A computational model to predict the effects of class I anti-arrhythmic drugs on ventricular rhythms

Abstract

A long-sought, and thus far elusive, goal has been to develop drugs to manage diseases of excitability. One such disease that affects millions each year is cardiac arrhythmia, which occurs when electrical impulses in the heart become disordered, sometimes causing sudden death. Pharmacological management of cardiac arrhythmia has failed because it is not possible to predict how drugs that target cardiac ion channels, and have intrinsically complex dynamic interactions with ion channels, will alter the emergent electrical behavior generated in the heart. Here, we applied a computational model, which was informed and validated by experimental data, that defined key measurable parameters necessary to simulate the interaction kinetics of the anti-arrhythmic drugs flecainide and lidocaine with cardiac sodium channels. We then used the model to predict the effects of these drugs on normal human ventricular cellular and tissue electrical activity in the setting of a common arrhythmia trigger, spontaneous ventricular ectopy. The model forecasts the clinically relevant concentrations at which flecainide and lidocaine exacerbate, rather than ameliorate, arrhythmia. Experiments in rabbit hearts and simulations in human ventricles based on magnetic resonance images validated the model predictions. This computational framework initiates the first steps toward development of a virtual drug-screening system that models drug-channel interactions and predicts the effects of drugs on emergent electrical activity in the heart.

Fig. 1

Simulated and experimental drug–Na channel interactions. Black and dotted lines depict the results of simulation; the symbols represent experimental data. (A) Steady-state channel availability. Currents measured at −10 mV with 10 μM flecainide (Flec.) (left) or 100 μM lidocaine (Lido.) (right) pulsed from −120 to −40 mV in 5-mV increments (normalized to tonic block at −120 mV) (17). (B) Dose dependence of use-dependent block (UDB) from 300 pulses to −10 mV for 25 ms from −100 mV at 5 Hz with indicated drug dose (20). Peak current at last pulse normalized to first [note that in drug-free condition, 2.8% loss of current occurs during the pulse protocol (because of inactivation and rundown), so the normalized value is 0.97]. (C) Recovery from UDB after pulses (to −10 mV for 25 ms at 25 Hz) from −100 mV with 10 μM flecainide (19) (left) or 300 μM lidocaine (right). Test pulses (−10 mV) were after variable recovery intervals at −100 mV. Currents were normalized to tonic block. (D) Frequency dependence of UDB. Protocol is the same as in (B) with 10 μM flecainide (19) (left) or 300 μM lidocaine (20) (right). (E) Dose dependence of tonic block evoked by depolarizing pulse from −100 to −10 mV. Block is peak current normalized to drug-free conditions.

Fig. 2

Effects of flecainide and lidocaine on cell excitability and conduction velocity in a human ventricular cell model (26). (A) Effects of 0.5 or 2 μM flecainide (Flec.) (left) and 5 or 20 μM lidocaine (Lido.) (right) as indicated on single-cell upstroke velocity (V/s) paced at 80 BPM. (B) Effects of 2 μM flecainide (left) and 20 μM lidocaine (right) on upstroke velocity (V/s) at the indicated frequency. (C) Effects of 0.5 μM (120 BPM) and 2 μM (120 and 160 BPM) flecainide (left) and 5 μM (120 BPM) and 20 μM (120 and 160 BPM) lidocaine (right) on conduction velocity in 1D tissue. (D) Minimum concentrations of flecainide (left) and lidocaine (right) required for conduction block at the indicated pacing frequencies.

Fig. 3

Complex dynamics in simulations and experiments with 2 μM flecainide at 160 BPM. (A) The extended time course of simulated action potentials (2 μM flecainide at 160 BPM) at 1, 2, and 4 min after addition of drug. Action potentials from cell 50 are shown. (B) Experimental action potentials in the rabbit epicardium paced at 160 BPM with 2 μM flecainide. Red arrows indicate failed stimuli.

Fig. 4

Prediction of arrhythmia propensity by the vulnerable window (VW). (A) Schematic for the VW protocol. (B) Schematic for the pacing protocol. (C) VW with 2 μM flecainide after pacing (S1) at 120 BPM. Cell position is shown on the y axis. The x axis indicates time and the z axis indicates voltage, with darker color indicating more depolarized potentials and light gray indicating repolarized tissue. An additional stimulus (S2) applied at cell 250 before the VW (blue dot) fails to excite refractory tissue (left). Premature impulses applied at the most premature beat (MPB) (red dot) and least premature beat (LPB) (green dot) cause arrhythmogenic unidirectional retrograde conduction. An impulse applied after the VW (orange dot) causes bidirectional conduction. (D) The Starmer metric, P(Arrhythmia) (33), was used to calculate arrhythmia susceptibility to 0 to 2 μM flecainide normalized to drug-free risk. (E) VW for lidocaine (20 μM) after pacing at 120 BPM. Abbreviations as for (C). (F) The Starmer metric, P(Arrhythmia) (33), was used to calculate arrhythmia susceptibility to 0 to 20 μM lidocaine normalized to drug-free risk.

Fig. 5

Effects of flecainide and lidocaine in a 2D cardiac tissue model. (A and B) Phase maps for (A) flecainide (2 μM) and (B) lidocaine (20 μM) at times as indicated under panels [scale above: red indicates wavefront and blue indicates fully repolarized (but not necessarily recovered from drug block) tissue]. Panels at right are the corresponding activation isochrones (time scale on right). A premature impulse was applied in the wake of the preceding wave (i) before the vulnerable window (VW), (ii) within the VW, or (iii) after the VW for flecainide (A) or lidocaine (B). See the Supplementary Material for the schematic of pacing protocol.

Fig. 6

Experimental validation of reentrant behavior with flecainide. (A) Snapshots of a nonsustained salvo transmural figure-of-eight reentry induced after rapid pacing with 2 μM flecainide. Electrode pacing site is denoted with an asterisk. (B) Optical action potential (AP). (C) Electrocardiogram (ECG) recording. Dashed blue line indicates time in (A). After pacing, a reentrant figure-of-eight wave breaks through in the top left field of view and travels down and to the right before spiraling back around. The blue arrows show the tip of the wave first traveling endocardially and then reentering into recovered epicardium (top left of tissue). The white solid arrows show the epicardial trajectory of the wave, whereas the dotted white arrows show the projected transmural path.

Fig. 7

Reentry in 3D models of the human ventricle. (A) Phase map of a sustained figure-of-eight reentry with 2 μM flecainide paced at 120 BPM. (B) Phase map of nonsustained reentry with 20 μM lidocaine paced at 120 BPM. The S1-S2 interval was 720 ms for flecainide and 670 ms for lidocaine. Sustained reentry occurred when applying S2 within the vulnerable window of the model with 2 μM flecainide (VW = 660 to 735 ms), but not for 20 μM lidocaine (VW = 630 to 685 ms).

Fig. 8

Drug effects in heart failure (HF). (A) The HF APD is prolonged and exhibits diastolic depolarization. (B) Results from Priebe and Beuckelmann, comparable to those in (A) (39). (C) For flecainide, the single uncoupled cellular upstroke velocity is shown for indicated frequencies. (D) For lidocaine, the single uncoupled cellular upstroke velocity is shown for indicated frequencies. (E) For flecainide, the minimum drug concentrations (in parentheses) required for conduction block are shown at indicated frequencies. (F) For lidocaine, the minimum drug concentrations (in parentheses) required for conduction block are shown at indicated frequencies. (G and H) Reentrant dynamics for half-maximal drug concentration (1 μM flecainide, 10 μM lidocaine) at 80 BPM. Shown are phase maps at indicated times.