Abstract 4373204: Placental-derived Senescence Associated Secretory Proteins Increase Atrial Fibrillation Susceptibility in Pregnancy

Abstract

Introduction: Structural heart disease, including peripartum cardiomyopathy (PPCM), is associated with increased atrial fibrillation (AF) risk during pregnancy. Our group recently identified a functional role of placental-derived senescence-associated secretory proteins (SASP), e.g. activin A (ActA), in PPCM pathophysiology. Whether placental senescence also contributes to increased arrhythmogenesis in pregnancy is unclear. Hypothesis: The placenta-derived SASP factor, ActA, contributes to AF pathogenesis in pregnancy. Methods: Placental senescence and ActA expression, along with AF inducibility, were assessed in pregnant cardiomyocyte-specific PGC1α-KO mice (PPCM model) versus flox littermate controls, at gestational day 16 (GD16). Placentas from PPCM mice were cultured ex vivo, and medium containing placental-derived SASP was injected into nonpregnant mice for 4 days prior to undergoing invasive electrophysiology studies (EPS). Nonpregnant mice similarly underwent serial injections of recombinant ActA and EPS. To gain mechanistic insights, RNA sequencing was performed in neonatal rat ventricular myocytes (NRVM) exposed to medium from ex vivo cultured senescent placentas. Results: Compared to littermate controls, PPCM mice displayed increased SA-bgal (senescence marker, 1.7-fold, p=0.05), ActA expression (2.6-fold, p=0.0001), and cardiac Fstl3 mRNA (ActA signaling marker, 2.2-fold, p< 0.0001). This was associated with a trend toward increased AF inducibility in pregnant PPCM mice (100%) vs controls (40%) (p=0.06, n=5-6). Injection of medium from ex vivo cultured PPCM placentas into nonpregnant mice induced trends toward higher AF inducibility (50% [Control media] vs 100% [PPCM media], p=0.2, n=4). Increasing circulating ActA alone was sufficient to induce AF in mice (33% [PBS] vs 100% [ActA], p=0.001, n=9-13). Isolated NRVMs exposed to senescent placenta medium exhibited increased Fstl3 mRNA expression (3.7-fold, p=0.014) along with downregulation of Ion Channel Activity, Substrate-Specific Channel Activity, and Gated Channel Activity pathways (P adj =0.0006). Conclusion: Placenta-derived SASP, such as ActA, are sufficient to increase AF inducibility in mice and may contribute to maternal cardiac electrical remodeling and arrhythmogenesis in pregnancy.