Abstract 18692: Reciprocal Regulation of Metabolic and Signaling Pathways Correlates with Disease Severity in Heart Failure
Background: Systolic heart failure (HF) is a complex systemic syndrome that can result from a wide variety of clinical conditions and genetic mutations. Despite phenotypic similarities, characterized by ventricular dilatation and reduced contractility, the extent of common and divergent gene expression between different forms of HF remains a matter of intense debate.
Methods and Results: Using a meta-analysis of more than 30 experimental (mouse, rat, dog) and human HF microarray studies, we demonstrate that gene expression changes are characterized by a coordinated and reciprocal regulation of major metabolic and signaling pathways. In response to a wide variety of stressors in animal models of HF, including ischemia, pressure overload, tachypacing, chronic isoproterenol infusion, Chagas disease, and transgenic mouse models, major metabolic pathways are invariably downregulated, while cell signaling pathways are upregulated. In contrast to this uniform transcriptional pattern which recapitulates a fetal gene expression program in animal models of HF, human HF studies displayed a greater heterogeneity, with some studies even showing upregulation of metabolic and downregulation of signaling pathways in HF. These discrepant results between animal and human studies are due to a number of factors, prominently cardiac disease and variable exposure to cold cardioplegic solution in non-failing human samples which can downregulate transcripts involved in oxidative phosphorylation (OXPHOS) within the first 6h, thus mimicking gene expression patterns observed in failing samples. Additionally, beta-blockers and ACE-inhibitor use in human HF was associated with higher levels of myocardial OXPHOS transcripts, thus partially reversing the fetal gene expression pattern. In human failing samples, downregulation of metabolism was associated with hemodynamic markers of disease severity.
Conclusions: Irrespective of the etiology, gene expression in failing myocardium is characterized by downregulation of metabolic transcripts and concomitant upregulation of cell signaling pathways. Gene expression changes along this metabolic-signaling axis in mammalian myocardium are associated with disease severity in human HF.
- © 2010 by American Heart Association, Inc.