̽��ֱ�� of Cambridge - atherosclerosis

High cholesterol levels at a young age significant risk factor for atherosclerosis

cjb250 — Wed, 04 Sep 2024 15:00:18 +0000

̽��ֱ��research also suggests that people who are taking lipid-lowering drugs such as statins to lower their cholesterol levels should remain on them, even if their cholesterol levels have fallen, as stopping treatment could increase their risk of atherosclerosis.

Atherosclerosis is one of the major causes of heart and circulatory disease. It involves the hardening and narrowing of the vessels that carry blood to and from the heart. It is caused by the build-up of abnormal material called plaques – collections of fat, cholesterol, calcium and other substances circulating in the blood.

Atherosclerosis is largely considered a disease of the elderly and so most screening, prevention and intervention programmes primarily target those with high cholesterol levels, generally after the age of 50.

But in a study published today in Nature, a team led by scientists at the ̽��ֱ�� of Cambridge shows that high cholesterol levels at a younger age – particularly if those levels fluctuate – can be even more damaging than high cholesterol levels that only begin in later life.

To study the mechanisms that underlie atherosclerosis, scientists often use animal modes, such as mice. ̽��ֱ��mice will typically be fed a high fat diet for several weeks as adults to see how this leads to the build up of the plaques characteristic of the condition.

Professor Ziad Mallat and colleagues at the Victor Phillip Dahdaleh Heart and Lung Research Institute at the ̽��ֱ�� of Cambridge decided to explore a different approach – to see whether giving mice the same amount of high fat food but spread over their lifetime changed their atherosclerosis risk.

“When I asked my group and a number of people who are experts in atherosclerosis, no one could tell me what the result would be,” said Professor Mallat, a British Heart Foundation (BHF) Professor of Cardiovascular Medicine.

“Some people thought it would make no difference, others thought it would change the risk. In fact, what we found was that an intermittent high fat diet starting while the mice were still young – one week on, a few weeks off, another week on, and so on – was the worst option in terms of atherosclerosis risk.”

Armed with this information, his team turned to the Cardiovascular Risk in Young Finns Study, one of the largest follow-up studies into cardiovascular risk from childhood to adulthood. Participants recruited in the 1980s returned for follow-up over the subsequent decades, and more than 2,000 of them had received ultrasound scans of their carotid arteries when they were aged around 30 years and again at around 50 years.

Analysing the data, the team found that those participants who had been exposed to high cholesterol levels as children tended to have the biggest build of plaques, confirming the findings in mice.

“What this means is that we shouldn’t leave it until later in life before we start to look at our cholesterol levels,” Professor Mallat said. “Atherosclerosis can potentially be prevented by lowering cholesterol levels, but we clearly need to start thinking about this much earlier on in life than we previously thought.”

̽��ֱ��mouse studies showed that fluctuating levels of cholesterol appeared to cause the most damage. Professor Mallat says this could explain why some people who are on statins but do not take them regularly remain at an increased risk of heart attack.

“If you stop and start your statin treatment, your body is being exposed to a yo-yo of cholesterol, which it doesn’t like, and it seems this interferes with your body’s ability to prevent the build-up of plaques,” he added.

̽��ֱ��reason why this is so damaging may come down to the effect that cholesterol has on specific types of immune cells known as ‘resident arterial macrophages’. These reside in your arteries, helping them to clear damaged cells and fatty molecules known as lipids, which include cholesterol, and stopping the build-up of plaques.

When the team examined these macrophages in their mouse models, they found that high cholesterol levels – and in particular, fluctuating cholesterol levels – changed them physically and altered the activity of their genes. This meant that the cells were no longer protective, but were instead detrimental, accelerating atherosclerosis.

̽��ֱ��research was funded by the British Heart Foundation.

Reference
Takaoka, M et al. Early intermittent hyperlipidaemia alters tissue macrophages to boost atherosclerosis. Nature; 4 Sept 2024; DOI: 10.1038/s41586-024-07993-x

Our risk of developing atherosclerosis – ‘furring’ of the arteries – can begin much earlier in life than was previously thought, highlighting the need to keep cholesterol levels low even when we are young, new research has discovered.

Atherosclerosis can potentially be prevented by lowering cholesterol levels, but we clearly need to start thinking about this much earlier on in life

Ziad Mallat

SolStock (Getty Images)

Teenagers eating pizza by the river

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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New Heart and Lung Research Institute opens

cjb250 — Mon, 11 Jul 2022 06:31:58 +0000

A major new institute opens today, bringing together the largest concentration of scientists and clinicians in heart and lung medicine in Europe.

