Abstract Tu056: A Two-Hit HFpEF-like Mouse Model with Accelerated Disease Onset

Abstract

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a heterogenous syndrome with multiple co-morbidities and has limited therapeutic options. To better understand the underlying mechanisms and develop novel therapies, it is important to focus on development of pre-clinical models that mimic the multi-factorial nature of HFpEF. Goal & Methodology: We aimed to develop a mouse HFpEF model by incorporating unfavourable metabolic axis, in db/db mice carrying mutation in lectin receptor, with Ang-II induced impaired hemodynamic conditions. Briefly, we infused Angiotensin II (Ang II, 1500 ng/kg/min) subcutaneously in 12-week-old wild type (WT) and db/db mice for 4 weeks (Fig 1). SGLT2 inhibitor (SGLT2i) was used as a pharmacological intervention. Results: The db/db + Ang II mice showed impaired diastolic function reflected by increase in E/A, E/e’ and global longitudinal strain. This increase was not observed in the db/db + Ang II mice upon treatment with SGLT2i. The ejection fraction was preserved across all groups. Interestingly, db/db + Ang II group did not develop cardiac hypertrophy & fibrosis as indicated by unchanged LV mass, picosirius red staining and unaltered expression of Nppa, Nppb & Acta2 transcripts. Investigation of lipid metabolism showed reduction of fatty acid synthase in db/db (+/-Ang II) groups in comparison to WT animals. Also, phosphorylation of ATP citrate lyase in db/db + Ang II group was diminished compared to db/db animals. Among the glucose metabolism markers, lactate dehydrogenase and pyruvate dehydrogenase showed decreasing trend in all groups compared to WT group. Conclusion: The present mouse model recapitulates metabolic and hemodynamic aspects of HFpEF pathophysiology. Our model is useful for basic research as well as quick evaluation of targets and assets focused on cardiac metabolism with the advantage of faster disease onset and clinically relevant echocardiographic endpoints.