Systo-diastolic coupling as a therapeutic target for heart failure with preserved ejection fraction

How well the heart works to pump blood around the body has traditionally been measured by the fraction of blood the heart pumps out with each heartbeat - the ejection fraction. It is now understood that, even if their ejection fraction is in the normal range, a person can still develop serious symptoms of heart failure like shortness of breath and their life-expectancy may be reduced. This form of heart failure with preserved ejection fraction is not well understood and few specific treatments for it are available. Recent work by us suggests that this form of heart failure is due to the heart struggling to contract so that, during each heartbeat, it has to contract more slowly for longer to do the same amount of pumping as a normal heart. The key to detecting this is to measure how well the heart contracts at the very beginning of each heart beat - the first-phase ejection fraction. In this project we will determine how this new measurement depends on the amount of blood that returns to the heart with each heart beat and the pressure that the heart has to push against. This will then tell us how we might best use existing medicines that are know to affect these two factors to treat heart failure with preserved ejection fraction. It will also help identify new treatments for this type of heart failure.

Heart failure with preserved ejection fraction (HFpEF) forms up to 50% of cases of heart failure, has similar high mortality to other forms of heart failure yet has few evidenced based treatments. HFpEF is thought to be due to impaired relaxation and filling of the left ventricle with contractile function and hence ejection fraction preserved. New data from ourselves challenge this view and suggest that a major cause of HFpEF is failure of the ventricle to contract efficiently early in systole with overall ejection fraction preserved at the expense of sustained contraction into late systole which impacts relaxation in diastole through an impairment of systo-diastolic coupling. A new metric of early systolic function, first-phase ejection fraction (EF1), is powerfully predictive of prognosis in HFpEF and in other conditions, the change of EF1 in response to treatment predicts outcomes. EF1 and systo-diastolic coupling therefore present an entirely new therapeutic target for HFpEF. In the present proposal we will use experimental probes to obtain a detailed understanding of the role of systo-diastolic coupling in HFpEF. This has the potential for near-term patient benefit through using established drugs to optimise EF1 and will validate EF1 for use as a target for novel drugs.