Abstract 12940: Shared Senescence Pathophysiology in Preeclampsia and Peripartum Cardiomyopathy

Abstract

Introduction: Peripartum cardiomyopathy (PPCM) is a rare form of pregnancy-related heart failure associated with preeclampsia. Our understanding of their shared pathophysiology is limited as are treatment options. Hypothesis: We hypothesized that plasma proteomic profiling would identify deleterious circulating proteins and provide insights into shared mechanisms driving preeclampsia and PPCM. Methods: We performed serum proteomic case-control studies in women with preeclampsia or PPCM to identify biological processes common to both conditions. The top candidate was validated in independent preeclampsia (n=58) and PPCM (n=114) cohorts. Preeclamptic placenta was examined as a potential source of circulating proteins. Therapeutic targeting the top candidate was examined in an animal model of PPCM. Results: Paradoxically, we found the senescence-associated secretory phenotype (SASP), a marker of biological aging, to be the most upregulated process in relatively young women with preeclampsia (normalized enrichment score [NES]=3.3;p adj =4.0x10 -6 ) or PPCM (NES=3.2;p adj =1.9x10 -5 ). 28 circulating proteins contributed to this common signal, and were strongly enriched in preeclamptic placenta, which expressed markers of increased senescence. The TGFb family member, Activin-A, was the most highly upregulated SASP gene in preeclamptic placentas (5-fold;p<0.001). Circulating Activin-A was elevated in preeclampsia (2.9-fold) and PPCM (2.5-fold) validation cohorts (p<0.001) and correlated with impaired left ventricular global longitudinal strain (r=0.3-0.5;p<0.001). In PPCM, Activin-A increased with worsening heart failure, reflected by NYHA class and BNP levels (p<0.05), and cardiac FSTL3 expression, an indicator of Activin-A signaling, was increased (2.2-fold;p=0.005). Inhibition of Activin-A receptors with a monoclonal antibody improved systolic function and adverse cardiac remodeling in a murine PPCM model. Conclusions: These data implicate placental senescence in the increased deleterious circulating proteins seen in preeclampsia and PPCM. We identify multiple new circulating factors associated with these diseases and demonstrate that targeting SASP proteins, such as Activin-A, can mitigate PPCM in mice.