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Microvasular Dysfunction and Reduced Cardiac Stress Reactivity in Postural Orthostatic Tachycardia Associated With Postacute COVID-19

2023; Lippincott Williams & Wilkins; Volume: 16; Issue: 7 Linguagem: Inglês

10.1161/circep.123.011881

1941-3149

Ali Mahdi, Klara Lodin, Ulrika Reistam, Artur Fedorowski, Malin Nygren‐Bonnier, Michael Runold, Judith Bruchfeld, Liyew Desta, John Pernow, Jannike Nickander, Marcus Ståhlberg,

Heart Rate Variability and Autonomic Control

HomeCirculation: Arrhythmia and ElectrophysiologyVol. 16, No. 7Microvasular Dysfunction and Reduced Cardiac Stress Reactivity in Postural Orthostatic Tachycardia Associated With Postacute COVID-19 Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBMicrovasular Dysfunction and Reduced Cardiac Stress Reactivity in Postural Orthostatic Tachycardia Associated With Postacute COVID-19 Ali Mahdi, Klara Lodin, Ulrika Reistam, Artur Fedorowski, Malin Nygren-Bonnier, Michael Runold, Judith Bruchfeld, Liyew Desta, John Pernow, Jannike Nickander and Marcus Ståhlberg Ali MahdiAli Mahdi Correspondence to: Ali Mahdi, MD, PhD, Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0386-7817 Division of Cardiology, Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (A.M., U.R., A.F.,L.D., J.P., M.S.). , Klara LodinKlara Lodin https://orcid.org/0009-0008-3759-5278 Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (K.L., J.N.). , Ulrika ReistamUlrika Reistam https://orcid.org/0000-0002-9192-8992 Division of Cardiology, Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (A.M., U.R., A.F.,L.D., J.P., M.S.). , Artur FedorowskiArtur Fedorowski https://orcid.org/0000-0002-5352-6327 Division of Cardiology, Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (A.M., U.R., A.F.,L.D., J.P., M.S.). , Malin Nygren-BonnierMalin Nygren-Bonnier Division of Physiotherapy, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden (M.N.-B.). , Michael RunoldMichael Runold Division of Respiratory Medicine and Allergy, Department of Medicine, Solna, Karolinska University Hospital, Stockholm, Sweden (M.R.). , Judith BruchfeldJudith Bruchfeld Division of Infection Diseases, Department of Medicine, Solna, Karlinska University Hospital, Karolinska Institutet, Stockholm, Sweden (J.B.). , Liyew DestaLiyew Desta Division of Cardiology, Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (A.M., U.R., A.F.,L.D., J.P., M.S.). , John PernowJohn Pernow https://orcid.org/0000-0003-4766-0922 Division of Cardiology, Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (A.M., U.R., A.F.,L.D., J.P., M.S.). , Jannike NickanderJannike Nickander https://orcid.org/0000-0001-5659-8142 Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (K.L., J.N.). and Marcus StåhlbergMarcus Ståhlberg Division of Cardiology, Department of Medicine, Solna, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden (A.M., U.R., A.F.,L.D., J.P., M.S.). Originally published19 Jun 2023https://doi.org/10.1161/CIRCEP.123.011881Circulation: Arrhythmia and Electrophysiology. 2023;16:413–414Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: June 19, 2023: Ahead of Print Postacute COVID-19 syndrome (PACS) affects a substantial proportion of patients infected with SARS-CoV-2.1 PACS is associated with a wide range of cardiovascular sequelae including postural orthostatic tachycardia syndrome (POTS).2 Endothelial dysfunction has been suggested to be a unifying pathological mechanism of cardiovascular complications in COVID-19.3 We tested the hypothesis that patients with PACS+POTS have impaired peripheral and myocardial microvascular endothelial function, reduced myocardial perfusion reserve, and native T1 reactivity (ΔT1).Highly symptomatic PACS patients with disabling symptoms (>50% sick leave) for at least 6 months, after a mild primary COVID-19 infection not requiring hospitalization and with