Abstract Body (Do not enter title and authors here): Introduction: Emerging evidence suggests a role for cellular senescence in the pathogenesis of age-related cardiac dysfunction. Senescence-associated secretory phenotype (SASP) is a hallmark of senescent cells, but the extent to which circulating SASP protein levels associate with cardiac dysfunction is not known.

Objectives: Determine associations of plasma SASP proteins with subclinical cardiac dysfunction and incident heart failure (HF).

Methods: Among 4,484 HF-free participants in the community-based Atherosclerosis Risk in Communities study who attended the 5^th study visit (2011-2013) and underwent protocol echocardiography, we measured 25 core SASP proteins (SomaScan aptamer-affinity assay). We assessed their associations with cardiac structure/function and incident adjudicated HF using multivariable linear and Cox proportional hazards models adjusted for demographics and clinical characteristics.

Results: The mean age was 76±5 years, 58% were female, 17% reported Black race, and mean LVEF was 66±6%. 439 incident HF events occurred over 8 [IQR 7-9] year follow-up. Eight of 25 core SASP proteins associated with risk of incident HF at FDR <0.05 (GDF15, IGFBP2, IGFBP7, TIMP2, TIMP1, MMP2, CTSB, CST3; Figure A). Among those, 6 proteins (TIMP1, TIMP2, IGFBP2, MMP2, IGFB7, GDF15) were associated with both incident HFrEF (n=179 events) and HFpEF (n=201 events) at FDR significance, while CST3 was only associated with HFpEF, and CTSB only with HFrEF. These 8 proteins were also generally associated with greater LV size and worse LA reservoir strain but showed differential associations with worse global longitudinal strain (IGFBP2, TIMP2, MMP2, CTSB) versus diastolic measures including E/e, LAVi, and PASP (CST3, IGFBP7; Figure B).

Conclusion: Plasma values of a subset of core SASP proteins associate with cardiac dysfunction and HF risk in older adults, supporting cellular senescence-related mechanisms as a contributor to late-life HF risk.