Drug Models of Cardiac Channelopathies

Chu-Pin Lo

Department of Financial and Computational Mathematics

Providence University, Taiwan

(數學年會, 2013.12.7, 中山大學)

Proteins involved in inherited arrhythmogenic disorders

Outline

Heart Modeling and Computation

Examples of Ion Channelopathies and Drug Models:

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT):

RyR2 Mutations: R4496C, A4860G,…

Casq2 Mutation & Flecainide Effects

Heart Modeling and Computation

Cell Model

From website

Some Ventricle Cell Model:

Guinea-Pig:

Luo-Rudy Series model (Luo 1994,Faber 2007, Gaur 2011)

Dog/Canine:

Winslow (1999), Fox model (2002), Hund-Rudy model (2004)

Rabbit:

Puglisi (2001), Shannon (2004), Mahajan (2008)

Human:

ten Tusscher (,2004, 2006), Grandi (2010), O’Hara (2011)

Tissue Structure

Heart Structure: Fiber-Sheet

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Tissue & Whole Heart Model

Example

Catecholaminergic Polymorphic

Ventricular Tachycardia (CPVT):

RyR2 Channel Mutations &

Flec Effects (Casq2 Mutation)

(From Bers, Nature 2002)

Calcium Handling in Ventricular Myocyte

http://edoc.hu-berlin.de/dissertationen/abdelaziz-ahmed-ihab-2004-09-20/HTML/chapter1.html

Bers 2002

RyR2 mutations

(R4496C, A4860G)

RyR2 mutation (R4496C)

Simulation Model of RyR2

Mutation (R4496C)

RyR2 Markov Model

G.M.Faber and Y.Rudy, 2007

RyR2 Model for CPVT R4496C

• Enhanced dependence on SR Ca2+ and

subspace Ca2+ concentrations of open

probability

• Reduced SOICR threshold

• Strengthened SOICR

Validated by Experiment Results

CPVT RyR2 mutation effect:

Reduced SOICR threshold

D. Jiang et al., PNAS 2004 Nian Liu et al., 2008

Therapeutic Targeted Sites of CPVT

Blocker for ICa,L ,IUP

Simulation Result: Block Effects of ICa,L & IUP

R.J. Sung & C.P.Lo, 2011

Simulation Result:Synergistic Block Effect of ICa,L and IUP

R.J. Sung & C.P.Lo, 2011

Experiment: ICaL blocker+beta blocker (1)

R. Rosso et al., 2011

Experiment: ICaL blocker+beta blocker (2)

R. Rosso et al., 2011

RyR2-A4860G mutation (D.Jiang, 2007)

(opposite effects to R4496C)

• diminished response of RyR2 to SR Ca2+

• attenuated SOICR

• causing catecholaminergic idiopathic VF

?? caused by Ca2+, Vm alternans

Flecainide Drug Effects

(Casq2 Mutation )

Flecainide Effects on CPVT

(RyR2-R4496C, Casq2 -/-)

Nian Liu et al.(2011)

(RyR2-R4496C)

B.C.Knollmann et al. (2009,2010,2011)

(Casq2 -/-)

Flecainide Effect on CPVT

Flecainide Effect on CPVT

CASQ2

mutation

RyR2

mutation

Flecainide Effects on

Individual Ion Channels

• INa: H. Liu et al. (2003), E. Ramos et al. (2004)

• RyR2: B.C.Knollmann et al. (2009,2010,2011)

• IKr: C.Y.Du et al. (2011)

• IK1: R.Caballero et al. (2010)

Flecainide Effects on INa

Flecainide effects on INa

Flec effects on INa: use-dependent

inhibition, resting block, voltage dependent

Flec effects on INa:

recovery property

Flecainide Effects on RyR2

Flecainide Effects on RyR2

Flec reduces Ca2+ waves & keeps SR level

Flec enhances Ca2+ spark

Single RyR2 Channel:

Flec induces bursting & substate

Flec effects on bursting parameters

Flec on RyR2 is dominant

Simulation Results on Flecainide

Drug Effects

Drug Effects on INa:

INa drug model scheme

Flec preferentially bind open state &

simple bimolecular binding

Flec does not appeciably interact with the inactivated state

Flec interacts with closed state

Results:

Resting & Exercise (use-dependent)

Results:

Voltage Dependence of Drug Effect

(Proof of Open State Blocker)

Results:

Recovery after Drug Treatment

Drug Effects on RyR2:

(Casq2-/- Case)

Model for SR Ca2+ Handling

(subcellular, stochastic local control)

Model for SR Ca2+ Handling

SR Structure

Jana M. Hartman (2010)

Flec enhances Ca2+ spark

Flec reduces Ca2+ wave

Flec Keep SR Ca2+ level

Flec induces substate

(single channel trace)

Flec effecs on DAD, TA

Conclusion

• validated CPVT RyR2-R4496C model

• validated flecainide state-dependent models

on INa and RyR2 (Casq2 -/-)

Thanks for your

Attention !