Metabolic Signatures of Pregnancy-Induced Cardiac Growth

The goal of this study was to develop an atlas of the metabolic, transcriptional, and proteomic changes that occur with pregnancy in the maternal heart. Timed pregnancy studies in FVB/NJ mice revealed significant increases in heart size by day 8 of pregnancy (mid-pregnancy; MP), which was sustained throughout the rest of the term compared with non-pregnant controls. Cardiac hypertrophy and myocyte cross-sectional area were highest 7 d after birth (post-birth; PB) and were associated with significant increases in end-diastolic and end-systolic left ventricular volumes and cardiac output. Metabolomics analyses revealed that, by day 16 of pregnancy (late pregnancy; LP), metabolites associated with nitric oxide production as well as acylcholines, sphingomyelins, and fatty acid species were elevated, which coincided with a lower activation state of phosphofructokinase and higher levels of pyruvate dehydrogenase kinase 4 (Pdk4). In the postpartum period, urea cycle metabolites, polyamines, and phospholipid levels were markedly elevated in the maternal heart. Cardiac transcriptomics in LP revealed significant increases in not only Pdk4, but also genes that regulate glutamate and ketone body oxidation, which were preceded in MP by higher expression of transcripts controlling cell proliferation and angiogenesis. Proteomics analysis of the maternal heart in LP and PB revealed significant reductions in several contractile filaments and mitochondrial complex subunits. Collectively, these findings describe the coordinated molecular changes that occur in the maternal heart during and after pregnancy.