Cardiac Calcium Dynamics
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Transcript of Cardiac Calcium Dynamics
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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
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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
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Bers diagram and movie
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Cardiac cells - EC Coupling
SR
Ca2+
Ca2+
serca
RyR
NCX
L-type channel(voltage gated)
Na+
Na+
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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?
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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
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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.
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Nonfailing Versus Failing Heart
SERCA pump - 80% of normal rate Red - cytoplasmic concentration of free Calcium Green - SR concentration of Calcium
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Peak Comparison of RyR-Gating
Red-SR concentration of Calcium
Green- inactivation gating variable
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Transient Behavior of Calcium
Nonfailing (left) versus Failing (right) Heart Failing Cell is Dumping Excess Calcium outside the Cell
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Model with Voltage-Gated L-Channel
Nonfailing Heart Failing Heart
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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
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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
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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
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Brynja KohlerBrynja KohlerAlex HimonasAlex HimonasBrian MartensenBrian MartensenTrygve NielssenTrygve NielssenBjorn SandstedeBjorn SandstedeMilena StanislavovaMilena StanislavovaSponsored by the Keener Cider FundSponsored by the Keener Cider Fund