Cardiac Calcium Dynamics

Basic references: 1. Keener and Sneyd, Mathematical Physiology 2. Fall, et al., Computational Cell Biology 3. Jafri, Rice, Winslow, Cardiac Calcium Dynamics:The Roles of Ryanodine Receptor Adaptation and Sarcoplasmic Reticulum Load, in Biophisical Journal, 1998 4. Piacentino, Weber et al., Cellular Basis of Abnormal Calcium Transients of Failing Human Ventricular Myocites, in Cellular Biology, 2003 5. Bers, Calcium Fluxes Involved in Control of Cardiac Myocyte Contraction, in Circulation Research, 2000

Intracellular Calcium is the central regulator of cardiac contractility

L-type channels are activated during the cardiac AP and Calcium enters the cell, also smaller amount enters via NCX

Calcium influx triggers Calcium release from the SR through the RyR - CICR

Calcium level elevates and Calcium binds to TnC activating contraction

Contraction is terminated as Calcium is transported back into SR by the SERCA pump and out of the cell by the NCX

Bers diagram and movie

Cardiac cells - EC Coupling

SR

Ca2+

Ca2+

serca

RyR

NCX

L-type channel(voltage gated)

Na+

Na+

Nonfailing Versus Failing Human Hearts

•What is the role of altered Calcium regulation in the depressed contractility of the failing human ventricular myocyte?•What is the cellular basis of deranged Calcium transients in the failing heart?

Observations about Failing Hearts in Piacentino, et al.

Significantly smaller Calcium transients Reduced uptake rates by the SERCA and

Decrease of the amount of Calcium stored in SR No significant change in NCX rate Calcium influx during the late portion of the AP

elevates the internal Calcium Longer Contraction due to the slower decay of

Calcium transients

Problem Formulation

We want to build and analyze a mathematical model of Calcium handling in cardiac myocytes to determine whether the verbal descriptions in Piacentino, et al. are realistic.

Nonfailing Versus Failing Heart

SERCA pump - 80% of normal rate Red - cytoplasmic concentration of free Calcium Green - SR concentration of Calcium

Peak Comparison of RyR-Gating

Red-SR concentration of Calcium

Green- inactivation gating variable

Transient Behavior of Calcium

Nonfailing (left) versus Failing (right) Heart Failing Cell is Dumping Excess Calcium outside the Cell

Model with Voltage-Gated L-Channel

Nonfailing Heart Failing Heart

Conclusions

Both models produce oscillations of Calcium NCX behavior does not change, as observed in

Piacentino, et al. paper Reduced SR Calcium stores in failing hearts due

to the slowing down of the SERCA pump We do not observe lower Calcium peaks in that

model

Good Ideas, Bad Results

Straightforward quasi-steady state reduction of the model for L-type channel in Jafri, et al. does not work

Keizer-Levine model for the RyR channel does not behave as expected with given parameters

Simple Two Pool model for RyR channel does not produce the desired result

Possible Improvements

We need a better model for the L-type channel (and NCX)

Include voltage and Calcium dependence Imredy-Yue model (L-type) Luo-Rudy model (both L-type and NCX) Full Jafri, et al. model

Brynja KohlerBrynja KohlerAlex HimonasAlex HimonasBrian MartensenBrian MartensenTrygve NielssenTrygve NielssenBjorn SandstedeBjorn SandstedeMilena StanislavovaMilena StanislavovaSponsored by the Keener Cider FundSponsored by the Keener Cider Fund