Sanjeev Bhalla, M.D.
(Columbia University College of Physicians and Surgeons);Associate Professor of Radiology; Assistant Radiology Residence Program Director, Mallinckrodt Institute of Radiology

Research Interests:
Dr. Bhalla is an expert in computed tomography of the chest, and is actively investigating the use of multi-detector array CT with 3-D reconstruction as an alternative to pulmonary angiography in the diagnosis of pulmonary arteriovenous malformations in HHT.

Email:
bhallas@wustl.edu

John P. Boineau, M.D.
(Duke University, 1959); Professor of Surgery, Medicine, and Biomedical Engineering, Co-Director, Cardiothoracic Surgery Research Laboratory, Co-Director, Nuclear Stress Lab, Barnes-Jewish Hospital; Director, Cardiac Rehabilitation, Barnes-Jewish West County Hospital

Research Interests:
Dr. Boineau’s interest in cardiac electrophysiology began in the 1950s when he realized that to understand both the various electrocardiographic abnormalities and the bases of cardiac arrhythmias, one would have to map the electrical activity of the abnormal heart directly. In the 1960s, it became apparent that the techniques for cardiac mapping developed by Scher in Seattle and Durrer in Amsterdam could be used to shed light on the mechanisms of the ECG and arrhythmias. Also that if an arrhythmogenic substrate could be identified and located by mapping, perhaps it could be directly eliminated surgically, and this might prove to be an alternative to the inefficacy of the cardiac drugs used at that time. Dr. Boineau visited the labs of Scher and Durrer and together with Dr. Madison Spach developed mapping laboratories for both experimental animal studies and for human studies in the OR.

His first work was in the exploration of the electrophysiologic alterations due to hypertrophy and congenital defects and how they were reflected in the ECG; this included both cardiac and body surface potential distribution (BSPD) mapping. These studies were extended to correlations between ventricular activation and BSPD in patients with various forms of heart disease, including RVH, LVH, myocardial infarction, conduction system disease, and preexcitation syndromes. Because of questions remaining about the relationships between activation and BSPD (ECGs) and the variable effects of the geometry and torso volume conductor, he organized a group to construct a mathematical computer simulation of activation and the resulting body surface potential distribution. This team included Drs. Theo Pilkington, Roger Barr, and Madison Spach.

In 1963, Dr. Boineau demonstrated that slow conduction was an important substrate for ventricular arrhythmias of myocardial infarction with delays (now referred to as late potentials) exceeding 250 msec or the durations of the ventricular refractory period. He later used this information in mapping studies in patients to locate these areas and ablate them with RF energy at surgery (1972). This work progressed more recently to cardiac potential distribution mapping of ventricular tachycardia to identify the specific reentrant pathways and ablate them. (In 1968, he developed a method for rapid mapping of total epicardial activation to locate accessory connections which were then divided by Dr. Will Sealy. Also in collaboration with Dr. E. N. Moore, he performed electrophysiologic anatomic correlation studies in two animals with congential preexcitation demonstrating the anatomy and activation of anomalous AV connections in two different animal species.

In 1975, he and his team mapped an animal with naturally occurring atrial flutter and identified two forms: the common or anticlockwise, and the uncommon or clockwise form of circus motion reentry in the right atrium between the discontinuities of the tricuspid annulus and the two cavae. In 1970 and in conjunction with Wayne Farlow, a digital computer simulation of ventricular activation and ventricular arrhythmias was developed based on measured conduction and repolarization data and the effect of premature depolarizations. The model was three-dimensional and simulated both the ventricular myocardium and the Purkinje network and their effects on these arrhythmias.

