A systematic review has identified specific microRNA expression changes associated with chronic thromboembolic pulmonary hypertension.
In the study, published in Pulmonary Circulation, researchers found seven consistently upregulated and nine consistently downregulated microRNAs (miRNAs) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) compared with controls.
The researchers systematically reviewed studies examining miRNA expression in patients with CTEPH compared with controls. The review included 9 studies with a total of 235 participants. All studies analyzed blood samples using quantitative real-time polymerase chain reaction (qRT-PCR).
The systematic review followed PRISMA guidelines and was registered in PROSPERO (CRD42024524469). Inclusion criteria encompassed studies on miRNA expression in CTEPH with comparative or analytic designs. Exclusion criteria included nonhuman studies, interventions, non-English texts, conference abstracts, and editorials.
The researchers searched the PubMed, EMBASE, Scopus, CENTRAL, and ProQuest databases. The Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool assessed bias risk. Results were synthesized narratively because of heterogeneity in study designs and methodologies.
Among the key findings were:
- Upregulated microRNA (miRNAs): miR-665, miR-3202, miR-382, miR-127, miR-664, miR-376c, and miR-30a
- Downregulated miRNAs: miR-20a-5p, miR-17-5p, miR-93-5p, miR-22, let-7b, miR-106b-5p, miR-3148, miR-320-a, and miR-320b
- Two upregulated miRNAs (miR-127 and miR-30a) were consistently associated with mechanisms inducing CTEPH development
- Five downregulated miRNAs (miR-20-a, miR-17-5p, miR-93-5p, let-7b, miR-106b-5p) were associated with protective effects against CTEPH.
Upregulated miRNAs:
- miR-665, miR-3202, and miR-382 were reported as upregulated in three studies each
- miR-127, miR-664, miR-376c, and miR-30a were reported as upregulated in one study each.
Downregulated miRNAs:
- miR-17-5p was reported as downregulated in three studies
- miR-106b-5p and miR-93-5p were reported as downregulated in two studies each
- miR-20a-5p, miR-22, let-7b, miR-3148, miR-320-a, and miR-320b were reported as downregulated in one study each.
Mechanisms:
- miR-127: promotes inflammation by activating the JNK pathway, leading to pulmonary artery smooth muscle cell (PASMC) remodeling
- miR-30a: associated with Factor VIII and Factor XI dysregulation; upregulation linked to acute myocardial infarction
- miR-20-a: inhibits tissue factor, preventing thrombotic events
- miR-17-5p: promotes apoptosis through tumor susceptibility gene 101
- miR-93-5p: suppresses vascular endothelial growth factor (VEGF) gene expression
- let-7b: increases apoptosis and inhibits vascular smooth muscle proliferation and remodeling
- miR-106b-5p: suppresses neuron-derived orphan receptor-1 (NOR-1), inhibiting PASMC proliferation, migration, and remodeling.
Additional statistics and data:
- The initial literature search yielded 313 unique studies
- After abstract screening, 39 full texts were reviewed
- Sample sources: 4 studies used plasma, 1 used serum, and 4 did not specify the blood sample type
- miRNA isolation methods varied: miRNeasy Serum/Plasma kit, RNAprep Pure Blood kit, TRI Reagent®, and TRIzol reagent were used
- miRNA concentration assessment: 3 studies used Qubit® Fluorometer, 2 used Nanodrop ND1000 spectrophotometer, and 4 did not specify
- Integrity analysis: 5 studies used Agilent 2100 Bioanalyzer, while 4 did not specify the method
- 8 studies employed qRT-PCR as a confirmatory assay, while 1 study used RT-PCR followed by 2−ΔΔCt calculation
- 7 studies measured miRNA expression as relative expression to the control group
- Risk of bias assessment: 6 studies were classified as high risk in the domain of patient selection as a result of their case-control design.
The review identified inconsistencies in the existing literature regarding five upregulated miRNAs (miR-665, miR-3202, miR-382, miR-664, and miR-376c) and four downregulated miRNAs (miR-22, miR-3148, miR-320-a, and miR-320b) in relation to CTEPH development.
The researchers noted several limitations, including heterogeneity in study designs and methodologies, potential selection bias in case-control studies, inability to establish causal relationships because of study designs, possible influence of pre-analytical and analytical factors on miRNA detection, potential differences in miRNA expression among ethnic groups, and inclusion of only English-language studies, potentially introducing language bias.
The identified miRNAs may serve as potential biomarkers for CTEPH diagnosis, prognosis, or treatment response. The researchers highlighted the need for further research to validate these findings and explore the therapeutic potential of targeting specific miRNAs in CTEPH.
The authors declared no conflict of interest.