Transcript Document

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
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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
+
Na
2+
Ca
NCX
Na+
Ca2+
RyR
SR
serca
L-type channel
(voltage gated)
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.
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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
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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
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SERCA pump - 80% of normal rate
Red - cytoplasmic concentration of free Calcium
Green - SR concentration of Calcium
Peak Comparison of RyR-Gating
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Red-SR concentration of
Calcium
Green- inactivation gating
variable
Transient Behavior of Calcium
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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
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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
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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
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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 Kohler
 Alex Himonas
 Brian Martensen
 Trygve Nielssen
 Bjorn Sandstede
 Milena Stanislavova
 Sponsored by the Keener Cider Fund
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