In 1980, with Dr. Richard Schuessler, he identified that the atrial impluse originated from a widely distributed area both within and beyond the sinus node. Often the atrial wavefront was observed to originate simultaneously from two to three different sites spread over a wide area of the right atrium along the crista terminalis. These different sites proved to be functionally differentiated to elaborate different but overlapping heart rate ranges. Later, this spatial-functional differentiation was related to differences in the beta-adrenergic receptor densities together with Drs. Beau, Rodefeld, and Schuessler. These studies were extended to patients to demonstrate a network of atrial pacemakers which included the lateral right atrium and lateral left atrium at its junction with the pulmonary veins. These extranodal sites appeared to be functionally integrated autonomically with the sinus node as part of an extensive atrial pacemaker complex. Subsequently, correlations between transmembrane recordings and disaggregated sinus node cells in studies with Wu and Schuessler demonstrated that the principal canine atrial pacemaker was a stellate or spider-shaped cell with multiple elongated dendritic-like projections. The membrane currents of these dominant cells differed from elliptical pacemaker cells which depolarized at a lower frequency. Later studies with Drs. Schuessler, Saffitz, and Kwong demonstrated that these spider cells separated by intervening tissue were connected to multiple other similar cells by punctate foci of connexon proteins. These minute pacemaker cell interconnections contrasted with the typical broader connections between physically adjacent, compacted myocardial cells. The arrangement was conjectured to be the basis of the summation-inhibition electrotonic interaction that determines the principal “envelope” frequency of a dominant pacemaker, and at the same time inhibits cell to cell propagation of wavefronts characteristic of myocardial activation spread.

In 1984, Dr. Boineau arrived at Washington University with the idea that atrial fibrillation might be eliminated by dividing the atrium into small segments which would not permit sustained reentry, while at the same time allowing spread of the sinus impulse over a continuous but circuitous pathway to the AV node. A procedure developed in conjunction with Drs. Schuessler, Cox, and others and pioneered by Dr. Cox in patients became known as the Maze procedure. This was the first approach to completely eradicate atrial fibrillation and has evolved with progression of technology and skill of clinical electrophysiologists and surgeons to a method for directly controlling this serious arrhythmia. More recently, an attempt to eliminate atrial fibrillation and also improve on atrial mechanical function resulted in the development of a second surgical approach, the Radial procedure, developed in conjunction with Drs. Nitta and Schuessler.

Currently, Dr. Boineau continues his involvement, although less directly, with Drs. Schuessler and Damiano, and others in studies to define the relationships between atrial segment size interacting with the degree of atrial refractory period inhomogeneity on the vulnerability to sustained atrial fibrillation in isolated perfused atrial preparations. It is anticipated that these data will be useful in planning future ablative procedure in patients with atrial fibrillation. Finally, the group is working on an automated technique for rapid, on-line identification of single or multiple focal reentrant circuits which could then be ablated with minimal damage, preserving as much normal atrial conduction and contraction as possible.

Website:
http://cardiology.wustl.edu/details.aspx?NavID=655

Email:
boineauJ@wudosis.wustl.edu

Clinical Interests: My career is predominantly a clinical one, treating patients with all manner of heart rhythm disorders. This includes medical management, device implantation (pacemakers, defibrillators, cardiac resynchronization devices), and mapping & ablation for arrhythmias.

• Research Interests:
• -Efficacy of defibrillation
• -Improving appropriate detection of arrhythmias by implantable devices
• -Hypothermia after cardiac arrest for cerebral protection
• -Quality of cardiopulmonary resuscitation (CPR) and its effect on outcomes after cardiac arrest

Website:
http://wuphysicians.wustl.edu/physician2.aspx?PhysNum=3563

Email:
jcooper@im.wustl.edu

Richard W. Gross, M.D., Ph.D.
(New York University Medical School, 1976; Cardiology Fellow, Barnes Hospital, St. Louis, 1978-81; Washington University, St. Louis, Ph.D., 1982); Professor of Medicine, Chemistry, and Developmental Biology; Director, Division of Bioorganic Chemistry and Molecular Pharmacology (Joint Appointment with the School of Medicine), Department of Internal Medicine, Department of Molecular Biology and Pharmacology and Department of Chemistry, Washington University School of Medicine

Research Interests:
Our research is focused on the chemical biology of membranes in health and disease. Biologic membranes are comprised of a structurally diverse array of thousands of distinct chemical entities in a bilayer configuration that are in constant motion providing a rich repertoire of chemical forces that can be used to modulate the conformation and function of transmembrane proteins such as ion channels and ion pumps. Through adaptation of a bilayer structure membranes serve as a hydrophobic scaffold for the organization of complex supramolecular chemical assemblies that are used in biologic systems as signaling platforms.