symptoms of orthostatic intolerance were recruited from the multidisciplinary post-COVID clinic at the Karolinska University Hospital, Stockholm. PACS diagnosis was based on the WHO criteria, and all patients underwent head-up tilt test.2 Twenty patients were diagnosed with POTS (PACS+POTS) based on an increment of 30 beats·min−1 or above 120 beats·min−1 within 10 minutes without a significant drop in blood pressure (20 mm Hg) of head-up tilt test while 23 had negative head-up tilt test (PACS-POTS). Age- and sex-matched healthy subjects without previous COVID-19 served as controls. Microvascular endothelial function was quantified as reactive hyperemia index using Endo-PAT2000 (Itamar Medical, Caesarea, Israel).3 Quantitative adenosine stress myocardial perfusion was performed in a subset of patients using a 1.5T or 3T cardiac magnetic resonance imaging (MAGNETOM Aera or Skyra; Siemens Healthcare, Erlangen, Germany). Native T1 maps were acquired with a prototype 5 s (3 s) 3 s modified look-locker inversion recovery sequence before and during stress. ΔT1 (%) was calculated as (stress−rest)/rest (%). The study was approved by the Swedish Ethical Review Authority, and the subjects gave their written informed consent. The data that support the findings of this study are available from the corresponding author upon reasonable request.The average age (and SD) was 41±14 years in controls (100% women), 40±10 in PACS+POTS (95% women), and 45±10 in PACS-POTS (96% women), respectively. Average time from symptom onset to inclusion was 18±3 months. Reactive hyperemia index was significantly lower in PACS+POTS compared with both healthy and PACS-POTS (Figure). No significant differences were detected in myocardial perfusion reserve (Figure, left). ΔT1 was lower in patients with PACS+POTS (Figure, right) compared with healthy individuals but not compared with PACS-POTS.Download figureDownload PowerPointFigure. Microvascular endothelial function and cardiac stress perfusion. A, Microvascular digital endothelial function in healthy subjects (n=15) and patients with postacute COVID-19 syndrome (PACS) with (+, n=20) or without (−, n=23) postural orthostatic tachycardia syndrome (POTS). The dotted line represents the cutoff for endothelial dysfunction (1.67). B, A subgroup of subjects underwent stress perfusion cardiac magnetic resonance with adenosine with quantification of myocardial perfusion reserve (B, left; n=12–21) and native T1 reactivity (ΔT1; B, right; n=11–21). Normality was checked with the Kolmogorov-Smirnov test. Significant differences were analyzed with the Kruskal-Wallis and Dunn multiple comparison test (A) or 1-way ANOVA and Tukey multiple comparison test (B). Data are presented as median and interquartile ranges.Our data shed light on one of many possible mechanisms of cardiovascular sequelae among patients with PACS by demonstrating a marked impairment in microvascular endothelial function in PACS+POTS. Furthermore, although no significant differences were observed in myocardial perfusion reserve across the groups, ΔT1 was reduced in PACS+POTS. Hence, peripheral microvascular function might mirror an end-organ endothelial microvascular dysfunction reflected as hypoperfusion. Although the exact mechanisms behind the ΔT1 response are not fully understood, it is largely mediated by endothelium-dependent mechanisms, while myocardial perfusion reserve is endothelium independent.4 Our findings support the hypothesis that cardiac endothelial injury may underlie vascular impairment in PACS+POTS. It is recognized as a limitation in the current study that a POTS group without prior COVID-19 was not included. However, the observed endothelial dysfunction is likely specific to COVID-19–related POTS, as previous research found no difference in reactive hyperemia index between healthy individuals and POTS patients without COVID-19.5 Mechanisms