Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Angiogenesis, vol. 26, pp. 547–563

Abstract

BACKGROUND: Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians. METHODS: In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n = 41, matched out of n = 204). MEASUREMENTS AND MAIN RESULTS: PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vFID; 3.42% ± 1.77% vs. 4.64% ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5-190.2] vs. 189.1 [179.4-197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8-0.9] vs. 0.88 [0.8-0.9], p = 0.007). When combining AVR and vFID, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R = - 0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters. CONCLUSION: Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management. TRIAL REGISTRATION: This study was previously registered at ClinicalTrials ("All Eyes on PCS-Analysis of the Retinal Microvasculature in Patients with Post-COVID-19 Syndrome". NCT05635552. https://clinicaltrials.gov/ct2/show/NCT05635552 ). Persistent endothelial dysfunction in post-COVID-19 syndrome. Acute SARS-CoV-2 infection indirectly or directly causes endotheliitis in patients. N = 41 PCS patients were recruited and retinal vessel analysis was performed to assess microvascular endothelial function. Images of SVA and DVA are illustrative for RVA data analysis. For each PCS patient and healthy cohort, venular vessel diameter of the three measurement cycles was calculated and plotted on a diameter-time curve. Patients exhibited reduced flicker-induced dilation in veins (vFID) measured by dynamic vessel analysis (DVA) and lower central retinal arteriolar equivalent (CRAE) and arteriolar-venular ratio (AVR) and a tendency towards higher central retinal venular equivalent (CRVE) when compared to SARS-CoV-2 infection naïve participants. Created with BioRender.com.

Authors 18

1. Timon Kuchler

   TUM Klinikum · Technical University of Munich

   Affiliation as printed

   School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

2. Roman Günthner

   TUM Klinikum · Technical University of Munich

   Affiliation as printed

   School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

3. Andrea Ribeiro

   TUM Klinikum · LMU Klinikum · Technical University of Munich · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Medizinische Klinik Und Poliklinik IV, LMU University Hospital Munich, Ziemssenstraße 5, 80336, Munich, Germany

   School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

4. Renate Ilona Hausinger

   TUM Klinikum · Technical University of Munich

   Affiliation as printed

   School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

5. Lukas Streese

   Hochschule Niederrhein

   Affiliation as printed

   Faculty of Health Care, Niederrhein University of Applied Sciences, Krefeld, Germany

6. Anna Wöhnl

   TUM Klinikum · Technical University of Munich

   Affiliation as printed

   School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

7. Veronika Kesseler

   TUM Klinikum · Technical University of Munich

   Affiliation as printed

   School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

8. Johanna Negele

   TUM Klinikum · Technical University of Munich

   Affiliation as printed

   School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

9. Tarek Assali

   TUM Klinikum · Technical University of Munich

   Affiliation as printed

   School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

10. Javier Carbajo-Lozoya

    TUM Klinikum · Technical University of Munich

    Affiliation as printed

    School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

11. Maciej Lech

    LMU Klinikum · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Medizinische Klinik Und Poliklinik IV, LMU University Hospital Munich, Ziemssenstraße 5, 80336, Munich, Germany

12. Kristina Adorjan

    LMU Klinikum · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Department of Psychiatry and Psychotherapy, LMU University Hospital Munich, Nußbaumstraße 7, 80336, Munich, Germany

13. Hans Christian Stubbe

    LMU Klinikum · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Medizinische Klinik Und Poliklinik II, LMU University Hospital Munich, Marchioninistraße 15, 81377, Munich, Germany

14. Henner Hanssen

    University of Basel

    Affiliation as printed

    Department of Sport, Exercise and Health, Preventive Sports Medicine and Systems Physiology, University of Basel, Basel, Switzerland

15. Konstantin Kotilar Aachen

    FH Aachen

    Affiliation as printed

    Aachen University of Applied Sciences, Heinrich-Mussmann-Str. 1, 52428, Jülich, Germany

16. Bernhard Haller

    TUM Klinikum · Technical University of Munich

    Affiliation as printed

    School of Medicine, Institute for AI and Informatics in Medicine, Technical University of Munich, Klinikum Rechts Der Isar, Ismaninger Str. 22, 81675, Munich, Germany

17. Uwe W. Heemann

    TUM Klinikum · Technical University of Munich

    Affiliation as printed

    School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany

18. Christoph Schmaderer corresponding

    TUM Klinikum · German Center for Infection Research · Technical University of Munich

    Affiliation as printed

    German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany. christoph.schmaderer@mri.tum.de

    School of Medicine, Klinikum Rechts Der Isar, Department of Nephrology, Technical University of Munich, Ismaninger Str. 22, 81675, Munich, Germany. christoph.schmaderer@mri.tum.de

    German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany