{
  "abstract": "Background and aim: Human in vitro models for atrial fibrillation (AF) remain limited in reproducing disease-specific remodeling. We leveraged a human-induced pluripotent stem cell-derived atrial cardiomyocyte (hiPSC-aCM) model, which was co-cultured with human atrial cardiac fibroblasts (haCFs) and subjected to an intermittent tachypacing protocol (ITPP) to mimic AF-associated phenotypes.\n\nMaterials and methods: Human iPSC-derived atrial cardiomyocytes (hiPSC-aCMs) were differentiated, purified, matured, and cultured alone or co-cultured with human atrial cardiac fibroblasts at defined seeding ratios (e.g., 90/10 or 70/30 hiPSC-aCM/haCF). Cultures were subjected to 7 days of intermittent tachypacing using electrical field stimulation. Functional electrophysiology and calcium handling were assessed by high-throughput optical mapping, arrhythmia inducibility testing, and genetically encoded or chemical calcium indicators. Structural and molecular remodeling were evaluated by immunocytochemistry, qPCR, and Western blot analysis.\n\nResults: ITPP increased spontaneous action potential (AP) frequency and shortened AP duration at 80% repolarization (APD 80% ), while reducing calcium transient (CaT) upstroke slope and amplitude. Co-cultures at a 70/30 hiPSC-aCM/haCF ratio exhibited marked structural remodeling, with a >100-fold increase in Collagen III expression ( P < 0.0001), decreased excitability (ΔHz = –61 ± 6%, P < 0.0001), prolonged APD 80% (Δ = +130 ± 10%, P < 0.0001), increased triangulation (ΔAPD Tri = +143 ± 13%, P < 0.0001), reduced upstroke slope (Δ = –66 ± 6%, P < 0.0001), conduction block (Δ = –52 ± 18%, P = 0.026), and impaired Ca ² ⁺ handling (upstroke slope Δ = –50 ± 8%, P < 0.0001; ΔdF/F0 = –34 ± 9%, P = 0.0003). Applying ITPP to the 70/30 co-culture induced AF-like remodeling, with increased spontaneous activity (ΔHz = +25 ± 8%, P = 0.02), shortened APD 80% (Δ = –16 ± 6%, P = 0.01), and reduced conduction velocity (ΔCV 100/0 vs. 70/30 = –27 ± 15%, P = 0.0005). Mechanistically, ITPP led to downregulation of phospholamban (PLN) and altered PLN-SERCA2a balance, along with upregulation of TGFB1 and natriuretic peptides, reflecting calcium-handling dysfunction and pro-fibrotic signaling.\n\nConclusion: Together, these findings establish a human-relevant platform in 2D culture that recapitulates key AF-associated structural and electrophysiological remodeling for mechanistic studies and therapeutic screening.",
  "abstract_shown": true,
  "affiliations": [
    "Medical School, University of Michigan",
    "Internal Medicine – Cardiovascular Medicine, University of Michigan",
    "Frankel Cardiovascular Center Cell Regeneration Core Laboratory, University of Michigan"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Paul Kozlowski"
    },
    {
      "affs": [
        1
      ],
      "name": "Kalai Mangai Muthukumarasamy"
    },
    {
      "affs": [
        2
      ],
      "name": "Tiago William Buranello"
    },
    {
      "affs": [
        2
      ],
      "name": "Sung Jo"
    },
    {
      "affs": [
        1
      ],
      "name": "Amrish Deshmukh"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Andre Monteiro da Rocha"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Hakan Oral"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cyv61c8snwtx0.bib",
  "cited_by": 0,
  "doi": "10.3389/fcvm.2026.1814075",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13727422/?tool=EBI",
  "id": "cyv61c8snwtx0",
  "issns": [
    "2297-055X"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fcvm.2026.1814075/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2705|Cardiac electrophysiology and arrhythmias"
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  "openalex": "W7223003464",
  "pdf_url": "https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2026.1814075/pdf",
  "pmcid": "PMC13727422",
  "pmid": "42978619",
  "published": "2026-10-20",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/cyv61c8snwtx0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:10Z",
      "native_id": "10.3389/fcvm.2026.1814075",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fcvm.2026.1814075/full"
    },
    {
      "first_seen": "2026-11-04T15:20:46Z",
      "native_id": "PMC:PMC13727422",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13727422"
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      "first_seen": "2026-11-06T12:23:18Z",
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2705|Cardiac electrophysiology and arrhythmias",
      "subfield": "cardiovascular"
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  ],
  "title": "hiPSC-derived new approach methodology (NAM) recapitulates hallmarks of atrial fibrillation",
  "title_text": "hiPSC-derived new approach methodology (NAM) recapitulates hallmarks of atrial fibrillation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:23:18Z",
  "url": "https://research.draconitic.com/paper/cyv61c8snwtx0",
  "venue": "Frontiers in Cardiovascular Medicine",
  "versions": []
}