In silico screening of the key cellular remodeling targets in chronic atrial fibrillation

Abstract

Chronic atrial fibrillation (AF) is a complex disease with underlying changes in electrophysiology, calcium signaling and the structure of atrial myocytes. How these individual remodeling targets and their emergent interactions contribute to cell physiology in chronic AF is not well understood. To approach this problem, we performed in silico experiments in a computational model of the human atrial myocyte. The remodeled function of cellular components was based on a broad literature review of in vitro findings in chronic AF, and these were integrated into the model to define a cohort of virtual cells. Simulation results indicate that while the altered function of calcium and potassium ion channels alone causes a pronounced decrease in action potential duration, remodeling of intracellular calcium handling also has a substantial impact on the chronic AF phenotype. We additionally found that the reduction in amplitude of the calcium transient in chronic AF as compared to normal sinus rhythm is primarily due to the remodeling of calcium channel function, calcium handling and cellular geometry. Finally, we found that decreased electrical resistance of the membrane together with remodeled calcium handling synergistically decreased cellular excitability and the subsequent inducibility of repolarization abnormalities in the human atrial myocyte in chronic AF. We conclude that the presented results highlight the complexity of both intrinsic cellular interactions and emergent properties of human atrial myocytes in chronic AF. Therefore, reversing remodeling for a single remodeled component does little to restore the normal sinus rhythm phenotype. These findings may have important implications for developing novel therapeutic approaches for chronic AF.

Figure 1. Illustration of cAF-remodeling processes accounted for in the model and consequent changes in electrophysiological properties and Ca²⁺ dynamics.

(A) Schematic presentation of the cell model. Ionic currents and ion concentrations are referred to with I_X and [X^z]_compartment, respectively. Furthermore, NKA =  sodium potassium ATPase, NCX =  sodium Ca²⁺ exchanger, PMCA =  plasma membrane Ca²⁺ ATPase, SERCA =  sarcoplasmic reticulum Ca²⁺ ATPase, PLB =  phospholamban, SLN =  sarcolipin and CRU =  calcium release unit or ryanodine receptor. Colour coding with red and blue refers to increased and decreased activity and/or expression of cellular components (proteins involved in ion transport), respectively. (B & C) cAF-remodeling shortens the AP and hyperpolarizes the membrane. Simulation results are compared to in vitro findings of Yu et al. and Dobrev et al. . (D & E) cAF-remodeling decreases the amplitude of CaT, diastolic Ca²⁺ concentration and SR Ca²⁺ content, corresponding to in vitro results of Voigt et al. (cyan bar), Voigt et al. (red bar), Wakili et al. (diastolic Ca²⁺) and Grandi et al. (CaT_amp and SR Ca²⁺ content). (F & G) Spatiotemporal view of the CaT along the radial direction of the virtual cell in nSR and cAF (x =  distance from sarcolemma).

Figure 2. Electrophysiological properties in cAF tissue in silico.

A–D) Restitution properties in a 1D tissue beam, compared to in vivo results of Franz et al. for action potential duration at 90% repolarisation (A), Yu et al. for effective refractory period (B), Feld et al. for conduction velocity (C) and wavelength (D). Simulation results are normalised to BCL =  [0.8 0.7 0.6 1.0] s in (A–D), respectively. E&F) Mapping of rotor center trajectories after initiation in 2D tissue shows that in cAF (F) the meandering trajectory occupies a lot less space compared to nSR (E).

Figure 3. Effect of individual remodeling targets on CaT and AP characteristics in cAF.

(A) normal sinus rhythm (nSR). (B) chronic atrial fibrillation (cAF: all). (C–F) four remodeled cellular components separately (L-type Ca²⁺ current, I_CaL; inward rectified K⁺ current, I_K1; Na⁺/Ca²⁺ exchanger current, I_NCX; and increased cell volume, dilation), respectively. Columns from left to right: action potential (AP), Ca²⁺ transient (CaT) averaged over cell volume, and spatiotemporal presentation of CaT (x =  distance from sarcolemma). Colour scale for right column: 0–1.5 µM corresponds to dark blue – dark red (similar to Figure 1 F&G). All results are obtained at BCL = 1000 ms.

Figure 4. Effect of reversing remodeling of individual targets on CaT and AP characteristics in cAF.

(A) chronic atrial fibrillation (cAF: all). (B–E) four restored cellular components (L-type Ca²⁺ current, I_CaL; inward rectified K⁺ current, I_K1; Na⁺/Ca²⁺ exchanger current, I_NCX; and increased cell volume, dilation), respectively. Columns from left to right: action potential (AP), Ca²⁺ transient (CaT) averaged over cell volume, and spatiotemporal presentation of CaT (x =  distance from sarcolemma). Colour scale for right column: 0–1.5 µM corresponds to dark blue – dark red (similar to Figure 1 F&G). All results are obtained at BCL = 1000 ms.

Figure 5. The strong link between intracellular Ca²⁺ and AP shape still exist in the cAF-remodeled virtual cell.

Clamping the CaT (A) in the subsarcolemmal space to be normal (as in nSR) speeds up the initial and slows later repolarisation phases of membrane voltage (B), due to indirect changes in I_NCX (C) and I_CaL (D).

Figure 6. Intracellular Ca²⁺ and Na⁺ accumulation in five virtual cell variants during increasingly fast pacing.

(A&B) Ca²⁺ accumulation and corresponding activation of the reverse mode of NCX in four cell model variants (normalized to nSR). (C&D) Na⁺ accumulation and corresponding activation of the forward mode of NCX (normalized to nSR).

Figure 7. Inducibility of DADs is decreased in cAF due to the stabilizing effect of remodeled I_K1.

DADs were induced with either an extra Ca²⁺ release from the junctional sarcoplasmic reticulum (A–C) or an extra current stimulus (D&E) at the time point of 1 second. Same protocol was used to study four model variants: normal sinus rhythm (nSR), chronic atrial fibrillation with all modifications (cAF: all), only modified inward rectified K⁺ current (cAF: IK1), and only ryanodine receptor Ca²⁺ sensitivity (cAF: RyR).

Figure 8. Summary of cellular remodeling affecting electrophysiological properties in cAF.

Analysis was done for both individual inclusion (Remodeling) and exclusion (Restoring) of cellular components to elucidate their contribution action potential duration at 90% repolarisation (APD₉₀), Ca²⁺ transient amplitude (CaT_amp), action potential triangulation (AP_tri), Na⁺ accumulation, inducibility of delayed afterdepolarisations (DAD induc.) and electrical excitability of the cell (cell exc.).