Abstract
Purpose
The development of chronic obstructive pulmonary disease (COPD) is often accompanied by pulmonary heart disease (PHD). However, PHD lacks effective diagnostic markers in its early stages, making it difficult to detect. miR-192-5p is closely associated with respiratory diseases and may serve as an effective diagnostic biomarker. This study aims to investigate the diagnostic value of miR-192-5p in PHD.
Patients and Methods
This study included patients with COPD alone (n=120) and those with COPD complicated with PHD (n=140). Serum miR-192-5p levels were detected using RT-qPCR, while TNF-α and IL-6 concentrations were measured via ELISA kits. Hospitalization-related diagnostic indicators were concurrently collected for comparative analysis. The diagnostic value of miR-192-5p was assessed using receiver operating characteristic curve analysis, and risk factors were identified through logistic regression analysis.
Results
miR-192-5p level is significantly downregulated in serum samples from non-PHD and PHD patients. It demonstrates diagnostic performance for PHD with an AUC of 0.789 (78.6% sensitivity, 64.2% specificity) and distinguishes healthy from non-PHD with an AUC of 0.873 (90.0% sensitivity, 70.0% specificity). And its low expression is one of the primary risk factors for PHD development. Further analysis reveals that miR-192-5p levels show a significant negative correlation with inflammatory markers and are closely associated with patients’ cardiopulmonary function indicators.
Conclusion
miR-192-5p is significantly downregulated in PHD, and low levels of miR-192-5p represent one of the risk factors for PHD development. It can effectively distinguish between healthy individuals and non-PHD patients, and demonstrating moderate diagnostic accuracy in distinguishing between non-PHD patients and PHD patients, and is expected to become a viable diagnostic biomarker.
Keywords: miR-192-5p, chronic obstructive pulmonary disease, pulmonary heart disease, inflammation
Introduction
Chronic obstructive pulmonary disease (COPD) is a respiratory disease with persistent airflow limitation and chronic airway inflammation.1 The prevalence rate among Chinese individuals aged 40 and above reaches 13.7%, affecting approximately 100 million patients.2 The long-term progression of COPD can lead to chronic pulmonary heart disease (PHD), with elderly patients being particularly susceptible to secondary heart failure. This significantly increases the risk of infection and mortality.3 More critically, these two conditions often coexist, jointly contributing to or exacerbating approximately 10% of hospitalizations. However, the diagnosis of one disease may mask the presence of the other, resulting in fewer than half of patients with comorbidities receiving appropriate evaluation and diagnosis.4 Currently, cardiac catheterization remains the gold standard for PHD diagnosis, but as an invasive procedure, it carries relatively high risks.5 Although transthoracic echocardiography (TTE) is widely used as a non-invasive screening tool, its accuracy is limited by operator dependency and poor acoustic windows, especially in COPD patients with emphysema.6 Other non-invasive methods such as chest CT and cardiac MRI are costly with limited accessibility, while serum biomarkers like BNP/NT-proBNP lack specificity due to interference from cardiac and renal dysfunction.7 Therefore, identifying simple, specific, and cost-effective diagnostic biomarkers is crucial for the comprehensive management of patients with complications.
In recent years, with advances in technology, the potential of microRNA (miRNA) as a biomarker for biological diagnosis has been progressively uncovered. For example, miR-3591-5p has demonstrated good diagnostic value in pulmonary arterial hypertension.8 miR-192-5p has been demonstrated to participate in the pathological regulation of multiple respiratory diseases and serves as the core target of this study. Its serum levels are significantly reduced in pediatric severe pneumonia with respiratory failure, demonstrating high diagnostic efficacy.9 Furthermore, miR-192-5p can be utilized to assess the risk of disease deterioration in COVID-19 patients.10 Its downregulation in asthma may promote disease progression via Th2-mediated inflammation and airflow obstruction.11 Crucially, analysis of the Gene Expression Omnibus (GEO) database reveals that miR-192-5p is also downregulated in COPD and can target multiple disease-related genes, positioning it as a key central regulatory molecule.12 Concurrently, miR-192-5p has been demonstrated to be closely associated with cardiovascular disease risk in middle-aged and elderly populations.13 Collectively, these findings suggest that miR-192-5p may contribute to the pathogenesis and progression of PHD, but its precise regulatory mechanisms warrant further investigation.
