Around 175,000 New Zealanders live with heart failure. It is another of those conditions that become more likely as we age and, although there is no cure, it can be managed with a range of medications.
Heart failure doesn’t mean the heart has actually failed or stopped, but that pumping enough blood around the body has become harder. This may be because the heart muscle has stretched and weakened, or it may have thickened and stiffened, or been irreversibly damaged by a heart attack. Either way, sufferers experience fluid build-up leading to a range of symptoms such as shortness of breath, extreme fatigue and swelling in the legs and feet. More than half of people diagnosed with heart failure will survive for five years and about 35% survive for 10 years.
Now, researchers at the University of Auckland are trialling a drug they believe has the potential to not only improve the heart’s ability to pump, but also reverse the progression of heart failure.
“This is a completely new class of drug with a different mechanism,” says Julian Paton, director of the university’s Manaaki Manawa Centre for Heart Research. “What it does, that the others do not, is reduce autonomic nervous system activation to the heart.”
Known as AF-130, the drug was first developed as a medication for unexplained chronic cough, a common and hard-to-treat ailment. It is a P2x3 receptor blocker and it seems to have multiple other uses. P2x3 receptors are channels that let sodium and calcium ions into the cells, which create electrical excitability and are key to communication with the brain. The chemical that stimulates these receptors is called ATP (adenosine triphosphate) and it is essential for many cellular processes.
“ATP is doing a lot in the body,” says Paton. “But what caught our attention is that in disease, it does too much.”
If ATP is doing too much, the nervous system is overactivated, which in turn leads to other problems. Persistent, unexplained cough, for instance, is believed to be caused by the nervous system unnecessarily activating the cough reflex.
Paton and his team have discovered that in conditions such as heart failure and high blood pressure there are more P2x3 receptors. “Maybe three, four or five times more, and that is a lot,” says Paton. “There’s also an increase in ATP.”
As a result, the sympathetic nervous system is activated. This triggers our flight-or-fight response, providing the body with a burst of energy by raising the heart rate to pump more blood. If you go on bombarding the heart with all this nervous overactivity, in time it can become damaged and less able to pump properly. “This drug prevents that overactivity,” says Paton. “It calms down the sympathetic nervous system very nicely and resets it.”
His team tested AF-130 in rats with heart failure and discovered that not only does it show promise for alleviating heart failure, it also prevents some forms of the breathing disorder sleep apnoea.
In sleep apnoea, a person’s breathing repeatedly stops and starts while they sleep. The disorder has been linked to poorer mental function and cardiovascular health, and it greatly increases the risk of developing heart failure. Currently, the only effective way of managing it is CPAP (continuous positive airway pressure) therapy. This involves wearing a mask connected by a hose to a CPAP machine to keep airways open. Often, people struggle to get comfortable using these devices.
Paton’s research suggests that tempering the nervous response with AF-130 helps regulate breathing. It may also be an effective treatment for high blood pressure, which is also associated with high levels of sympathetic nervous activity. The drug is in the process of being approved in the United States as a treatment for chronic cough and that should pave the way for trials in humans to investigate its other uses.
“New Zealand has a fantastic opportunity in this space,” says Paton. “We’re geared up to do these trials and we have a very diverse population in Auckland.”
He admits to encountering some scepticism at the notion that a single drug could have such a broad application. “But we’re dealing with a common mechanism. We know that sympathetic nervous activity worsens both heart failure and high blood pressure. If we take this overactivation of the system out of the equation, that’s going to alleviate a number of conditions.”
