What determines the optimal pharmacological treatment of atrial fibrillation? Insights from in silico trials in 800 virtual atria

Abstract

The best pharmacological treatment for each atrial fibrillation (AF) patient is unclear. We aim to exploit AF simulations in 800 virtual atria to identify key patient characteristics that guide the optimal selection of anti‐arrhythmic drugs. The virtual cohort considered variability in electrophysiology and low voltage areas (LVA) and was developed and validated against experimental and clinical data from ionic currents to ECG. AF sustained in 494 (62%) atria, with large inward rectifier K+ current (IK1) and Na+/K+ pump (INaK) densities (IK1 0.11 ± 0.03 vs. 0.07 ± 0.03 S mF–1; INaK 0.68 ± 0.15 vs. 0.38 ± 26 S mF–1; sustained vs. un‐sustained AF). In severely remodelled left atrium, with LVA extensions of more than 40% in the posterior wall, higher IK1 (median density 0.12 ± 0.02 S mF–1) was required for AF maintenance, and rotors localized in healthy right atrium. For lower LVA extensions, rotors could also anchor to LVA, in atria presenting short refractoriness (median L‐type Ca2+ current, ICaL, density 0.08 ± 0.03 S mF–1). This atrial refractoriness, modulated by ICaL and fast Na+ current (INa), determined pharmacological treatment success for both small and large LVA. Vernakalant was effective in atria presenting long refractoriness (median ICaL density 0.13 ± 0.05 S mF–1). For short refractoriness, atria with high INa (median density 8.92 ± 2.59 S mF–1) responded more favourably to amiodarone than flecainide, and the opposite was found in atria with low INa (median density 5.33 ± 1.41 S mF–1). In silico drug trials in 800 human atria identify inward currents as critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics. imageKey points Atrial fibrillation (AF) maintenance is facilitated by small L‐type Ca2+ current (ICaL) and large inward rectifier K+ current (IK1) and Na+/K+ pump. In severely remodelled left atrium, with low voltage areas (LVA) covering more than 40% of the posterior wall, sustained AF requires higher IK1 and rotors localize in healthy right atrium. For lower LVA extensions, rotors can also anchor to LVA, if the atria present short refractoriness (low ICaL) Vernakalant is effective in atria presenting long refractoriness (high ICaL). For short refractoriness, atria with fast Na+ current (INa) up‐regulation respond more favourably to amiodarone than flecainide, and the opposite is found in atria with low INa. The inward currents (ICaL and INa) are critical for optimal stratification of AF patient to pharmacological treatment and, together with the left atrial LVA extension, for accurately phenotyping AF dynamics.

in-Silico TRials guide optimal stratification of ATrIal FIbrillation patients to Catheter Ablation and pharmacological medicatION: The i-STRATIFICATION study

“…Every virtual patient presented a unique combination of ionic current profile and atrial anatomy, resulting in 400 human bi-atrial models with variability in anatomy and electrophysiology. Regional heterogeneities in conduction velocity and anisotropy were also included (Supplemental Table 3), setting the baseline plane wave velocity to 80 cm/s in the bulk tissue 11,16 17 . Moreover, the same LVA degree was modelled in the right atrium, since structural remodelling occurs in both atria 18 .…”

“…Figure 1 shows the 15% bi-atrial LVA extension on a representative anatomy. LVA were simulated as regions of 30% decreased longitudinal conductivity, increased anisotropy (i.e., 8:1 longitudinal to transversal conductivity ratio) and 50%, 40% and 50% reductions in ICaL, INa and IK1, respectively 11 .…”

“…After the virtual application of PVI, spiral wave re-entries were imposed in the atria as the initial conditions of the simulation and AF dynamics were analysed for 7 s of activity 11 . This protocol mimicked AF initiation from nonspecific triggers outside the pulmonary veins, and a detailed description of the protocol is provided in the Supplemental Material.…”

“…Due to their multiscale nature and scalability, human in-silico trials (i.e., clinical trials conducted in large cohorts of virtual patients using human-based computer modelling and simulation) can assist in identifying and explaining individual patient characteristics that guide optimal therapy selection 10,11 . The aim of our i-STRATIFICATION study is to provide evidence for the optimal stratification of patients with AF recurrence after PVI to 13 state-of-the-art pharmacological and ablation therapies, through in-silico trials.…”

Constructing bilayer and volumetric atrial models at scale

“…Therapy approaches for irregular heart rhythms including atrial fibrillation (AF) are suboptimal, which is in part because these therapies are not personalized to the patient. Personalized computational models may be used to predict individual patient response to therapy [1], to predict patient outcomes, to guide individual therapy [2] or for in silico trials [3]. Atrial models may be constructed from a variety of different data types, including electroanatomical mapping (EAM) shells or medical imaging data (magnetic resonance imaging (MRI) or computed tomography (CT)), which are segmented to produce a personalized anatomy.…”