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<p>Atrial fibrillation (AF) and heart failure (HF) frequently coexist and worsen one another’s outcomes. To investigate shared molecular mechanisms, we compared atrial gene regulatory networks (GRNs) in the mouse <i>Tbx5</i> conditional knockout (<i>Tbx5</i> cKO) AF model and the transverse aortic constriction (TAC) HF model. Here we show highly correlated changes in atrial transcriptional and genomic profiles, including downregulated atrial <i>Tbx5</i> expression in both mouse and human HF. More than 100 transcription factor genes were coordinately dysregulated in the atria of the <i>Tbx5</i> cKO and TAC models. The wild-type atrial TBX5-driven GRN, including <i>Klf15</i>, a repressor of cardiomyocyte hypertrophy, was disrupted in <i>Tbx5</i> cKO and TAC models. Conversely, a disease-specific network featuring <i>Sox9</i> emerged in activated fibroblasts of <i>Tbx5</i> cKO and TAC models. Our results identify coordinated disruption of TBX5-dependent atrial gene regulation in AF and HF, suggesting that a shared genomic injury response may underlie the reciprocal risk between these conditions.</p>

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A reduced TBX5-dependent gene regulatory network links atrial fibrillation and heart failure

  • 期刊论文

  • 发表日期：

    2026年2月23日

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  • Sonja Lazarevic,
  • Carlos Perez-Cervantes,
  • Zhezhen Wang,
  • Kaitlyn M. Shen,
  • Margaret Gadek,
  • Junhua Xiao,
  • Naoko Yamaguchi,
  • Johnathon M. Hall,
  • Yildiz Koca,
  • Douglas J. Chapski,
  • Manuel Rosa-Garrido,
  • Marcello Rubino,
  • Rangarajan D. Nadadur,
  • Timothy A. McKinsey,
  • Thomas M. Vondriska,
  • Alexander J. Ruthenburg,
  • Sebastian Pott,
  • David S. Park,
  • Ivan P. Moskowitz

摘要

Atrial fibrillation (AF) and heart failure (HF) frequently coexist and worsen one another’s outcomes. To investigate shared molecular mechanisms, we compared atrial gene regulatory networks (GRNs) in the mouse Tbx5 conditional knockout (Tbx5 cKO) AF model and the transverse aortic constriction (TAC) HF model. Here we show highly correlated changes in atrial transcriptional and genomic profiles, including downregulated atrial Tbx5 expression in both mouse and human HF. More than 100 transcription factor genes were coordinately dysregulated in the atria of the Tbx5 cKO and TAC models. The wild-type atrial TBX5-driven GRN, including Klf15, a repressor of cardiomyocyte hypertrophy, was disrupted in Tbx5 cKO and TAC models. Conversely, a disease-specific network featuring Sox9 emerged in activated fibroblasts of Tbx5 cKO and TAC models. Our results identify coordinated disruption of TBX5-dependent atrial gene regulation in AF and HF, suggesting that a shared genomic injury response may underlie the reciprocal risk between these conditions.