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Is coronavirus a disease of the blood vessels? An Overview from British Heart Foundation

British Heart Foundation -Heart Matters Commentary. July 1, 2020

Is coronavirus a disease of the blood vessels?

As we learn more about coronavirus, it is becoming clear that it affects more than just the lungs. Phoebe Kitscha explores how and why Covid-19 affects the whole circulatory system, and the research that is trying to tackle it.

  • Why coronavirus is a blood vessel problem

  • Treating coronavirus by stopping blood clots

  • Could statins help protect blood vessels against coronavirus-related damage?

  • Could heart drugs like ACE inhibitors and ARB’s help protect blood vessels from coronavirus?

  • Ongoing research

Why coronavirus is a blood vessel problem

When the coronavirus that causes Covid-19 emerged at the end of 2019, it was initially thought that – like other coronaviruses affecting humans – it mainly caused lung problems.

But as the outbreak progressed, cases emerged suggesting that some of the most severe complications of the disease affect more than just the lungs. From reports of ‘sticky blood’ raising the risk of deep vein thrombosis, heart attack or stroke, to neurological effects, to painful red and swollen areas on the feet known as ‘Covid toe’ – many of these symptoms are thought to be linked to effects on our blood vessels.

In particular, these symptoms may be caused by the way that Covid-19 affects the lining of the blood vessels, called the endothelium. This layer of cells is not a solid barrier – it can allow or block certain substances through depending on conditions in the body. It also has a vital role in allowing our blood vessels to function normally.

A healthy, well-functioning endothelium helps to keep our blood vessels relaxed and open to the flow of blood. It also releases substances that help to prevent harmful blood clots and inflammation. But if the endothelium is damaged, these processes may not work effectively, known as endothelial dysfunction.

This is a key factor in the development of heart and circulatory conditions. For example, it is linked to the formation of fatty plaques in our arteries, which can rupture, leading to heart attacks and strokes.

In April 2020, a paper published in The Lancet gave the first evidence that the coronavirus that causes Covid-19 can infect endothelial cells. The molecule ACE2 (which the virus binds to in order to enter our cells and reproduce itself) can be found on the surface of endothelial cells.

In May, another study of the lungs of seven people who died from Covid-19 found higher ACE2 levels in lung endothelial cells, alongside evidence of severe injury to blood vessels. The researchers showed that the disease is linked to the formation of tiny clots within capillaries (our smallest blood vessels) in the lungs. There were nine times as many of these clots in people with Covid-19 as in the lungs of people who died from flu.

By damaging the endothelium, coronavirus infection has the potential to cause abnormal blood clotting, ‘leaky’ vessels and reduced blood flow. In the lungs, these effects cause clots and fluid to accumulate, which means the lungs are less able to get oxygen into the body. And these endothelial effects could have consequences from head to toe.

In the brain, damage to endothelial cells in the blood-brain barrier could lead to inflammation. In limbs, reduced blood flow could lead to ‘Covid toe’. Combined with the virus’s effects on the immune system, where overactivation of our inflammation systems can also make the blood more likely to clot, this could help to explain the range of symptoms people with Covid-19 can develop.

This may also help to explain why people with certain heart and circulatory conditions seem to be at a higher risk of developing severe complications of Covid-19. If another condition, such as diabetes or high blood pressure, has already damaged the endothelium, the virus’s impact is magnified.

While this sounds worrying, it raises the possibility that treatments already used to help limit blood clotting and improve the function of the circulatory system could be vital to saving lives.

Treating coronavirus by stopping blood clots

Estimates suggest up to 30% of people with severe Covid-19 develop dangerous blood clots. A study in a US hospital also showed that people hospitalised with Covid-19 who received an anticoagulant (a blood-thinning drug) during their stay seemed to have better outcomes than those who didn’t.

Now that more doctors are aware of this, many give drugs to limit blood clotting to patients with Covid-19 soon after they come into hospital. These might include:

  • antiplatelet drugs such as aspirin, usually prescribed after a heart attack

  • anticoagulant drugs, which help prevent strokes

  • thrombolytic (‘clot-busting’) drugs used to quickly break up clots that can cause a heart attack or stroke

Research will help to reveal how well these different medications can reduce severe coronavirus complications. For example, BHF-funded scientist Dr Nicola Mutch at the University of Aberdeen is investigating whether clot-busting drugs could be repurposed to treat Covid-19. Delivering these drugs to the lungs with a nebulizer could be a rapid way of clearing clots from the lungs of critically ill patients to help them get the oxygen they need. Dr Mutch and her team also want to find out whether blood tests to help doctors identify those at risk of clots from Covid-19, and what substances or signals the blood test would need to look for.

