Novel, targeted therapy for heart failure with a preserved ejection fraction

Background: Heart failure with preserved ejection fraction (HFpEF) is increasing in prevalence and is associated with high morbidity and mortality currently no effective evidence-based therapies are available, resulting in an emerging epidemic. The cellular and molecular pathophysiology underpinning HFpEF are complex. Accumulating evidence demonstrates that pro-inflammatory and oxidative stress (excessive production of reactive oxygen species (ROS) pathways are critical contributors to the development and progression of HFpEF. Among many of the pathways activated by inflammation and oxidative stress, apoptosis signalling-regulated kinase 1 (ASK1) is the convergence point and regulates multiple downstream signalling networks that respond to the dual challenges of inflammatory and oxidative stress and are major factors that promote the development of HFpEF pathologies. Hence, ASK1 is likely to be a novel target for HFpEF therapy. Project aim: This project is to investigate novel ASK1 inhibitors for the treatment of cardiovascular disease including HFpEF using suitable animal models established in our group. This study will test the ability of the compound/s to both prevent and/or reverse myocardial fibrosis and inflammation associated with the HFpEF phenotype. Techniques: It is anticipated that this study will involve the use of animal models in mice, cardiac function measurement with echocardiography and pressure-volume relationship analysis, Western blotting, immunohistochemistry, and gene expression analysis with PCR.