To investigate the diagnostic value of miR-192-5p for PHD, we measured miR-192-5p levels in serum samples from COPD patients and PHD patients, and analyzed the correlation between miR-192-5p levels and indicators of cardiopulmonary function. We aim to provide valuable information for the diagnosis of comorbid conditions.
Materials and Methods
Patient Inclusion
This study enrolled COPD patients admitted to the department of respiratory medicine at Hangzhou First People’s Hospital Tonglu Campus between July 2024 and April 2025. The 260 enrolled COPD patients were divided into two groups based on the presence of PHD: 120 COPD patients without PHD (non-PHD group, n=120) and 140 COPD patients with PHD (PHD group, n=140). Concurrently, healthy individuals undergoing physical examinations at the hospital during the same period were selected as the control group (n=160). The inclusion criteria are as follows: Healthy control group: No history of chronic respiratory diseases; normal pulmonary function and chest CT scan results; no cardiovascular disease, liver or kidney dysfunction, or malignant tumors; and no acute infections within the past 3 months. Non-PHD group: Patients meeting diagnostic criteria for non-PHD obstructive lung disease14 with chronic respiratory symptoms and a FEV1/FVC ratio < 0.70 following bronchodilator treatment. Meet all of the following conditions: 1) Clinically stable, with no acute exacerbations in the past 4 weeks, and no use of systemic corticosteroids or antibiotics; 2) Echocardiographic criteria: Pulmonary artery systolic pressure < 36 mmHg, estimated using the tricuspid regurgitation method (The cut-off values for echocardiographic parameters were selected based on the recommendations of the European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines for the diagnosis of pulmonary hypertension);15 Right ventricular wall thickness < 5 mm; right ventricular end-diastolic diameter < 20 mm; no right ventricular enlargement or hypertrophy; no signs of right heart failure, including jugular vein distension, positive hepatojugular reflux, or lower extremity edema. PHD Group Inclusion Criteria: met diagnostic criteria for COPD and PHD,16 including the mandatory criterion of a pulmonary artery systolic pressure ≥ 36 mmHg as determined by echocardiography, as well as any one of the following criteria: 1) Echocardiography demonstrating widened pulmonary artery diameter and signs of right ventricular enlargement or hypertrophy; 2) History of COPD; 3) Fatigue and dyspnea on exertion; 4) Physical examination revealing signs of PHD; 5) Characteristic radiographic or electrocardiographic changes suggestive of PHD; 6) Meeting diagnostic criteria for COPD. Exclusion Criteria: 1) Concurrent pulmonary diseases such as bronchial asthma, pulmonary embolism, interstitial lung disease, pneumoconiosis, or lung abscess; cardiovascular diseases include ischemic heart disease, hypertensive heart disease, valvular heart disease, cardiomyopathy, congenital heart disease, and severe arrhythmias. 2) Severe hepatic or renal insufficiency, malignant tumors, or hematological disorders; 3) Patients with autoimmune diseases or those currently undergoing immunosuppressive therapy; 4) Presence of psychiatric disorders rendering the subject unable to cooperate with the study. This study was supported by the Ethics Committee of Hangzhou First People’s Hospital Tonglu Campus, and all patients signed informed consent forms. (Ethics Approval Number: IRB-2023-34; Approval Date: 2023–08-27) The procedures used in this study adhere to the tenets of the Declaration of Helsinki.
Sampling and Collection of Clinical Data
Venous blood was drawn from all subjects, and serum was obtained after centrifugation. Collected serum was stored at −80°C for subsequent testing. Samples were protected from repeated freeze-thaw cycles; hemolyzed samples were re-collected, and discarded samples were disposed of according to regulations. Subject age, gender, and smoking history information were collected based on data entered into the system.
