A consensus more than 90-years-old on the mechanisms which regulate the day-night rhythm in heart rate has been fundamentally challenged by an international team of scientists from Manchester, London, Milan, Maastricht, Trondheim and Montpellier.
The vagus nerve – one of the nerves of the autonomic nervous system which supplies internal organs including the heart – has long been thought to be responsible for the slower night-time heart rates.
But the University of Manchester-led study on mice and rats discovered that the vagus nerve is unlikely to be directly involved and instead the sinus node – the heart’s natural pacemaker – has its own clock, a biological clock.
The sinus node, they find, knows when it is night and slows the heart rate accordingly.
The British Heart Foundation funded findings, published in Heart Rhythm, shine new light on this fundamental biological question of why the heart rate is slower at night and why dangerously slow heart rates – called bradyarrhythmias – can occur when we’re asleep.
The team behind the study demonstrated that changes in the ‘funny channel’ – also known as HCN4, a key protein that controls the heart rate – at different times of the day and night can explain the changes in heart rate.
The team found that blocking the funny channel with ivabradine, an angina treatment, removed the difference in heart rate between day and night.
The team found a role for the clock gene called BMAL1 as a regulator of the funny channel and this could one day lead to a treatment for dangerous bradyarrhythmias when we’re asleep.
Though the research was carried out in mice and rats, funny channels and clock genes play similar roles in all mammals – including humans – which is why the research has a universal significance.
Lead author Dr Alicia D’Souza, a British Heart Foundation Intermediate Fellow from The University of Manchester said: “The heart slows down when we sleep and there can even be pauses between heart beats. Strangely, this is especially true in elite athletes. The longest documented pause is 15 seconds – a very long time to wait for your next heartbeat!
“For the very first time, we have tested an alternative hypothesis that there is a circadian rhythm in the intrinsic pacemaker of the heart – the sinus node.
“Our study shows that in mice, this is indeed the case and that explains why the heart rate is slower at night.
“These basic mechanisms of heart rate regulation are conserved in mammals – including humans – and therefore widely accepted concepts that are taught in schools may one day need to be revised.”
The sinus node – sometimes known as the sinoatrial node – generates electrical impulses which cause the heart to beat. It consists of a cluster of cells in the upper part of the right upper chamber of the heart.
Previous assumptions about the vagus nerve’s impact on the heart were based on a technique-called ‘heart rate variability’.
There are over 26,000 scientific papers based on heart rate variability published over 60 years. But the team’s previous British Heart Foundation-funded work demonstrated that heart rate variability is fundamentally flawed and says nothing about the vagus nerve.
"The heart slows down when we sleep and there can even be pauses between heart beats. Strangely, this is especially true in elite athletes. The longest documented pause is 15 seconds – a very long time to wait for your next heartbeat! For the very first time, we have tested an alternative hypothesis that there is a circadian rhythm in the intrinsic pacemaker of the heart - the sinus node. Our study shows that in mice, this is indeed the case and that explains why the heart rate is slower at night."
Professor Christopher Yau
In the present study the authors used a range of measurements to assess electrical activity and genes in the heart’s pacemaker. These included studying heart rhythm and activity levels and further exploration of ionic currents, proteins and regulatory proteins called transcription factors.
Cali Anderson, a British Heart Foundation-funded PhD student and co-author added: “It is well known that the resting heart rate in humans varies over 24 hours and is higher during the day than at night.
“But for over 90 years, the daily changes in our heart rate has been – and we believe over simplistically – assumed to be the result of a more active vagus nerve at night.
“In the future these findings could have important therapeutic potential in the way we are able to understand and treat heart rhythm disturbances.”
Dr Noel Faherty, Senior Research Advisor at the BHF, said: “This research challenges a near century old consensus on how heart rate is regulated.
“A slower heart rate at night by itself is quite normal in most people, but understanding the mechanisms that govern the heart’s basic functions are crucial building blocks for tackling more complicated questions about heart rhythm disturbances.
“Worryingly, our ability to fund research like this in the future is threatened by the devastating fall in income caused by coronavirus. It is more important than ever that the public continue to support our work so that we can continue to make progress in treating and preventing heart and circulatory disease in the UK.”
The paper: A circadian clock in the sinus node mediates day-night rhythms in Hcn4 and heart rate is published in Heart Rhythm is published in Heart Rhythm