most dangerous occurrence is when this single spiral initiates the creation of even more spirals, leading to a runaway process of many small pacemakers. Two theoretical findings in homogeneous heart tissue are that a single spiral may break into multiple spirals and that rapidly rotating spirals push slowly rotating spirals to domain boundaries. These two findings together fail to explain how real cardiac tissue can support multiple stable spirals with different periods of rotation. We have found that a thin inhomogeneous region of tissue can form a functionally protective barrier between spirals rotating at different rates. The only requirement of the insulating region is that it partially block alternating wavefronts from the fast spiral. Furthermore, many properties of the model can result in functional insulation and multiple insulating regions can result in the broad frequency spectrum characteristic of cardiac fibrillation. The results suggest that the healthy ventricle, although containing intrinsic inhomogeneities, is functionally connected, while disease may create functionally disconnected regions. This simple mechanism may shed light on why defibrillation and pacing are not always successful, and why some patients are more susceptible to a transition from tachycardia to fibrillation.

Dynamic pathways in the brain

It is thought that the complex functions of the brain are due to the dynamic organization of populations of neurons into neural pathways. When information enters a neural pathway it may be transformed, forming the basis for processing. Although the densely connected network of neurons define all possible pathways, it is the non-linear dynamics of individual neurons that define which pathways are active and which are not at a particular time. We have proposed that the study of brain function should therefore combine both the non-linear dynamics of individual neurons and network analysis of neural connections. To tie together these two overlapping fields, we have proposed a concept called dynamic impedance, which is simply how "willing" a cell is to listen to inputs. In this way, an individual neuron may act as a simple switch, but at the same time participate in the processing that occurs along a pathway. Using dynamic impedance, we have shown how information moves through the brain due to which pathways are available at the time. Therefore, the pathways that are followed are not always the same and depend upon many factors. Furthermore, the information may be changed as it follows a particular pathway, forming a rudimentary basis for neural processing.

Publications

Books

JV Tranquillo, " Quantitative Neurophysiology" Morgan and Claypool 2008 (Updated 2009)

Select Publications

JV Tranquillo, N Badie CS Henriquez N Bursac, "Collison-based Spiral Acceleration in Cardiac Media: Roles of Wavefront Curvature and Excitable Gap", Biophysical Journal 2010 98:7 1119-1128
JV Tranquillo, M Howes, "Intrinsic Inhomogeneities and the Coexistence of Spirals with Different Periods of Rotation", Physical Review E 2008 78:051914
JV Tranquillo, A Sunkara, "Can we Trust the Transgenic Mouse: Insights from Computer Simulations" Lecture Notes in Computer Science: Functional Imaging and Modeling of the Heart (Special Edition). 2007. 4466: 210-219
A Grant, JV Tranquillo, "Action Potential and QT Prolongation not Sufficient to cause Torsade de Pointes: Role of Action Potential Triangulation" J Cardiovasc Electrophysiol. 2007 18:204-5
Z Zhang, JV Tranquillo, N Bursac, A Grant, "Sodium Channel Kinetic Changes that Produce Brugada Syndrome or Primary Conduction System Disease" Amer J of Physiol. 2007 292:399-407.
JV Tranquillo, J Hlavacek and CS Henriquez, "An Integrative Model of Mouse Cardiac Electrophysiology: From Cell to Torso" EuroPace. 2005 Suppl 2: 56-70
JV Tranquillo, D Burwell and CS Henriquez, "Analytical Model of Extracellular Potentials in a Tissue Slab with a Finite Bath" IEEE Trans on BME. 2005 52(2): 334-338
JV Tranquillo, MR Franz, BC Knollmann, A Henriquez, DA Taylor and CS Henriquez, "Genesis of the Monophasic Action Potential: Role of the Interstitial Resistance and Boundary Gradients", Amer J of Physiol. 2004 286(4): H1370-H1381
D Weinstein, JV Tranquillo, CS Henriquez and C Johnson, "BioPSE Case Study: Modeling Stimulation and Visualization of Three Dimensional Mouse Heart Propagation" J of Bioelectromag 2003 5(1): 314-315
BC Knollmann, JV Tranquillo, SG Sirenko, CS Henriquez and MR Franz, "Microelectrode Study of the Genesis of the Monophasic Action Potential by Contact Electrode Technique" J Cardiovasc Electrophysiol. 2002 13(12):1246-1252

Book Chapters

CS Henriquez, JV Tranquillo, D Weinstein, E Hsu and CR Johnson, "Three Dimensional Propagation in Mathematical Models: Integrative Mode of the Mouse Heart" in Cardiac Electrophysiology: From Cell to Bedside 4th edition. Ed. Douglas Zipes and Jose Jalife. Saunders WD Co, Philadelphia, PA 2004.
CS Henriquez and JV Tranquillo, "Modeling the Impact of Cardiac Tissue Structure on Current Flow and Wavefront Propagation" in Quantitative Cardiac Electrophysiology. Ed. Candido Cabo and David Rosenbaum. marchel Dekker Inc. New York. 2002.

