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

Background and Aims Patients with persistent atrial fibrillation (AF) experience 50% recurrence despite pulmonary vein isolation (PVI), and no consensus is established for second treatments. The aim of our i-STRATIFICATION study is to provide evidence for stratifying patients with AF recurrence after PVI to optimal pharmacological and ablation therapies, through in-silico trials. Methods A cohort of 800 virtual patients, with variability in atrial anatomy, electrophysiology, and tissue structure (low voltage areas, LVA), was developed and validated against clinical data from ionic currents to ECG. Virtual patients presenting AF post-PVI underwent 13 secondary treatments. Results Sustained AF developed in 522 virtual patients after PVI. Second ablation procedures involving left atrial ablation alone showed 55% efficacy, only succeeding in small right atria (<60mL). When additional cavo-tricuspid isthmus ablation was considered, Marshall-Plan sufficed (66% efficacy) for small left atria (<90mL). For bigger left atria, a more aggressive ablation approach was required, such as anterior mitral line (75% efficacy) or posterior wall isolation plus mitral isthmus ablation (77% efficacy). Virtual patients with LVA greatly benefited from LVA ablation in the left and right atria (100% efficacy). Conversely, in the absence of LVA, synergistic ablation and pharmacotherapy could terminate AF. In the absence of ablation, the patient’s ionic current substrate modulated the response to antiarrhythmic drugs, being the inward currents critical for optimal stratification to amiodarone or vernakalant. Conclusion In-silico trials identify optimal strategies for AF treatment based on virtual patient characteristics, evidencing the power of human modelling and simulation as a clinical assisting tool. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work received funding from the European Union Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No.860974 and the EPSRC Impact Acceleration Account Award (UKRI Grant Reference - EP/X525777/1) (to AD). The project was also supported by a Wellcome Trust Senior Fellowship in Basic Biomedical Sciences (214 290/Z/18/Z to BR), the CompBioMed and CompBiomed2 Centre of Excellence in Computational Biomedicine (European Union Horizon 2020; grant agreement 675 451 and 823 712), the Oxford Biomedical Research Centre and the CompBiomedX EPSRC-funded project (EP/X019446/1). We acknowledge additional support from the Oxford BHF Centre of Research Excellence (RE/13/1/30 181), PRACE, Piz Daint at the Swiss National Supercomputing Centre, Switzerland (ICEI-PRACE grant icp019) and Fapemig. For the purpose of Open Access, the authors have applied a CC BY public copyright licence to any Author Accepted Manuscript (AAM) version arising from this submission. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript