Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS)
Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endo...
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| Vydáno v: | Journal of translational medicine Ročník 20; číslo 1; s. 138 - 11 |
|---|---|
| Hlavní autoři: | , , , , , , , , , , , , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
London
BioMed Central
22.03.2022
BioMed Central Ltd Springer Nature B.V BMC |
| Témata: | |
| ISSN: | 1479-5876, 1479-5876 |
| On-line přístup: | Získat plný text |
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| Abstract | Background
Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.
Methods
We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.
Results
Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.
Conclusion
A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. |
|---|---|
| AbstractList | Background
Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.
Methods
We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.
Results
Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.
Conclusion
A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. Abstract Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. Methods We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. Results Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. Conclusion A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. Methods We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. Results Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. Conclusion A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. Keywords: Post-COVID syndrome, Myalgic encephalomyelitis/chronic fatigue syndrome, Endothelial dysfunction, Reactive hyperaemia index, Endothelin-1 Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. Methods We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. Results Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. Conclusion A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.BACKGROUNDFatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS.We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.METHODSWe studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers.Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.RESULTSFive of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs.A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.CONCLUSIONA subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups. |
| ArticleNumber | 138 |
| Audience | Academic |
| Author | Wittke, Kirsten Hanitsch, Leif Bellmann-Strobl, Judith Freitag, Helma Sotzny, Franziska Konietschke, Frank Haffke, Milan Scheibenbogen, Carmen Kedor, Claudia Seifert, Martina Scherbakov, Nadja Doehner, Wolfram Paul, Friedemann Rudolf, Gordon Bauer, Sandra |
| Author_xml | – sequence: 1 givenname: Milan orcidid: 0000-0001-6245-1534 surname: Haffke fullname: Haffke, Milan email: milan.haffke@charite.de organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 2 givenname: Helma surname: Freitag fullname: Freitag, Helma organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 3 givenname: Gordon surname: Rudolf fullname: Rudolf, Gordon organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 4 givenname: Martina surname: Seifert fullname: Seifert, Martina organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Berlin Institute of Health at Charité–Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), DZHK (German Center for Cardiovascular Research) – sequence: 5 givenname: Wolfram surname: Doehner fullname: Doehner, Wolfram organization: Berlin Institute of Health at Charité–Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), DZHK (German Center for Cardiovascular Research), Department of Cardiology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Center for Stroke Research Berlin (CSB), Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 6 givenname: Nadja surname: Scherbakov fullname: Scherbakov, Nadja organization: Berlin Institute of Health at Charité–Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), DZHK (German Center for Cardiovascular Research), Department of Cardiology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Center for Stroke Research Berlin (CSB), Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 7 givenname: Leif surname: Hanitsch fullname: Hanitsch, Leif organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 8 givenname: Kirsten surname: Wittke fullname: Wittke, Kirsten organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 9 givenname: Sandra surname: Bauer fullname: Bauer, Sandra organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 10 givenname: Frank surname: Konietschke fullname: Konietschke, Frank organization: Institute of Biometry and Clinical Epidemiology, Charité–Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 11 givenname: Friedemann surname: Paul fullname: Paul, Friedemann organization: Experimental and Clinical Research Center (ECRC), Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, NeuroCure Clinical Research Center (NCRC), Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Max Delbrueck Center for Molecular Medicine, Experimental and Clinical Research Center (ECRC) – sequence: 12 givenname: Judith surname: Bellmann-Strobl fullname: Bellmann-Strobl, Judith organization: Experimental and Clinical Research Center (ECRC), Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, NeuroCure Clinical Research Center (NCRC), Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin, Max Delbrueck Center for Molecular Medicine, Experimental and Clinical Research Center (ECRC) – sequence: 13 givenname: Claudia surname: Kedor fullname: Kedor, Claudia organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 14 givenname: Carmen surname: Scheibenbogen fullname: Scheibenbogen, Carmen organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin – sequence: 15 givenname: Franziska surname: Sotzny fullname: Sotzny, Franziska organization: Institute for Medical Immunology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität Zu Berlin |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35317812$$D View this record in MEDLINE/PubMed |
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Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of... Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients... Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of... Abstract Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset... |
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| SubjectTerms | ACE2 Angiopoietin Angiotensin Angiotensin-converting enzyme 2 Biological markers Biomarkers Biomedical and Life Sciences Biomedicine Blood pressure Chronic fatigue syndrome Coronaviruses COVID-19 COVID-19 - complications Endothelial Cells Endothelial dysfunction Endothelin 1 Endothelium Enzymes Fatigue Fatigue Syndrome, Chronic Health aspects Heart rate Humans Hyperemia Hypoglycemia Illnesses of Unknown Etiology Infections Interleukin 8 Intolerance Long COVID Medicine/Public Health Myalgic encephalomyelitis/chronic fatigue syndrome Patients Peptidyl-dipeptidase A Post-COVID syndrome Reactive hyperaemia index Risk factors SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 |
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| Title | Endothelial dysfunction and altered endothelial biomarkers in patients with post-COVID-19 syndrome and chronic fatigue syndrome (ME/CFS) |
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