Targeting the carotid body by P2X3 receptor blockade in people with heart failure with preserved ejection fraction

Summary

Heart failure affects over 1-million people and is separated into two categories: heart failure with reduced pumping function (HFrEF) and heart failure with normal pumping function (HFpEF). Both have a poor prognosis and reduced quality of life, however, HFpEF has limited treatment options.

People with heart failure are more breathless during physical activity, leading to impaired ability to perform daily activities. One reason is that the carotid body (CB), a small gland in the neck that controls breathing, has become oversensitive (like setting the thermostat on your radiators too high). CB oversensitivity can be lowered by dopamine, however, dopamine needs to be given via a vein and has other actions in the body that limit its use. It may be possible to target the CB better with a new tablet called gefapixant, which is licenced in the UK to treat chronic cough. In animals, gefapixant normalises CB overactivity and dysregulated breathing, although whether it has similar actions in humans is unknown.

We plan to conduct a small study to determine whether in people with HFpEF: 1) gefapixant can lower CB overactivity and 2) gefapixant is tolerated and feasible to use during exercise. Gefapixant could improve breathlessness in patients with HFpEF, improving quality-of life; however, it first needs to be established whether gefapixant is an effective tool for reducing CB overactivity.

Data from the proposed study will be used as proof-of-concept for a NIHR Doctoral Clinical Academic Fellowship application for Dr Mouy, who is currently an NIHR Academic Clinical Fellow.