Could statins help protect blood vessels against coronavirus-related damage?

Medication to limit clotting may turn out to be an effective approach. But protecting the endothelium from damage caused by Covid-19 in the first place could also help to stop clots from forming.

The healthy endothelium releases several substances that help to limit blood clotting. These include:

  • Thrombomodulin – which helps to activate anti-clotting factors in the blood

  • Nitric oxide – which helps to keep blood vessels relaxed and can help limit activation of platelets (cells in the blood that clump together forming clots)

  • Tissue plasminogen inhibitor (tPA) – which helps to break down clots. Many clot-busting drugs (such as alteplase – used in the UK as an emergency treatment for stroke) are a synthetic form of this molecule.

A molecule found in endothelial cells called ‘KLF2’ plays a vital role in maintaining healthy levels of the substances that keep our blood vessels working properly, including those listed above. But levels of KLF2 can fall considerably if the endothelium becomes damaged or when there is inflammation. This causes these protective systems to break down. Several drugs can help maintain KLF2 levels, including some types of statin which can activate KLF2 in endothelial cells. This protective effect on the endothelium may in part explain why statins can have beneficial effects on the heart and circulatory system that go beyond their cholesterol-lowering activity. (Statins also help to reduce inflammation, stabilise plaques in the blood vessel wall, and may reduce the risk of blood clots from forming.) Importantly, this could help to explain some of the evidence emerging suggesting people who already take statins may have better outcomes from Covid-19. In June, a study looking at the hospital records of people hospitalised with Covid-19 in China showed that those who were taking a statin seemed to be at a lower risk of dying. But this type of ‘observational’ evidence cannot prove that the lower death rate seen was directly caused by taking a statin. Experts are now calling for the potential beneficial effects of statins in Covid-19 to be tested in randomised clinical trials – the gold standard way of testing a treatment. Could heart drugs like ACE inhibitors and ARBs help protect blood vessels from coronavirus? Another factor when it comes to healthy blood vessels is a hormone called angiotensin II. This helps to narrow the blood vessels, which increases blood pressure. Blood pressure drugs called ACE inhibitors and angiotensin receptor blockers (ARBs) target this system of blood pressure regulation to relax blood vessels and prevent damage to the heart and kidneys. But angiotensin II can also have inflammation of endothelial cells, causing endothelial dysfunction, reducing production of nitric oxide, and potentially increasing the likelihood of clots forming. In people with Covid-19, it’s thought that the balance between angiotensin II and angiotensin 1-7 (which has the opposite effect to angiotensin II on blood pressure and blood vessels) is tipped towards having too much angiotensin II. Usually, this balance is maintained by ACE2 – but that may be working less well because as we saw earlier, the coronavirus binds to it to get into the body and reproduce itself. Drugs that could help restore the proper balance of angiotensin II levels, such as ARBs, may therefore help people with Covid-19. A recent study of 1,200 patients with Covid-19 in two London hospitals co-authored by BHF Professor Ajay Shah suggested that those on ACE inhibitors or ARBs were less likely to die or need to be transferred to a critical care unit. But this type of evidence that cannot prove cause and effect is not enough on its own to change how doctors treat patients. Experts have cautioned that until we have good clinical trial evidence, we cannot draw firm conclusions about the benefits of ACE inhibitors or ARBs in treating Covid-19, and people should only take this type of medication as advised by their doctor. Several randomised clinical trials of these drugs in people hospitalised with Covid-19 are under way. A new drug called TRV027 is also set to be trialled in people who have Covid-19 at UK hospitals. It will have support from researchers at the BHF Centre of Research Excellence at Imperial College London. This drug was previously tested as a potential treatment for heart failure. While TRV027 was not effective at improving heart failure symptoms, this study showed that is safe – making it possible that it could be used successfully for other conditions. TRV027 is thought to block angiotensin II and could perhaps also have the opposite effect on the blood vessels (similarly to angiotensin (1-7). The researchers believe this could help to halt many of the dangerous processes which occur in Covid-19, such as lung damage and blood clots. Ongoing research We now understand much more about the damaging effects of Covid-19 on our blood vessels. We also have some promising avenues to explore to try to prevent this damage. But there is still more to learn. The BHF has long funded research into ways to protect the blood vessels in heart and circulatory conditions. One of the reasons that we fund research into circulatory conditions, not just conditions affecting the heart, is that our blood vessels connect everything. Many researchers are now stepping up efforts to translate these findings into new ways to help people with blood-vessel related problems caused by Covid-19. The BHF is fully committed to supporting our researchers to help them to do so. Phoebe Kitscha is a Research Advisor at the BHF


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