Seemingly healthy people can collapse without warning – when the heart’s rhythm suddenly breaks down. No chance to get help. Now, a landmark study in Denmark – published in the New England Journal of Medicine – shows that increasing the body’s potassium level slightly can cut the risk of life-threatening arrhythmia among the most vulnerable people with heart disease. This simple intervention – dietary adjustments and a cheap, well-known medicine – appears to constitute a new, targeted treatment.
Every year, millions of women and men around the world lose their lives to cardiovascular disease – and death often strikes without warning. For many people, it starts as a silent build-up of atherosclerosis in the blood vessels, which gradually narrow, creating difficulty for oxygenated blood to reach the heart. For years, they may not notice anything, but suddenly a blood clot in the heart – or the brain – can appear, and the person often dies immediately.
If the blood vessels to the heart become too narrow or if there is a blood clot, the heart can start to beat chaotically. The electrical signals that normally control the heart’s rhythm like a metronome can suddenly fail – and this is one of the most common reasons why people collapse without warning.
The same applies to several other heart diseases, predominantly hereditary ones located in the heart muscle itself or the electrical system of the heart.
“For people at the highest risk, it is often necessary to implant a defibrillator, which in the event of malignant cardiac arrhythmia can deliver a shock and thus protect against sudden death,” explains Henning Bundgaard, Senior Consultant in Cardiology at the Heart Centre at Rigshospitalet and Professor at the University of Copenhagen, Denmark.
“We have long been looking for new and more effective ways to treat cardiac arrhythmia,” say his senior consultant colleagues Christian Jøns and Niels Risum.
But their new study, POTCAST, now shows that part of the solution may have been right in front of their eyes all along: in the body’s potassium levels.
“Potassium is central to the heart’s electrical function and stability – and both too little and too much can cause it to beat out of rhythm,” notes Niels Risum.
“The surprising thing is that just a small increase in potassium – still within the normal range – reduced the risk of life-threatening arrhythmia by one quarter. A number in a blood test can determine who lives and who dies,” adds Christian Jøns.
Potassium – the heart’s overlooked key
This discovery challenges a longstanding belief in cardiology: that as long as potassium levels are within the normal range, they are good enough. Understanding the significance of the results requires examining the biological background of the study.
“One element that has long been suspected of playing a role in arrhythmia is the body’s potassium level. Potassium is central to the heart’s electrical function and stability, and both too low and too high levels can disrupt the heart’s rhythm.”
Many previous observations and studies – including several studies based on Denmark’s health registries – indicated that low-normal potassium increases the risk, but only now has the randomised POTCAST study shown that increasing the potassium level can actually change the outcome – and thus open a new way of preventing dangerous arrhythmia – and thus probably also sudden death among people at high risk.
“We have this normal range,” say the three researchers. “And then we said: if we move from low to high-normal within the reference interval, but still within the normal range – does that change anything?”
From idea to groundbreaking trial
However, no one had previously dared to test the idea in a controlled trial – what if it does not work or is even dangerous? The idea became POTCAST – a randomised trial that tested for the first time whether raising potassium levels could prevent life-threatening arrhythmia.
The study was conducted in close collaboration between Rigshospitalet, Herlev and Gentofte Hospital and Zealand University Hospital, Roskilde.
“We chose to tweak something as basic as a single number in the blood test – and then we had the patience to follow these people for years to determine whether it had the effect we theoretically expected,” says Henning Bundgaard.
The study targeted patients with implanted cardiac defibrillators (ICDs): clinically assessed to be at high risk of life-threatening arrhythmia. And that is precisely what makes the results clinically relevant, emphasises Christian Jøns:
“These are among the most vulnerable patients we have. If we can make a difference for them with something as simple as dietary adjustments combined with a well-known and inexpensive medication, then the potential is enormous.”
Behind POTCAST lies a broader recognition that doctors may not be aware of the significance – or potential – of a wide range of common factors they measure clinically. Several of these could perhaps be adjusted and provide benefits. As Bundgaard puts it: “I think we need to get much better at looking at the small biological knobs we can actually turn.”
With POTCAST, he and his colleagues have now shown that potassium can be just such a knob – thus opening the door to new strategies for preventing life-threatening arrhythmia and, presumably, sudden cardiac death.
How the patients got more potassium
The study included 1,200 people with heart disease at high risk of malignant cardiac arrhythmia or sudden cardiac death – all with ICDs and relatively low but still normal potassium levels.
“This is important because they were not deficient – we tested whether a small increase from 4.01 to 4.36 mmol/L – within the normal range – could make a difference,” explains Henning Bundgaard.
The participants were randomly divided into two equal groups. One group received standard treatment, and the other received targeted treatment to raise their potassium levels.
The strategy was based on previous observational association studies, which have shown that the risk of sudden cardiac death is significantly higher at the low end of the range.
The patients targeted for treatment received dietary guidance, potassium tablets and/or a mild diuretic medication that raises potassium levels in the blood.
“We adjusted the treatment with blood tests every two weeks until we had stabilised the participants at the high end of the normal range, after which they were followed up every six months,” says Christian Jøns.
They were then monitored for more than three years, with all serious events recorded and assessed by an independent expert committee.
