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UPDATE FROM THE EDITORS: We would like to inform our readers that the studies mentioned in the following text have been withdrawn at the request of the authors, Mandeep Mehra of Brigham and Women’s Hospital, Frank Ruschitzka of Zurich University Hospital, and Amit Patel of the University of Utah. The publication Lancet has withdrawn Mehra’s study on Covid-19 and possible treatment of the disease with chloroquine and hydroxychloroquine. The New England Journal of Medicine has also withdrawn the study on a possible positive effect of antihypertensive drugs in the treatment of Covid-19. The reason in both cases was that the researchers themselves were not involved in collecting the underlying data and cannot guarantee its accuracy after doubts had arisen.

The SARS-CoV-2 novel coronavirus is now believed to be responsible for nearly 375,000 deaths worldwide, and infected more than six million people according to official figures. Virologists claim that the number of unreported cases is many times higher. And the numbers are still rising. The longer this pandemic lasts, the more that researchers are finding out about this virus and COVID-19, the disease it causes.

Although it was initially assumed that Covid-19 was a respiratory disease, autopsy results have shown that the virus affects a wide variety of organs in the body. The list of symptoms is growing longer almost by the day. Coughing, fever, and aching limbs are still considered ‘typical’ symptoms of COVID-19. Yet according to a study by the University of Göttingen, (Germany), only a fraction of all infections are detected. The reason for this is that the disease frequently seems to run its course without symptoms, especially in young people.

After several doctors started noticing skin changes on some of their patients’ feet in April, reports from the University Hospital of Messina, (Italy), as well as a study from the University Hospital of Madrid, (Spain) have since confirmed these observations. A study published in the British Journal of Dermatology shows that skin changes were primarily found in younger people “who had mild or asymptomatic disease progressions.”

Symptoms of an asymptomatic illness progression

Another study from Italy shows that in addition to what is referred to as ‘COVID toes‘ (a chilblain-like rash on the toes), rashes on other parts of the body can also be among the symptoms of COVID-19. For example, red, itchy skin rashes or welts and pustules like chickenpox on the upper part of the body, which can also spread across the entire body. The Spanish study reported that itchy pustules were found in 19 % of the 375 subjects. As it turns out, rashes are one of the most common external symptoms seen in Italy.

Another symptom is blood clots, which, like COVID toes and head-to-toe rashes, have only been recognized after some time as being symptoms of COVID-19. According to the latest findings, and since about 40 % of all virus-related deaths are due to cardiovascular complications such as heart attacks or strokes, researchers now believe that the disease is more likely to be a vascular rather than a respiratory infection. All symptoms have one thing in common: blood circulation is impaired.

“All these COVID-related complications were a mystery to us. We see blood clotting, we see kidney damage, we see inflammation of the heart, we see stroke, we see encephalitis,” William Li, MD, president of the Angiogenesis Foundation, was quoted as saying on the independent media platform medium.com.“Countless seemingly unrelated phenomena that are not normally seen in SARS or H1N1, or to be frank, aren’t seen in the majority of infectious diseases.”

Much more than a respiratory disease

Dr. Mandeep Mehra, the medical director of the Cardiovascular Center at Brigham and Women’s Hospital, (USA), explains to the publication: “When you add up all the data that is being gathered, it turns out that this virus is most likely a vascular virus, which means that it attacks the blood vessels. According to a study carried out by Mehra and a team of scientists, the SARS CoV-2 virus can infect endothelial cells, i.e. the lining on the interior surface of blood vessels. These cells protect the cardiovascular system by releasing proteins that regulate everything from blood clotting to immunological responses. Results of the study revealed that the virus had damaged the endothelial cells in the lungs, heart, kidneys, liver, and intestines.

Damage to the endothelial cells could consequently be responsible for the high incidence of cardiovascular damage and sudden heart attacks, even in young people, as it leads to inflammation inside these blood vessels. This in turn leads to a situation where all accumulated plaque – which would have otherwise remained stable or been controlled by medication – is loosened and causes a heart attack.

Rife with ACE2 receptors

“The idea that is emerging is that this is not just a respiratory disease, instead it is a respiratory disease in the first instance, but is actually a vascular disease that kills people by attacking the blood vessels,” Mehra states. The physicians assume that the virus enters the body via ACE2 receptors on the cell surface of respiratory tracts in the nose and throat. The virus then migrates from the alveoli (lung sacs) into the blood vessels, which are also rife with ACE2 receptors.

“The virus enters the lungs, destroys the lung tissues, and people start to cough. The destruction of the lung tissues causes some blood vessels to rupture,” Mehra explains. “Then the virus starts infecting one endothelial cell after another, triggering a local immune response and inflaming the endothelium.”

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Why ventilators often do not help

To date, a respiratory virus that infects blood cells and circulates through the body is practically unheard of. Neither influenza viruses such as H1N1 nor the original SARS virus have been able to spread via the lungs. According to Benhur Lee, MD, Professor of Microbiology at the Icahn School of Medicine at Mount Sinai Hospital, (New York), the difference between SARS and SARS-CoV-2 is presumably due to an additional protein that each of the viruses needs to activate and spread. “Although both viruses bind themselves to cells via ACE2 receptors, an additional protein is still needed in order to break down the virus so that its genetic material is able to enter the infected cell.”

The additional protein that the original SARS virus needs is only present in lung tissue. Whereas the protein for the activation of SARS-CoV-2 is present in all cells, especially in the endothelial cells. “SARS-CoV-2 is split by a protein known as furin, and this is a grave threat because furin is present in all of our cells, it is ubiquitous.

Damage to blood vessels could also explain why people with pre-existing conditions such as high blood pressure, high cholesterol, diabetes, and heart disease are at a higher risk of serious conditions or even death from the disease. Moreover, this could also be the reason why artificial ventilation is often not effective enough, given that the exchange of oxygen and carbon dioxide in the blood is just as important for supplying the rest of the body with oxygen.

ACE inhibitors and statins as a form of treatment

In the event that it is established that COVID-19 is a vascular disease, the best course of treatment might not be an antiviral one. Instead, it could be one that is already available. For example, in another study that was published in the New England Journal of Medicine which involved almost 9,000 COVID-19 patients, Mehra showed that the use of statins and ACE inhibitors was associated with a higher overall survival rate. Statins reduce the risk of heart attack by lowering cholesterol levels, preventing plaque or helping to stabilize existing plaque.

“It has been proven that both statins and ACE inhibitors have an extremely protective effect on vascular disorders,” Mehra points out. “Most of their benefits within the continuum of cardiovascular disease – whether it concerns hypertension, stroke, heart attack, arrhythmia, or heart failure – in each case, the mechanism by which they protect the cardiovascular system, also promotes the stabilization of the endothelial cells. What we are implying is that perhaps the best antiviral treatment is not necessarily an antiviral therapy. The most effective therapy might actually be a medicine that stabilizes the vascular endothelial cells.”