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: 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. 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.

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 I K1 and I Ca

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 Ca 2+ 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 AB

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: Wehrens et al (2003) Cell 113:829

Conclusions The computationally simulated cell and tissue models can be used to simulate diseases with abnormal functions of I Ca,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.