Gene expression profiling reveals potential prognostic biomarkers associated with the progression of heart failure

Abstract

Background: Heart failure (HF) is the most common cause of morbidity and mortality in developed countries. Here, we identify biologically relevant transcripts that are significantly altered in the early phase of myocardial infarction and are associated with the development of post-myocardial infarction HF.

Methods: We collected peripheral blood samples from patients with ST-segment elevation myocardial infarction (STEMI): n = 111 and n = 41 patients from the study and validation groups, respectively. Control groups comprised patients with a stable coronary artery disease and without a history of myocardial infarction. Based on plasma NT-proBNP level and left ventricular ejection fraction parameters the STEMI patients were divided into HF and non-HF groups. Microarrays were used to analyze mRNA levels in peripheral blood mononuclear cells (PBMCs) isolated from the study group at four time points and control group. Microarray results were validated by RT-qPCR using whole blood RNA from the validation group.

Results: Samples from the first three time points (admission, discharge, and 1 month after AMI) were compared with the samples from the same patients collected 6 months after AMI (stable phase) and with the control group. The greatest differences in transcriptional profiles were observed on admission and they gradually stabilized during the follow-up. We have also identified a set of genes the expression of which on the first day of STEMI differed significantly between patients who developed HF after 6 months of observation and those who did not. RNASE1, FMN1, and JDP2 were selected for further analysis and their early up-regulation was confirmed in HF patients from both the study and validation groups. Significant correlations were found between expression levels of these biomarkers and clinical parameters. The receiver operating characteristic (ROC) curves indicated a good prognostic value of the genes chosen.

Conclusions: This study demonstrates an altered gene expression profile in PBMCs during acute myocardial infarction and through the follow-up. The identified gene expression changes at the early phase of STEMI that differentiated the patients who developed HF from those who did not could serve as a convenient tool contributing to the prognosis of heart failure.

Figure 1

Outline of study design.

Figure 2

Top enriched GO categories among genes differentially expressed on admission versus 6 months after AMI.

Figure 3

Top scoring interaction network for 77 differentially expressed transcripts in the acute phase of MI. The network is classified as ‘Cell-To-Cell Signaling and Interaction, Hematological System Development and Function, Immune Cell Trafficking’. Genes or gene products are represented as nodes, and the biological relationship between two nodes is represented as solid line (direct relationships) or dotted line (indirect relationship). Upregulated and downregulated genes are shown in red and green shading, respectively, with color intensity related to the fold change in expression.

Figure 4

Outline of selection and distribution of patients from HF, non-HF, and control groups.

Figure 5

Gene changes over time for investigated HF biomarkers in study and validation groups. Gene expression changes were investigated in HF, non-HF, and control groups at different time points after AMI (on day 1, 4 to 6 days, 1 month, and 6 months) using RT-qPCR. Red line: study group, black line: validation group. Data represent gene expression ratio ± standard error. The error bars are absent when smaller than the size of the symbols. Statistical significance: *P <0.05; **P <0.01; ***P <0.001.

Figure 6

ROC curves for FMN1 , JDP2 , and RNASE1. AUC, area under the curve; ROC, receiver operating characteristic.