At the start of the pandemic, the concerns of the medical profession quickly focused on the complications observed in the pulmonary system. In the most severe cases, breathing difficulties appear very quickly, requiring intubation. But the more the weeks pass, the more the deleterious effect of SARS-CoV-2 becomes clear. And the complications turned out to be much more extensive. Scientists at the University Hospital of Zurich have just highlighted the cardiovascular impact of the virus.
The first serious cases mainly presented complications in the respiratory system, such as pneumonia. But gradually, doctors saw more and more complications at the cardiovascular level, leading to multiple organ failures, unrelated to pneumonia.
SARS-CoV-2 infects its host via the angiotensin converting enzyme 2 receptor (noted ACE2); this enzyme is found on the surface of cells in several organs, including the lungs, heart, kidneys, and intestine. ACE2 receptors are also expressed by endothelial cells, which are located on the inner layer of blood vessels – and therefore are in direct contact with the blood and affect all organs. Now, experiences in vitro have shown that SARS-CoV-2 can directly infect human blood vessels. Faced with this finding, a team from the University Hospital of Zürich suspected and demonstrated the involvement of endothelial cells in the course of the disease. Their results have just been published in the journal The Lancet.
Traces of cell death and damaged vessels
The group of researchers from Zurich, led by Zsuzsanna Varga, therefore examined tissue samples from deceased patients to verify their hypothesis. The first case studied was a 71-year-old kidney transplant patient with coronary artery disease and high blood pressure. Even under artificial respiration, his condition quickly deteriorated leading to the failure of several organs; patient died on 8e day. Analysis post mortem of the transplanted kidney revealed the presence of the virus in endothelial cells (see fig. A and B below).
Evidence of endothelial cell dysfunction in the tissue of a patient who died from COVID-19. The arrows in (A) and (B) denote aggregates of viral cells. The arrows in (C) and (D) show the infiltration of mononuclear cells. Credits: Z. Varga et al.
Histological analyzes also revealed significant inflammation of the endothelial cells, as well as the apoptotic bodies (fragments of cells, characteristic of cell death), in the heart, the small intestine (fig. C) and the lung (fig D). An accumulation of mononuclear cells was observed in the lungs and most of the small pulmonary vessels appeared congested.
The second case study was a 58-year-old woman with diabetes, high blood pressure and obesity. She too quickly developed respiratory failure and then organic failure. After part of the small intestine was removed, circulatory failure occurred in the right ventricle, leading to myocardial infarction and then death. Again, histology post mortem revealed inflammation of endothelial cells in the lungs, heart, kidneys and liver, as well as necrosis of liver cells. Histology of the small intestine has also shown endothelitis of the submucosal vessels.
Finally, the third case was a 69-year-old man with hypertension. He was quickly placed on artificial respiration. Echocardiography showed a reduction in the ejection fraction – the percentage of blood ejected from a heart cavity during a heartbeat – in the left ventricle. Circulatory failure followed, with mesenteric ischemia (the arteries supplying the intestine were affected); resection of the small intestine was performed and the patient survived. The histology of the removed tissues revealed a prominent inflammation of the endothelium of the submucosal vessels, as well as of the apoptotic bodies.
Systemic vascular inflammation
Conclusion: the virus attacks the immune system not only through the lungs – as previously thought – but also via the ACE2 receptors of endothelial cells, which cross several organs. The endothelium gradually degrades and no longer manages to perform its functions, whereas it is essential for the maintenance of vascular homeostasis; it must contain the blood in the vessels, allow the exchange of nutritive substances between the blood and the rest of the organism, inhibit blood coagulation and control vasomotricity (the modulation of the diameter of the vessels according to changes in the environment ).
Hence the multiple organ failures observed in some patients: endothelial dysfunction leads to more vasoconstriction (the diameter of the vessels decreases), resulting in ischemia of organs (the organs are no longer sufficiently irrigated) and inflammation of the associated tissues . ” COVID-19 can affect the blood vessels of all organs “Summarizes Frank Ruschitzka, director of the cardiology clinic at the University Hospital of Zürich, who now suggests calling this clinical picture” COVID-endothelitis “.
The results of Varga and his team confirm that therapies aimed at stabilizing the vascular system, while tackling viral replication, prove to be entirely timely. The team specifies that this type of treatment would be particularly relevant for treating vulnerable patients with pre-existing endothelial dysfunction; a condition commonly associated with males, smoking, hypertension, diabetes, obesity and cardiovascular disease.
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This study also explains why younger, healthy patients develop fewer complications: their endothelium is generally in “better shape” than that of the elderly or the chronically ill with hypertension, diabetes or cardiovascular disease. They are therefore better able to defend themselves against the virus.
If it is now known that the disease can damage the heart or cause pulmonary embolism, or even block blood vessels in the brain or gastrointestinal system, other side effects are starting to emerge from the intensive care unit. Several dysfunctions of the central nervous system have been reported: anosmia or ageusia (loss of smell and taste), stroke, disturbances of consciousness and disorientation, encephalitis (inflammation of the brain), myelitis (inflammation of the spinal cord), syndrome Guillain-Barré (damage to peripheral nerves and paralysis).
Future studies need to determine if SARS-CoV-2 is truly neuro-invasive. In other words, the scientists are trying to find out whether these neurological symptoms are manifestations of the disease itself, or whether they too are linked to a systemic inflammatory response.
Sources: The Lancet, Z. Varga et al. and USZ
