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Cardiac Calcium Dynamics

Cardiac Calcium Dynamics. Basic references: 1. Keener and Sneyd, Mathematical Physiology 2. Fall, et al., Computational Cell Biology

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Cardiac Calcium Dynamics

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  1. 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

  2. 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

  3. Bers diagram and movie

  4. Cardiac cells - EC Coupling Na+ Ca2+ NCX Na+ Ca2+ RyR L-type channel (voltage gated) SR serca

  5. 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?

  6. 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

  7. 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.

  8. Nonfailing Versus Failing Heart • SERCA pump - 80% of normal rate • Red - cytoplasmic concentration of free Calcium • Green - SR concentration of Calcium

  9. Peak Comparison of RyR-Gating • Red-SR concentration of Calcium • Green- inactivation gating variable

  10. Transient Behavior of Calcium • Nonfailing (left) versus Failing (right) Heart • Failing Cell is Dumping Excess Calcium outside the Cell

  11. Model with Voltage-Gated L-Channel Failing Heart Nonfailing Heart

  12. 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

  13. 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

  14. 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

  15. Brynja Kohler • Alex Himonas • Brian Martensen • Trygve Nielssen • Bjorn Sandstede • Milena Stanislavova • Sponsored by the Keener Cider Fund

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