Functional Role Of Placental Senescence In Peripartum Cardiomyopathy

Introduction: Peripartum cardiomyopathy (PPCM) and preeclampsia (PEC) are leading causes of maternal mortality with limited therapies. Circulating factors in late pregnancy contribute to cardiac dysfunction in PPCM and PEC. We recently identified senescence-associated secretory proteins (SASP), markers of biological aging, as the most highly upregulated circulating proteins in PPCM and PEC. The mechanisms driving this paradoxical aging pathophysiology in these pregnancy-induced heart failure (HF) syndromes are unknown. Hypothesis: The placenta becomes markedly senescent by term. We hypothesized that 1) amplified placental senescence causes the increase in circulating SASP in PPCM and PEC, and 2) attenuating placental senescence might improve cardiac function in PPCM. Methods: We performed comprehensive senescence assessments in placental samples from women with preeclampsia vs . matched pregnant controls. We assessed the effects of placental senescence in human iPSC-derived cardiomyocytes (iPSC-CM) and the PGC1α-KO PPCM murine model. Results: Placentas from PEC women displayed multiple markers of amplified senescence, including increased p16 and p21 expression (2 & 4 fold, p<0.03), decreased DNA methylation (-1.7 fold, p<0.04), and increased overall SASP expression (2 fold; p<0.001). In iPSC-CM, PEC plasma induced pathologic gene expression profiles (Nppa, Nppb, Myh7) and increased Activin-A signaling (Fstl3, Serpine1, Ccn2), a key SASP factor that contributes to cardiac dysfunction in PEC and PPCM. The senolytic Fisetin attenuated placental senescence in pregnant PGC1α-KO mice, reducing placental p16 and p21 expression (-2 & -3 fold, p<0.01) and Activin-A levels (-2 fold, p<0.03). Compared to vehicle-treated pregnant PGC1α-KO mice, Fisetin-treated animals had 35% higher left ventricular fractional shortening (31% vs . 42%; p<0.001), along with reductions in cardiac Nppa expression and Activin signaling. No changes in cardiac senescence or adverse effects on fetal development were observed with Fisetin. Conclusion: We identify amplified placental senescence as part of the core pathobiology underlying PPCM and PEC, and present proof-of-concept evidence for senolytic therapeutic approaches in pregnancy-induced HF.