Endothelial Function and COVID-19

Coronavirus disease 2019 (COVID-19), secondary to infection by severe acute respiratory
syndrome coronavirus type 2 (SARS-CoV-2) has caused a global pandemic with significant
adverse effects on the health, social and economic systems in different countries of the
world.

The entry receptor utilized by SARS-CoV-2 is Angiotensin-Converting Enzyme 2 (ACE-2),
localized at the membrane of epithelial and endothelial cells and muscle cells of blood
vessels. Hypothetically, this interaction of SARS-CoV-2 with essential elements of the blood
vessels may conduct to endothelial dysfunction. In fact, it has been demonstrated several
degrees of endothelial compromise in the kidney, small bowel and lungs from histological
analysis in fatidic cases.

The pathophysiological mechanisms by which vascular endothelial dysfunction can complicate
the evolutionary course of viral infections are of two types:

1. On the one hand, acute endothelial dysfunction can produce ischemic events as a
consequence of thrombotic or vasomotor processes. Some of these events are acute
coronary syndromes, pulmonary thromboembolism and peripheral angiopathy, all of which
have been reported in COVID-19 patients.

2. On the other hand, vascular endothelial dysfunction can trigger or amplify systemic
inflammatory reactions leading to multi-organ failure. Vascular hyperpermeability
generated by vascular endothelial dysfunction is key in the processes of infiltration of
immune cells and in the amplification of the inflammatory response that occurs in the
context of the cytokine storm associated with the viral infection. This process
contributes to release large amounts of IL 6, IL-1B and TNF alpha by vascular
endothelial cells, thus the expression of vascular adhesion molecules.

In this study, the investigators sought to evaluate the status of vascular endothelial
function in COVID-19 patients from a non-invasive approach.

The evaluation of systemic vascular endothelial function will be performed non-invasively
using peripheral arterial tonometry with EndoPat system (Itamar). It is a technique that
determines the endothelial-dependent changes in arterial tone of the vascular network of the
index finger of both hands. Using bio-sensors placed on the pad of the index finger of both
hands, an assessment of arterial tone is carried out at three stages: 1) at baseline; 2)
during an ischemia caused by the inflation of a pressure cuff in one of the arms to occlude
the brachial artery for 5 minutes; 3) and in a situation of reactive hyperemia during the
recovery of arterial irrigation after deflating the pressure cuff. The arterial tone signals
detected by plethysmography at the three described times are converted into digital signals
for each arm explored, and the EndoPat software automatically determines the hyperemic
vascular response.

To avoid biases in the analysis of systemic vascular endothelial function in COVID-19
patients, the research team led by Dr. Amir Lerman from the Mayo Clinic, Rochester, USA will
blindly carry out the analysis of the EndoPat results. For this, the EndoPat study reports
will be sent in an analyzable format for each patient included in the study, completely
anonymized and at blind fashion with respect to the group that patient belongs, the moment in
which EndoPat assessment was made (days from the onset of symptoms in the case of the study
group), blinded for the results of blood tests related to inflammation, and for the clinical
evolution of the patient.