A murine cardiometabolic HFpEF model using high-fat diet and Angiotensin II significantly increased LV mass (p=0.0126) and heart/tibia ratio (p=0.0043) in males compared to controls.
A murine model combining high-fat diet and Angiotensin II infusion successfully replicates features of cardiometabolic HFpEF, including increased LV mass and fibrosis, providing a platform for testing targeted anti-inflammatory therapies.
Abstract Background/purpose Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome that is associated with multiple comorbidities (1). Metabolic stress together with comorbidities result in low-grade inflammation, which may drive HFpEF development. Clinical analysis on biomarkers revealed that elevated cytokine levels, including interleukin (IL)-6, are associated with a poor prognosis in HFpEF (2). Nevertheless, treatments targeting inflammatory pathways have yet to show functional benefits in HFpEF. We hypothesise that the development of HFpEF can be prevented or slowed, by targeting the pro-inflammatory pathways. But because HFpEF is a heterogeneous disease, it is unlikely that one treatment will work for all the different groups (1). We aim to characterise pro-inflammatory mechanisms underlying HFpEF progression to inform personalised anti-cytokine treatments. Methods We are studying the immune profile of a murine cardiometabolic HFpEF model, as part of a consortium where each member is modelling a different phenogroup within HFpEF. Metabolic stress is induced via a high-fat diet (60% fat), and chronic hypertension is achieved via 1% salt water and an osmotic pump that releases Angiotensin II (AngII, 0.5 mg/kg/day). Both male and ovariectomised females C57BL/6J mice are used. This model is evaluated for functional changes in blood pressure, glucose tolerance testing (GTT), echocardiographic measurements and exercise tolerance test. LV mass is measured via echocardiography, and structural, cellular and molecular changes are assessed by histology and flow cytometry. To get better understanding of the pro-inflammatory pathways and uncover potential targets that are linked to the development of this HFpEF phenogroup, we will be performing cytokine assays on blood and comparing this both to patient cytokine profiles in a similar phenogroup and to the results from our consortium partners that are modelling other phenogroups in mice. We will use antibodies and developed nanobodies against identified targets as well as using known targets such as IL-1β and IL-6. Preliminary results The male AngII mice had a significant increase in bodyweight (p=0,0068; n=4) and increased heart/tibia ratio (p=0,0043; n=4) compared to their male controls. LV mass was also significantly increased (p=0,0126; n=4) compared to their male controls, measured by echocardiography. Total fibrosis was significantly increased (p=0,0104; n=4) in female mice with a pump, compared to their female controls. Conclusion Our hope is that neutralising pro-inflammatory cytokines in phenogroup specific manner will improve anti-inflammatory therapeutic options.
Cami et al. (Fri,) conducted a other in Heart failure with preserved ejection fraction (HFpEF). High-fat diet, 1% salt water, and Angiotensin II vs. Controls was evaluated. A murine cardiometabolic HFpEF model using high-fat diet and Angiotensin II significantly increased LV mass (p=0.0126) and heart/tibia ratio (p=0.0043) in males compared to controls.