P643Stochastic ion-channel gating contributes to beat-to-beat variability of repolarization duration and its rate dependence

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Abstract

Purpose

Increased beat-to-beat variability of repolarization duration (BVR) has been described as a more reliable proarrhythmic marker than repolarization prolongation per se in various conditions. The mechanisms underlying BVR, its exaggeration in pathologies and its rate dependence (RD) remain incompletely understood. Action potential duration (APD) changes are proportional to initial APD due to the non-linearity between membrane current (Im) and APD (Zaza JMCC 09). We hypothesized that both this intrinsic mechanism and active gating mechanisms contribute to BVR and BVR-RD. We employed a computational canine ventricular myocyte model with the aim of investigating these factors.

Methods

We extended the model with stochastic channel gating. Action potentials and Im were generated during steady-state pacing at various cycle lengths (CLs). BVR was quantified as short-term APD variability (STV: Σ(|APDi + 1-APDi|)/[nbeats × √2]) and compared to data from isolated canine ventricular myocytes.

Results

The deterministic model showed no BVR. In contrast, stochastic channel gating resulted in BVR that increased with CL, consistent with experimental observations (Figure A,B). BVR was not determined by fluctuations in diastolic interval (DI) since fixed DI pacing resulted in identical BVR-RD. BVR increased when APD was prolonged via current injection; confirming APD dependence of APD changes. Im variability was CL dependent, implying contribution of the active component. Simulations without active component (using CL-independent Im variability) had only partly reduced BVR-RD, unveiling the intrinsic component. Stochastic INa and IKr had the largest impact on BVR (Figure C).

Conclusion

Both active, stochastic ion-channel gating and the intrinsic non-linear relationship between APD and Im contribute to BVR-RD.

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