Mechanisms of Chemical Atrial Defibrillation by Flecainide and Ibutilide

Figures

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  FIGURE 1. Wild-Type Na+ Channel Model Topology The model includes 3 closed states (C3, C2, C1), open state (O), a slow inactivation state (IS), 2 closed inactivation states (IC2 and IC3), and a fast inactivation state (IF). Black states are “normal” gating mode, whereas red states indicate burst mode, representing a small fraction of noninactivating channels.

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  FIGURE 2. Schematic of the Model Used to Simulate Re-Entrant Atrial Arrhythmia 1,500 or 340 Grandi-Bers simulated healthy cells were connected in a ring shape to allow self-sustaining re-entrant activity. The pathlength (physical distance) was chosen based on the cycle length ~= 400 ms to ensure adequate space for repolarization and to allow continuous propagation around the ring.

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  FIGURE 3. Assessing the Impact of Flecainide and Ibutilide on Atrial Refractory Periods Atrial action potential adaptation curves show a prolonged refractory period indicated as action potential duration at 90% repolarization (APD90) at various pacing frequencies (A) with flecainide (Flec) alone or (B) ibutilide alone and (C and D) with combined drugs (Flec and ibutilide). Cells were paced for 1,000 beats at each cycle length, and the last APD90 was recorded. *Drug combinations that were used in atrial tissue simulations (see Figures 4 and 5). PCL = pacing cycle length.

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  FIGURE 4. Effects of Flecainide and Ibutilide on Effective Refractory Period We simulated an atrial fiber composed of 1,500 cells connected by resistances to simulate gap junctions. Refractory periods were recorded in 1-dimensional fibers with drug applications alone (gray and blue bars) or combinations (pink and purple bars). (A) Change in effective refractory period (ERP) with flecainide (Flec) 1.0 μmol/L and ibutilide (ibu) 0.01 μmol/L (B) Change in ERP with Flec 1.5 μmol/L and ibu 0.02 μmol/L.

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  FIGURE 5. Prediction of Drug Combinations in a Simulated Self-Sustaining Model of Atrial Re-Entry A stimulus was applied on the first cell of a 1-dimensional model of Grandi-Bers 1,500 simulated cells connected by resistances to simulate gap junctions to induce propagation along the fiber. The ends of the 1-dimensional tissue model were then connected when the voltage in the middle of cell was >−40 mV to allow continuous propagation around the ring to induced unidirectional re-entry. (A) Control case (B and C) with flecainide alone or (D to F) Ibutilide alone and (G to I) with combined drugs (flecainide and ibutilide) were applied in the model. Simulations showing the effectiveness of the predicted ideal combined drug concentration to quickly terminate self-sustained re-entry. The stars represent drug combinations.

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  FIGURE 6. Prediction of Drug Combinations in a Simulated Rapid Atrial Re-Entry Simulated drug combinations in the presence of Ach (0.015 μmol/L) during atrial flutter to allow self-sustaining re-entrant rhythm at a rapid rate (~350 beats/min). (A) Control case in 32 the presence Ach (B and C) with flecainide alone or (D to F) ibutilide alone and (G to I) different combination of drugs were applied. Higher dose flecainide (1.5 μmol/L) combined with ibutilide (0.02 μmol/L) quickly stopped the re-entry.

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  FIGURE 7. Simulations of QT and QTc Intervals Using a Modified ORd Model The modified ORd model simulated QT (A) and QTc (B) intervals compared with clinical data.57 A 1-dimensional tissue 4 cm in length was used in the simulations to minimize end effects. The cable was paced for 50 beats at varying frequencies.

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  FIGURE 8. Simulated Drug Effects on QT, QTc, QRS Intervals, and Conduction Velocity Using a Modified ORd Model The modified ORd model simulated changes in QT (A), QTc (B), QRS intervals (C), and conduction velocity (D) with ibutilide alone (0.02 μmol/L: red), flecainide (Flec) alone (1.5 μmol/L: orange), or in combination (ibutilide 0.02 μmol/L + flecainide 1.5 μmol/L: purple) from drug-free case.

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  FIGURE 9. Computational Screen of Arrhythmia Vulnerability in the TRIaD (A) Action potential triangulation for population cells for control, ibutilide (ibu) alone, flecainide (Flec) alone, and ibutilide + flecainide. The inset illustrates action potential triangulation. (B) Simulated beat-to-beat instability of action potentials to small perturbations before and after application of drugs. Beat-to-beat variability of repolarization duration (BVR) indicating beat-to-beat instability is shown. The inset highlights the beat-to-beat variability of action potential duration at 90% repolarization (APD90). (C) Action potential adaptation curves showing APD90 at various pacing frequencies with or without drugs, demonstrating drug reverse use dependence. (D) The last action potential after a long pause (5,000 ms) is shown for control, ibutilide 0.02 μmol/L, flecainide 1.5 μmol/L, and ibutilide 0.02 μmol/L + flecainide 1.5 μmol/L conditions.

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  FIGURE 10. Study Effects of Flecainide on Ventricular Cells by Varying Ion Channel Inhibition (A) 300 ventricular cells were generated by randomly varying IC50 of flecainide on IKr between 1.5 and 3.9 μmol/L, INaL between 3.4 and 44 μmol/L, as well as late INa current range within 0.1% to 0.2% of peak INa for each case. Cells were paced at 1 Hz for 500 beats. The last beat was recorded for APD90. (B) Effects of late Na+ block on rate dependence and APD adaptation curves. Rate dependent curves measured as APD90 at steady state for each pacing cycle length (from 600–1,200 ms), and APD adaptation curves with or without drug applications (control cases) were constructed (solid lines). With additional late Na+ block from 10% to 100% block with 10% increments (dashed lines). Abbreviations as in Figure 9.

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  CENTRAL ILLUSTRATION. In a Simulated Self-Sustaining Model of Atrial Re-Entry, A Combination of Flecainide and Ibutilide Effectively Terminated Re-Entry Our analysis suggests that combining low doses of flecainide and ibutilide constitutes a promising option for acute chemical atrial defibrillation. Additionally, we predict the safety impact of this drug combination on ventricular electrophysiology. TdP = torsade de pointes.