This means that there might be a best time of day for individuals receiving treatment for atherosclerosis to take their medication, suggest researchers from Ludwig Maximilian University (LMU) in Munich, Germany.

“Our study,” notes senior author Oliver Söhnlein, a professor in LMU’s Institute for Cardiovascular Prevention, “shows how circadian patterns can be used for timed therapeutic intervention possibly with lower side effects and higher efficacy.”

He and his colleagues report their findings in a paper now published in the journal Cell Metabolism.

Atherosclerosis and circadian rhythm

Atherosclerosis is a condition in which fatty deposits build up inside arteries and gradually cause them to become hard and narrow. These deposits are called plaques, and they are made of fat molecules, cholesterol, calcium, and other substances in the blood.

They build up slowly over many years — even decades — restricting flow of oxygen- and nutrient-rich blood to the point that it causes heart disease, heart attack, stroke, and sometimes death.

Circadian rhythms are patterns of biology and behavior that follow a cycle of around 24 hours. They can be observed in nearly all living things, from cells and bacteria to plants and animals. Scientists have even observed them in laboratory-cultured cells.

The control and timing of circadian rhythms are dictated by clock genes that instruct cells how to make the proteins that run their biological clocks. The body’s many biological clocks are kept in sync by a master clock in the brain.

Circadian patterns and chronopharmacology

There is mounting evidence that biological clocks are closely linked to the cardiovascular system. Well known examples of this include heart rate and blood pressure, which are known to vary according to time of day.

Circadian patterns have also been observed in the biology of blood vessel tissue, formation of platelets, and the onset of arrhythmia, heart attack, stroke, and other cardiovascular diseases. There is also evidence that disrupting circadian rhythm can be a risk factor for such diseases.

Given that circadian rhythm is so intimately linked to biological processes, it would be reasonable to assume that it also impacts the effectiveness of drugs.

However, despite decades of research on biological clocks, circadian rhythm is “only seldom considered by clinicians, drug developers, or regulators.”

The new study concerns the field of chronopharmacology, in which scientists are increasingly examining the effect of circadian rhythm on biological response to drugs.

Immune cell recruitment pattern is circadian

Prof. Söhnlein and his team at LMU research the biology of atherosclerosis at the molecular level. They explain that as the disease progresses, immune cells congregate at the sites where plaque builds up.

These immune cells send out signals that attract further cells to attempt to tackle the damage, but eventually, the immune repair mechanism breaks down and inflammation sets in.

However, the researchers note that while inflammation may take years to develop, the pattern of “recruitment” of immune cells behind the inflammation follows a circadian rhythm. They confirmed this by observing mice with atherosclerosis.

They found that there were times of the day when the number of white blood cells arriving at the site of inflammation increased threefold.

The team also noticed that this peak of immune cell activity in atherosclerotic deposits occurred 12 hours out of phase with the recruitment of white blood cells into the “microcirculation” of small blood vessels.

“The recruitment of white blood cells in the microcirculation is important for acute infections such as for example a lung or bladder infection,” Prof. Söhnlein explains.

Implications for drug timing

This 12-hour shift could be very useful from a treatment point of view. The drug should be given so that it stops recruitment of immune cells at the site of atherosclerotic inflammation, but not at sites where they are necessary for microcirculation. Could giving it at the “right time” ensure this?

The team showed that this might work by testing it in a model of the early stages of atherosclerosis.

First, the scientists identified the molecular pathway that recruits the white blood cells. Then, they showed that blocking it during the “activity phase” of white blood cell migration to atherosclerotic sites did not affect microcirculation migration.

“At certain times of the day, three times as many leukocytes travel to the center of arterial inflammation as it is the case for other times.”

Prof. Oliver Söhnlein

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