Mechanisms of Ventricular Arrhythmias: From Molecular Fluctuations to Electrical Turbulence

Supplementary Data

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  Supplemental Figure 1. Complex focal excitations and reentry in tissue. a. Multiple shifting foci (stars) in a homogeneous tissue due to dynamic instabilities, in which the foci continuously disappear and reborn, shifting in space and time. b. Spiral wave breakup, in which the waves are unstable, continuously disappear and reborn through breaks of the existing ones. c. Mother-rotor fibrillation, in which a stable rotor (indicated by the arrow) emanates wavefronts which fail to be 1:1 conduction due to heterogeneities in refractoriness, resulting in wavebreaks away from the rotor. d. Scroll wave breakup in in three-dimensional tissue slab. e. Scroll wave breakup in a model of dog ventricles. The panels shown are voltage snapshots from computer simulations, with voltage levels indicated by the color bar. Panels a-c are simulations of two-dimensional tissue models; panel d is a simulation of a three-dimensional tissue slab; and panel e is a simulation of a dog ventricle model. The left panel in e is a voltage snapshot of the heart surface and the right panel is voltage snapshot of the entire ventricle in which voltage higher than a certain value is colored red (otherwise no color) for three-dimensional visualization.

  
  
  

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  Supplemental Figure 2. Restitution and alternans. a. Voltage traces showing the protocol used for measuring S1S2 APD restitution curve, i.e., a train of S1 stimulus with a certain cycle length is applied to pace the cell into a steady state and then an S2 stimulus is applied for a certain S1S2 interval. The same pacing protocol is repeated with different S1S2 intervals which give rise to different diastolic intervals (DIs) preceding the S2 stimulus and APDs of S2 beat. By plotting APD against the preceding DI, one obtains the S1S2 APD restitution curve. b. An S1S2 APD restitution curve (APD vs preceding DI) from a rabbit ventricular myocyte. c. Conduction velocity (CV) restitution curve (CV vs preceding DI) which can be measured using a similar protocol as the S1S2 APD restitution curve but needs to be carried out in tissue.

  
  
  

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  Supplemental Figure 3. Bi-excitability. a. An I_Na-mediated spiral wave in which the voltage recovers fully to around -80 mV after each excitation (black trace) and I_Na is activated to generate the upstroke (red trace). Note that the color changes from blue to red in the voltage snapshot. b. In the same tissue as in a, a different initiation protocol produces an I_Ca,L-mediated spiral wave, in which the voltage recovers only partially to around -50 mV (black trace) and the upstroke is mediated by I_Ca,L without I_Na activation (red trace). Note that the color changes from green to red in the voltage snapshot. c. Two snapshots showing mixed I_Na- and I_Ca,L-mediated conduction (different parameter settings from a and b). White arrows point to I_Na-mediated conduction. All computer simulations are from homogeneous two-dimensional tissue models (From Chang et al, Ref.28 with permission), indicating that the patterns are dynamic in origin and do not require pre-existing heterogeneity.

  
  
  

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  Supplemental Figure 4. Spike-and-dome action potential morphology initiating phase-2 reentry. a. Action potentials with no I_to (black), intermediate I_to (red), and large I_to (blue). b. APD versus I_to conductance. c. Phase-2 reentry (modified from Ref. 107). Green arrow indicates the direction of a pacing beat. Red arrow indicates that the AP dome in the upper region re-excites the repolarized cells near the middle, which then propagates retrogradely, resulting in phase-2 reentry.

  
  
  

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  Supplemental Figure 5. EAD dynamics. a. Voltage traces showing a 1 ms delay in S2 stimulus from an S1 action potential result in an EAD (red trace). b. APD restitution in the presence of EADs. The steep and discontinuous change in the APD restitution curve is caused by the all-or-nothing property shown in a. c. APD vs. beat number showing a chaotic behavior. The result was obtained by iterating the following equation: , where PCL is the pacing cycle length and f is the restitution function from b. (From Ref.14 with permission) d. Voltage traces showing irregular EAD appearance. Upper trace is a recording from dog Purkinje fiber (Courtesy of Robert Gilmour). Lower trace is a recording from an isolated rabbit ventricular myocyte subjected to hypokalemia ([K⁺]_o=2.7 mM) (from Ref.18 with permission).

  
  
  

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  Supplemental Figure 6. DADs. a. A DAD (arrow) caused by a spontaneous Ca²⁺ wave in a Ca²⁺-overloaded ventricular myocyte with EADs (arrows), illustrating voltage (upper), whole-cell Ca²⁺ fluorescence (middle), and a line scan of Ca²⁺ fluorescence (bottom). Asterisk and the white arrows indicate the origin of the Ca²⁺ wave from the center of the cell and its propagation to the ends, respectively. Reproduced from Xie et al. (from Ref.89 with permission). b. Voltage traces showing pacing-induced DADs in HF cells (indicated by arrows), but not in the normal cell, reproduced from Yeh et al (from Ref.87 with permission).