{
  "abstract": "Background Abnormal sarcoplasmic reticulum (SR) Ca2+ release through ryanodine receptor 2 (RyR2) is a well-established mechanism of ventricular arrhythmias. Whether persistent RyR2 dysfunction can also initiate the structural remodeling characteristic of arrhythmogenic cardiomyopathy (ACM) remains unknown. We tested the hypothesis that chronic RyR2-mediated Ca2+ leak is sufficient to couple electrical instability to progressive cardiomyopathy. Methods We generated a rabbit carrying the severe gain-of-function RyR2-V2475F mutation and characterized disease progression using longitudinal cardiac phenotyping, continuous electrocardiographic monitoring, cellular electrophysiology and Ca2+ imaging, histopathology, biochemical analyses, and single-nucleus RNA sequencing (snRNA-seq). Therapeutic potential was evaluated by continuous treatment with the selective RyR2 inhibitor ent-verticilide for two months. Results RyR2-V2475F rabbits developed spontaneous ventricular tachyarrhythmias, sudden cardiac death, and progressive right ventricular (RV)-dominant fibrofatty cardiomyopathy recapitulating major features of human ACM. Malignant ventricular arrhythmias preceded overt structural remodeling and were associated at the cellular level with early spontaneous Ca2+ release and early afterdepolarizations. Early disease was characterized by remodeling of excitation-contraction coupling with preserved SR Ca2+ load and contractile function despite RyR2 dysfunction; upon disease progression, these compensatory changes were accompanied by SR Ca2+ depletion, impaired RV contractility and reduced left ventricular filling. Single-nucleus transcriptomics identified early fibroblast expansion and predicted cardiomyocyte-centered paracrine signaling before advanced fibrofatty infiltration. Cardiomyocytes also exhibited an altered lipid-metabolic transcriptome and intracellular lipid accumulation, accompanied by enhanced mitochondrial Ca2+ uptake. Selective RyR2 inhibition markedly reduced ventricular tachycardia burden and preserved RV contraction and LV filling during disease progression. Conclusions Severe RyR2 gain-of-function can lead to both malignant ventricular arrhythmias and progressive arrhythmogenic cardiomyopathy in a large-animal model, establishing persistent intracellular Ca2+ dysregulation as a mechanistic link between electrical and structural heart disease. The ability of selective RyR2 inhibition to suppress arrhythmias and preserve cardiac function identifies RyR2 as a potentially actionable therapeutic target in arrhythmogenic cardiomyopathy.",
  "abstract_shown": true,
  "affiliations": [
    "University of Wisconsin-Madison"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "name": "J. Zheng"
    },
    {
      "name": "D. Ponce-Balbuena"
    },
    {
      "name": "S. Estrada"
    },
    {
      "name": "L. Xiao"
    },
    {
      "name": "E. B. Rios Perez"
    },
    {
      "name": "A. M. Gowda"
    },
    {
      "name": "C. E. Korcarz"
    },
    {
      "name": "K. M. Hansen"
    },
    {
      "name": "D. J. Blackwell"
    },
    {
      "name": "M. P. Thorpe"
    },
    {
      "name": "W. S. Akers"
    },
    {
      "name": "J. Wu"
    },
    {
      "name": "J. N. Johnston"
    },
    {
      "name": "A. M. Gomez"
    },
    {
      "name": "J.-P. Benitah"
    },
    {
      "name": "B. C. Knollmann"
    },
    {
      "name": "Y. E. Chen"
    },
    {
      "name": "H. H. Valdivia"
    },
    {
      "affs": [
        0
      ],
      "name": "F. J. Alvarado"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1ge7kna3ywy5f.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.02.763829",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.11.02.763829v1.full",
  "id": "1ge7kna3ywy5f",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.11.02.763829v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "physiology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.11.02.763829v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-02",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1ge7kna3ywy5f.ris",
  "sources": [
    {
      "first_seen": "2026-11-04T00:21:42Z",
      "native_id": "10.64898/2026.11.02.763829",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.11.02.763829v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:physiology",
      "subfield": "physiology"
    }
  ],
  "title": "RyR2-Mediated Ca2+ Leak Drives Progressive Arrhythmogenic Cardiomyopathy",
  "title_text": "RyR2-Mediated Ca2+ Leak Drives Progressive Arrhythmogenic Cardiomyopathy",
  "type": "preprint",
  "updated_at": "2026-11-05T00:21:10Z",
  "url": "https://research.draconitic.com/paper/1ge7kna3ywy5f",
  "venue": "bioRxiv",
  "versions": []
}