COVID-19 baffled doctors and scientists around the world with its strange symptoms and disproportionate mortality rates. Months after the onset of the pandemic, researchers may finally be closer to understanding how the disease manifests itself in patients. An important clue lies in the circulatory system.
Early on, most COVID-19 patients showed signs and symptoms of a pneumonia-like disease, leading to the assumption that it is chiefly a disease of the lungs. But as time elapsed, the virus infected many more people, and the larger sample size of infected patients has substantially evolved our understanding of the clinical manifestations of COVID-19.
Doctors treating these patients have observed a wide range of rather bizarre symptoms, from blood clots and strokes to red, swollen toes – also known as “COVID toes”. However, these mysterious symptoms seem to have one thing in common – a damaged circulatory system. Moreover, patients with cardiovascular comorbidities are at a higher risk of severe disease, with up to 40% of COVID-19 deaths associated with cardiovascular complications.
These clinical observations have led researchers to weave their findings into an important hypothesis. They now believe that COVID-19 could be farther-reaching than initially thought, and could impair the circulatory system, leading to damage of virtually any organ. Many patients have ended up with damage to their vital organs, such as the brain, kidney and heart. In fact, cardiovascular complications have been a bigger threat than the lung disease itself.
How does COVID-19 manifest as a circulatory system disease?
Scientists have shown that SARS-CoV-2, like some other coronaviruses, binds to the ACE-2 molecule – a protein receptor on the cell surface – to penetrate and infect the host cell. These ACE-2 receptors are present in the lungs, but also on the surface of the endothelial cells lining the blood vessels. By infecting and damaging the endothelial cells, SARS-CoV-2 attacks the blood vessels, leading to abnormal leaky vessels with reduced blood flow.
This mechanism is rather unheard of in most respiratory viruses. Even other coronaviruses like SARS, which also interacts with the ACE-2 receptor, do not show such widespread effects. Scientists believe that the answer to this has a molecular basis. While ACE-2 enables viral entry into the host cells, another activating protein enables these viruses to release their genetic content and replicate. But the expression of the activating protein for SARS is limited to the lungs. The activating protein for SARS-CoV-2 is present everywhere – including the endothelial cells.
This could explain why patients with comorbidities like cardiovascular disease or high blood pressure are at an increased risk of severe COVID-19. Their pre-existing condition could have already damaged their blood vessels, making these patients particularly vulnerable to further damage by the virus.
In the lungs, endothelial damage can manifest as clotted blood vessels in the air sacs, leading to fluid accumulation and difficulty breathing – the typical symptoms of COVID-19. Because of high ACE-2 expression in the lungs, scientists believe that the blood vessels of the lungs are likely to be a key target for the virus. Severe destruction of the lung tissue can break open the nearby blood vessels. The virus can attack these endothelial cells one after the other, and severely damage the system of blood vessels, culminating in a local inflammatory response.
But endothelial cells are not limited to the lungs. Blood vessels extend over 60,000 miles from head-to-toe to circulate blood throughout the body. “Is this one way that COVID-19 can impact the brain, the heart, the COVID toe? Does SARS-CoV-2 traffic itself through the endothelial cells or get into the bloodstream this way? We don’t know the answer to that”, says Dr. William Li, the president of the Angiogenesis Foundation.
Another theory suggests that systemic inflammation could be due to the overactive immune responses against the virus. This mechanism is commonly observed in other respiratory viruses as well, so it remains unclear why COVID-19 is so severe.
It could be a combination of the two theories. Damaged endothelium could expose the underlying membrane and trigger the inflammatory immune response induced by the virus. This could result in more clotting factors and platelets being recruited, making the blood more likely to clot and hence cause poor circulation.
A change in treatment strategy?
These research findings provide useful clues to researchers investigating treatment strategies. In some patients with severe disease, even ventilators do not seem to help much. Studies show that up to a third of COVID-19 patients develop dangerous blood clots – could these clots be to blame? Fluid accumulation can make it difficult to breathe and lowers oxygen intake, but providing supplemental oxygen cannot support the patient for long. No matter how much oxygen is supplied, if the blood vessels in their lungs are impaired, they will not be able to facilitate oxygen exchange.
If COVID-19 is indeed a vascular disease, it could open doors to pre-existing therapies that are already in use for patients with circulatory system diseases. Dr Nicola Mutch, a principal investigator at the University of Aberdeen, is currently investigating the potential of clot-busting drugs for such patients. Her research is also devising ways to deliver these drugs to the lungs using a nebuliser to rapidly clear clots to help critically ill patients breathe.
Some scientists are also exploring a “prevention is better than cure” approach. Several drugs that protect blood vessels and maintain the healthy endothelium already exist in the market. Statins, for example, can play a protective role and have been shown to lower risk of COVID-19-associated mortality in China. They can activate a molecule called KLF2 to help endothelial cells release important substances that prevent clotting and keep the blood vessels healthy. Statins can also lower blood pressure, stabilise and reduce plaques on the blood vessel wall to lower risk of a heart attack.
Other drugs like angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) could be beneficial as well. These drugs target angiotensin II, a hormone that primarily regulates blood pressure. However, these drugs also upregulate the expression of ACE-2 receptors on cells. It may seem counterintuitive to use them against SARS-CoV-2, but most studies so far have shown that these drugs do not increase mortality rates in COVID-19 patients.
“It turns out that both statins and ACE inhibitors are extremely protective on vascular dysfunction”, says Dr. Mandeep Mehra, medical director of the Brigham and Women’s Hospital Heart and Vascular Center.
Could we repurpose these to keep our blood vessels healthy and prevent blood clots from forming in the first place? Experts have cautioned against drawing conclusions before clinical trials can substantiate the claimed benefits. As more studies are rapidly underway, research appears to be heading in the right direction. It provides new avenues of therapeutic strategies to explore to establish control over the disease and curb death rates.
“What we’re saying is that maybe the best antiviral therapy is not actually an antiviral therapy. The best therapy might actually be a drug that stabilizes the vascular endothelial. We’re building a drastically different concept”, Dr. Mehra says.
Written by Simran Kapoor and edited by Ailie McWhinnie.
Simran’s thoughts… Perhaps the biggest challenge with COVID-19 is the lack of understanding of what it actually is. Doctors were left baffled by the bizarre symptoms, often feeling helpless as they found themselves unable to help some patients despite them being on ventilators in critical care units. But science and research can help tremendously in times like this. Research groups all over the world are developing an invaluable repertoire of knowledge about COVID-19. Even if a vaccine may not be available by the end of this year, our understanding of this virus is certainly growing. This gives a lot of us hope that doctors will soon be able take on COVID-19 cases with a sense of confidence. Better treatments come from better understanding of clinical manifestations. And better treatment can help lift the death sentence associated with severe COVID-19 cases.
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