These highly specialized signaling assemblies facilitate the transmission of chemical information between intracellular membrane compartments as well as the intercellular flow of information between cells. Biologic membranes also serve as the intracellular storage depot of latent lipid second messengers of signal transduction (e.g., esterified arachidonic acid) that are hydrolyzed by phospholipases in response to changes in a cell’s external environment or after receipt of a chemical or electrical signal from distant cells. Finally, biologic membrane bilayers are the fundamental structural elements responsible for the trafficking of proteins, lipids and nucleic acids to different compartments within cells or, through membrane fusion, for the release of information from a genetically programmed specialized cell into the blood stream (e.g., insulin release into the blood stream from b cells in the pancreas). Our laboratory uses and develops many different chemical methods to study the structure and function of membrane systems to both advance our understanding of the fundamental processes underlying the chemistry of biologic membranes and to use this information to develop new strategies to have a favorable impact on the major disease processes of the 21st century.

Recently, industrialized nations have been afflicted with an epidemic of obesity precipitating the metabolic syndrome (hypertension, diabetes and atherosclerosis). To identify the chemical mechanisms through which obesity predisposes to these disease processes, we have developed a novel technology, termed shotgun lipidomics, which allows the direct identification and quantitation of hundreds of lipid molecular species directly from organic extracts of tissue or biologic fluids.

Shotgun lipidomics is comprised of intrasource separation, multidimensional mass spectrometry, and array analysis. Through the judicious use of stable isotopes, alterations in the kinetics of specific membrane chemical processes, and the dynamics of lipid-protein and lipid-lipid interactions can be readily examined with unprecedented speed and accuracy. Currently we are using this technology to explore altered heart metabolism (metabolomics) through a systematic chemical biology approach. Through the identification of critical metabolic nodes specific to disease states and the effects of pharmaceuticals on the influx and efflux of metabolites into common intermediates, new insights into dysfunctional lipid metabolism in disease and the effects of therapeutic agents can be gathered.

During the last decade, we have made substantial progress in understanding the chemical mechanisms regulating the intracellular phospholipases that release lipid second messengers. Through recombinant DNA techniques, we now express large quantities of these proteins to study their structure and regulatory mechanisms through a variety of chemical and molecular biologic methods. Of particular current interest are the mechanisms that regulate the recognition of membrane surfaces by signaling phospholipases and the resultant alterations in protein structure and function they engender.The recent identification of new signaling mechanisms mediated through phospholipase-calmodulin membrane-associated signaling platforms is rapidly expanding our understanding of the partnership of membranes and proteins in signaling functions. Through exploiting new advances in proteomics using both electrospray ionization (ESI) and matrix assisted laser desorption/ionization (MALDI) quadrupole time of flight spectrometer, high throughput analyses of the specific chemical mechanisms, and protein-target interactions regulating signaling phospholipases in multiple biologically relevant context can be made. Through this work, we seek to understand the mechanisms activating signaling proteins and identify new targets for pharmaceutical intervention.

Website:
http://chemistry.wustl.edu

Email:
rgross@wustl.edu

Leonid Livshitz, Ph.D.
(Ph.D., Institute of Technology, Haifa, Israel, 2002; Post Doctoral Research, Case Western University, Cleveland, OH 2004); Research Assistant Professor, Biomedical Engineering

Research Interests:

Dr. Livshitz's research interests focus on the mechanisms underlying arhythmmogenic effects of the calcium and calcium-dependent regulatory pathways on the onset of cardiac arrhythmias. The approach of this research is to use a combination of nonlinear dynamics, computational biology and numerical modeling. This approach allows the study of temporal and spatial interactions between calcium and electrical (action potential) subsystems in the cardiac tissue. Particularly studying how destabilization of these interactions at the subcellular and single cell levels can lead to action potential and calcium transients alternans or trigger calcium waves which are both precursors to arrhythmia.Currently research focuses on development of the computer model based on the structural organization of the cardiac cell that will integrate the electrical and calcium subsystems, as well as the PKA and CaMKII regulatory pathways. The model will be used to study the properties, mechanisms and arrhythmogenic consequences of calcium waves.

Websites:
http://www.cbac.wustl.edu

Email:
lmlivshitz@biomed.wustl.edu

Ali Nekouzadeh, Ph.D.
(Ph.D., Washington University, St. Louis, MO, 2005); Research Assistant Professor, Biomedical Engineering

Research Interests:

Modeling mechanical and electrical properties of tissues, cells and cell components.I am working on modeling the molecular mechanism of ion channel gating of voltage dependent channels, in particular Iks channels. I plan to continue my current study to uncover how different mutations alter the normal function of ion channels to help finding effective treatments.

