系统科学概论系统科学概论 ——自组织与动力学案例 ——自组织与动力学案例 11

2012.22012.2

心脏是如何工作的？

Project 1 - Chaos and Cardiac FibrillationProject Leader: Alan Garfinkel, Ph.D.Faculty: Zhilin Qu,PhD Fagen Xie, PhD Boris Kogan, PhD James Weiss, MD Donald Walter,PhD Alan Karma, PhD (Northeastern) Steve Evans, MD (Einstein) Harold Hastings, PhD (Hofstra) Post-docs: Junzhong Yang, PhD Zengru Di, PhD Elizabeth Cherry, PhD Flavio Fenton, PhDGrad students: Drury Woodson Jong Kil

Project 2 - Reentrant Wavefronts in Ventricular Fibrillation

Project Leader: Peng-Sheng Chen MDFaculty: Hrayr S. Karagueuzian, PhD Michael C. Fishbein, MD Lan S. Chen, MD Shien-Fong (Marc) Lin, PhD

Core A - Computer Alan Garfinkel, PhD Scott Lamp, BS

Core B - Laboratory Services & Bio-instrumentation Michael Fishbein, MD Joshua Goldhaber, MD John Parker, BS

Core C - Administrative James Weiss, MD

UCLA SCOR in Sudden Cardiac Death(1995-2005)

Project 3 - Metabolic Regulation of Cellular K BalanceProject Leader: James Weiss, MDFaculty: Scott John, PhD Bernard Ribalet, PhD Paavo Korge, PhDPost-docs: Kalyanam Shivkumar, MD, PhD David Cesario, MD

Post-docs: Chikaya Omichi, MD Shengmei Zhou, MD Moshe Swissa, MD Che-Ming Chang, MD Hideki Hayashi, MD Miguel Valderrabano, MD Ali R. Hamzei, MD Yasushi Miyauchi, MD

Yuji Okuyama, MDAkira Hamabe, MDAngela Park, MDDave Kim, MDBryan Wahl, MDAjay Naik, MDKelly Kim, MD

CARDIAC FIBRILLATION

Ventricular fibrillation• 220,000 sudden deaths annually in U.S.

Atrial fibrillation• 6% of population over age 65• 1/3 of all strokes over age 65• doubled mortality rate

SUDDEN CARDIAC DEATH

VTinitiation

PVC HypothesisCAST

SWORD

VT to VFtransition

?

VFmaintenance

?

The Basic Unit

10 m

Na+

K+

-80 mV

T tubule

Ca2+

T-tubules

myofilaments

T-tubule membrane

Sarcoplasmicreticulum

Ca2+

(80-90%)

Ca2+ (10-20%)

Ca release channel(Ryanodine receptor)

Ca2+

SR Ca ATPase

Ca channel

Extracellular space

3D Confocal Image of T-tubule System

Courtesy of Joy Frank, PhD& Alan Garfinkel, PhDUClA CardiovascularResearch Laboratory

Courtesy of Joy Frank, PhDUCLA CardiovascularResearch Laboratory

Ca

Ca

Ca

DH

PR

s

DHPRRyR

s

RyR

s

SR Ca sto

res

T-tubular membrane

Sarcoplasmicreticulum

Ca2+

(80-90%)

Ca2+ (10-20%)

Ca release channel(Ryanodine receptor)

SR Ca ATPase

Ca channel

3Na+

Na+-Ca2+

ExchangerSL Ca2+-ATPase

Ca2+

Calsequestrin

Na+

Na+

Na+

Na+Na+

Na+

Na+

Na+Na+

Na+

Na+

Na+ = 125 mM

Na+ = 10 mM

K+ = 11 mM

K+ = 125 mM

Ion Channels (Na+, K+, Ca+, etc.)

outside

inside

Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. J. Physiol. (Lond.) 1952;117:500-544.