PhD Thesis

JV Tranquillo, " Relationship Between the Monophasic Action Potential and Transmembrane Action Potential: A Theoretical, Experimental and Computational Study" Duke University 2004

Recent Conference Proceedings

JV Tranquillo, "The Co-existence of Spirals with Multiple Rates of Rotation" APS March Meeting 2009 Pittsburgh,PA
N Crosby and JV Tranquillo, "Burst Switching Between Incoherence and Synchrony" APS March Meeting 2009 Pittsburgh, PA
JV Tranquillo, N Badie and N Bursac, "Negative Curvature as a Mechanism for the Acceleration of Multi-wave Reentry" BMES 2008, 10/2/08 St. Louis, MO
JV Tranquillo, "A Novel Mechanism for the Initiation and Evolution of Cardiac Fibrillation", BMES 2007, 9/29/07 Los Angeles, CA
A Hosseinbor and JV Tranquillo, "Classification of Cardiac Arrhythias using Nonlinear Analysis of Electrograms", BMES 2007, 9/29/07 Los Angeles, CA
EH Banerjee and JV Tranquillo, "A First Step Toward and Understanding of the Unique Characteristics of the Mouse Electrocardiogram" BMES 2007, 9/28/07 Los Angeles, CA
N Badie, JV Tranquillo, N Bursac, "Micropatterned Heart Slice Cultures for Studies of Intramural Cardiac Electrophysiology", American Heart Association 2006, 11/15/06 Chicago, IL
A Sunkara and JV Tranquillo, "Mutations in Cardiac Ion Channels have Different Effects on Mice and Humans", BMES 2006. 10/13/06. Chicago, IL
M Howes and JV Tranquillo, "Spiral Wave Breakup to Cardiac Fibrillation is Sensitive to the Site of Reentry Initiation", BMES 2006. 10/14/06. Chicago, IL
JV Tranquillo and N Bursac "The Role of Resitution and Ion Currents in the Acceleration of Functional Reeentry", BMES 2005. 9/29/05 Baltimore, MD.
JV Tranquillo, AO Grant, Z Zhang and N Bursac "DK1479 and DK1500 Mutations Result in Burgada Syndrome", BMES 2005. 9/29/05 Baltimore, MD.
JV Tranquillo "in silico Transgenic Mouse Models: From Ion Channel to Body Surface", SIAM conference on Dynamical Systems. 5/22/05 Snowbird, UT.
N Bursac and JV Tranquillo. "Experimental and Computational Studies on Complex Spiral Waves in 2D Cardiac Substrates" American Physical Society. 3/5/05 Los Angeles, CA.
JV Tranquillo, J Hlavacek, KJ Sampson and CS Henriquez. "Impact of APD Dispersion on the Mouse T-Wave", BMES. 10/14/2004 Philadelphia, PA.
JV Tranquillo and CS Henriquez. "Factors that Impact the MAP Timecourse" Heart Rhythm Society. 5/21/2004 San Fransciso, CA.
JV Tranquillo, P Rosenstiel, CS Henriquez and DA Taylor. "Using Computer Models to Guide Cell Therapies" Keystone Symposia. 4/1/2003 Steamboat Springs, CO.
KJ Sampson, SF Roberts, JV Tranquillo, J Pormann and CS Henriquez. "Action Potential Duration (APD) Dispersion in the Mouse heart: A Computer Model of the Impact of Electrotonic Coupling" Keystone Symposia. 1/14/2003 Santa Fe, NM.
JV Tranquillo and CS Henriquez. "MRI to Model" IEEE Computer Visualization Conference. 10/28/02 Boston, MA.
JV Tranquillo, MR Franz, BC Knollmann and CS Henriquez. "Monophasic Action Potentials In Murine Heart: A Model Study" BMES-IEEE. 10/24/02 Houston, TX.
JV Tranquillo, MR Franz, BC Knollmann and CS Henriquez. "3D Bidomain Modelling of the Sources Underlying a Monophasic Action Potential" Heart Rhythm Society. 5/9/02 San Diego, CA.