Gene expression analysis of ischemic and nonischemic cardiomyopathy: shared and distinct genes in the development of heart failure

Abstract

Cardiomyopathy can be initiated by many factors, but the pathways from unique inciting mechanisms to the common end point of ventricular dilation and reduced cardiac output are unclear. We previously described a microarray-based prediction algorithm differentiating nonischemic (NICM) from ischemic cardiomyopathy (ICM) using nearest shrunken centroids. Accordingly, we tested the hypothesis that NICM and ICM would have both shared and distinct differentially expressed genes relative to normal hearts and compared gene expression of 21 NICM and 10 ICM samples with that of 6 nonfailing (NF) hearts using Affymetrix U133A GeneChips and significance analysis of microarrays. Compared with NF, 257 genes were differentially expressed in NICM and 72 genes in ICM. Only 41 genes were shared between the two comparisons, mainly involved in cell growth and signal transduction. Those uniquely expressed in NICM were frequently involved in metabolism, and those in ICM more often had catalytic activity. Novel genes included angiotensin-converting enzyme-2 (ACE2), which was upregulated in NICM but not ICM, suggesting that ACE2 may offer differential therapeutic efficacy in NICM and ICM. In addition, a tumor necrosis factor receptor was downregulated in both NICM and ICM, demonstrating the different signaling pathways involved in heart failure pathophysiology. These results offer novel insight into unique disease-specific gene expression that exists between end-stage cardiomyopathy of different etiologies. This analysis demonstrates that transcriptome analysis offers insight into pathogenesis-based therapies in heart failure management and complements studies using expression-based profiling to diagnose heart failure of different etiologies.

Comparison of Mesenchymal Stem Cell Efficacy in Ischemic Versus Nonischemic Dilated Cardiomyopathy

“…Nevertheless, both diseases are marked by some degree of fibrosis, remodeling, and a variable amount of viable, yet dysfunctional, myocardium 13, 17, 18. In addition, both are characterized by immune dysregulation with elevated circulating levels of inflammatory cytokines 19, 20. Persistent inflammation is a possible mechanism for the increased reactive oxygen species, nitroso‐redox imbalance, fibrosis, apoptosis, and impaired angiogenesis seen in LV remodeling 17, 21.…”

MicroRNAs in myocardial ischemia: identifying new targets and tools for treating heart disease. New frontiers for miR-medicine

“…A number of transcriptome studies have been applied to CvD, with the aim of improving diagnosis, prognosis, and therapeutic assessment [5][6][7]. Myocardial biopsies of patients suffering from acute/chronic myocardial ischemia, as well as animal models of ischemia and reperfusion (I/R), have revealed changes in gene expression which seem to be specific for the cardiac ischemic injury [8][9][10]. MicroRNAs (miRNAs) are important regulators of gene expression, constituting a major area of investigation in cardiovascular research [11].…”

Predict, prevent and personalize: Genomic and proteomic approaches to cardiovascular medicine

“…In the field of heart failure, many studies have performed binary comparisons of gene expression, such as failing and nonfailing heart (35-38), dilated and hypertrophic cardiomyopathy (39), and before and after left ventricular assist device placement (40)(41)(42). Other studies have included three-way comparisons: ischemic and nonischemic cardiomyopathy relative to nonfailing hearts (43,44), or failing and left ventricular assist device-supported hearts relative to nonfailing hearts (45).…”