1. Methods for Computer Simulation Methods for computer simulation were illustrated following the flow chart in the next page. Please select the user-defined mode button, and enter 6 parameters in each box (Steps 1- 3). Then, click on ‘Enter’ to start the program (Step 4). The phase response curve (PRC) will appear in the lower right panel as a blue line. In the upper right panel, the spectrum graph with the blue line shows the VPC ratio at the sinus cycle length corresponding to the mean sinus cycle length in our text. The red line in the right panel indicates the VPC-VPC interval at the same sinus cycle length. If the model button (C1-C4 and I2) was selected, all parameters will be pre-determined according to the table in reference 1. ECG simulation is possible by clicking on the ‘Plot ECG’ button (Step 5). In the next panel, please select the required sinus cycle length to simulate the ECG. The parasystole cycle length is pre-set at 2,000 ms. Push ‘Enter’ to start the ECG simulation (Step 6). The corresponding PRC will appear in the upper middle panel. The phase transition plot will be displayed in the upper right panel. Click on ‘Next ECG’ to continue for a further ECG simulation (Step 7). The figures under each ECG show the R-R interval without discriminating VPCs. The limiting condition for the RIVB can be estimated by repeating the ECG simulation. Additional references to 6) and 7) in the text: 1.Ikeda N, Yoshizawa S, Sato T. Difference equation model of a ventricular parasystole as an interaction between cardiac pacemakers based on the phase response curve, J theor Biol, 1983: 103; 439-465, 2. Ikeda N, Takeuchi A, Hamada A, Goto H, Mamorita N, Takayanagi K: Model of bi- directional modulated parasystole as a mechanism for cyclic bursts of ventricular premature contractions. Biol Cybern 2004: 91; 37-47.

2. Flow chart

3. phase response curve b Phase response curve approximation by a piecewise linear function with a set of parameters (a, b, c,  ). Parameters: a, b, c (0< c <999),  (0<  <1) Refractory period of the normal QRS: gamma (0< gamma <1) Refractory period of the ectopic focus: delta (0< delta <1) -c  a

4. Step 1: Select parameters on SIMULATOR model Model simulator How to use Parameters enter Plot ECG (next page) Spectrum plot delete quit Variable model model

5. Step 2 and 3. Select 6 parameters: Model simulator How to use Parameters enter Plot ECG (next page) Spectrum plot delete quit Variable model model

6. Step 4. Push enter to make VPC-VPC interval, VPC ratio map (upper panel) and PRC (lower panel). Red vertical arrow indicates the upper limit for the RIVB at sinus cycle length of 1,176 ms. How to use Parameters enter Plot ECG (next page) Spectrum plot delete quit Variable model

7. Step 5. Click on ‘Plot ECG’ (upper panel) and select SCL (=1 s) on the next page (lower new panel) enter ECG Plot delete How to use Next ECG quit SCL variation Parameters enter Plot ECG (next page) Spectrum plot delete quit Variable model

8. Step 6. Push ‘enter’ to reproduce ECG at selected SCL (=1.159 s). Note the location of vertical red arrow on the PRC. enter ECG Plot delete How to use Next ECG quit SCL variation

9. Step 6. SCL=0.745 s. Compensatory bigeminy was followed by interpolated trigeminy. enter ECG Plot delete How to use Next ECG quit SCL variation

10. Step 6. RIVB at SCL=1.176 s. This is the limiting condition for RIVB, which can be estimated by comparing the next ECG. enter ECG Plot delete How to use Next ECG quit SCL variation

11. Step 6. No RIVB at 1,177ms. enter ECG Plot delete How to use Next ECG quit SCL variation

12. Statistical analysis. Figure 4: regression lines