CCB Final Project Proposal: Investigating the Roles of SERCA and NCX in Heart Failure Using Minimal Models of

Ca2+ Oscillation and Traveling Wave

Lulu Chu & Chenhong Zhu08-02-12

CHSL

Rationale: Nonlinear Functional Changes in Aortic Banding Heart Failure Animal Model

Ion Channel/Pump of Interest

Quantitative Change Literature

SERCA pump Protein Expression 85%Vmax 18-32%EC50 30-50%

Kiss et al. 1995, Rocchetti et al. 2008, Miccheletti et al. 2007,

NCX Protein Expression and current density 2-2.5 fold

Ahmed et al. 2000,

ICaL Peak: No change, 30%, 30%

Ahmed et al. 2000, Ryder et al. 1993, Ming et al. 1994

Peak Cai transient decreased by 30%, CaSR decreased by 32%, APD elongated by 20-40% (Siri et al, 1993, Rocchetti et al. 2008, Charvatova et al. 2004)

Other ion channels/pumps: INa, NaK, Nai, Cell geometry (Capacitance)

Project Objective 1 and Method• Objective: To understand how functional changes in SERCA or

NCX influence the Cai oscillation and the transient amplitude/frequency in a compartmental model using parametric studies and bifurcation analysis based on experimental data

• Method:– Identify a good minimal ODE model for Ca dynamics including targets

of interest and simulate in XPP– Include realistic buffering effect in cytosol and SR (Greenstein &

Winslow 2006)– Replace PMCA with NCX formulation from Luo&Rudy 1994 or Weber

et al. 2001 – Parametric studies of SERCA, NCX, and determine which has a more

profound impact on Ca oscillation amplitude and frequency in heart failure conditions

Preliminary Results: Calcium Dynamics

Cytosol

SR

SERCA

LeakRyR

LCC

PMCA/NCX

Model replication

Preliminary Resultsnormal

Reduced SERCA

Increased Extrusion

Normal

Cai vs vSERCA

Cai vs vPMCA

normal

normal

Project Objective 2 and Method• Objective: Better understand Cai traveling wave in 1D space

with the fire-diffuse-fire model and investigate how SERCA or NCX or RyR changes results in wave propagation failure.

• Method: – Derive a new 1D PDE for Cai which includes the buffering

effect in cytosol based on rapid buffer approximation (RBA) and fluxes of interests

– Implement the model using finite difference scheme in XPP or Matlab to do numerical integrations with new parameters set from the first objective

– Parametric studies of SERCA and NCX functions and investigate how they change normal behavior of Cai wave speed and propagation

Model Plan for 1D Ca Traveling Model

• RBA

• Treat all the fluxes as point sources• Use finite difference method

Anticipated Difficulties

• XPP numerics issue• Implementation with 1D PDE model and

position of Ca reaction (influx/efflux)