{
  "abstract": "Response to antiarrhythmic drugs varies markedly across patients with atrial fibrillation (AF), suggesting that treatment efficacy depends on the interaction between drug-specific mechanisms and patient-specific electrophysiological substrate. Here, we used population-based computational models to investigate how electrophysiological substrate and inter-individual ionic variability influence pharmacological efficacy and the underlying mechanisms. Two populations of human atrial models were generated from distinct substrates: a reference left atrial model and a second model incorporating inward-rectifier-enhancement (IRE) through a 2-fold increase in IK1 and IK,ACh. Both populations were independently calibrated against the same experimental datasets from patients with paroxysmal AF (pAF), yielding pAF and IRE-pAF populations. Sustained reentrant activity was induced in two-dimensional tissue simulations and subsequently used to assess cardioversion efficacy of flecainide, vernakalant and tertiapin-Q. Despite satisfying the same calibration criteria, IRE-pAF population exhibited a more arrhythmogenic phenotype: shorter refractoriness, higher dominant frequency (DF) and greater rotor stability. Antiarrhythmic efficacy markedly differed between substrates. Flecainide cardioversion decreased in IRE-pAF compared with pAF (34% vs 21%), whereas IK,ACh-targeting therapies preserved or improved efficacy in IRE-pAF (vernakalant: 41% vs 44%, tertiapin-Q: 11% vs 18%). Across drugs and substrates, rotor DF strongly influenced cardioversion outcome, with higher-frequency rotors showing lower termination rates. Drug-induced DF reduction emerged as a key mechanism associated with successful cardioversion, whereas effective refractory period (ERP) prolongation alone did not consistently explain treatment efficacy. In pAF, vernakalant achieved higher cardioversion efficacy than flecainide despite a smaller increase in ERP and greater DF reduction. Ionic analyses further showed that elevated IK,ACh favored responses to vernakalant and tertiapin-Q. These findings demonstrate that cardioversion efficacy emerges from the interaction between electrophysiological substrate, rotor dynamics and drug-specific mechanisms. In particular, substrates differing in inward rectifier activity exhibit distinct response patterns, while DF emerges as a robust marker of pharmacological susceptibility and a potential guide for drug-mediated AF termination.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "V. Puche-Garcia"
    },
    {
      "name": "D. Filgueiras-Rama"
    },
    {
      "name": "L. Martinez-Mateu"
    },
    {
      "name": "L. Romero"
    },
    {
      "name": "J. Saiz"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/37cxm06hp00y4.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.18.752633",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752633v1.full",
  "id": "37cxm06hp00y4",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752633v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "bioengineering"
    ],
    [
      "openalex",
      "2705|Cardiac electrophysiology and arrhythmias"
    ]
  ],
  "openalex": "W7213983641",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752633v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-18",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/37cxm06hp00y4.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:23:37Z",
      "native_id": "10.64898/2026.09.18.752633",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.18.752633v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioengineering",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "Electrophysiological dependent antiarrhythmic drug response in population-based models of paroxysmal atrial fibrillation",
  "title_text": "Electrophysiological dependent antiarrhythmic drug response in population-based models of paroxysmal atrial fibrillation",
  "type": "preprint",
  "updated_at": "2026-10-30T12:23:37Z",
  "url": "https://research.draconitic.com/paper/37cxm06hp00y4",
  "venue": "bioRxiv",
  "versions": []
}