presentation (c.p.lo) 13
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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 !
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