{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T09:37:04Z","timestamp":1788341824838,"version":"build-2803163510"},"reference-count":34,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T00:00:00Z","timestamp":1739836800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["KLI 1064-B"],"award-info":[{"award-number":["KLI 1064-B"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["21176"],"award-info":[{"award-number":["21176"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["KLI 876-B"],"award-info":[{"award-number":["KLI 876-B"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Medical Scientific Fund of the Mayor of the City of Vienna","award":["KLI 1064-B"],"award-info":[{"award-number":["KLI 1064-B"]}]},{"name":"Medical Scientific Fund of the Mayor of the City of Vienna","award":["21176"],"award-info":[{"award-number":["21176"]}]},{"name":"Medical Scientific Fund of the Mayor of the City of Vienna","award":["KLI 876-B"],"award-info":[{"award-number":["KLI 876-B"]}]},{"name":"Austrian Science Fund","award":["KLI 1064-B"],"award-info":[{"award-number":["KLI 1064-B"]}]},{"name":"Austrian Science Fund","award":["21176"],"award-info":[{"award-number":["21176"]}]},{"name":"Austrian Science Fund","award":["KLI 876-B"],"award-info":[{"award-number":["KLI 876-B"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Endothelial dysfunction mediated by elevated levels of autoantibodies against vasoactive peptides occurring after COVID-19 infection is proposed as a possible pathomechanism for orthostatic intolerance in long COVID patients. This case-control study comprised 100 long COVID patients from our prospective POSTCOV registry and three control groups, each consisting of 20 individuals (Asymptomatic post-COVID group; Healthy group = pan-negative for antispike protein of SARS-CoV-2; Vaccinated healthy group = no history of COVID-19 and vaccinated). Autoantibodies towards muscarinic acetylcholine receptor M3, endothelin type A receptor (ETAR), beta-2 adrenergic receptor (Beta-2 AR), angiotensin II receptor 1 and angiotensin 1-7 (Ang1-7) concentrations were measured by enzyme-linked immunosorbent assay in long COVID patients and controls. Orthostatic intolerance was defined as inappropriate sinus tachycardia, postural tachycardia, orthostatic hypotonia and other dysautonomia symptoms, such as dizziness or blurred vision (n = 38 long COVID patients). Autoantibody concentrations were compared with routine laboratory parameters and quality of life questionnaires (EQ-5D). The concentration of ETAR autoantibodies were significantly higher in long COVID, Asymptomatic and Vaccinated groups compared to the antispike protein pan-negative Healthy group. A trend towards higher plasma levels of Beta-2 AR and Ang1-7 was measured in long COVID patients, not related to presence of orthostatic intolerance. ETAR autoantibody concentration showed significant positive correlation with the EQ-5D item \u201cProblems in performing usual activities\u201d.<\/jats:p>","DOI":"10.3390\/biom15020300","type":"journal-article","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T06:41:12Z","timestamp":1739860872000},"page":"300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Circulating Autoantibodies Against Vasoactive Biomarkers Related to Orthostatic Intolerance in Long COVID Patients Compared to No-Long-COVID Populations: A Case-Control Study"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3064-1277","authenticated-orcid":false,"given":"Emilie","family":"Han","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3855-7643","authenticated-orcid":false,"given":"Katrin","family":"M\u00fcller-Zlabinger","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ena","family":"Hasimbegovic","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Poschenreithner","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1576-9029","authenticated-orcid":false,"given":"Nina","family":"Kastner","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babette","family":"Maleiner","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2505-8554","authenticated-orcid":false,"given":"Kevin","family":"Hamzaraj","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9819-0361","authenticated-orcid":false,"given":"Andreas","family":"Spannbauer","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5061-7354","authenticated-orcid":false,"given":"Martin","family":"Riesenhuber","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Vavrikova","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Domanig","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0141-7639","authenticated-orcid":false,"given":"Christian","family":"Nitsche","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8040-8086","authenticated-orcid":false,"given":"Dominika","family":"Lukovic","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6444-8598","authenticated-orcid":false,"given":"Thomas A.","family":"Zelniker","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7083-2107","authenticated-orcid":false,"given":"Mariann","family":"Gy\u00f6ngy\u00f6si","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"C258","DOI":"10.1152\/ajpcell.00224.2020","article-title":"Decoding SARS-CoV-2 Hijacking of Host Mitochondria in COVID-19 Pathogenesis","volume":"319","author":"Singh","year":"2020","journal-title":"Am. J. Physiol.Cell Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"106975","DOI":"10.1016\/j.vph.2022.106975","article-title":"Endothelial Dysfunction in Acute and Long Standing COVID-19: A Prospective Cohort Study","volume":"144","author":"Oikonomou","year":"2022","journal-title":"Vasc. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Santoro, L., Falsetti, L., Zaccone, V., Nesci, A., Tosato, M., Giupponi, B., Savastano, M.C., Moroncini, G., Gasbarrini, A., and Landi, F. (2022). Impaired Endothelial Function in Convalescent Phase of COVID-19: A 3 Month Follow Up Observational Prospective Study. J. Clin. Med., 11.","DOI":"10.3390\/jcm11071774"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100122","DOI":"10.1016\/j.lanepe.2021.100122","article-title":"Post-COVID Syndrome in Non-Hospitalised Patients with COVID-19: A Longitudinal Prospective Cohort Study","volume":"6","author":"Augustin","year":"2021","journal-title":"Lancet Reg. Health Eur."},{"key":"ref_5","first-page":"1","article-title":"Serum Proteomic Profiling Reveals Potential Inflammatory Biomarkers in Long-COVID Patients: A Comparative Analysis with Healthy Controls","volume":"27","author":"Medori","year":"2023","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"eadg7942","DOI":"10.1126\/science.adg7942","article-title":"Persistent Complement Dysregulation with Signs of Thromboinflammation in Active Long Covid","volume":"383","author":"Hoch","year":"2024","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1038\/s41467-023-44432-3","article-title":"Muscle Abnormalities Worsen after Post-Exertional Malaise in Long COVID","volume":"15","author":"Appelman","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s10456-023-09878-5","article-title":"Damage to Endothelial Barriers and Its Contribution to Long COVID","volume":"27","author":"Wu","year":"2023","journal-title":"Angiogenesis"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Berbari, A.E., and Mancia, G. (2018). Vasoactive Peptides. Disorders of Blood Pressure Regulation, Springer. Updates in Hypertension and Cardiovascular Protection.","DOI":"10.1007\/978-3-319-59918-2"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/s41577-023-00904-7","article-title":"The Immunology of Long COVID","volume":"23","author":"Altmann","year":"2023","journal-title":"Nat. Rev. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Miedema, J.R., Janssen, M.L., Th\u00fcsen, J.V.D., Endeman, H., Langerak, A.W., Hellemons, M.E., Van Nood, E., Peeters, B.W.A., Baart, S.J., and Schreurs, M.W.J. (2023). Antibodies against Angiotensin II Receptor Type 1 and Endothelin A Receptor Are Increased in COVID-19 Patients. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1204433"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Civieri, G., Iop, L., and Tona, F. (2022). Antibodies against Angiotensin II Type 1 and Endothelin 1 Type A Receptors in Cardiovascular Pathologies. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020927"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1152\/physiolgenomics.00062.2017","article-title":"Distribution and Function of the Muscarinic Receptor Subtypes in the Cardiovascular System","volume":"50","author":"Saternos","year":"2018","journal-title":"Physiol. Genom."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Prato, M., Tiberti, N., Mazzi, C., Gobbi, F., Piubelli, C., and Longoni, S.S. (2024). The Renin\u2013Angiotensin System (RAS) in COVID-19 Disease: Where We Are 3 Years after the Beginning of the Pandemic. Microorganisms, 12.","DOI":"10.3390\/microorganisms12030583"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"103445","DOI":"10.1016\/j.autrev.2023.103445","article-title":"Severity of Neurological Long-COVID Symptoms Correlates with Increased Level of Autoantibodies Targeting Vasoregulatory and Autonomic Nervous System Receptors","volume":"22","author":"Seibert","year":"2023","journal-title":"Autoimmun. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sotzny, F., Filgueiras, I.S., Kedor, C., Freitag, H., Wittke, K., Bauer, S., Sep\u00falveda, N., Mathias Da Fonseca, D.L., Baiocchi, G.C., and Marques, A.H.C. (2022). Dysregulated Autoantibodies Targeting Vaso- and Immunoregulatory Receptors in Post COVID Syndrome Correlate with Symptom Severity. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.981532"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.thromres.2021.11.027","article-title":"Sustained Inflammation, Coagulation Activation and Elevated Endothelin-1 Levels without Macrovascular Dysfunction at 3 Months after COVID-19","volume":"209","author":"Willems","year":"2022","journal-title":"Thromb. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1016\/j.ijsu.2014.07.013","article-title":"The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: Guidelines for Reporting Observational Studies","volume":"12","author":"Altman","year":"2014","journal-title":"Int. J. Surg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3109\/07853890109002087","article-title":"EQ-SD: A measure of health status from the EuroQol Group","volume":"33","author":"Rabin","year":"2001","journal-title":"Ann. