Potential biomarkers predicting risk of pulmonary hypertension in congenital heart disease: the role of homocysteine and hydrogen sulfide.

BACKGROUND Pulmonary hypertension (PH) is a common complication of congenital heart disease (CHD). Although risk stratification is vital for prognosis and therapeutic guidance, the need for understanding the role of novel biomarkers cannot be overlooked. The aim of the present study was to investigate the changes of homocysteine and hydrogen sulfide levels and find potential biomarkers for early detection and treatment. METHODS Between September 2012 and April 2013, we prospectively collected data on 158 pediatric patients with left to right shunt CHD at our institution. Standard right heart catheterizations were performed in all cases. Seventy-seven cases were associated with PH. The levels of homocysteine and hydrogen sulfide were detected with fluorescence polarization immunoassay and a sensitive silver-sulphur electrode, respectively. Enzyme-linked immunosorbent assay was used to determine the expression of methylenetetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CBS), and cystathionine gamma-lyase (CSE). Radioimmunoassays were used to obtain folic acid and vitamin B12 levels. RESULTS The difference in the levels of homocysteine, folic acid, vitamin B12, hydrogen sulfide, as well as the MTHFR and CSE expression between patients with PH and without PH were statistically significant (all P < 0.05). Homocysteine had the best sensitivity and specificity to predict PH (P < 0.001). Subgroup analysis showed that the levels of homocysteine and hydrogen sulfide, and the expression of CSE and MTHFR between patients with dynamic and obstructive PH were significantly different (all P < 0.05). Based on the ROC curve, homocysteine had the best sensitivity and specificity to predict obstructive PH (P = 0.032), while CSE had the most significant sensitivity and specificity to predict the dynamic PH (P = 0.008). CONCLUSIONS Increased levels of homocysteine and decreased levels of hydrogen sulfide were significantly negatively correlated in PH associated with CHD. The underlying mechanism involved the decreased expression of MTHFR and CSE along with vitamin B12 deficiency. Homocysteine and hydrogen sulfide are potential biomarkers to predict PH.