Abstract Body: Introduction: Placental-derived senescence-associated secretory proteins (SASPs), e.g. activin A (ActA), contribute to peripartum cardiomyopathy (PPCM) pathophysiology. PPCM is associated with increased risk of arrhythmias, including ventricular tachycardia (VT) and atrial fibrillation (AF). Whether SASPs contribute to increased arrhythmogenesis in PPCM and pregnancy are unclear.

Hypothesis: Placenta-derived SASP factors contribute to arrhythmia pathogenesis in pregnancy.

Methods: Invasive electrophysiology studies (EPS) and senescence assessments were done in a) pregnant cardiomyocyte-specific PGC1α-KO mice (PPCM model) versus flox littermate controls (n=14-12/group) and b) nonpregnant wild-type mice injected with conditioned medium (CM) from ex vivo cultured placentas from PPCM mice versus control medium (n=4). In parallel, RNA sequencing was performed in neonatal rat cardiomyocytes (NRCM) exposed to CM from ex vivo cultured senescent placentas to gain mechanistic insights.

Results: Compared to littermate controls, PPCM mice displayed increased placental senescence-associated-βgalactosidase (1.7-fold, p=0.05) and ActA (2.6-fold, p=0.0001) expression, with increased cardiac Fstl3 mRNA expression (ActA signaling marker, 2.2-fold, p< 0.0001). This was associated with increased AF (93% versus 33%, p=0.003) and VT (43% versus 8%, p=0.08) inducibility in PPCM mice versus controls. Injection of CM from ex vivo cultured PPCM placentas into nonpregnant mice induced similar trends toward higher AF (100% [PPCM media] versus 50% [Control media], p=0.2) and VT inducibility (75% versus 0%, p= 0.1). Isolated NRCMs exposed to CM from ex vivo cultured senescent placentas exhibited increased Fstl3 mRNA expression (3.7-fold, p=0.01) along with downregulation of Ion Channel Activity, Substrate-Specific Channel Activity, and Gated Channel Activity pathways (P_adj=0.0006).

Conclusion: Increased placental senescence is associated with increased arrhythmogenic susceptibility in PPCM mice, and its SASP are sufficient to increase arrhythmia inducibility in nonpregnant mice. Taken together, these data suggest that placental secreted factors may directly contribute to maternal cardiac electrical remodeling and arrhythmogenesis in pregnancy.