{
  "abstract": "Objective: Heart failure (HF) is a major global health concern characterized by impaired excitation-contraction coupling and extensive structural remodeling of the myocardium, often modeled using a potent vasoactive and neurohumoral mediator, endothelin-1 (ET-1). This study investigates whether AAV6-mediated delivery of the Cav1.3-C-terminus, acting as an auto-trans-regulator of gene transcription, can restore electrophysiological and contractile functions in an ET-1-induced HF model using hiPSC-CMs.\n\nMethods: hiPSC-CM monolayers were treated with 10 nM ET-1 for 48 hours to induce HF-like phenotype and then co-treated with an AAV6-Cav1.3-C-terminus. We subsequently evaluated gene expression via RT-qPCR, single-cell electrophysiological properties via patch-clamp, and contractile function using custom video analysis software.\n\nResults: ET-1 treatment induced a HF-associated remodeling phenotype, characterized by significant upregulation of hypertrophic ( NPPA , NPPB , and ACTA1 ) and extracellular matrix-associated ( COL1A1 ) genes, along with increased cell membrane capacitance. This structural remodeling was accompanied by marked electrophysiological alterations, including downregulation of KCNH2 , CACNA1D , CACNA1C , and SCN5A , reduced potassium, calcium, and sodium current densities, and prolonged action potential duration. ET-1 impaired both the spontaneous beating rate and contraction amplitude of the monolayers. Co-treatment with the Cav1.3-C-terminus successfully restored CACNA1D and KCNH2 gene expression to baseline levels, accompanied by normalized L-type calcium and potassium current densities, normalized APD prolongation, and completely restored the chronotropic and inotropic functions to control levels.\n\nConclusions: ET-1-treated hiPSC-CMs model effectively recapitulates the electrophysiological and contractile dysregulations of HF. Gene therapy by Cav1.3-C-terminus provides robust functional rescue myocardial contractility, highlighting its potential as a novel therapeutic strategy for HF.\n\nSignificance statement: Heart failure (HF) involves structural, electrical and contractile dysfunctions with limited curative options. This study highlights a novel gene therapy utilizing the auto-trans-regulatory properties of the Cav1.3 C-terminus. In an endothelin-1-induced HF model using human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs), AAV6-mediated delivery of the Cav1.3-C-terminus successfully reversed pathological remodeling. By normalizing action potential duration, critical ion channel expression (CACNA1D, CACNA1C KCNH2), and rescuing mechanical contractility, this gene therapy approach offers a highly promising, targeted therapeutic strategy for tackling the complex pathophysiology of heart failure.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 3,
  "authors": [
    {
      "name": "Yvonne Sleiman"
    },
    {
      "name": "Jean-Baptiste Reisqs",
      "orcid": "0000-0001-9881-6670"
    },
    {
      "name": "Mohamed Boutjdir"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0d0r4z55xyhsf.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.27.762268",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762268v1.full",
  "id": "0d0r4z55xyhsf",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762268v1",
  "language": "en",
  "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",
      "cell biology"
    ],
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2705|Cardiac electrophysiology and arrhythmias"
    ]
  ],
  "openalex": "W7224085747",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762268v1.full.pdf",
  "pmcid": "PMC13734026",
  "pmid": "42990367",
  "published": "2026-10-27",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/0d0r4z55xyhsf.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:30:11Z",
      "native_id": "10.64898/2026.10.27.762268",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.27.762268v1"
    },
    {
      "first_seen": "2026-11-08T12:23:41Z",
      "native_id": "PMC13734026",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.27.762268"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:cell biology",
      "subfield": "cell-biology"
    }
  ],
  "title": "Cav1.3-C-terminus Restores Electrical and Contractile Functions in hiPSC-derived Cardiomyocytes Model of Heart Failure",
  "title_text": "Cav1.3-C-terminus Restores Electrical and Contractile Functions in hiPSC-derived Cardiomyocytes Model of Heart Failure",
  "type": "preprint",
  "updated_at": "2026-11-08T12:23:41Z",
  "url": "https://research.draconitic.com/paper/0d0r4z55xyhsf",
  "venue": "bioRxiv",
  "versions": []
}