Impact of antenatal iron deficiency on maternal heart function-A hypothesis-generating translational study

Background and aimsIron deficiency (ID) and myocardial iron depletion (MID) are causally linked to heart failure (HF) in the general population and in preclinical models. ID is common amongst pregnant women, but its impact on cardiac adaptations to pregnancy is unknown. This study examines that impact, and its potential relevance to peripartum cardiomyopathy (PPCM). MethodsWe provided female mice with iron-replete or iron-deficient diets, and monitored cardiac function and morphology longitudinally in pregnancy and postpartum. In women with no HF (n=64), we explored the associations between antenatal iron parameters and echocardiographic parameters in late pregnancy and at 6-12 months postpartum. We also performed a case (n=55), control (n=170) study comparing iron markers and assessing their association with PPCM risk. ResultsIn mice, ID prevented postpartum reversal of pregnancy-induced hypertrophy, reduced postpartum LVEF, and caused profound MID. In women with no HF, low hepcidin, high transferrin and low serum iron were respectively associated with higher LVESV, lower LVEF and higher CMR T1-mapping (lower myocardial iron) in postpartum. In the PPCM study, serum iron, hepcidin and haemoglobin were significantly lower in cases than controls, and were independently associated with risk of PPCM. Mechanistically, myocardial proteomics revealed that ID caused sustained postpartum activation of pyruvate dehydrogenase kinase 4, a master cardiometabolic switch enzyme with a well-recognised role in HF. ConclusionsThis study links antenatal maternal ID to postpartum systolic dysfunction, and implicates MID and cardiometabolic switching as potential mechanisms. It suggests these links may potentially contribute to the pathophysiology of PPCM. TRANSLATIONAL PERSPECTIVEO_LIIron deficiency (ID), even without anaemia, is linked to risk of incident HF in the general population and to worse outcomes in those with pre-existing HF. Preclinical studies demonstrated a causal role for myocardial iron depletion (MID) in this context. C_LIO_LIID is common during pregnancy, but its impact on the maternal heart, and its adaptations to the haemodynamic stress of pregnancy are unknown C_LIO_LIBy revealing that antenatal ID is associated with postpartum systolic dysfunction and with PPCM, this study points to ID as a novel risk factor for maternal HF. C_LIO_LIBy revealing the role of MID in this context, this study highlights the potential of intravenous iron therapies, which we have previously shown to raise myocardial iron, to reduce risk of maternal HF. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/26347784v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@9cebe0org.highwire.dtl.DTLVardef@41da1corg.highwire.dtl.DTLVardef@15679f0org.highwire.dtl.DTLVardef@5fa12d_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACT C_FIG