Could a vaccine protect us against heart attacks?

cjb250 — Thu, 20 May 2021 07:15:46 +0000

Professor Ziad Mallat and his team have been shortlisted for a £30 million grant from the British Heart Foundation. If successful, atherosclerosis – hardening of the arteries – could become a thing of the past.

Observation of blood vessel cells changing function could lead to early detection of blocked arteries

cjb250 — Thu, 01 Nov 2018 10:00:25 +0000

̽��ֱ��muscle cells that line the blood vessels have long been known to multi-task. While their main function is pumping blood through the body, they are also involved in ‘patching up’ injuries in the blood vessels. Overzealous switching of these cells from the ‘pumping’ to the ‘repair’ mode can lead to atherosclerosis, resulting in the formation of ‘plaques’ in the blood vessels that block the blood flow.

Using state-of-the art genomics technologies, an interdisciplinary team of researchers based in Cambridge and London has caught a tiny number of vascular muscle cells in mouse blood vessels in the act of switching and described their molecular properties. ̽��ֱ��researchers used an innovative methodology known as single-cell RNA-sequencing, which allows them to track the activity of most genes in the genome in hundreds of individual vascular muscle cells.

Their findings, published today in Nature Communications, could pave the way for detecting the ‘switching’ cells in humans, potentially enabling the diagnosis and treatment of atherosclerosis at a very early stage in the future.

Atherosclerosis can lead to potentially serious cardiovascular diseases such as heart attack and stroke. Although there are currently no treatments that reverse atherosclerosis, lifestyle interventions such as improved diet and increased exercise can reduce the risk of the condition worsening; early detection can minimise this risk.

“We knew that although these cells in healthy tissues look similar to each other, they are actually quite a mixed bag at the molecular level,” explains Dr Helle Jørgensen, a group leader at the ̽��ֱ�� of Cambridge’s Division of Cardiovascular Medicine, who co-directed the study. “However, when we got the results, a very small number of cells in the vessel really stood out. These cells lost the activity of typical muscle cell genes to various degrees, and instead expressed a gene called Sca1 that is best known to mark stem cells, the body’s ‘master cells’.”

̽��ֱ��ability to detect the activity (or ‘expression’) of thousands of genes in parallel in these newly-discovered cells has been a game-changer, say the researchers.

“Single-cell RNA-sequencing has allowed us to see that in addition to Sca1, these cells expressed a whole set of other genes with known roles in the switching process,” says Lina Dobnikar, a computational biologist based at Babraham Institute and joint first author on the study. “While these cells did not necessarily show the properties of fully-switched cells, we could see that we caught them in the act of switching, which was not possible previously.”

To confirm that these unusual cells originated from muscle cells, the team used another new technology, known as lineage labelling, which allowed the researchers to trace the history of a gene’s expression in each cell.

“Even when the cells have entirely shut down muscle cell genes, lineage labelling demonstrated that at some point either they or their ancestors were indeed the typical muscle cells,” says Annabel Taylor, a cell biologist in Jørgensen’s lab and joint first author on the study.

Knowing the molecular profile of these unusual cells has made it possible to study their behaviour in disease. Researchers have confirmed that these cells become much more numerous in damaged blood vessels and in atherosclerotic plaques, as would be expected from switching cells.

“We were fortunate in that single-cell RNA-sequencing technologies had been rapidly evolving while we were working on the project,” says Dr Mikhail Spivakov, a genomics biologist and group leader at MRC London Institute of Medical Sciences, who co-directed the study with Jørgensen. Dr Spivakov carried out the work while he was a group leader at the Babraham Institute. “When we started out, looking at hundreds of cells was the limit, but for the analysis of atherosclerotic plaques we really needed thousands. By the time we got to doing this experiment, it was already possible.”

In the future, the findings by the team may pave the way for catching atherosclerosis early and treating it more effectively.

“Theoretically, seeing an increase in the numbers of switching cells in otherwise healthy vessels should raise an alarm”, says Jørgensen. “Likewise, knowing the molecular features of these cells may help selectively target them with specific drugs. However, it is still early days. Our study was done in mice, where we could obtain large numbers of vascular muscle cells and modify their genomes for lineage labelling. Additional research is still required to translate our results into human cells first and then into the clinic.”

̽��ֱ��research was funded by the British Heart Foundation and UK Research and Innovation.

Reference
Dobnikar, L, Taylor, AL et al. Disease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy vessels. Nature Communications; 1 Nov 2019; DOI: 10.1038/s41467-018-06891-x

A study in mice has shown that it may be possible to detect the early signs of atherosclerosis, which leads to blocked arteries, by looking at how cells in our blood vessels change their function.

Annie Cavanagh

Blood clot forming in arterial plaque

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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