MicroRNA-98 Can Serve as a Diagnostic Marker for Congenital Heart Disease-Associated Pulmonary Artery Hypertension

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MicroRNA-98 Can Serve as a Diagnostic Marker for Congenital Heart Disease-Associated Pulmonary Artery Hypertension

Congenital heart disease (CHD) remains a leading cause of infant mortality among congenital abnormalities. Pulmonary artery hypertension (PAH), a critical complication of CHD, contributes significantly to morbidity and mortality. Recent studies have highlighted the role of microRNAs in cardiovascular pathologies, with microRNA-98 (miR-98) emerging as a potential regulator of cardiac hypertrophy. This study investigates the diagnostic utility of circulating miR-98 in CHD-associated PAH, exploring its relationship with hemodynamic parameters and disease severity.

Study Design and Participant Characteristics

This single-center retrospective analysis included 60 pediatric patients diagnosed with CHD at Beijing Anzhen Hospital between December 2016 and December 2017. Diagnoses were confirmed via color echocardiography, with exclusion criteria encompassing pulmonary diseases, heart valve disorders, heart failure, hematological conditions, HIV infection, and severe hepatic or renal dysfunction. Ethical approval was obtained (No. KY2017-051-03), ensuring compliance with institutional guidelines.

The cohort comprised 28 males and 32 females, aged 2 months to 10 years. Participants were stratified into two groups based on pulmonary artery mean pressure (PAMP): CHD-non-PAH (PAMP <25 mmHg, n=15) and CHD-PAH (PAMP ≥25 mmHg, n=45). The CHD-PAH group was further subclassified by World Health Organization (WHO) functional class (IV). Baseline characteristics, including cardiac index (CI), heart rate, and stroke volume, showed no significant intergroup differences, ensuring comparability (Supplementary Table 1).

Hemodynamic and Molecular Assessments

Pulmonary artery systolic pressure (PASP) was estimated using tricuspid regurgitation pressure gradients via color Doppler echocardiography. Cardiac index, heart rate, and stroke volume were measured with a VBP-10 Doppler cardiovascular detection kit. Fasting radial artery blood samples were collected, with serum separated for RNA extraction using the TRIzol one-step method. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) quantified miR-98 expression, normalized to the reference gene U6. Primer sequences were as follows:

  • miR-98: Forward 5’-GCTGAGGTAGTAAGTTGTATTG-3’, Reverse 5’-CAGTGCGTGTCGTGGAGT-3’
  • U6: Forward 5’-GTGCGTGTCGTGGAGTCG-3’, Reverse 5’-AACGCTTCACGAATTTGCGT-3’

Key Findings

1. miR-98 Expression and PAH Severity

Serum miR-98 levels were significantly reduced in CHD-PAH patients compared to CHD-non-PAH controls (P<0.05). A graded decline in miR-98 expression correlated with worsening WHO functional class (Figure 1C), suggesting a role in PAH progression.

2. Correlation with Hemodynamic Parameters

miR-98 expression exhibited a strong positive correlation with cardiac index (P<0.05, Figure 1B) and a negative correlation with PASP (P<0.05, Figure 1D). Lower miR-98 levels paralleled elevated PASP, indicating its potential as a biomarker for hemodynamic compromise.

3. Diagnostic Performance of miR-98

Receiver operating characteristic (ROC) analysis demonstrated robust diagnostic accuracy for miR-98 in distinguishing CHD-PAH from CHD-non-PAH. The area under the curve (AUC) was 0.929 (95% CI: 0.833–1.000, P<0.001), with sensitivity and specificity of 91.1% and 93.3%, respectively (Figure 1E). Positive and negative predictive values were 97.62% and 77.78%, underscoring its clinical utility.

Mechanistic Insights and Clinical Implications

Reduced miR-98 expression has been linked to pulmonary artery endothelial cell proliferation, a hallmark of PAH pathogenesis. Preclinical studies indicate that miR-98 downregulation exacerbates hypoxia-induced vascular remodeling, while its overexpression attenuates pathological hypertrophy. These findings align with the observed inverse relationship between miR-98 levels and PAH severity in CHD patients.

The study highlights miR-98’s dual role as a diagnostic marker and potential therapeutic target. Its association with CI and PASP underscores its relevance in monitoring right ventricular function, a critical determinant of PAH outcomes. The high diagnostic accuracy of miR-98 (AUC 0.929) positions it as a non-invasive tool for early PAH detection in CHD populations, complementing echocardiographic assessments.

Limitations and Future Directions

While this study provides compelling evidence for miR-98’s diagnostic utility, several limitations warrant consideration. The retrospective design and single-center cohort may limit generalizability. Future multicenter prospective studies with larger samples are needed to validate these findings. Mechanistic investigations exploring miR-98’s role in PAH pathways—such as endothelial dysfunction, inflammation, and right ventricular adaptation—could elucidate therapeutic opportunities.

Conclusion

This study establishes serum miR-98 as a promising diagnostic biomarker for CHD-associated PAH. Its significant downregulation in PAH patients, correlation with hemodynamic indices, and high diagnostic accuracy highlight its clinical relevance. Integrating miR-98 profiling into routine assessments may enhance early diagnosis and risk stratification, ultimately improving outcomes for children with CHD-PAH.

doi.org/10.1097/CM9.0000000000001193

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