-60

-40

-20

0

20

40

20151050

time (ms)

mV

Zeng J, Laurita KR, Rosenbaum DS, Rudy Y. Circ. Res.

77:140-152, (1995)

dVm/dt = -Iionic + Iext)/ Cm

Cardiac Action Potential Model

TIME (msec)

0 100 200 300 400 500 600 700 800 900 1000

-100

-80

-60

-40

-20

0

20

50000 steps in 4.43 seconds

V (

mV

)

2 ms

15 m

A

= Runge-Kutta 4th order, DT = .02 ms

FitzHugh-Nagumo Model: Barkley Dynamics:

du/dt= f(u,v)=u(1-u)[u-(v+b)/a]/, dv/dt=g(u,v)=u-v

b

v= au-b

g(u,v)=0

u

v

20181614121086420

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

TIME

x, y

u

v

vanCapelle FJL, Durrer D. Computer simulation of arrhythmias in a network of coupled excitable elements. Circ. Res. 1980;47:454-466.

0

:

)(

Vn

conditionboundaryNeumann

VfII

t

kkion

/ .VDCI

Vmion

.

Plane Wave

Spiral Wave

Spiral Wave Breakup

What Causes The Waves To Break?Traditional Answer: Pre-existing Tissue Heterogeneities

(anatomic or electrophysiological) Slope < 1

1

2

S2

Diastolic Interval

S1

APD

Wavelength Is Also Controlled Dynamically by Electrical Restitution (in the absence of pre-existing heterogeneities)

Electrical Restitution (S1S2 Method)

A

9 cm

Fig.7

S2S1S1

E

0 50 100 150 200

50

100

150

ICa

50%

control

B

AP

D (

ms)

DI (ms)0 50 100 150

0.04

0.05

0.06

ICa

50%

controlC

CV

(cm

/ms)

DI (ms)

D

APD Restitution CV Restitution

THE SLOPE! >1 : + gain amplifier<1 : - gain attentuator

Dynamic Wavebreak:The Role of APD Restitution Steepness

2

3

1

Slope < 1

Slope > 1

Y

X

Y < X

Y X

Steep Slope

Y

Shallow Slope

X

0 200 400 600 800 1000 1200 1400

-80

-40

0

V (

mV

)

t (ms)

0 200 400 600 800 1000 1200 1400

-80

-40

0

V (

mV

)

t (ms)

d

c

a aA B

bb

0 50 1000

50

100

150

c

b

AP

D (

ms)

DI (ms)0 50 100 150

0

50

100

c

b

AP

D (

ms)

DI (ms)

c

d

Body EKGMyocyteChannel

Reduction

Integration

Whole Heart

Current Action potential Electrical wave EKG

Research Approaches for VF

Emergent parameters and properties:APD restitution, CV restitution,

pre-existing heterogeneities, spiral wave, spatiotemporal chaos

Reductionism

ComplexitySelf-organizing behavior

Pattern formationWhat are the global parameters ?

Methodology of 20th Century Physics and Biology

Transcription Factors

MatterLiving OrganismsMacroeconomy

Genome Letters: ‘abcdefghijklmnopqrstuv

xyz’

Molecules (biophysics & Words: ‘cat’, ‘dog’, ‘momm

y’, ‘daddy’ structural biology)

Organelles Sentences: ‘We, the people of the .… ….the United States of America.’

Cells Paragraphs:‘It was the best of times, it was….. Thus did the year one ….’

Organs Chapters: Chapter 1. ‘Call me Is

mael…’

Living organisms Books: War and Peace by Leo Tolst

oy

Genomic Biology in the 21st Century

What is life?21st Century Complex Systems Scien

ceAnswer as yet unknown, but approachable

The four greatest questions pondered ever since the dawn of human civilization:

What’s for dinner? Will she go out on a date with me?

What is nature?20th Century PhysicsM theory – the 11-dimensional universe that

explains everything, but is beyond the scope of experimental verification (requires big bang conditions)