A little more potassium – much less arrhythmia
After three months, most patients had reached their target. On paper, the difference was tiny – from 4.0 to 4.4 in blood tests. But in reality, that small shift meant that many more patients avoided life-threatening arrhythmia.
The targeted effort led to 136 incidents in the intervention group versus 175 in the control group over a follow-up period of just under 40 months. This corresponds to every twelfth patient avoiding a serious outcome – a combined outcome of life-threatening arrhythmia, hospitalisation for arrhythmia or heart failure and death.
“These are people who live with an ICD under their skin – every day with the fear that it may have to save their lives,” says Henning Bundgaard. “For every 12 we help, one avoids facing death.”
Saving a life for just DKK 5 per day
It was particularly the number of ICD shocks and documented cases of ventricular tachycardia that declined: from 122 to 92 cases. Further, there were fewer hospitalisations for cardiac arrhythmia and heart failure, and the number of deaths was slightly lower without reaching statistical significance.
“Yes – and of course it is also the ultimate thing: people dropping dead, right?” says Bundgaard. “So when you see fewer shocks and less arrhythmia, that is a very strong signal.”
An important point is that the effect did not require any advanced technology or expensive treatments. The strategy consisted of simple measures that patients could tolerate and maintain over time.
“The remarkable thing is that the strategy is both well tolerated and costs less than DKK 5 per day,” adds Niels Risum.
He points out that the strategy is therefore easy to imagine being rolled out on a large scale if the results are confirmed.
A discovery that could change heart medication
Previous observations had indicated that patients at the low end of the normal range for potassium had a higher risk of sudden cardiac death – but without controlled trials, this had not affected practice.
“Observational data is generally not sufficient to influence guidelines,” says Henning Bundgaard.
In POTCAST, the researchers therefore tested for the first time whether a small increase from low-normal to high-normal levels could make a difference.
“And the remarkable thing is that it worked,” he notes. “Just a few tenths more in the blood reduced the number of cases of life-threatening arrhythmia by 24%.”
When a cheap pill outperforms high-tech medicine
POTCAST shows that the lives of the most vulnerable patients can be saved. The next big test will be to determine whether the strategy can also help many more people – before they reach the point at which they need an ICD. The fact that such a simple and inexpensive strategy can have such a strong effect opens new perspectives for prevention. As Henning Bundgaard puts it:
“I think if you were a pharmaceutical company and had a drug you could give that worked, you would be really, really happy. It is also remarkable that this strategy is very well tolerated.”
What is special is that the strategy does not require new technology or advanced medicine – just a thorough risk assessment and simple measures such as dietary changes and tablets.
“You do not have to develop something monstrously expensive, but maybe you can eat more of certain foods or go down to the pharmacy and buy a cheap pill.”
Henning Bundgaard points out that this logic – understanding biology and then taking targeted but simple measures – could pave the way for many more studies in the future.
And this is exactly where REACT, a major research project in Denmark, comes in: it aims to identify healthy people who are carrying hidden atherosclerosis – long before the disease breaks out.
“I can see REACT forming the basis for more studies of this type if we can find the right areas to explore.”
REACT: detecting disease before it strikes
The POTCAST study investigated whether the risk of life-threatening arrhythmia can be reduced among people who are already seriously ill, whereas REACT has a completely different aim: to find the disease before it causes damage.
“REACT focuses on understanding why atherosclerosis occurs – long before people become ill,” explains Henning Bundgaard. “We will be able to identify who is entering the risk zone while they still feel healthy.”
For the first time, the project is mapping the prevalence of atherosclerosis and its risk factors in the general population. More than 16,000 young and middle-aged people in Denmark and Spain are being examined from head to toe: their lifestyle factors are being measured and they are undergoing blood and urine tests, electrocardiography, eye examinations, whole-genome sequencing, advanced molecular profiling, neck ultrasounds and full-body computed tomography scans of their blood vessels.
“In the first phase of REACT, we are mapping the incidence of atherosclerosis from ages 18 to 70 years – and we are gathering everything that we know – or suspect – may affect the risk of developing atherosclerosis: genes, lifestyle, biochemistry and scans,” says Bundgaard. “This is the foundation on which we can build future interventions.”
A 20-year head start: stop heart disease before it starts
Linking these data to information about who actually develops atherosclerosis enables both individual risk factors and protective factors to be identified. According to Bundgaard, this enable the next wave of intervention studies – such as the potassium study – to be designed, but much earlier in the course of the disease and much more targeted to the individual.
“We may have a window of 10, 20 or 30 years during which atherosclerosis develops silently. If we can find them there, we believe that, with minor interventions, we can avoid major disasters later on.”
In other words, REACT can incubate the preventive heart medicine of the future – not only in the form of drugs but also dietary, sleep and exercise interventions. If the results are strong enough to be translated into nationwide screening programmes, this will require support from many sides – first and foremost from the population but also from the many partners involved in the healthcare system – and from politicians. This ambition goes far beyond a single study:
“There has been talk that one day we may be able to eradicate cardiovascular disease,” he says. “When you know that atherosclerosis is behind 75–85% of the patients with heart disease, that is what we are really aiming for.”
