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

Background and aims Iron 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). Methods. We 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. Results In 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. Conclusions This 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