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Project summary

The “stiff” type of heart failure, where the heart cannot relax properly, has become the most common type of heart failure. It has overtaken the traditional form of heart failure, where the heart cannot squeeze effectively: this type of heart failure peaked after the heart attack epidemics of the 1950s and 60s. The 5-year mortality for both types of heart failure is 75%, and the median survival for both is 2.1 years.

While a range of therapies has been developed for the better-understood impaired-squeeze type of heart failure, shockingly there are no therapies for the stiff, impaired-relaxation type of heart failure. This bears repeating: there are no therapies for the most common type of heart failure. This stiff type of heart failure is called Heart Failure preserved Ejection Fraction, or HFpEF, to highlight that heart failure occurs despite preserved squeeze or “ejection fraction”.

We have recently identified key pathogenic changes in human and model system HFpEF left ventricular myocardium. For example, we have determined for the first time that the stiff failing heart can generate its own ketone bodies for fuel. We have also determined that the heart becomes locally hypothyroid, and that the HFpEF myocardium accumulates toxic lipid species. We have identified therapeutic strategies based on each of these discoveries.

We perform investigation of human heart tissue in conjunction with Dr Sean Lal from Sydney Heart Bank (over 17,000 samples, one of the largest in the world). We run a dedicated HFpEF clinic in our hospital, in which we use cardiac MRI to carefully characterise key features of HFpEF including extracellular volume, microvascular disease and fibrosis. Every patient in our HFpEF clinic also receives a home sleep study (obstructive sleep apnoea is a common comorbid condition), vascular studies, endocrinologist review, dietician review, quality of life review and advanced multi-omic analyses.

We have extensive tools to probe mechanism: a C57Bl/6J HFpEF model (confirmed by echocardiography), a rat model in which we also perform ex vivo working heart analysis; an ex vivo cardiac tissue slice model, 7T cardiac MRI and NMR spectroscopy; myocardial and plasma proteomics and metabolomics; stable-isotope flux analyses; in silico enzymatic and docking modelling for drug target identification; and in conjunction with HRI’s Dr Xuyu Liu, a drug modification technology to enhance therapeutic effectiveness. We also perform primary cardiomyocyte culture isolation from our human HFpEF myocardial tissue and our murine HFpEF myocardium to further probe mechanism.