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Tachycardia-Induced Cardiomyopathy As a Chronic Heart Failure Model in Swine
Published on: February 17, 2018
Transcriptomic profiling of the canine tachycardia-induced heart failure model: global comparison to human and murine
Zhong Gao1, Hai Xu, Deborah DiSilvestre
1Center for Cardiovascular Bioinformatics and Modeling, The Johns Hopkins University School of Medicine and Whiting School of Engineering, Baltimore, MD 21218, USA.
Insights
Canine tachycardia pacing models reveal shared and distinct gene expression changes in heart failure (HF) ventricles. This study compares canine HF transcriptomes to human and mouse models, offering insights into HF molecular pathways.
Area of Science:
- Cardiovascular Biology
- Molecular Genetics
- Comparative Pathology
Background:
- Cardiac gene expression alterations are fundamental to ventricular dysfunction in human heart failure (HF).
- The canine tachycardia pacing model effectively replicates key hemodynamic, echocardiographic, and electrophysiological changes seen in human HF.
- Understanding transcriptomic differences across species is crucial for developing effective HF therapies.
Purpose of the Study:
- To compare gene expression profiles in the left and right ventricles (LV, RV) of normal and end-stage failing canine hearts.
- To compare canine HF transcriptomic profiles with those from human and murine HF models.
- To elucidate molecular pathways underlying end-stage tachycardia-induced HF and interspecies transcriptomic variations.
Main Methods:
- Utilized a canine tachycardia pacing-induced heart failure model.
- Performed comparative transcriptomic analysis of left and right ventricles in normal and failing canine hearts.
- Compared canine HF gene expression data with existing human and murine HF datasets.
Main Results:
- In end-stage HF, the canine LV showed downregulation of genes involved in energy production, cardiac contraction, and excitation-contraction coupling.
- Most transcriptomic changes in canine HF were conserved between the LV and RV.
- Genes uniquely downregulated in the canine LV were associated with aerobic energy production, actin regulation, and receptor signaling.
- Interventricular differences in gene expression were observed in failing canine hearts, involving transcription factors like MEF2, MITF, and ATF4.
- Human HF involves broad gene downregulation, while experimental HF models primarily show energy pathway downregulation; human ischemic HF and canine HF share upregulated pathway similarities.
Conclusions:
- The canine tachycardia pacing model provides valuable insights into the molecular mechanisms of heart failure.
- Significant transcriptomic similarities and differences exist between canine, human, and murine HF models.
- Comparative transcriptomics can identify conserved and species-specific molecular pathways in heart failure, guiding therapeutic strategies.
Abstract:
Alterations of cardiac gene expression are central to ventricular dysfunction in human heart failure (HF). The canine tachycardia pacing-induced HF model is known to reproduce the main hemodynamic, echocardiographic and electrophysiological changes observed in human HF. In this study, we use this HF model to compare gene expression profiles in the left and right ventricles (LV, RV) of normal and end-stage failing canine hearts and compare the transcription profiles to those in human and murine models of HF. In end-stage HF, the LV exhibits down regulation of genes involved in energy production, cardiac contraction, and modulation of excitation-contraction coupling as compared with normal LV. The majority of transcriptomic changes between normal and end-stage canine HF were shared by the RV and LV. Genes down regulated only in the LV included those involved in aerobic energy production pathways, regulation of actin filament length, and enzyme-linked receptor protein signaling pathways. In normal canine hearts, genes encoding specific components of the contractile apparatus exhibit LV-RV asymmetric expression patterns; in failing hearts, cardiac fetal transcription factors MEF2 and MITF and the stress-responsive transcription factor ATF4 showed interventricular differences in expression. The comparison among the canine tachypacing, mouse transgenic, and human HF reveals that human disease involves down regulation of genes in a broad range of biological processes while experimentally induced HF is associated with down regulation of energy pathways, and that human ischemic HF and canine HF share a similar over representation of transcriptional pathways in the up regulated genes. This study provides insights into the molecular pathways leading to end-stage tachycardia-induced HF, and into global transcriptomic differences between the animal HF models and human HF.
