Transcriptome from circulating cells suggests dysregulated pathways associated with long-term recurrent events following first-time myocardial infarction

J Mol Cell Cardiol. 2014 Sep;74:13-21. doi: 10.1016/j.yjmcc.2014.04.017. Epub 2014 May 4.

Abstract

Background: Whole-genome gene expression analysis has been successfully utilized to diagnose, prognosticate, and identify potential therapeutic targets for high-risk cardiovascular diseases. However, the feasibility of this approach to identify outcome-related genes and dysregulated pathways following first-time myocardial infarction (AMI) remains unknown and may offer a novel strategy to detect affected expressome networks that predict long-term outcome.

Methods and results: Whole-genome expression microarray on blood samples from normal cardiac function controls (n=21) and first-time AMI patients (n=31) within 48-hours post-MI revealed expected differential gene expression profiles enriched for inflammation and immune-response pathways. To determine molecular signatures at the time of AMI associated with long-term outcomes, transcriptional profiles from sub-groups of AMI patients with (n=5) or without (n=22) any recurrent events over an 18-month follow-up were compared. This analysis identified 559 differentially-expressed genes. Bioinformatic analysis of this differential gene-set for associated pathways revealed 1) increasing disease severity in AMI patients is associated with a decreased expression of genes involved in the developmental epithelial-to-mesenchymal transition pathway, and 2) modulation of cholesterol transport genes that include ABCA1, CETP, APOA1, and LDLR is associated with clinical outcome.

Conclusion: Differentially regulated genes and modulated pathways were identified that were associated with recurrent cardiovascular outcomes in first-time AMI patients. This cell-based approach for risk stratification in AMI could represent a novel, non-invasive platform to anticipate modifiable pathways and therapeutic targets to optimize long-term outcome for AMI patients and warrants further study to determine the role of metabolic remodeling and regenerative processes required for optimal outcomes.

Keywords: Acute myocardial infarction; blood; microarray; pathway analysis; transcriptome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter 1 / genetics
  • ATP Binding Cassette Transporter 1 / metabolism
  • Adult
  • Aged
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / metabolism
  • Biological Transport
  • Case-Control Studies
  • Cholesterol / metabolism
  • Cholesterol Ester Transfer Proteins / genetics
  • Cholesterol Ester Transfer Proteins / metabolism
  • Disease Progression
  • Epithelial-Mesenchymal Transition / genetics
  • Female
  • Follow-Up Studies
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Inflammation / diagnosis
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / pathology
  • Male
  • Metabolic Networks and Pathways / genetics*
  • Middle Aged
  • Myocardial Infarction / diagnosis
  • Myocardial Infarction / genetics*
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / pathology
  • Prognosis
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism
  • Transcriptome*

Substances

  • ABCA1 protein, human
  • APOA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Apolipoprotein A-I
  • CETP protein, human
  • Cholesterol Ester Transfer Proteins
  • LDLR protein, human
  • Receptors, LDL
  • Cholesterol