Center for Cardiovascular Bioinformatics & Modeling (www.ccbm.jhu.edu)

1
Center for Cardiovascular Bioinformatics
Modeling(www.ccbm.jhu.edu)
Bioinformatics Modeling Core
D. W. Reynolds Cardiovascular Clinical Research
Center (www.reynolds.jhmi.edu) JHU-NHLBI
Proteomics Center (www.proteomics.jhu.edu) Canine
Microarray Core Facility SCOR in SCD
IBM Life Sciences Innovations Institute
2
Heart Failure is the Leading Cause of Sudden
Cardiac Death (SCD)
MR Imaging of Canine Heart Pre- and Post- Failure
Heart Failure

• Mechanical pump failure leading to reduced
  cardiac output
• Diverse origins
• Common end-stage phenotype
• The primary U.S. hospital discharge diagnosis
• Incidence 400,000/year, prevalence of 4.5
  million
• 15 mortality at 1 Yr, 80 mortality at 6 Yr
• leading cause of Sudden Cardiac Death in the US

Chamber Dilation Wall Thinning
3
Goal
To understand the molecular basis of SCD
Experiments (Human, Canine, Rabbit)
Cell Membrane Transporter Function
Cell Electro- Physiology
Gene/Protein Expression
Cardiac Imaging
Ventricular Conduction
Patient Data
Microarrays 2D PAGE Mass Spec (MALDI-TOF,
TOF-TOF, SELDI)
MR Diffusion Tensor Imaging Spin-Tagging
Heterologous Expression Systems Whole Cell
Patch-Clamp Recording
Ca2, Na V NADH, FADH, Vmito, Ca2mito
Electrode Arrays
Modeling Data Analysis
4
Data Organization
HTML
SOAP
WebsphereTM
(Not Completed)
SQL
SOAP
SOAP
Database Federation Software
Data Analysis Visualization
Models
MAGE-DB
ProteinDB
IMAGING
Cardiac Anatomic Database System
CLINICAL
Electro Physiology
CaGE
5
Computing Infrastructure
6
MAGE-DB Database

• Goal - provide researchers with an integrated
  web-based environment for the analysis,
  visualization and storage of gene expression
  data.
• MAGE-OM MicroArray and Gene Expression Object
  Model is a standard for the representation of
  microarray data.
• MAGE-ML is a XML format based on MAGE-OM.
• The MAGE/DB2 database is a relational mapping of
  MAGE-OM optimized for IBM/DB2.

7
Proteomics Data Flow Data Organization, Analysis
and Modeling
Store Experiment Metadata And ProGenesis Gel
Spot Data
Protein-DB
Models
Query and Analyze Data Sets
8
ProteinDB Schema
9
Protein-DB Data Loader Web Interface

• Allows for entry of experiment specific data and
  data file uploads to database

10
Gel and Spot Image Analysis
11
The Heart Failure Phenotype
MR heart image pre- (A) and post- (B) tachycardia
pacing
12
Common Pool Models of the Myocyte

• A myocyte model is the set of (nonlinear) ODEs
  needed to describe the time and voltage-dependent
  behavior of
• ionic currents
• membrane potential
• intracellular ionic concentrations
• Models are high dimensional ( 60 state
  variables)
• Model properties can be studied using
• direct numerical integration of model equations
• bifurcation analysis (parameter dependence)

Existing Myocyte Models
Iserca2a
13
Altered Expression of EC Coupling Proteins and
the Cellular Phenotype of Heart Failure
Altered Gene Expression in End-Stage Canine and
Human Heart Failure
Kaab et al (1996). Circ. Res. 78(2) 262 Yung et
al (2003). Genomics. in press online
Genes Encoding K Currents
Genes Encoding EC Coupling Proteins
KCND3 (Ito1) 66 ATP2A2 (62)
KCNJ12 (IK1) 32 NCX1
(75)


Little Effect on AP and Ca2 Transient
Major Effect on AP and Ca2 Transient
Greenstein Winslow (2002). Biophys. J. 83(6)
2918
14
Integrating from Cell to Ventricular
FunctionDTMR Imaging of Ventricular Anatomic
Structure
DTMRI vs HISTO Fiber Angles
DTMRI Reconstruction of Canine Ventricles
Scollan et al (1998). Am. J. Physiol. 275
H2308 Holmes, A. et al (2000). Magn. Res. Med.,
44157
Scollan et al (2000). Ann. BME. 28(8) 934 Helm
et al (2004). Mag. Res. Imaging, in review Beg
et al (2004). Mag. Res. Med., in review
15
Generalized Anatomic Database Interface and
Analysis Platform
16
Finite Element Models of Cardiac Ventricular
Anatomy

• User selects number of volume elements/nodes
• Matlab GUI for visual control of the fitting
  process
• All imaging datasets, FE models, and FEM software
  are available at www.ccmb.jhu.edu

Endocardial Fibers FEM Model
Epicardial Fibers FEM Model
17
Modeling Electrical Conduction in the Cardiac
VentriclesEADs Can Trigger Ventricular
Arrhythmias
Reaction-Diffusion Equation
EADs Trigger Reentry and Polymorpic VT
Winslow et al (2000). Ann. Rev. Biomed. Eng., 2
119-155
18
Closing the Loop on Whole-Heart Experimentsand
Models
256 Epicardial Electrode Array
MR Image and Model Ventricular Anatomy
Measure Electrode Positions
19
Closing the Loop on Whole-Heart Experiments and
Models (cont.)

• Electrically mapped and DTMR imaged 4 normal and
  3 failing canine hearts
• 256-electrode sock array, 5mm electrode spacing
• Complete anatomical and electrical reconstruction
  performed on one normal canine heart

Winslow et al. (2002). Novartis Foundation
Symposium 247 In Silico Simulation of Biological
Processes, pgs. 129-150, John Wiley Sons, Ltd.
2002.
20
Acknowledgements
Supported by the NIH (HL60133, HL70894, HL61711,
HL72488, P50 HL52307, NO1-HV-28180, ), the Falk
Medical Trust, the Whitaker Foundation, the D. W
Reynolds Foundation and IBM Corporation