Novel therapy for heart failure

Associate Professor Bing Wang, Baker Heart and Diabetes Institute

2020 Vanguard Grant

Years funded: 2021-2022

The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing and represents approximately 50 % of heart failure (HF) cases. HFpEF is associated with high morbidity and mortality and there are NO effective evidence-based therapies for HFpEF resulting in an emerging epidemic. Accordingly, the development of effective treatments for HFpEF is widely acknowledged as one of the highest priorities in cardiovascular medicine.

The cellular and molecular pathophysiology underpinning HFpEF are complex. Clinical and experimental studies have shown that fibrosis and inflammation are critical contributors to the pathologies of HFpEF. The vicious cycle of inflammation and fibrosis together with other drivers such as metabolic factors accompanied by obesity resultant cardiovascular remodelling lead to the well characterised HFpEF phenotype.

Our project team is at the forefront of HFpEF research internationally. Building on our previous research, we have developed a novel small molecule compound, VCP979, targeting the key drivers of fibrosis and inflammation, namely Discoidin Domain Receptor Tyrosine Kinase 1 (DDR1) and p38MAPK. DDR1 can be activated by collagen, a protein that causes fibrosis. VCP979 is a dual DDR1/p38MAPK inhibitor and possesses many drug-like properties and significant in vitro and in vivo efficacy in models of cardiovascular diseases (myocardial infarction and ischemic reperfusion) with low toxicity. This proposal will investigate the therapeutic potential of VCP979 in animal models of HFpEF including high-fat diet aged-mice and angiotensin-infusion induced HF. Studies will be performed to demonstrate the potential of VCP979 as prevention and treatment of HFpEF in the above-mentioned animal models. The cardiac function will be assessed with both echocardiography & invasive pressure-volume relationship with catheterisation.

This translational research will validate VCP979 as a new therapy leading to a novel management strategy for HFpEF.