behind microvascular endothelial dysfunction in PACS-associated POTS are unclear but may include reduced NO, prostacyclin, muscarinic M3 receptor dysregulation, or autoimmune-mediated endothelial injury.In summary, although limited in size, our study provides evidence that microvascular endothelial dysfunction is common in patients with PACS-associated POTS >1 year after mild primary infection. We hope that our observation provides a starting point for future studies regarding biological mechanisms, pathophysiological relevance, relation to symptoms and functional impairment, as well as treatment strategies targeting long-term microvascular endothelial dysfunction following COVID-19.ARTICLE INFORMATIONAcknowledgmentsThe technical assistance of David Ersgård is gratefully acknowledged.Sources of FundingThis work was supported by the Swedish Heart and Lung Foundation (20210062 and 20210543), the Swedish Research Council (2021-06531), and the Stockholm County Council (964100).Nonstandard Abbreviations and AcronymsΔT1native T1 reactivityPACSpostacute COVID-19 syndromePOTSpostural orthostatic tachycardia syndromeDisclosures None.FootnotesFor Sources of Funding and Disclosures, see page 414.Correspondence to: Ali Mahdi, MD, PhD, Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden. Email ali.mahdi@ki.seReferences1. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, Cook JR, Nordvig AS, Shalev D, Sehrawat TS, et al. Post-acute COVID-19 syndrome.Nat Med. 2021; 27:601–615. doi: 10.1038/s41591-021-01283-zCrossrefMedlineGoogle Scholar2. Johansson M, Stahlberg M, Runold M, Nygren-Bonnier M, Nilsson J, Olshansky B, Bruchfeld J, Fedorowski A. Long-haul post-COVID-19 symptoms presenting as a variant of postural orthostatic tachycardia syndrome: the Swedish experience.JACC Case Rep. 2021; 3:573–580. doi: 10.1016/j.jaccas.2021.01.009CrossrefMedlineGoogle Scholar3. Mahdi A, Collado A, Tengbom J, Jiao T, Wodaje T, Johansson N, Farnebo F, Farnert A, Yang J, Lundberg JO, et al. Erythrocytes induce vascular dysfunction in COVID-19.JACC Basic Transl Sci. 2022; 7:193–204. doi: 10.1016/j.jacbts.2021.12.003CrossrefMedlineGoogle Scholar4. Shah SA, Reagan CE, French BA, Epstein FH. Molecular mechanisms of adenosine stress T1 mapping.Circ Cardiovasc Imaging. 2021; 14:e011774. doi: 10.1161/CIRCIMAGING.120.011774LinkGoogle Scholar5. Chopoorian AH, Wahba A, Celedonio J, Nwazue V, Smith EC, Garland EM, Paranjape S, Okamoto LE, Black BK, Biaggioni I, et al. Impaired endothelial function in patients with postural tachycardia syndrome.Hypertension. 2021; 77:1001–1009. doi: 10.1161/HYPERTENSIONAHA.120.16238LinkGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kell D, Khan M, Kane B, Lip G and Pretorius E (2024) Possible Role of Fibrinaloid Microclots in Postural Orthostatic Tachycardia Syndrome (POTS): Focus on Long COVID, Journal of Personalized Medicine, 10.3390/jpm14020170, 14:2, (170) Fedorowski A, Fanciulli A, Raj S, Sheldon R, Shibao C and Sutton R (2024) Cardiovascular autonomic dysfunction in post-COVID-19 syndrome: a major health-care burden, Nature Reviews Cardiology, 10.1038/s41569-023-00962-3 Mahdi A, Zhao A, Fredengren E, Fedorowski A, Braunschweig F, Nygren-Bonnier M, Runold M, Bruchfeld J, Nickander J, Deng Q, Checa A, Desta L, Pernow J and Ståhlberg M (2023) Dysregulations in hemostasis, metabolism, immune response, and angiogenesis in post-acute COVID-19 syndrome with and without postural orthostatic tachycardia syndrome: a multi-omic profiling study, Scientific Reports, 10.1038/s41598-023-47539-1, 13:1 July 2023Vol 16, Issue 7 Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCEP.123.011881PMID: 37334702 Originally publishedJune 19, 2023 Keywordsheart diseaseshumansperfusionpostacute COVID-19 syndromevascular diseasesPDF download Advertisement SubjectsAutonomic Nervous SystemEndothelium/Vascular Type/Nitric OxideMechanismsPathophysiology