Arrhythmogenic Current Generation by Myofilament-Triggered Ca2+ Release and Sarcomere Heterogeneity

Figures

• 

  Figure 1. Schematic of cardiac excitation-contraction coupling as presented by Bers (70), showing the calcium transport in a ventricular myocyte with the sarcolemma, subsarcolemmal compartment (SS), the L-type calcium channel (L-type), the sarco/endoplasmic reticulum calcium-ATPase (SERCA), and the sarcoplasmic reticulum (SR). The red arrows indicate calcium influx resulting in an increase in cytosolic calcium concentration, leading to contraction of the myofilaments, which is the feedback mechanism of mechanoelectric feedback (MEF) from EP to mechanics. The black arrows show the pathway for calcium removal from the cell. In particular, the black arrow from the myofilaments shows the calcium release from TnC into the cytosol during relaxation, which is the feedforward mechanism of MEF from mechanics to EP. The time course of an AP (blue line), a CaT (red line), and contraction (force) (green line) are shown at the bottom. RyR, ryanodine receptor; TnC, troponin C.

• 

  Figure 2. Simulation data and the corresponding experimental data of Wakayama et al. (22) (top) and Takamatsu et al. (19) (bottom), which were employed for the model parameterization using the parameter-fitting algorithm of Bueno-Orovio et al. (36). (Top) The effect of square waveform stretch experiments at 10% stretch (red line), 5% stretch (green line), control (dashed black line), and 10% compression (blue line) are shown on the (A) simulated CaT, (B) experimentally measured CaT, (C) simulated normalized force (here, normalized force refers to the maximal normalized force given full activation as described in (34)), and (D) experimentally measured force. (E) Simulated square waveform stretch experiments and (F) experimentally recorded square waveform stretch experiments are shown. The solid black line in (A) shows the CaT in the original, uncoupled Shannon et al. model (32) and in (C) the normalized force for the original, uncoupled Rice et al. model (34). (G) Similar to the experimental data reported in Fig. 2 C of (19) (dashed blue lines), the computational model (sarcomere resting length of 1.89 μm) reproduces a linearly propagating calcium wave through the myocyte with a velocity of…

• 

  Figure 3. Schematic for two of the 50 units of the 1D model. The black arrows indicate the calcium diffusion between the SS compartments (top) described by the diffusion time constant τSS, the SR compartments (middle) described by the diffusion time constant τSR, and the cytosolic compartments (bottom) described by the diffusion time constant τSR. The red arrow shows how changes in length of the sarcomere in unit i (δSLi) affects the length of the adjacent sarcomere in unit (i + 1) (δSLi). RyR, ryanodine receptor.

• 

  Figure 4. Statistical representation of the lower (left) and upper (middle) bound for the vulnerability window in which myofilament-triggered calcium waves occur at Cao = 4 mM, as well as the timing of the fastest myofilament-triggered calcium wave (right) for model (IH5) (15% stretch, blue triangles), model (IH10) (15% stretch, red dots), and model (IH10) (12.5% stretch, green squares). To see this figure in color, go online.

• 

  Figure 5. (A) Calcium wave velocity increased from the lower bound of the vulnerability window to the peak velocity and decreased to the lower bound of the vulnerability window. (B) The maximal CaT at the wave increased from the lower bound of the vulnerability window to the peak velocity and decreased to the lower bound of the vulnerability window. (C) The maximal SR calcium concentration at the wave increased from the lower bound of the vulnerability window to the peak velocity and decreased to the lower bound of the vulnerability window. (D) Calcium wave velocity depended on the magnitude of the CaT. (E) The magnitude of the calcium-mediated DAD depended on the magnitude of the CaT. (F) The magnitude of the calcium-mediated DAD depended on the calcium wave speed. To see this figure in color, go online.

• 

  Figure 6. (A) Myofilament-triggered calcium wave of myocyte of model (IH10) at 15% stretch at the lower bound of the vulnerability window. (B) The fastest myofilament-triggered calcium wave of myocyte 3 of model (IH10) at 15% stretch with 8% increase in wave velocity is shown. (C) The myofilament-triggered calcium wave of myocyte 11 of model (IH10) is shown at 15% stretch at the lower bound of the vulnerability window. (D) The fastest myofilament-triggered calcium wave of myocyte 11 of model (IH10) is shown at 15% stretch with a 340% increase in calcium wave velocity due to multiple initiation sites and a higher CaT. To see this figure in color, go online.

• 

  Figure 7. (A) Simulations of myocyte 1 of model (IH5) at Cao = 4.2 mM for no stretch (dashed black lines), 1% stretch (red lines), and 2% stretch (blue lines) for membrane potential (top left), averaged whole-cell cytosolic calcium concentration (bottom left), averaged whole-cell SR calcium concentration (top middle), averaged whole-cell calcium buffering on TnC (bottom middle), averaged whole-cell normalized force (top right) (here, normalized force refers to the maximal normalized force given full activation as described in (34)), and the stretch protocol (bottom right). (B) Calcium waves for no stretch (left), 1% stretch (middle), and 2% stretch (right) are shown. The wave velocity increases by ∼280% from no stretch to 1% stretch and again by ∼180% from 1% stretch to 2% stretch. (C) Simulations of myocyte 1 of model (IH5) at Cao = 4 mM are shown for inhibited SERCA (blue lines), stimulated SERCA (red lines), and control (dashed black lines) for membrane potential (top left), averaged whole-cell cytosolic calcium concentration (bottom left), averaged whole-cell SR calcium concentration (top middle), averaged whole-cell calcium buffering on TnC (bottom middle), averaged whole-cell…

• 

  Figure 8. (A) Maximal SR calcium concentration (blue lines) and maximal sarcomere length changes (red lines) for each unit of the myocyte for simulations of model (H10) with two groups of sarcomeres with a shorter resting length (1.7955 μm) compared to the resting length of all other sarcomeres in the myocyte (1.89 μm). (B) The calcium wave of model (H10) with two groups of sarcomeres with a shorter resting length (1.7955 μm) is compared to the resting length of all other sarcomeres in the myocyte (1.89 μm). (C) Maximal SR calcium concentration (green lines) and maximal sarcomere length changes (red lines) for each unit of the myocyte for simulations of model (H10) with two groups of sarcomeres with a longer resting length (1.9845 μm) are compared to the resting length of all other sarcomeres in the myocyte (1.89 μm). (D) The calcium wave of model (H10) with two groups of sarcomeres with a longer resting length (1.9845 μm) is compared to the resting length of all other sarcomeres in the myocyte (1.89 μm). To see this figure in color, go online.

• 

  Figure 9. Schematic illustration of myofilament-triggered calcium waves. The red arrow indicates calcium release from the myofilaments due to stretch-release. The black arrows show the pathway for calcium reuptake to the SR via SERCA. If the resulting increase in calcium content in the SR reaches the threshold for spontaneous calcium release, the RyR clusters are activated and release calcium into the dyadic space. The orange arrow shows the diffusion pathway of calcium from the dyadic space into the cytosol of the same unit and then into the adjacent unit. In the neighboring unit, calcium release from the SR may again be triggered by an increase in cytosolic calcium concentration, which results in calcium reuptake to the SR. RyR, ryanodine receptor. To see this figure in color, go online.