Proceedings of The Physiological Society

University of Oxford (2011) Proc Physiol Soc 23, PC251

Poster Communications

Computer Simulation of Human Atrial Fibrillation due to S140G and V141M Mutations of the Kv7.1 Gene

S. Kharche1,2, T. Burchell1, C. E. Astles1, H. Zhang1

1. School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom. 2. Department of Electronics and Computer Science and Systems, University of Bologna, Bologna, Italy.


  • Figure 1. Experimental data and model simulations. In all panels, filled circles represent experimental data under Control conditions, gray squares represent V141M experimental data, and triangles denote S140G experimental data. Solid lines show model simulations for Control, gray lines for V141M, and dashed lines for S140G. A: Steady state of IKs activation. B: I-V relationships under Control and mutant conditions. C: Simulated AP profiles. D: CV restitution.

Mutations of the slowly activating delayed potassium ion current (IKs) regulating gene KvLQT1 (Kv7.1) have been implicated in the genesis of atrial fibrillation (AF). This computational study quantifies the mechanisms by which altered IKs ion current function affects cell and tissue level electrical behaviour. Control and mutant atrial IKs voltage clamp experimental data [1] were analysed to quantify alterations of maximum conductance (gKs) and steady state activation parameters of voltage half activation, (V1/2) and slope (k) (Fig. 1, A and B). The time kinetics were found to be unaltered in the Hodgkin Huxley formulation of IKs. The estimated parameters were incorporated into the Courtemanche et al. [2] (CRN) cell model to simulate alterations of action potential (AP) profiles and underlying ionic currents due to the mutations. The cell models were further incorporated into 1D strands and 2D sheets of homogeneous atrial tissue models to study the effects of the mutations on tissue level conduction propagation behaviour [3]. Under Control conditions, gKs is 0.129 nS/pF, V1/2 is 19.1 mV, and k is 12.7 mV. The S140G experimental data gave gKs to be 0.04128 nS/pF, V1/2 to be -29.94 mV, and k to be 14.9 mV. The V141M gave a gKs of 0.0258 nS/pF, V1/2 of -21.13 mV, and k of 22.75 mV. Upon incorporating the Control and mutant IKs ion current models into the CRN AP model, AP duration (APD) was reduced from 312.14 ms under Control conditions, to 232.17 ms under S140G conditions, and 255.08 ms under V141M conditions (Fig. 1, C). Both mutations increased the maximum slope of APD restitution. Cellular effective refractory period (ERP) was reduced from 380 ms in Control, to 300 ms under S140G conditions, and 323 ms under V141M condtions. In 1D models, solitary wave CV was found to be 0.27 mm/ms under Control conditions, and reduced to 0.255 mm/ms (S140G) and 0.265 mm/ms (V141M) under mutant conditions. CV restitution revealed that the tissues' capacity to sustain high pacing rate conduction waves increased from 350 ms (Control) to 179.8 ms (S140G) and 246.2 ms (V141M) (Fig. 1, D). In 2D simulations, the re-entrant waves self terminated within 1.8 ms while under S140G and V141M conditions the re-entry persisted for the duration of simulated 10 s. The re-entrant wave tips were stable under the mutant conditions. The mutations reduced cellular APD and ERP dramatically. The mutations reduced CV while the tissues' ability to sustain conduction propagation at high pacing rates was increased. The reduced APD and CV gave rise to a reduced wavelength of propagating waves, indicating the augmented propensity of tissue level AF due to the gene mutations. This is reflected in the 2D simulations where stability of re-entry was drastically increased. This study has identified the biophysical alterations of human atrial IKs that potentially gives rise to chronic AF.

Where applicable, experiments conform with Society ethical requirements