RT-qPCR
Total RNAs from serum were isolated with TRIzol reagent (Invitrogen, USA). RNA concentration and purity were assessed by NanoDrop 2000 spectrophotometer (Thermo Fisher Scientific); samples with A260/A280 ratios between 1.8–2.1 and A260/A230 ratios > 1.5 were considered acceptable These RNAs were reversely transcribed into cDNA using PrimeScript RT reagent kit (TaKaRa, Dalian, China) and then amplified using miScript SYBR-Green PCR kit (TaKaRa) on a 7500 Fast RT-PCR system (Applied Biosystems, Foster City, USA). The final levels were calculated by the 2−ΔΔCT method.
Inflammation Marker Testing
The CRP concentration in serum was measured using an immunoturbidimetric assay.
The concentrations of IL-6 and TNF-α in serum were measured using the IL-6 ELISA Kit (CSB-E04638h, Huamei Bio) and the TNF-α ELISA Kit (CSB-E04740h, Huamei Bio). In brief, after adding 100 μL of standard or sample to the pre-coated microplate wells, incubate at 37°C for 90 minutes, followed by thorough washing. Add the biotin-labeled detection antibody and incubate at 37°C for 60 minutes. After washing, add the avidin-HRP incubation mixture and continue incubating at 37°C for 30 minutes. Add TMB substrate and incubate at 37°C in the dark for 15 minutes. Measure absorbance at 450 nm using a microplate reader and calculate IL-6 and TNF-α concentrations based on the standard curve.
Cardio-Pulmonary Function Testing
Pulmonary function parameters [forced expiratory volume in one second (FEV1), FEV1 as a percentage of forced vital capacity (FEV1/FVC)] were measured using a spirometer (YM0070814, Grete GmbH, Germany). Each subject underwent three measurements, with the optimal pulmonary function value serving as the final result. NT-proBNP concentrations were determined using the Elecsys® proBNP II assay kit (09744959190, Roche). Patients underwent echocardiography within 48 hours of admission to obtain left ventricular ejection fraction (LVEF) and pulmonary artery systolic pressure (PASP) data.
Data Analysis
Data were analyzed using SPSS 27.0. The chi-square test was used to compare categorical variables between two groups. The independent samples t-test was used to compare the means of normally distributed variables between two groups and analysis of variance (ANOVA) was used to compare variables among three groups. Pearson correlation analysis was employed for correlation analysis, with the correlation coefficient denoted as r. Binary logistic regression analysis was used to evaluate risk factors, and the ROC curve was used to determine the diagnostic value of miR-192-5p. All statistical tests were considered statistically significant at P < 0.05.
Results
Comparison of Clinical Data Among Subjects
As shown in Table 1, the healthy group, non-PHD group, and PHD group were well matched in demographic characteristics including age, gender distribution, smoking status, and GOLD stage (P > 0.05). Conversely, significant intergroup differences were observed in inflammatory markers (CRP, IL-6, TNF-α), pulmonary function (FEV1/FVC), and cardiac parameters (NT-proBNP, LVEF, PASP), with P < 0.001. These indicators progressively worsened from healthy controls to non-PHD patients, with the most severe abnormalities observed in the PHD cohort, indicating more pronounced systemic inflammation, pulmonary dysfunction, and cardiac impairment in PHD patients.
Table 1.
