Potential Application of Computational Cellular Biology for

Cardiac Antiarrhythmic Drug Discovery

Ruey J. Sung, MD, FAHA,FHRS講座教授

中央大學生命科學研究所Professor Emeritus

Stanford University School of Medicine, Stanford, CA

Translational Medicine

Basic Science Clinical Medicine

Computational Biology

• Hodgkin AL and Huxley AF, A Quantitative Description of Membrane Current and its Application to Conduction and Excitation in Nerve, 1952, J. Physiol, 117:500-544.

• FitzHugh (1966) (1)The effect of temperature on action potential of squid axon. (2)Modified the original Hodgkin-Huxley equations by a temperature factor.

• Guttman and Barnhill (1970) Found repetitive firing by increasing temperature.

Major ionic currents

Cardiac ion currents and cloned subunits

-80 mV

+30 mV

200 msec

Phase 0 : Upstroke

Phase 3: Rapid Repolarization (relative refractory, responding to large stimulus)

Phase 4: Diastole (excitable)

Phase 1: Early Repolarization (refractory)

Phase 2: Slow Repolarization (refractory)

Phase of Cardiac Action Potential

Refractoriness: time during which a second wave can not be initiated.

Action Potential

From: Efimov, Introduction to Biomedical Engineering and Cardiac

Bioelectricity. http://efimov.wustl.edu/class/EBME105/EBME105_3.pdf

APD (or ERP)

single cell

-60mV

Luo-Rudy Model

Causing Nernst potential (reverse potential).

Cardiac Cell Models

From: dos Santos and Bauer, Steps towards the modelling of myocardial inflammation. http://www.fisiocomp.ufjf.br/seminarios/talk150205.pdf

Application of HH model in other AP generating system—cardiac LRd model

Wu SN Chin. J. Physiol. (2004)

Rudy and Silva (2006) Q Rev Biophys 39: 57

Correlation between Simulation and Experiment

Formulations for IK1 and ICa

Intracellular Calcium Transients and Ionic Events

Luo-Rudy Model

the ventricular wall

Antzelevitch and Fish

Electrical Heterogeneity within the ventricular Myocardium

Single and Multicellular LRd Ventricular Myocyte Models

Luo and Rudy (1994)

The LRd Model

Clancy and Rudy (2001) Cardiovasc Res 50: 301

Addition of Markovian Scheme to LRd Model

Luo-Rudy 2007

Faber et al (2007) Biophy J 92:1552

Faber and Rudy( 2007) Cardiovasc Res 75:73

The Luo-Rudy Model: Bulk Myoplasm, Junctional Sarcoplasmic Reticulum (SR), Net SR, Mitochondria, and T-tubular Subspace

Initiation of Torsades de Pointes in LQTS

Tristani-Firouzi et al. J Clin Invest 2002; 110:381

Tawil et al. Ann Neurol 1994; 35: 326

Andersen-Tawil Syndrome Timothy Syndrome

Gene-Specific Multisystem Involvement in LQTS

• LQT7 and LOT8 also known as Andersen-Tawil syndrome and Timothy syndrome, respectively, are each a multisystem disease.

• LQT7 is caused by mutations in KCJN2 which encodes the cardiac and skeletal muscle inward rectifier K+ channel, Kir2.1, and LQT8 is due to mutations in CACNA1C that encodes the pore-forming α-subunit of the cardiac L-type Ca2+ channel.

• Both clinically manifest exercise-induced polymorphic VT.

• LQT8 is the most malignant LQTS as patients seldom survive beyond 3 years of age.

Splawski et al (2004) Cell,119:19

Andersen-Tawil Syndrome Simulation

Sung et al, Am J Physiol, 2006;291:H2597

A B

Timothy Syndrome Simulation

Sung et al

Timothy Syndrome Simulation

A B

Sung et al

Pseudo-ECG Obtained From the 1-D Multicelullar Strand (LRd) Model

Sung et al

Cellular Electrophysiology in Congestive Heart Failure (CHF)

Wehrens et al (2003) Cell 113:829

Strategy for Targeted Therapy

Marks (2003) Circulation 107:1456

Kaye, Hoshijima, and Chien, Annu Rev Med 2008;9:13

Wehrens XHT, et al. Cell, 2003;113:829-840Wehrens et al (2003) Cell 113:829

Conclusions• The computationally simulated cell and tissue models

can be used to simulate diseases with abnormal functions of ICa,L, RyR2 and/or other ion channels such as

Timothy syndrome, catecholaminergic polymorphic ventricular tachycardia, cadiomyopathies, CHF, etc.

• Consequently, not only arrhythmogenic mechanisms can be defined but also potential targeted sites of therapy can be identified.

• The above principles can then be applied for developing novel anti-arrhythmic drugs and/or cellular therapy.

Michailova and McCulloch, 2002

Thank you for your attention.