Heart failure (HF) is a devastating condition with limited insight into its pathogenesis. Heart failure with preserved ejection fraction (HFpEF), is the most prevalent form of HF in elderly populations, particularly postmenopausal women. It is a condition with limited insight into its pathogenesis and therapies. Current HFpEF treatments, such as blood pressure control, diuretics, and aldosterone receptor antagonists, are only modestly effective. Recent studies have identified cardiac adipose tissueas a metabolically active tissue contributing to cardiac dysfunction. Paracardial fat (PF) volume correlates strongly with cardiometabolic risk factors and diastolic dysfunction, suggesting a critical role in HFpEF pathogenesis.
Our researchers identified Th17 and IL17A as novel therapeutic targets and provide a new treatment method for mitigating age-associated cardiac diastolic dysfunction. Aging induces a shift in immune cell populations within PF, characterized by an increase in pro-inflammatory Th17 and Th1/Th17 cells. These cells secrete IL17A and IFN-γ, which drive PF remodeling and impair cardiac function. Experimental delivery of IL17 mRNA into the paracardial fat of young mice induced features of HFpEF—including adipocyte hypertrophy, cardiac inflammation, and impaired diastolic function—without affecting systolic performance. Neutralization of IL17A using secukinumab (an FDA approved IL-17 monoclonal antibody) reversed these pathological changes and improved diastolic parameters in aged mice. In summary, this invention proposes immunomodulatory interventions—such as IL17A neutralization and inhibition of Th17 differentiation—as effective strategies to restore PF-heart homeostasis and improve cardiac outcomes.
Neutralizing IL17 improved diastolic function in aged female mice. (A) Workflow of aged female mice receiving secukinumab injections via the tail vein. (B) Motion-mode (M-mode) ultrasound, pulsed-wave Doppler, and tissue Doppler echocardiography performed on mice injected with secukinumab. (C) Ejection fraction (%), (D) Fractional shortening (%), (E) E/E’ ratio, and (F) isovolumic relaxation time in mice treated with secukinumab relative to IgG1 control.