Website:
http://www.cbac.wustl.edu

Email:
ali@biomed.wustl.edu

Jingyi Shi, Ph.D.
Research Faculty, Biomedical Engineering, Research Assistant Professor

Research Interests:
biophysics, molecular biology, ion channels in physiology and disease, channel structure-function relationship, ultrasound-mediated drug and gene delivery; Ion channels are the molecular units of electrical activity in all cell types. Bioelectricity is generated and modulated as different types of channels open and close in response to various stimuli, such as the binding of a neurotransmitter from outside the cell, a second messenger from inside the cell, or a change in the voltage across the membrane. The Cui lab research interests focus on the mechanisms underlying conformational changes that occur as the channels open and close and on the interaction of ion channels with other molecules during cellular electrical activity. The approach in our research is to use a combination of molecular biology, protein biochemistry, patch clamp techniques, and biophysical analysis and kinetic modeling. This approach allows us to manipulate channel protein structure, estimate the number of distinct conformational states of the channel protein, and determine the energy associated with the transitions among these states. Current projects involve two potassium channels: 1) The BK type calcium-activated potassium channels, which are important in, among other physiological processes, the control of blood vessel diameter and neurotransmitter release. They are implicated in hypertension and epilepsy; 2) The I_Ks potassium channels that play a key role in the rhythmic control of the heart rate. Defects in the channel protein have been shown to cause severe inherited cardiac arrhythmias that often lead to syncope and sudden death.

Website:
http://biomed.wustl.edu

Email:
jshi@biomed.wustl.edu

Jennifer N. A. Silva, M.D.
(St. George’s University School of Medicine, 2002) Instructor in Pediatrics, Director of Pediatric Electrophysiology, Washington University School of Medicine in St. Louis, Division of Pediatric Cardiology

Clinical Interests:

• Clinical Electrophysiology/Arrhythmias
• Inherited Channelopathies
• Transcatheter ablations
• Pacemakers/Defibrillators
• Heart Failure and Cardiac Resynchronization Therapy
• Sudden Cardiac Death

Research Interests:

• Clinical Applications of Noninvasive Electrocardiographic Imaging (ECGI)

In working with Dr. Yoram Rudy, Dr. Silva has applied ECGI to pediatric patients to create 3-dimensional epicardial electroanatomical maps, focusing on pediatric heart failure patients undergoing cardiac resynchronization therapy. By better understanding a patients’ electrophysiologic substrate prior to this proceudre, they hope to improve patient selection and outcomes in this population.

• Pediatric Cardiac Resynchronization Therapy

Website: http://peds.wustl.edu/Faculty/Silva_J

Email: silva_j@kids.wustl.edu

Gautam K. Singh, M.D., M.R.C.P.
(M.D., Patna Medical College, India, 1982; M.R.C.P., Royal College of Physicians, London, U.K., 1988); Pediatric Cardiologist at St. Louis Children’s Hospital, Director of The Preventive Cardiology Clinic at St. Louis Children’s Hospital and Associate Professor of Pediatrics, Washington University School of Medicine

Research Interests:
Cardiac mechanics in congenital heat disease particulary with single ventricular physiology by non-invasive cardiac imaging; non-invasive cardiac tissue characterization and cardiac kinematic in fetuses and children affected by cardiac disease, metabolic abnormalities and obesity; tissue characterization and cardiac mechanics in developing fetus in animal model.

Clinical Interests:
Diagnosis, treatment and prevention of congenital heart disease, preventive pediatric cardiology, fetal cardiology, non-invasive cardiac imaging.

Website:
http://www.stlouischildrens.org/content/mediaprofilesingh.htm#

Email:
singh_g@wustl.edu

CBAC Faculty Alumni:

• Amir A. Amini, Ph.D.
• Kyongtae T. Bae , M.D., Ph.D.
• Michael Cain, M.D.
• Daniel P. Kelly, M.D.
• Bruce Lindsay, Ph.D.
• Achi Ludomirsky, M.D.
• Vladimir P. Nikolski, Ph.D.
• Edward Rhee, Ph.D.
• Jeffrey E. Saffitz , M.D., Ph.D.