Antenatal inflammation drives postpartum cardiac dysfunction in hypertensive disorders of pregnancy

Hypertensive disorders of pregnancy (HDPs), including preeclampsia and gestational hypertension, are strongly associated with maternal cardiac dysfunction during and after pregnancy. We hypothesized that maternal inflammation drives persistent postpartum cardiac maladaptation after HDPs. We conducted a prospective longitudinal study assessing cardiac function and circulating inflammatory profiles during pregnancy and 3–6 months postpartum, complemented by a preclinical mechanistic mouse model recapitulating key antenatal and postpartum immune and cardiac features of HDPs. Here we show that distinct antenatal inflammatory signatures, including elevated chemokines, correlated with adverse left ventricular structure and function 3–6 months postpartum, despite resolution of systemic inflammation. Mechanistically, our preclinical HDP mouse model demonstrates that reduced antenatal progesterone, also observed in patients with HDPs, drives inflammation and postpartum cardiac dysfunction. Antenatal (embryonic day 14.5), but not postpartum (postpartum day 28), progesterone treatment prevented postpartum cardiac dysfunction, identifying both a potential mechanistic and therapeutic strategy to reduce long-term maternal cardiovascular morbidity.