Contents

📒 Li 2012

Mechanisms by which Cytoplasmic Calcium Wave Propagation and Alternans Are Generated in Cardiac Atrial Myocytes Lacking T-Tubules—Insights from a Simulation Study1

Sciwheel.

Introduction

  • the mechanisms underlying Ca2+ wave propagation and [Ca2+]i alternans in cardiac myocytes lacking t-tubules (atrial cells in small mammals) are still unclear
  • Here: biophysically detailed computer model for Ca2+ release and Ca2+ wave propagation in cardiac myocytes lacking t-tubules

Methods

Mathematical model of Ca2+ wave propagation in atrial myocytes

https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/0f01ab35-e172-412f-81b2-b8cf56e530d4/gr1_lrg.jpg

  • Adapted from Tao et al. equations to simulate Ca2+-wave propagation in atrial myocytes that lack t-tubules
  • A cell divided into 13 elements with a spatial resolution of 2 μm

Stimulation protocol and simulated intracellular Ca2+-wave propagation

  • on each voltage-clamp pulse, Ca2+ influx via VOCCs triggered CICR at the peripheral units, resulting in large [Ca2+]i transients in these regions
  • localized [Ca2+]i transients diffused inward toward the central region, provoking successive CICR that led to Ca2+-wave propagation.
  • Ca2+ wave did not fully propagate to the center. the [Ca2+]i transients (Fig. 1 B ii) and the SR Ca2+ release (Fig. 1 B iii) were large in the periphery of the cell but small in the central region
  • These simulation results matched experimental observations in rat (15,19), guinea-pig (20), and cat (4) atrial myocytes that lack t-tubules.

Model validation

  • sustaining the intracellular Ca2+ waves through increasing Ca2+ influx by elevating the extracellular Ca2+ concentration
  • increasing the RyR sensitivity by decreasing the threshold of RyR for CICR
  • elevating the SR content by pausing pacing for 10 s while increasing SERCA Ca2+ uptake (Pup increased by 75%) to allow SR Ca2+ content accumulation
  • increases in the Ca2+ influx, the RyR sensitivity, or the SR content helped to sustain full Ca2+-wave propagation from the periphery to the center of the cell, producing a more homogeneous [Ca2+]i, similar to experimental results.

Results

Effect of increasing Ca2+ influx

  • An increase in Ca2+ influx via elevating [Ca2+]o has been shown to help facilitate full Ca2+-wave propagation toward the center region and to reduce the [Ca2+]i spatial heterogeneity in atrial cells
  • Also in increasing the maximum channel conductance of the VOCCs (gCaL)

https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/9b28fb99-b3dd-4e46-8b56-e08a999b8c74/gr2_lrg.jpg

  • There is a time delay in the [Ca2+]i and [Ca2+]SR transients between the peripheral and central regions => propagation rather than synchronized

Effect of increasing RyR sensitivity

https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/881d3ced-c3ad-4c4c-bb16-46e782facd32/gr3_lrg.jpg

  • reducing the threshold of RyR for CICR (Krel)
  • When Krel was reduced by 10%, a complete Ca2+ wave spreading toward the interior region of the cell was established temporarily. But amplitude is smaller.
  • Due to the reduced SR content, propagation of the Ca2+ wave toward the center of the cell was unstable, leading to alternans

Effect of increased SR content

https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/d91594c6-4266-459f-8322-8ab4f477e069/gr4_lrg.jpg

  • increased SR Ca2+ content (Fig. 4Bi, lower), leading to a period of complete Ca2+ wave propagation into the center of the cell; then Ca alternans
  • enhancing the SR Ca2+ uptake (ii): hindered the inward Ca2+ wave propagation at first. Then a stable complete Ca2+ wave was observed (Fig. 4 A ii) when the SR Ca2+ content was significantly elevated in both central and peripheral regions

Effect of partial inhibition of SERCA pump

https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/0d66ad59-38bd-4960-b05d-7479e117dfe8/gr5_lrg.jpg

  • SERCA pump rate (Pup) was decreased by 10%: alternans
  • increasing the threshold of SERCA Ca2+ uptake (Kup) by 20% + SERCA pump rate (Pup) was increased by 50% : enhanced Ca2+-wave propagation; the amplitude of [Ca2+]i transients was greatly enhanced in the interior region of the cell

Exploring the mechanisms for Ca2+ alternans

Ca2+ diffusion

https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/c3f07a1b-6da9-4dfb-b44c-10f1c077ecbe/gr6_lrg.jpg

  • increase of the time constant of the Ca2+ diffusion (τ) => [Ca2+]i alternans (bifurcation)
  • complicated pattern of alternans are possible
  • cancelling Ca diffusion (rapid equilibrium) eliminates Ca alternans
  • Ca diffusion dramatically increased the steepness of dependence on SR Ca content
  • Increasing Kup shifted the dependence curve leftward (smaller SR Ca2+ content region)

Ca2+ influx & RyR sensitivity & the SERCA pump

https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/f002688f-cc5a-4561-addb-28f8db70f78e/gr7_lrg.jpg

  • When gCaL was increased over the range 100%–500% of its control value, a cascade of bifurcations occurred
  • More dramatic in the central region than in the peripheral region
  • With decreasing Krel, a cascade of bifurcations occurred, leading to [Ca2+]i alternans with various patterns
  • When Kup was increased from 100% to 140% of its control value, a cascade of bifurcations was triggered, decreased SR uptake due to increased Kup resulted in a low level of SR Ca2+ content and, consequently, reduced [Ca2+]i transient amplitude

Spontaneous Ca2+ release

https://els-jbs-prod-cdn.literatumonline.com/cms/attachment/adc096db-9c2f-47a5-ab56-999b0ac122b5/gr8_lrg.jpg

  • Overloading the SR Ca2+ content may produce spontaneous Ca2+ release from the SR
  • Increased Ca2+ influx (gCaL increased to 370%) and SERCA pump activity (Pup increased to 150%) => irregular pattern of [Ca2+]i transients

Discussion

Findings

  • Model validated by its ability to reproduce typical Ca2+-wave propagation patterns of atrial myocytes without t-tubules
  • reproduce experimentally observed effects of modulations of various aspects of Ca2+ cycling, such as Ca2+ influx, SERCA pumps (SR Ca2+ uptake), and RyRs (SR Ca2+ release), on spatial distribution of Ca2+ transients
  • steep relationship between the SR Ca2+ content and the cytoplasmic Ca2+ concentration due to Ca transient propagation, more prone to Ca alternans
  • theoretical exploration of possible associations between the occurrence of Ca2+ alternans and parameters related to calcium handling
  • Spontaneous Ca2+ release observed

Mechanisms of incomplete Ca2+-wave propagation in cardiac cells without t-tubules

Mechanisms of Ca2+ alternans in cardiac cells devoid of t-tubules

References


  1. Li Q, O’Neill SC, Tao T, Li Y, Eisner D, Zhang H. Mechanisms by which cytoplasmic calcium wave propagation and alternans are generated in cardiac atrial myocytes lacking T-tubules-insights from a simulation study. Biophys J. 2012;102(7):1471-82. PMC3318133 ↩︎