Peripartum dapagliflozin improves late-life maternal cardiovascular outcomes in a murine model of superimposed preeclampsia.

Abstract

Hypertensive disorders of pregnancy are important risk factors for later-life cardiovascular diseases. SGLT2 (sodium-glucose cotransporter-2) inhibition improves outcomes in heart failure, a later-life risk that disproportionately affects those with preeclampsia superimposed on chronic hypertension. SGLT2 inhibition during pregnancy and the postpartum period has not been effectively modeled or tested in superimposed preeclampsia as a potential cardiovascular risk-reducing intervention. This study aimed to (1) confirm the phenotype of superimposed preeclampsia in the BPH/2J mouse model, (2) test the short- and long-term obstetrical and cardiovascular effects of administering an SGLT2 inhibitor (dapagliflozin) in pregnancy and the immediate postpartum period in this model, and (3) identify molecular effects of SGLT2 inhibition in cardiovascular tissues during and after a treated pregnancy. We established the BPH/2J model of superimposed preeclampsia and then randomly assigned pregnant BPH/2J mice with implanted telemetry devices to dapagliflozin-enriched chow or control chow starting early in gestation through 21 days after delivery. Maternal cardiovascular and obstetrical outcomes including circulating plasma protein markers, urine studies, obstetrical ultrasounds, and tissue histopathology were compared between the groups. Hearts and aortae were analyzed using serial echocardiography and spatial transcriptomics in late gestation or at 6 months postpartum. BPH/2J mice had baseline chronic hypertension that worsened in pregnancy with the development of proteinuria and elevated plasma sFlt-1 levels, consistent with superimposed preeclampsia. Mid-gestation systolic blood pressures were higher in the untreated group than the dapagliflozin-treated group (+2.87 mm Hg; P<.001). There were no differences in the number of pups or estimated fetal pup weights between the groups, whereas amniotic fluid volume, placental size, and markers of placental perfusion were improved in the dapagliflozin-treated group. The untreated group had higher aortic peak velocities in late pregnancy compared with the dapagliflozin-treated group (748.1 vs 561.9 mm/s; P=.004×10^-3). One maternal death occurred in the untreated group, with no events in the dapagliflozin-treated group. In late life, the untreated group had significant loss of left ventricular function relative to their prepregnancy baseline, whereas dapagliflozin-treated mice had relatively preserved left ventricular function (-20.0% vs -7.6% change; P=.004×10^-3; 49.0%±6.34% untreated-baseline to 30.5%±6.78% untreated-aged; 44.9%±8.63% treated-baseline to 36.5%±6.39% treated-aged). Tissue transcriptomic analyses and Masson's trichrome staining demonstrated attenuation of cardiac fibrosis and extracellular remodeling processes with SGLT2 inhibition. In a murine model of superimposed preeclampsia, dapagliflozin treatment during pregnancy and the puerperium improved physiological cardiovascular parameters during gestation and cardiac function later in life. This may be related to observed molecular effects of SGLT2 inhibition treatment, particularly its antifibrotic and metabolic actions associated with reduced markers of fibrotic pathologic remodeling in treated BPH/2Js during and after pregnancy.