Genes linked with inflammatory processes are differentially expressed in patients with chronic heart failure and pain

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2022-09
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American English
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Abstract

Background and Aims Pain is a significant problem among patients with chronic heart failure (HF). The mechanisms underlying pain in HF remain poorly understood. Gene expression analysis using mRNA sequencing can highlight mechanistic underpinnings of complex symptoms such as pain. The aim of this study was to identify differentially expressed genes linked with pain in patients with HF with pain compared with patients with HF but without pain. The research question was: what genes linked with pain are differentially expressed between patients with HF and pain compared to patients with HF without pain? Methods Data were collected as part of a parent randomized controlled trial to test the efficacy of a computerized cognitive intervention for memory among patients with chronic HF (R01 NR016116). Blood specimens, pain measures, and sociodemographic characteristics were collected during the baseline visit in the parent trial. Data from 40 patients with HF: 20 with pain and 20 without pain, were analyzed in the current study. Pain presence (yes/no) was assessed using 1 item of the Health Utilities Index Mark-3 questionnaire. Sociodemographic data collected were age, self-reported gender, race and ethnicity, years of education, marital status, depressive symptoms (Patient Health Questionnaire-8), and health-related quality of life (Minnesota Living with Heart Failure Questionnaire). Clinical characteristics included body mass index, left ventricular ejection fraction (LVEF), and New York Heart Association heart failure class. Differences in demographic and clinical variables between the pain and no pain groups were examined using independent samples t-tests and chi square. The mRNA was isolated from whole blood and sequenced using a 150bppaired-end read configuration. Genes were tested for differential expression between HF patients with pain and without pain using DESeq2. Genes were considered differentially expressed if the log fold change between groups was ≥ ± 0.58 with a false discovery p-value < 0.05. Differentially expressed genes were examined using protein-protein interactions analysis, disease-related biological pathways, and existing pain literature. Independent samples t-tests were used to identify statistically significant differences in gene expression between the pain and no pain groups. Target genes of interest were validated through real-time polymerase chain reaction in a different sample of 24 patients: 10 with pain and 14 without pain, selected from the parent study and matched to the discovery sample on age and gender. Results Among the patients with pain, the mean age was 66.45 ± 6.21 years compared to 62.65 ± 13.87 years in the patients with pain. Most patients were men (60% in the pain group vs. 70% in the no pain group) and White(75% vs. 60%, respectively). The sample was primarily New York Heart Association class II (42.5%), with an average LVEF of 42.56% ± 13.58%. There were no statistically significant differences in demographic or clinical status variables between patients with and without pain. A total of 334 differentially expressed genes were identified (279 upregulated and 55 downregulated); they were mostly involved in neutrophil degranulation pathways (n = 57, false discovery p-value = 7.9e-17), followed by extracellular matrix organization pathways (n = 19, false discovery p-value = 4.5e-03). The protein-protein interactions analysis produced a network of 288 nodes and 497 edges, compared to the expected number of 182 edges(enrichment p-value < 1.0e-16), with a core network consisting of 15 co-expressed genes. From this core network of 15 genes, 7 target genes of interest were identified: (1) cathepsin G (CTSG), (2) lactotransferrin(LTF), (3) lipocalin-2 (LCN2), (4) matrix metallopeptidase 8 (MMP8), (5) matrix metallopeptidase 9 (MMP9), (6)proprotein convertase subtilisin/kexin type 9 (PCSK9), and (7) neutrophil defensin 3 (DEFA3). All 7 genes were connected to inflammatory pathways and inflammatory pain conditions (e.g., arthritis) in existing pain literature. All 7 genes were upregulated in patients with HF and pain compared to those with HF and without pain. Three of these 7 genes (MMP8,PCSK9,andDEFA3) were also validated in the second sample of 24patients with HF. Conclusions This study identified 7 genes that were differentially expressed in patients with chronic HF and pain compared to patients with HF but no pain. Of these, 3 were validated in an additional sample which further strengthens the proposed connection of these genes with pain. The genes were significantly enriched in inflammatory and extracellular matrix organization and may play a role in development of chronic pain among patients with HF. This study is novel in that the biologic mechanisms underlying pain in this population have not been previously examined using gene expression analysis. Further research is needed with a more ethnically diverse sample and more robust pain measures, particularly regarding severity and locations of pain.

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Smith, A. B., Dorsey, S. G., Mocci, E., Jung, M., Pressler, S. J., International Association for the Study of Pain 2022 World Congress on Pain, "Genes linked with inflammatory processes are differentially expressed in patients with chronic heart failure and pain.," International Association for the Study of Pain, Toronto, Canada. (September 2022).
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The parent study was funded by the National Institute of Nursing Research (R01 NR016116). This current study was funded by an Advancing Early Research Opportunities (AERO) Grant from the Rita and Alex Hillman Foundation. This study was supported by a T32 postdoctoral Fellowship from the National Institute of Nursing Research (T32 NR018407).
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