General Information of the Study Subjects
| Healthy (n=160) | non-PHD (n=120) | PHD (n=140) | P Value | |
|---|---|---|---|---|
| Age (years) | 68.85±6.83 | 68.87±10.61 | 67.33±7.25 | 0.389 |
| Female/Male | 54/106 | 38/82 | 47/93 | 0.925 |
| Smoking (Yes/No) | 71/89 | 69/51 | 74/66 | 0.081 |
| CRP (pg/mL) | 3.45±1.04 | 12.51±3.72 | 14.50±4.13 | <0.001 |
| IL-6 (pg/mL) | 3.58±1.41 | 11.62±4.08 | 13.50±3.68 | <0.001 |
| TNF-α (pg/mL) | 1.01±0.25 | 2.70±0.96 | 3.19±1.21 | <0.001 |
| FEV1/FVC (%) | 84.10±14.08 | 61.95±10.96 | 59.91±11.71 | <0.001 |
| NT-proBNP (pg/mL) | / | 318.64±93.05 | 473.85±188.91 | <0.001 |
| LVEF (%) | / | 59.52±7.31 | 56.95±9.09 | <0.001 |
| PASP (mmHg) | / | 39.92±13.01 | 57.00±18.08 | <0.001 |
| GOLD stage (2–4) | / | 30/52/38 | 37/60/43 | 0.800 |
Abbreviations: PHD, pulmonary heart disease; CRP, C-reactive protein; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure; GOLD, Global Initiative for Chronic Obstructive Lung Disease.
The Diagnostic Value of miR-192-5p
miR-192-5p levels in the healthy were significantly higher than those in the non-PHD group and PHD group patients (P < 0.001), and levels in the non-PHD group were significantly higher than those in the PHD group (Figure 1A). ROC curve analysis confirmed that miR-192-5p demonstrated excellent discriminatory performance. Its AUC value for distinguishing healthy controls from non-PHD patients reached 0.873 (sensitivity = 90.0%, specificity = 70.0%), while the AUC value for differentiating non-PHD from PHD patients was 0.789 (sensitivity = 78.6%, specificity = 64.2%) (Figure 1B and C).
Figure 1.
Expression and diagnostic value of miR-192-5p in PHD. (A) miR-126 is downregulated in PHD. (B) miR-192-5p effectively distinguishes healthy individuals from non-PHD patients. (C) miR-192-5p effectively distinguishes between non-PHD and PHD patients. *** P < 0.001.
Correlation Between miR-192-5p Levels and Inflammation and Cardiopulmonary Function
In PHD patients, miR-192-5p levels were associated with CRP (P = 0.024), TNF-α (P = 0.036), NT-proBNP (P = 0.018), FEV1/FVC (P = 0.028), LVEF (P = 0.043) and PASP (P = 0.042), but showed no significant association with smoking status (P = 0.240) or IL-6 levels (P = 0.171) (Table 2). Correlation analysis revealed that the relative of miR-192-5p level showed significant negative correlations with CRP (r = −0.759, P < 0.001), IL-6 (r = −0.695, P < 0.001), and TNF-α (r = −0.764, P < 0.001) (Figure 2A–2C). It also showed negative correlations with cardiac markers NT-proBNP (r = −0.619, P < 0.001) and PASP (r = −0.716, P < 0.001), and positive correlations with functional indicators FEV1/FVC (r = 0.701, P < 0.001) and LVEF (r = 0.672, P < 0.001) (Figure 3A–3D), indicating that reduced miR-192-5p expression in PHD patients correlates with increased systemic inflammation, impaired lung function, and worsening cardiac function. These results indicate that miR-192-5p levels are closely associated with inflammation and cardiopulmonary function in patients with PHD.
Table 2.
Association Between miR-192-5p and Clinical Features of PHD Patients
| Feature | Cases (n = 140) | miR-192-5p | P Value | |
|---|---|---|---|---|
| Low Expression (n = 71) | High Expression (n = 69) | |||
| Smoking | 0.240 | |||
| No | 66 | 30 | 36 | |
| Yes | 74 | 41 | 33 | |
| CRP (pg/mL) | 0.024 | |||
| <14.50 | 82 | 35 | 47 | |
| ≥14.50 | 58 | 36 | 22 | |
| IL-6 (pg/mL) | 0.171 | |||
| <13.50 | 75 | 34 | 41 | |
| ≥13.50 | 65 | 37 | 28 | |
| TNF-α (pg/mL) | 0.036 | |||
| <3.19 | 83 | 36 | 47 | |
| ≥3.19 | 57 | 35 | 22 | |
| FEV1/FVC (%) | 0.028 | |||
| <59.91 | 80 | 47 | 33 | |
| ≥59.91 | 60 | 24 | 36 | |
| NT-proBNP (pg/mL) | 0.018 | |||
| <579.18 | 69 | 28 | 41 | |
| ≥579.18 | 71 | 43 | 28 | |
| LVEF (%) | 0.043 | |||
| < 56.95 | 75 | 44 | 31 | |
| ≥ 56.95 | 65 | 27 | 38 | |
| PASP (mmHg) | 0.042 | |||
| <58.47 | 73 | 31 | 42 | |
| ≥58.47 | 67 | 40 | 27 | |
Abbreviations: PHD, pulmonary heart disease; CRP, C-reactive protein; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure.
