Abstract
Twin-twin transfusion syndrome (TTTS) is a rare but serious cause of fetal cardiomyopathy with poorly understood pathophysiology and challenging prognostication. This study sought a nonbiased, comprehensive assessment of amniotic fluid (AF) microRNAs from TTTS pregnancies and associations of these miRNAs with clinical characteristics. For the discovery cohort, AF from ten fetuses with severe TTTS cardiomyopathy were selected and compared to ten normal singleton AF. Array panels assessing 384 microRNAs were performed on the discovery cohort and controls. Using a stringent q < 0.0025, arrays identified 32 miRNAs with differential expression. Top three microRNAs were miR-99b, miR-370 and miR-375. Forty distinct TTTS subjects were selected for a validation cohort. RT-PCR targeted six differentially-expressed microRNAs in the discovery and validation cohorts. Expression differences by array were confirmed by RT-PCR with high fidelity. The ability of these miRNAs to predict clinical differences, such as cardiac findings and later demise, was evaluated on TTTS subjects. Down-regulation of miRNA-127-3p, miRNA-375-3p and miRNA-886 were associated with demise. Our results indicate AF microRNAs have potential as a diagnostic and prognostic biomarker in TTTS. The top microRNAs have previously demonstrated roles in angiogenesis, cardiomyocyte stress response and hypertrophy. Further studies of the mechanism of actions and potential targets is warranted.
Highlights
Twin-twin transfusion syndrome (TTTS) is a rare but serious condition which affects 10–15% of monochorionic twin pregnancies and is a major cause of fetal cardiomyopathy
MiR-375-3p seems important in congenital heart disease (CHD) as it has a role in cardiac dysfunction and in cardiogenesis. miR-375 upregulation appears protective against hypoxia-induced apoptosis of cardiomyocytes via forkhead box P1 (FOXP1) and Bcl like protein 2 (Bcl2l2) upregulation, which may be associated with the observed lower expression of miR-375 in TTTS who had later demise (p = 0.0324)
Differences in miR-375-3p expression have been demonstrated in maternal serum of those affected by fetal CHD, suggesting it may be a potential biomarker [26]
Summary
Twin-twin transfusion syndrome (TTTS) is a rare but serious condition which affects 10–15% of monochorionic twin pregnancies and is a major cause of fetal cardiomyopathy. It is postulated that placental vascular connections develop between twins during the mid-trimester phase of rapid placental growth and facilitate an imbalance of fluid and vasoactive mediators between twins. This results in a hypovolemic state in the donor twin and a fluid- and pressure-overloaded state in the recipient twin, which progresses to a hypertensive cardiomyopathy. TTTS is a placental disease with significant cardiac ramifications
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