系统科学概论 —— 自组织与动力学案例 1

1. 系统科学概论——自组织与动力学案例1 2012.2

2. 心脏是如何工作的？

3. UCLA SCOR in Sudden Cardiac Death(1995-2005) 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 Project 2 - Reentrant Wavefronts in Ventricular Fibrillation Project Leader: Peng-Sheng Chen MD Faculty: Hrayr S. Karagueuzian, PhD Michael C. Fishbein, MD Lan S. Chen, MD Shien-Fong (Marc) Lin, PhD Project 1 - Chaos and Cardiac Fibrillation Project 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, PhD Grad students: Drury Woodson Jong Kil 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, MD Akira Hamabe, MD Angela Park, MD Dave Kim, MD Bryan Wahl, MD Ajay Naik, MD Kelly Kim, MD Project 3 - Metabolic Regulation of Cellular K Balance Project Leader: James Weiss, MD Faculty: Scott John, PhD Bernard Ribalet, PhD Paavo Korge, PhD Post-docs: Kalyanam Shivkumar, MD, PhD David Cesario, MD

4. 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

5. VT to VF transition VF maintenance VT initiation ? ? PVC Hypothesis CAST SWORD SUDDEN CARDIAC DEATH

7. The Basic Unit 10 mm

8. Ca2+ Na+ K+ -80 mV T-tubules T tubule myofilaments

9. Ca2+ (10-20%) Extracellular space Ca channel T-tubule membrane Ca release channel (Ryanodine receptor) Ca2+ (80-90%) SR Ca ATPase Sarcoplasmic reticulum Ca2+

10. 3D Confocal Image of T-tubule System Courtesy of Joy Frank, PhD & Alan Garfinkel, PhD UClA Cardiovascular Research Laboratory

11. Courtesy of Joy Frank, PhD UCLA Cardiovascular Research Laboratory

12. RyRs DHPR Ca DHPRs Ca RyRs Ca SR Ca stores

13. Na+-Ca2+ Exchanger SL Ca2+- ATPase Ca2+ (10-20%) 3Na+ Calsequestrin Ca channel T-tubular membrane Ca release channel (Ryanodine receptor) Ca2+ Ca2+ (80-90%) Sarcoplasmic reticulum SR Ca ATPase

14. Na+ Na+ Na+ Na+ =125 mM Na+ Na+ Na+ Na+ =10 mM Na+ Na+ K+ =125 mM Na+ K+ =11 mM Na+ Na+

15. IonChannels (Na+,K+, Ca+, etc.) outside inside

17. 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.

18. mV time(ms)

19. Cardiac Action Potential Model dVm/dt = -S (Iionic + Iext)/ Cm Zeng J, Laurita KR, Rosenbaum DS, Rudy Y. Circ. Res.77:140-152, (1995)

20. 50000 steps in 4.43 seconds 20 0 -20 V (mV) -40 -60 -80 -100 0 100 200 300 400 500 600 700 800 900 1000 TIME (msec) 2 ms 15 mA = Runge-Kutta 4th order, DT = .02 ms

21. FitzHugh-NagumoModel: Barkley Dynamics: du/dt= f(u,v)=u(1-u)[u-(v+b)/a]/, dv/dt=g(u,v)=u-v u g(u,v)=0 1 0.9 v 0.8 0.7 0.6 v= au-b x, y 0.5 0.4 b 0.3 v 0.2 0.1 u 0 0 2 4 6 8 10 12 14 16 18 20 TIME

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

23. ¶ V = - + I / C D V Ñ . Ñ ion m t ¶ å å = = I I f ( V ) ion k k Neumann boundary condition : r . = n V 0 Ñ

24. Plane Wave Spiral Wave Spiral Wave Breakup

25. 1 2 What Causes The Waves To Break? Traditional Answer: Pre-existing Tissue Heterogeneities (anatomic or electrophysiological) Slope < 1

26. APD S2 S1 Diastolic Interval

27. Electrical Restitution (S1S2 Method) APD Restitution CV Restitution THE SLOPE! >1 : + gain amplifier <1 : - gain attentuator Wavelength Is Also Controlled Dynamically by Electrical Restitution (in the absence of pre-existing heterogeneities)

28. 2 1 3 Dynamic Wavebreak: The Role of APD Restitution Steepness Slope < 1 Slope > 1

29. X Steep Slope Shallow Slope Y  X Y Y Y < X X

30. A B a a b 150 b 100 100 c APD (ms) APD (ms) 50 c 50 0 0 0 50 100 0 50 100 150 DI (ms) DI (ms) b b c c d d 0 0 -40 -40 V (mV) V (mV) -80 -80 0 200 400 600 800 1000 1200 1400 0 200 400 600 800 1000 1200 1400 t (ms) t (ms)

36. Reduction Body EKG Whole Heart Myocyte Channel EKG Current Action potential Electrical wave Integration Emergent parameters and properties: APD restitution, CV restitution, pre-existing heterogeneities, spiral wave, spatiotemporal chaos Research Approaches for VF

37. Methodology of 20th Century Physics and Biology Reductionism Matter Living Organisms Macroeconomy Transcription Factors Complexity Self-organizing behavior Pattern formation What are theglobal parameters ?

38. Genomic Biology in the 21st Century Genome Letters: ‘abcdefghijklmnopqrstuvxyz’ Molecules (biophysics & Words: ‘cat’, ‘dog’, ‘mommy’, ‘daddy’ structural biology) OrganellesSentences: ‘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 ….’ OrgansChapters: Chapter 1. ‘Call me Ismael…’ Living organisms Books: War and Peaceby Leo Tolstoy

39. 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 Physics M theory – the 11-dimensional universe that explains everything, but is beyond the scope of experimental verification (requires big bang conditions) What is life? 21st Century Complex Systems Science Answer as yet unknown, but approachable