Figure 2.
The relationship between miR-192-5p and inflammation. miR-192-5p levels showed a significant negative correlation with (A) CRP, (B) IL-6, and (C) TNF-α concentrations.
Figure 3.
The relationship between miR-192-5p and cardiopulmonary biomarker function. miR-192-5p levels were correlated with (A) FEV1/FVC ratio, (B) NT-proBNP concentration, (C) LEFV values, and (D) PASP concentration.
miR-192-5p Levels are a Protective Factor for PHD
Logistic regression analysis indicated that miR-192-5p level (OR = 0.156, P < 0.001) was a protective factor against PHD. Conversely, CRP (OR = 1.945, P = 0.026), IL-6 (OR = 2.015, P = 0.020), FEV1/FVC (OR = 0.530, P = 0.036), NT-proBNP (OR = 2.136, P = 0.012), and PASP (OR = 2.393, P = 0.004) were independent risk factors. Smoking, TNF-α levels and LVEF showed no significant association with PHD risk (P > 0.05) (Table 3). This analysis confirmed that low levels of miR-192-5p expression are an independent risk factor for PHD, with predictive value comparable to that of inflammatory markers and cardiopulmonary function indices.
Table 3.
Logistic Regression Analysis of Risk Factors for PHD
| Variable | OR | 95% CI for OR | P Value | |
|---|---|---|---|---|
| Lower | Upper | |||
| miR-192-5p | 0.156 | 0.084 | 0.289 | < 0.001 |
| Smoking | 0.789 | 0.440 | 1.414 | 0.425 |
| CRP (pg/mL) | 1.945 | 1.081 | 3.498 | 0.026 |
| IL-6 (pg/mL) | 2.015 | 1.116 | 3.637 | 0.020 |
| TNF-α (pg/mL) | 1.353 | 0.752 | 2.436 | 0.313 |
| FEV1/FVC (%) | 0.530 | 0.293 | 0.958 | 0.036 |
| NT-proBNP (pg/mL) | 2.136 | 1.183 | 3.857 | 0.012 |
| LVEF (%) | 0.572 | 0.313 | 1.045 | 0.069 |
| PASP (mmHg) | 2.393 | 1.319 | 4.341 | 0.004 |
Abbreviations: PHD, pulmonary heart disease; CRP, C-reactive protein; IL-6, interleukin-6; TNF-α, tumor necrosis factor-α; LVEF, left ventricular ejection fraction; PASP, pulmonary artery systolic pressure.
Discussion
COPD and its complications place a heavy burden on patients’ families. In COPD, environmental irritants induce chronic lung and airway inflammation, causing airway structural remodeling and excessive mucus production, which leads to airflow limitation and chronic hypoxia. Prolonged hypoxia ultimately triggers PHD activation.17,18 Early symptoms of PHD are often subtle, and pulmonary function tests may show no abnormalities. Failure to recognize the condition at this stage can easily lead to disease progression.19 Therefore, early detection of effective diagnostic biomarkers is crucial for PHD treatment. This study identified miR-192-5p downregulation in PHD patients and its correlation with inflammatory and cardiopulmonary indicators, suggesting its potential as a diagnostic biomarker.
