Mechanistic insight into spontaneous transition from cellular alternans to arrhythmia—A simulation study

Figures

• 

  Fig 1. Cellular model properties with an altered INa. Results were obtained by implementing three SgNa values (SgNa = 0.6, 1.0, 1.5), mimicking a reduced INa, control and an increased INa respectively. A(i-ii). Representative AP alternans generated by modified rabbit EPI cell model. B. Recorded INa current traces during AP alternans. C. Recorded ICaL current traces during AP alternans. D. Steady-state APD variations dependent on PCLs. E-F. The maximum and average differences of APD (E) and dV/dtmax (F) between the large and small AP during the range of PCLs that the model alters. G. ERP variations dependent on PCLs. H. APD restitution curves using S1-S2 protocol of the single cell models. I. The maximum slopes of the APD restitution curves in (H). DI: diastolic interval; PCL: pacing cycle length.

• 

  Fig 2. 1D simulation results with an altered INa. Results were obtained by implementing three SgNa values (SgNa = 0.6, 1.0, 1.5), mimicking a reduced INa, control and an increased INa respectively. A(i). Computed PCL-dependent steady-state CV. A(ii). Maximal and averaged differences of CV between the fast and slow AP propagation during the range of PCLs producing conduction alternans. B(i). CV restitution curve computed by using the S1-S2 protocol. B(ii). The maximum slope of the CV restitution curve as shown in Fig B(i).

• 

  Fig 3. Representative 1D simulation results with SgNa = 1.0, PCL = 140ms. A. Space-time plot of AP propagation on 1D strand. B. APD (B(i)) and CV (B(ii)) variations at location a (marked in A) dependent on simulated beats. C. Spatial distributions for APD (C(i)) and CV (C(ii)) for beat 1,2,3,13,14. D. Time course traces for location a, b, c, d, e marked in A.

• 

  Fig 4. Role of INa in alternans conduction in the 1D tissue model. A. Reduced INa (SgNa = 0.6) leading to discordant alternans and conduction block with PCL = 140ms. B. Control INa (SgNa = 1.0) leading to discordant alternans with PCL = 140ms; C. Increased INa (SgNa = 1.5) leading to discordant alternans and conduction block with PCL = 140ms. D. Concordant alternans generated in control INa (SgNa = 1.0) with PCL = 150ms. E. Map of genesis of concordant, discordant and conduction block in the PCL-SgNa parameter space. F. Computed DI between two consecutive excitation waves at the marked beats and locations for generation of conduction break in (A-C).

• 

  Fig 5. Snapshots of conduction of AP alternans in 2D tissue and time series of APs. APs were recorded from three different registration sites (cell A, cell B and cell C marked at the tissue shown in the top-left panel of A(i)). PCL = 140ms. A(i-ii). Tissue with reduced INa (SgNa = 0.6). B(i-ii). Control tissue (SgNa = 1.0). C(i-ii). Tissue with increased INa (SgNa = 1.5). Black and red stars marked two consecutive stimulus pulses as shown in the top-panel of A(ii), and corresponding excitation waves in the tissue (panels in A(i) and B(i) and C(i)), as well as APs recorded from the three registration sites (A(ii) and B(ii) and C(ii)).

• 

  Fig 6. Role of INa in transition from discordant alternans to re-entrant arrhythmias. A(i). Snapshots of excitation waves in a homogeneous tissue with control INa. PCL = 140ms. A(ii). Time series of APs recorded from 3 different registration sites, cell A, B and C as marked by black dots in the top-left panel. B(i). Snapshots of excitation waves in a homogeneous tissue with increased INa. PCL = 140ms. B(ii). Time series of APs recorded from 3 different registration sites, cell A, B and C as marked by black dots in the top-left panel of A(i). Red arrow: marking for beginning of re-entry. Blue arrow: marking for termination of re-entry. Black and red stars marked two consecutive stimulus pulses. Simulations presented here were done with D = 0.18 mm2/ms.

• 

  Fig 7. Role of inhomogeneity in transition from discordant alternans to re-entrant arrhythmias. A. Snapshots of excitation waves in an inhomogeneous tissue with increased INa. PCL = 140 ms. B. Time series of APs recorded from 3 different registration sites, cell A, B and C as marked by black dots in the top-left panel. Red arrow: marking for the beginning of re-entry. Inhomogeneous tissue was simulated by assigning cells to dead cells randomly in the tissue.

• 

  Fig 8. Role of anisotropy in transition from discordant alternans to re-entrant arrhythmias. A. Snapshots of excitation waves in a homogeneous but anisotropic tissue with increased INa. PCL = 140 ms. B. Time series of APs recorded from 3 different registration sites, cell A, B and C as marked by black dots in the top-left panel. Red arrow: marking for the beginning of re-entry; Blue, black and red stars marked three consecutive stimulus pulses from the 10th stimulus.