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1002\/jmv.27415","article-title":"The COVID-19 Yorkshire Rehabilitation Scale (C19-YRS): Application and Psychometric Analysis in a Post-COVID-19 Syndrome Cohort","volume":"94","author":"Preston","year":"2022","journal-title":"J. Med. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Chadda, K.R., Blakey, E.E., Huang, C.L.-H., and Jeevaratnam, K. (2022). Long COVID-19 and Postural Orthostatic Tachycardia Syndrome-Is Dysautonomia to Be Blamed?. Front. Cardiovasc. Med., 9.","DOI":"10.3389\/fcvm.2022.860198"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.anai.2024.08.008","article-title":"Current Concepts in Long COVID-19 Brain Fog and Postural Orthostatic Tachycardia Syndrome","volume":"133","author":"Tavee","year":"2024","journal-title":"Ann. Allergy Asthma Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Arany\u00f3, J., Bazan, V., Llad\u00f3s, G., Dominguez, M.J., Bisbal, F., Massanella, M., Sarrias, A., Adeli\u00f1o, R., Riverola, A., and Paredes, R. (2022). Inappropriate Sinus Tachycardia in Post-COVID-19 Syndrome. Sci. Rep., 12.","DOI":"10.1038\/s41598-021-03831-6"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gao, P., Liu, J., and Liu, M. (2022). Effect of COVID-19 Vaccines on Reducing the Risk of Long COVID in the Real World: A Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph191912422"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e012559","DOI":"10.1161\/JAHA.119.012559","article-title":"Impact of Cardiovascular Neurohormones on Onset of Vasovagal Syncope Induced by Head-up Tilt","volume":"8","author":"Torabi","year":"2019","journal-title":"J. Am. Heart Assoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"93","DOI":"10.33549\/physiolres.934689","article-title":"Association of Polymorphisms in Endothelin-1 and Endothelin Receptor a Genes with Vasovagal Syncope","volume":"71","author":"Lazurova","year":"2022","journal-title":"Physiol. Res."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gy\u00f6ngy\u00f6si, M., Hasimbegovic, E., Han, E., Zlabinger, K., Spannbauer, A., Riesenhuber, M., Hamzaraj, K., Bergler-Klein, J., Hengstenberg, C., and Kammerlander, A. (2023). Improvement of Symptoms and Cardiac Magnetic Resonance Abnormalities in Patients with Post-Acute Sequelae of SARS-CoV-2 Cardiovascular Syndrome (PASC-CVS) after Guideline-Oriented Therapy. Biomedicines, 11.","DOI":"10.3390\/biomedicines11123312"},{"key":"ref_28","unstructured":"Vernon, S.D., and Bateman, L. (2024, December 30). Valacyclovir Plus Celecoxib for Post-Acute Sequelae of SARS-CoV-2 (PASC), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06316843."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Khazaal, S., Harb, J., Rima, M., Annweiler, C., Wu, Y., Cao, Z., Abi Khattar, Z., Legros, C., Kovacic, H., and Fajloun, Z. (2022). The Pathophysiology of Long COVID throughout the Renin-Angiotensin System. Molecules, 27.","DOI":"10.3390\/molecules27092903"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wiech, M., Chroscicki, P., Swatler, J., Stepnik, D., De Biasi, S., Hampel, M., Brewinska-Olchowik, M., Maliszewska, A., Sklinda, K., and Durlik, M. (2022). Remodeling of T Cell Dynamics During Long COVID Is Dependent on Severity of SARS-CoV-2 Infection. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.886431"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/s41590-021-01113-x","article-title":"Immunological Dysfunction Persists for 8 Months Following Initial Mild-to-Moderate SARS-CoV-2 Infection","volume":"23","author":"Phetsouphanh","year":"2022","journal-title":"Nat. Immunol."},{"key":"ref_32","unstructured":"Zhang, W. (2024, December 30). A Randomized Controlled Basket Study Protocol for Evaluating Immunomodulatory Interventions in Post-Acute Sequelae of SARS-CoV-2 InfEction (RISE), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06597682."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Thompson, J.S., Thornton, A.C., Ainger, T., and Garvy, B.A. (2023). Long-Term High-Dose Immunoglobulin Successfully Treats Long COVID Patients with Pulmonary, Neurologic, and Cardiologic Symptoms. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1033651"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1097\/PHM.0000000000002559","article-title":"Effects of Cardiopulmonary Rehabilitation on Cardiorespiratory Fitness and Clinical Symptom Burden in Long COVID: Results from the COVID-Rehab Randomized Controlled Trial","volume":"104","author":"Besnier","year":"2024","journal-title":"Am. J. Phys. Med. Rehabil."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/2\/300\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:36:44Z","timestamp":1760027804000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/2\/300"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,18]]},"references-count":34,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["biom15020300"],"URL":"https:\/\/doi.org\/10.3390\/biom15020300","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,18]]}}}