Abstract 10875: Metabolic Reprogramming of the Failing Fetal Heart in Twin-Twin Transfusion Syndrome

Abstract

Adult heart failure is associated with reactivation of the fetal metabolic program, including impaired mitochondrial oxidative phosphorylation and a shift toward glycolysis. In the fetus, the metabolic response to cardiac stress is less clear. We used twin-twin transfusion syndrome (TTTS) as a model to uncover metabolic adaptations of the fetus to cardiovascular stress. TTTS is a unique complication that occurs in monochorionic-diamniotic twins (one placenta, two amniotic sacs) when unequal blood flow between twins within the shared placenta is the set up for donor-recipient physiology (Fig 1a). This circulatory imbalance is detected by sonographic signs of donor hypovolemia and recipient hypervolemia. We analyzed second trimester amniotic fluid to identify alterations in metabolism of TTTS recipient twins (n=22) vs. singleton controls (n=10) using untargeted metabolomics (LC/MS). All TTTS cases were severe (stage III; abnormal Dopplers indicating increased afterload and/or right heart failure). Due to dilution of amniotic fluid molecules in TTTS, data for each sample was normalized to protein concentration. Evaluation of differential metabolites in TTTS cases revealed two distinct clusters of disease (Fig. 1b). Compared with TTTS cluster 1 and controls, cluster 2 showed significantly increased lactate and alanine production, and evidence of redox stress (Fig. 1c). No differences in clinical characteristics or outcomes were observed between TTTS cluster 1 vs. 2 (maternal age, gestational age, fetal sex, disease severity, preterm birth, and perinatal death). Our findings reveal subclinical heterogeneity of stage III TTTS and suggest that some fetuses undergo metabolic reprogramming under conditions of cardiac stress, shifting even further toward energy-efficient glucose utilization. These differences in fetal response may represent different points along the same spectrum vs. inherent differences in the ability of fetuses to adapt to stress.