Download Document

BENG 87:
Engineering Models
of the Heart
Bers, Nature, 2002
Andrew McCulloch
Measure inputs IN VITRO
Validate outputs IN VIVO
BIOENGINEERING MODELS
OF THE HEART
Implement model IN SILICO
Apply model to MEDICINE
Measure Model Inputs
ANATOMY
Rabbit Ventricular Anatomy
knife
BASE
plunger
APEX
endo>0
epi<0
RIGHT VENTRICLE
LEFT VENTRICLE
Fitted transmural fibre field
Nielsen PMF, LeGrice IJ, Smaill BH & Hunter PJ. Am. J. Physiol. 260 (4), H1365-H1378, 1991
Collagen orientation & density distributions
Porcine Anatomic Models
Stevens C et al (2003) PBMB
Pullan AJ et al (2001) ABME
Grieshaber J et al (2002)
Smith NP et al (2002) ABME
Measure Model Inputs
TISSUE PROPERTIES
Isolated arrested heart
preparation
Camera
&
VCR
Aorta
Dissecting
Microscope
O 2+CO 2
Pump
LV
Balloon
Isolated Heart
Pressure
Transducer
&
Volume
Infusion
Isolated Papillary Muscle
Testing
Dissecting Scope
& Video Camera
Top View
VCR
1 g Capacitive
Force
Transducer
Mirror at 45°
to view muscle
side-view &
estimate CSA
Bath
RV Papillary Muscle
perfused with
95%O2 + 5% CO2
at 27°C
MotorizedStage
withController
[cyclic loading: 3mm/min]
Cardiac Collagen Fibers
10 mm
WTWildtype
Heterozygous
Het
oim oim
oim RV Papillary Muscle:
36-39% greater uniaxial strain
Stress (mN/mm2)
10
WT
8
oim
6
4
n=9 WT, n=7 oim
P<0.05
2
0
0
0.05
0.1
0.15
Strain
0.2
0.25
Measure Model Inputs
CELLULAR
PROPERTIES
Myocyte Contractile Mechanics
sarcomere
length 2.0
µm
2.15 µm
tension
1 µN
3 sec
3.5 min
Bluhm, McCulloch, Lew. J Biomech. 1995;28:1119-1122
Model Implementation
COMPUTATIONAL
METHODS
The Heart Physiome Project
torso
heart
tissue
Cellular processes
cell-cell
connections
3D cell
genes
proteins
transcription
& translation
Hunter, PJ and Borg, TK. Integration from proteins to organs: The Physiome Project.
Nature Reviews Molec & Cell Biol. 4:237-243, 2003
Multi-Scale Structurally Integrated Models
•
•
•
•
•
•
•
•
•
•
1m
person
1 mm
electrical length scale of cardiac tissue
1 mm
cardiac sarcomere spacing
1 nm
pore diameter in a membrane protein
109 s (70 yrs)
human lifetime
106 s (10 days)
protein turnover
103 s (1 hour)
digest food
1s
heart beat
1 ms
ion channel HH gating
1 ms
Brownian motion
Requires a hierarchy of inter-related models
gene reg.
networks
pathway
models
stochastic
models
ODEs
PDEs (continuum models)
Not validated at whole heart level
Activation sequence
Karl Tomlinson
Tomlinson KA, Pullan AJ & Hunter PJ. SIAM J Applied Maths. 63(1):324–350, 2002
Structural Integration:
Induction of Reentrant Ventricular Arrhythmia
Natalia Trayanova, Computational Cardiac
Electrophysiology Lab, Tulane University
Structural Integration:
Defibrillation (unsuccessful)
Natalia Trayanova, Computational Cardiac
Electrophysiology Lab, Tulane University
Structural Integration:
Defibrillation (successful)
Natalia Trayanova, Computational Cardiac
Electrophysiology Lab, Tulane University
Structural Integration:
Ventricular Wall Mechanics
System-Scale Integration
University of Washington (Bassingthwaighte), University of Utah (Johnson),
University of Auckland (Hunter), University of Michigan (Athey)
<New Treatment Options>
Cardiac resynchronization therapy
• CRT reduces the delay of
contraction between the
right and the left heart
chambers
Heart Failure: Clinical Relevance
Structural and Functional Integration:
Cardiac Resynchronization Therapy (CRT)
for Congestive Heart Failure (CHF)
Left Bundle Branch
Block and CHF
Bi-Ventricular
Pacing for CRT
Usyk TP and McCulloch AD (2003) J Electrocardiol (in press)
Structural Integration: Scaling Up
The Utah Torso Model
Chris Johnson and Rob MacLeod, Scientific Computing and
Imaging Institute, and CVRTI, University of Utah
Physiological Validation
MURINE MODELS
Physiological Testing
MECHANOELECTRIC
FEEDBACK
Mechanical Perturbation and Ventricular Arrhythmia
Impact
Commotio Cordis
(Link et al., 1998)
Chest thump can
terminate VT
(Pennington et al., 1970)
LV Pressure
(mm Hg)
… and convert VF
(Barret, 1971)
Time (seconds)
Optical Mapping of Electrical Activity
(heat)
516 ± 46 nm
bandpass filter
300 W
Xe arc lamp
dichroic
mirror
high speed
CCD camera
400 fps
PC
bifurcating
fiber optics
> 610 nm
high pass filter
Standard
CCD camera
Optical Recordings
Feature extraction
% DF/F
Phase-shift
spatial filtering
time (sec)
% DF/F
Raw signal
time (sec)
Maps of Activation and Repolarization
Activation
80% Repolarization
0.07
0.20
0.15 sec
0 sec
Action Potential Duration (80%)
0.26
LV epicardial
pacing
0.20 sec
Clinical Applications
IMAGING & DEVICES
Patient-Specific Models: Ventricular Reduction
Surgery for End-Stage Heart Failure
•
•
“Batista” ventricular reduction surgery performed in patients with
idiopathic dilated cardiomyopathy
MRI myocardial “tagging” performed before and 3 months after
surgery
Before
After
Young AA, Dokos S, Powell KA, Sturm B, McCulloch AD, Starling RC,
McCarthy PM, White RD (2000) Cardiovasc Res 49(2):308-318
Bioengineering Applications
Measure inputs IN VITRO
Validate outputs IN VIVO
BIOENGINEERING MODELS
OF THE HEART
Implement model IN SILICO
Apply model to MEDICINE
http://cmrg.ucsd.edu/