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Cardiovascular autonomic dysfunction in post-COVID-19 syndrome: a major health-care burden

Nature Reviews Cardiology (2024)Cite this article

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Abstract

Cardiovascular autonomic dysfunction (CVAD) is a malfunction of the cardiovascular system caused by deranged autonomic control of circulatory homeostasis. CVAD is an important component of post-COVID-19 syndrome, also termed long COVID, and might affect one-third of highly symptomatic patients with COVID-19. The effects of CVAD can be seen at both the whole-body level, with impairment of heart rate and blood pressure control, and in specific body regions, typically manifesting as microvascular dysfunction. Many severely affected patients with long COVID meet the diagnostic criteria for two common presentations of CVAD: postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. CVAD can also manifest as disorders associated with hypotension, such as orthostatic or postprandial hypotension, and recurrent reflex syncope. Advances in research, accelerated by the COVID-19 pandemic, have identified new potential pathophysiological mechanisms, diagnostic methods and therapeutic targets in CVAD. For clinicians who daily see patients with CVAD, knowledge of its symptomatology, detection and appropriate management is more important than ever. In this Review, we define CVAD and its major forms that are encountered in post-COVID-19 syndrome, describe possible CVAD aetiologies, and discuss how CVAD, as a component of post-COVID-19 syndrome, can be diagnosed and managed. Moreover, we outline directions for future research to discover more efficient ways to cope with this prevalent and long-lasting condition.

Key points

  • Cardiovascular autonomic dysfunction (CVAD), in particular postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia, are among the most frequent and distinct phenotypes of post-COVID-19 syndrome; one-third of highly symptomatic patients can be affected.

  • CVAD arises from a malfunction of the autonomic control of the circulation, and can involve failure or inadequate or excessive activation of the sympathetic and parasympathetic components of the autonomic nervous system.

  • As well as global circulatory disturbances, CVAD in post-COVID-19 syndrome can manifest as microvascular and endothelial dysfunction, with local symptoms such as headache, brain fog, chest pain, dyspnoea and peripheral circulatory symptoms, including skin discolouration, oedema, Raynaud-like phenomena, and heat and cold intolerance.

  • A structured diagnostic work-up based on a detailed patient history, cardiovascular autonomic testing, long-term electrocardiogram and blood-pressure monitoring, and ancillary cardiac and peripheral vascular tests will lead to an appropriate diagnosis.

  • Management of CVAD in post-COVID-19 syndrome should involve a correct diagnosis, patient education, and both non-pharmacological and pharmacological methods; a tailored exercise training programme, blood volume expansion and compression garments are especially effective.

  • Pharmacological approaches target heart rate control, blood volume expansion, promotion of vasoconstriction and venoconstriction, and reduction of hyperadrenergic drive.

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Fig. 1: Global and local manifestations of cardiovascular autonomic dysfunction.
Fig. 2: Typical tilt table test and 24-h ECG manifestations of cardiovascular autonomic dysfunction in post-COVID-19 syndrome.
Fig. 3: Typical 24-h ABPM manifestations of cardiovascular autonomic dysfunction in post-COVID-19 syndrome.
Fig. 4: Diagnostic work-up of suspected CVAD in patients with post-COVID-19 syndrome.

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Acknowledgements

A. Fedorowski was supported by the Swedish Heart Lung Foundation (grant no. 20220319). A. Fanciulli received research grants from the Austrian Exchange Program, Dr Johannes and Hertha Tuba Foundation, FWF-Austrian Science Fund, Medical University of Innsbruck and US MSA Coalition. S.R.R. received funding from the Canadian Institutes of Health Research to study autonomic function in long COVID (GA4-177741) and research grants from the Heart and Stroke Foundation of Canada, Dysautonomia International and Standing Up To POTS. C.A.S. received research grants from Alnylam, American Heart Association, National Institutes of Health, National Heart, Lung, and Blood Institute and National Institute of Diabetes and Digestive and Kidney Diseases.

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Authors and Affiliations

  1. Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden

    Artur Fedorowski

  2. Department of Medicine, Karolinska Institute, Stockholm, Sweden

    Artur Fedorowski

  3. Department of Clinical Sciences, Lund University, Malmö, Sweden

    Artur Fedorowski & Richard Sutton

  4. Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria

    Alessandra Fanciulli

  5. Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada

    Satish R. Raj & Robert Sheldon

  6. Autonomic Dysfunction Center, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

    Satish R. Raj & Cyndya A. Shibao

  7. Department of Cardiology, Hammersmith Hospital, National Heart & Lung Institute, Imperial College, London, UK

    Richard Sutton

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Contributions

A. Fedorowski, A. Fanciulli, S.R.R. and C.A.S. researched data for the article. All the authors contributed to discussions of content, wrote the manuscript, and reviewed/edited it before submission.

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Correspondence to Artur Fedorowski.

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Competing interests

A. Fedorowski has received speaker fees from Bristol-Myers Squibb, Finapres Medical Systems and Medtronic, and is a consultant to Argenx and Medtronic in the field of syncope, cardiovascular autonomic dysfunction and postural orthostatic tachycardia syndrome. A. Fanciulli has received royalties from Springer Verlag, and speaker fees and honoraria from the Austrian Autonomic Society, Broadview Ventures, Elsevier, GE Healthcare, Stopp-HSP and Theravance Biopharma. S.R.R. has served as a consultant for Amneal Pharmaceuticals, Antag Therapeutics, Argenx BV, Regeneron and Theravance Biopharma, and receives an honorarium from Elsevier for being Associate Editor of Autonomic Neuroscience. C.A.S. has received speaker fees and honoraria from Argenx and Theravance Biopharma, and is a consultant for Antag Therapeutics and Theravance Biopharma. R. Sutton has received consulting fees from Medtronic and payment for expert testimony in medicolegal cases in the UK; was a member of the clinical events committee for the BioSync study; and is secretary to the Executive Board of the World Society of Arrhythmias. R. Sheldon declares no competing interests.

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Fedorowski, A., Fanciulli, A., Raj, S.R. et al. Cardiovascular autonomic dysfunction in post-COVID-19 syndrome: a major health-care burden. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-023-00962-3

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