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LMB and AstraZeneca explain how our body clock affects heart rhythms, with implications for shift workers, the elderly and the timing of medicines



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Research that could explain why shift workers are more prone to heart problems, and why the elderly are more likely to have a cardiac event in the morning, has been published by the MRC LMB, and it could help us improve the timing of medicines.

Dr John O'Neill, at the MRC Laboratory of Molecular Biology. Picture: Keith Heppell
Dr John O'Neill, at the MRC Laboratory of Molecular Biology. Picture: Keith Heppell

If you’re reading this in the morning after a night’s sleep, your heart rate will be considerably higher than it was a few hours ago.

We know that signals from the nervous system play a key role in driving this variation in our cardiac activity.

But now researchers at the MRC Laboratory of Molecular Biology in Cambridge have shown how circadian rhythms - that is, what we often term the ‘body clock’ - within our heart cells make an equally important contribution.

The researchers, from John O’Neill’s group in the LMB’s Cell Biology Division, working with Peter Newham at AstraZeneca and other collaborators, say this has important clinical implications.

Taken together with other recent research from Dr O’Neill’s group, the findings suggest it is very likely that the reason shift workers are more vulnerable to threatening cardiac events is due to an uncoupling of the clocks in the brain from the clocks within heart cells.

How heart-rate varies during day and night. Graphic: MRC Laboratory of Molecular Biology
How heart-rate varies during day and night. Graphic: MRC Laboratory of Molecular Biology

Dr O’Neill said: “We know that when your circadian rhythm goes wrong during ageing or because of various lifestyle choices or because of genetic lesions, there is an increased incidence with a whole range of different diseases, such as cardiovascular, neurodegeneration, diabetes and so forth. So that’s why we need to understand it.”

Our ‘body clock’ is present in every cell, orchestrated by a master clock in the suprachiasmatic nuclei of the hypothalamus, in our brain.

This directs our physiological rhythms - the cycles of sleeping and waking, hormone levels and temperature - which help us to keep us aligned with the light and dark of day and night.

In the morning, our heart rate rises in anticipation of higher workload as we begin our daily activities.

John O'Neill's group at the MRC Laboratory of Molecular Biology. Picture: MRC LMB
John O'Neill's group at the MRC Laboratory of Molecular Biology. Picture: MRC LMB

These activities also prompt changes in the make-up of our cells. Up to a fifth of cellular proteins are under circadian control and in our habitually active phases, the expression of most of these proteins peaks in what the researchers describe as ‘translational rush hours’.

But something has to give to enable this increase in the number of these cytosolic proteins - that is, those suspended in the aqueous component of the cell’s cytoplasm.

Alessandra Stangherlin, lead author of the study published in Nature Communications, made the initial discovery that cellular ion levels fluctuate to compensate for the daily changes in macromolecular crowding of proteins. Ions are exported from the cell to make room for them.

The researchers found concentrations of potassium, sodium and chloride ions fall by as much as 30 per cent as protein levels increase. It had previously been thought ion concentrations were quite consistent.

At night, the process reverses, with protein levels decreasing and ion levels rising.

It is an important new insight into how different cell types maintain homeostasis while accommodating changes in what is inside them.

Dr John O'Neill at the MRC Laboratory of Molecular Biology. Picture: MRC LMB
Dr John O'Neill at the MRC Laboratory of Molecular Biology. Picture: MRC LMB

The researchers focused on the heart to understand the importance of this finding.

There, different levels of sodium and potassium inside and outside of cells enable the electrical impulse that causes heart cells to contract, driving our heartbeat.

When these sodium and potassium levels change throughout the day to accommodate the necessary protein changes, the intrinsic activity of heart cells has to vary.

This enables our hearts to sustain a higher beat rate during the daytime. In nocturnal mice, it does the same but at night-time.

In both cases, the heart is therefore able to manage the fluctuations in demand that are needed during the period of wakefulness.

Disruption of circadian clocks due to lifestyle factors, such as working night shifts, has previously been linked to increased incidence of numerous diseases, such as arrhythmias and other heart disorders.

It is also established that the elderly are at higher risk of cardiac events in the morning.

‘Body clocks’ are present in every cell
‘Body clocks’ are present in every cell

Dr O’Neill said: “The potential impacts of our findings is that it allows us to maybe understand the increased incidence of adverse cardiovascular events that occur during the morning, particularly in the old and also in shift workers.

“The idea would be that shift work and ageing both lead to a disruption of these daily rhythms in ion transport within heart cells and this is what makes them more vulnerable to things going wrong, such as arrhythmias, when an increased demand is placed on the heart, particularly in the early morning.”

The paper’s findings suggest that in older people reduced amplitude of daily cardiac sodium and potassium rhythms mean that the heart is less able to manage the changes in demand, such as sustaining increased cardiac function in the morning.

It is hoped that this new understanding of the mechanisms by which heart cell clocks constrain cardiac capacity could lead to important breakthroughs in new medicines, and also inform preventative measures.

“It opens up the exciting possibility of more effective treatments for cardiovascular conditions, for example by delivering drugs at the right time of day,” said Dr O’Neill.

The work is part of the LMB and AstraZeneca’s BlueSky collaboration.

Peter Newham, VP, oncology safety, AstraZeneca R&D, said: “The fundamental biology of how the body clock works is really not fully understood, or appreciated, especially in drug discovery. The concept of chrono-pharmacology is a really exciting and under-appreciated opportunity. How do we best time our drugs to be coincident with the body clock to give again the maximum chance of efficacy in some critical diseases with unmet need?”

Dr Stangherlin added: “Industry and academia often have a different perspective on scientific questions and different approaches, so I think having inputs from both sides is really interesting and stimulating and can expand one’s way of thinking.”

The work was funded by UKRI MRC, the Human Frontier Science Program, the Royal Society of Edinburgh and the Wellcome Trust.

AstraZeneca's R&D Centre on Cambridge Biomedical Campus, close to the MRC LMB building. Picture: AstraZeneca
AstraZeneca's R&D Centre on Cambridge Biomedical Campus, close to the MRC LMB building. Picture: AstraZeneca

Dr Megan Dowie, MRC head of molecular and cellular medicine, said: “This really interesting research supported through the MRC AstraZeneca Blue Sky Initiative shows the incredible potential for innovative academic-industry relationships to push the frontiers of discovery science.

“It addresses fundamental, unanswered questions about how the body works and points to exciting new possibilities for therapeutic innovations.”

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