Abstract Body: BACKGROUND:
Heart failure with preserved ejection fraction (HFpEF) is a growing clinical challenge with limited treatment options. Major risk factors for HFpEF include age, obesity or metabolic disease, and hypertension.

METHODS:
We analyzed plasma proteomic data from ~50K subjects in the UK Biobank to identify circulating proteins correlating with age, BMI, blood pressure, and heart failure (HF). Insulin-like growth factor binding 7 (IGFBP7), a circulating senescence factor with recognized prognostic value in HF, emerged as the top candidate. We then used IGFBP7 germline knockouts (KOs) and hepatic AAV8-IGFBP7 overexpression as loss- and gain-of-function models to examine the role of IGFBP7 in diastolic dysfunction and HFpEF in aged (22-month-old) and 2-Hit HFpEF (High-fat diet [HFD], L-NAME) mice (6-7-month-old). Circulating IGFBP7 levels were measured by ELISA.

RESULTS:
Circulating IGFBP7 levels increased in 22-month-old C57BL/6j aged mice (1.29-fold in male mice, P=0.012, N=10-5; 1.55 fold in female mice, P<0.001, N=12-7) and the 2-Hit HFpEF model (1.29-fold in 8 weeks, P<0.001, N=12-15; 1.66-fold in 15 weeks, P<0.001, N=10-9). IGFBP7 KOs showed less diastolic dysfunction (MV E/A, 0.70-fold in male and female mice, P=0.003, N=14-11) and reduced LV mass (0.77-fold in female mice, P=0.003, N=8-6) in 22-month-old mice. IGFBP7 KOs also showed less diastolic dysfunction (MV E/E’, 0.74-fold in male mice, P<0.001, N=18-16; 0.70-fold in female mice, P<0.001, N=11-13) and fibrosis (0.63-fold in female mice, P<0.001, N=7-10), and reduced LV mass (0.85-fold in male mice, P=0.003, N=18-16; 0.78-fold in female mice, P<0.001, N=11-13) in the 8-weeks 2-Hit HFpEF model in 6-8 month-old mice. AAV8-IGFPB7-induced increases in circulating IGFBP7 aggravated diastolic dysfunction (1.30-fold in female mice, P<0.001, N=14-15) in the 8-week 2-Hit Model. Cardiac RNA-sequencing results that implicate potential mechanistic contributors will be discussed.

CONCLUSIONS:
Circulating IGFBP7 levels correlate with age, BMI, blood pressure, and heart failure in a large general population cohort. Studies in two separate models demonstrate that IGFPB7 regulates cardiac DD, fibrosis, and hypertrophy, contributing to HFpEF. These studies suggest IGFBP7 is a common mediator in age- and metabolic-stress-induced HFpEF. Circulating IGFBP7 warrants further evaluation as a tractable therapeutic target in HFpEF.