Inflammatory responses are key factors in the progression of COPD to PHD. Persistent airway inflammation induces pulmonary vascular remodeling, leading to pulmonary hypertension and ultimately causing right ventricular hypertrophy and dysfunction.20 Approximately 70% of COPD patients exhibit elevated levels of at least one inflammatory marker, and the activity of these markers continues to increase with worsening disease severity.21 CRP is a nonspecific acute-phase reactant whose levels are significantly elevated in patients with COPD complicated by cor pulmonale. Changes in its concentration reflect the risk of acute exacerbations and serve as a convenient indicator for assessing disease activity.22 Elevated IL-6 levels correlate with reduced muscle mass and decreased exercise endurance, making it an indicator of frailty and clinical deterioration in COPD patients.23 Furthermore, IL-6 directly acts on cardiomyocytes and vascular smooth muscle cells, inducing cardiomyocyte apoptosis, reducing myocardial contractility, and exacerbating right ventricular dysfunction.24,25 PHD patients exhibiting elevated TNF-α expression demonstrate higher acute exacerbation rates and more pronounced right ventricular dysfunction.26 Notably, miR-192-5p levels were negatively correlated with all three inflammatory cytokines, suggesting its potential role in modulating inflammation during PHD progression.
Existing studies have extensively reported that miR-192-5p is downregulated in respiratory diseases and closely correlates with inflammatory cytokine levels. For instance, low miR-192-5p levels demonstrate high diagnostic value in severe pneumonia and respiratory failure, suggesting poorer patient prognosis.9 In this study, miR-192-5p not only distinguished healthy individuals from COPD patients but also better differentiated COPD patients from PHD patients. This finding aligns with previous research conclusions, further confirming the conserved regulatory role of miR-192-5p in respiratory diseases. Additionally, miR-192-5p has demonstrated inflammation-related functions across multiple organs and tissues. miR-192-5p protects against intestinal injury in colitis by suppressing ALCAM expression and reducing IL-6 production in intestinal epithelial cells.27 Furthermore, it alleviates gouty arthritis by targeting EREG.28 The above evidence suggests that miR-192-5p may control inflammatory responses in PHD patients by regulating relevant pathways while also serving as a diagnostic biomarker.
Cardiorespiratory function is also a common clinical evaluation criterion for PHD. NT-proBNP is a classic biomarker for diagnosing heart failure, with its levels closely correlated to the degree of ventricular remodeling.29 PASP is a commonly used clinical non-invasive indicator for assessing the severity of pulmonary hypertension, whereas pulmonary hypertension is a core pathophysiological component of PHD.30 This study found that miR-192-5p levels were negatively correlated with NT-proBNP and PASP, indicating that miR-192-5p reflects the severity of cardiopulmonary dysfunction in patients. Previous research has demonstrated that miR-192-5p levels are significantly downregulated in patients with heart failure and reduced ejection fraction.31 This suggests miR-192-5p may participate in PHD development by regulating genes associated with cardiopulmonary function. Logistic regression analysis revealed that low miR-192-5p expression is an independent risk factor for PHD in COPD patients. This finding holds significant implications for early risk assessment in COPD patients. Currently, clinical risk assessment for the progression of COPD to PHD primarily relies on indicators such as pulmonary function tests and echocardiography, which often show significant changes only in the middle to late stages of the disease. miR-192-5p enables non-invasive detection through serum testing with high sensitivity, serving as an early high-risk warning indicator for pulmonary heart disease in COPD patients.
This study has several limitations. First, due to experimental constraints, not all potential risk factor indicators were included. Second, although the correlation between miR-192-5p and multiple clinical indicators was explored, its specific molecular mechanism in regulating PHD progression requires further clarification through cell models and animal experiments.
In summary, this study confirms that the expression of miR-192-5p is significantly downregulated in the serum of PHD patients and is closely associated with inflammatory markers and cardiopulmonary function indicators. This suggests its potential value as a biomarker for early diagnosis and severity assessment of the disease.
Conclusion
miR-192-5p appears downregulated in PHD and may serve as a potential risk indicator for PHD in COPD patients. These preliminary findings could provide candidate biomarkers for early diagnosis and risk assessment, offering a basis for further investigation into underlying mechanisms and potential therapeutic strategies.
Disclosure
The authors declare that they have no competing interests in this work.
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