This document discusses cardiovascular autonomic dysfunction in post-COVID patients. It begins with a case study of a 41-year-old woman who developed post-COVID symptoms like fatigue, palpitations and orthostatic intolerance. Tests showed she had postural orthostatic tachycardia syndrome (POTS). Between 10-15% of COVID patients develop long COVID, and 30% of highly symptomatic long COVID patients have POTS. Tilt testing, active standing tests and Holter monitoring can help diagnose POTS and other forms of autonomic dysfunction. Treatment focuses on lifestyle changes, compression garments, increasing fluids and salts, and regulating heart rate and blood pressure with medications. Further research is still

1. Cardiovascular Autonomic
Dysfunction in the Post-COVID
Landscape: Detection and
Management
Senior Consultant & Associate Professor
Syncope and Dysautonomia Unit
Karolinska University Hospital
Artur Fedorowski, MD, PhD

2. Cardiovascular Autonomic Dysfunction in the Post-
COVID Landscape:
Detection and Management
Feb 23, 2023
Artur Fedorowski
MD, PhD, Assoc. Prof., FESC
Dept. of Cardiology, Karolinska University Hospital, Stockholm, Sweden

3. How did it all begin?

4. Unexplained post-
COVID symptoms
• Active and healthy 41-year-old
woman (mild asthma only), married,
two children, a team leader in an
educational institution.
• She fell ill with suspected COVID-19
infection in March 2020 and
developed chronic fatigue,
palpitations, orthostatic intolerance,
problems with concentration and GI
symptoms;

5. Unexplained post-
COVID symptoms
• She was examined with CT
thorax/abdomen (July -20),
echocardiography (July -20), Holter
ECG (August -20), spirometry with
DLCO (Sep-20) and panel of
laboratory tests with normal results
except for slightly elevated average
24h heart rate of 89 bpm (66-153).
Cardiac MRI normal.
• Referred to the autonomic lab at
university hospital in Malmö (S)

6. Active standing test (beat-to-beat)
155 bpm
Blood pressure
Heart rate
-40 mmHg
Lightheadedness
Standing

7. Valsalva maneuvre
Blood pressure
Heart rate
“Overshoot”

8. Tilt testing
135 bpm
Blood pressure
Heart rate
Lightheadedness Deep breathing test
Blood pressure
oscillations

9. Interpretation of CV autonomic tests
• Pathologic active standing test (sinus tachycardia = POTS; BP fall = initial
orthostatic hypotension)
• Pathologic Valsalva (hyperadrenergic response = frequently seen in POTS)
• Pathologic tilt testing (sinus tachycardia max 143 bpm with symptom
reproduction) = POTS dx confirmed (so called “hyperadrenergic type”)
• Normal deep breathing response = normal parasympathetic control
Johansson M et al. J Am Coll Cardiol Case Rep (2021); 3:573-580.

10. Post Acute COVID Syndrome (PACS)/ Long COVID
1Post-acute COVID-19 is defined as persistent symptoms and/or delayed or long-term complications beyond 4 weeks from the onset of infection.
1 Nalbandian, A. et al. Nat Med 27, 601–615 (2021)
2 Ballering, A. et al. Lancet 400, 452-61 (2022)
3 Raman, B. et al. Eur Heart J 43, 1157-1172 (2022)
10-15% of COVID-19 patients
develop chronic symptoms2
Major symptoms of PACS/Long
COVID are now recognized as
POTS3
Up to 30% of highly-symptomatic
long COVID patients suffer from
POTS and related CV
dysautonomias3

11. How big is the problem?

12. 12
10-15%
Young and Middle-aged Women overrepresented

13. ”Long COVID is an often debilitating illness that occurs in at least 10% of severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) infections…At least 65 million individuals worldwide are estimated to have long COVID, with cases increasing daily …Long
COVID encompasses multiple adverse outcomes, with common new-onset conditions including cardiovascular, thrombotic and
cerebrovascular disease, type 2 diabetes, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and dysautonomia,
especially postural orthostatic tachycardia syndrome (POTS)”
Davis HE et al. Nat Rev Microbiol (2023); https://doi.org/10.1038/s41579-022-00846-2

14. ARTUR FEDOROWSKI Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
Definition of dysautonomia/ autonomic dysfunction
a disorder of the autonomic nervous system that causes disturbances in all
or some autonomic functions and may result from the course of a disease
(as diabetes) or from injury or poisoning
Merriam-Webster Dictionary (merriam-webster.com)

15. Typical manifestations of post-acute COVID-
19 syndrome-related cardiovascular
autonomic dysfunction.
POTS and inappropriate sinus tachycardia are
the most prevalent phenotypes, found in
~30% of highly symptomatic patients.
Global and local symptoms usually
coexist. Wide spectrum of overlapping
symptoms create a diagnostic dilemma
for many doctors.
Fedorowski, A., Sutton, R. Nat Rev
Cardiol (2023)

16. Canadian Journal of Cardiology DOI: (10.1016/j.cjca.2022.12.002)
Hira R et al. Canadian Journal of Cardiology (2022) DOI: 10.1016/j.cjca.2022.12.002
POTS 21/70

17. Canadian Journal of Cardiology DOI: (10.1016/j.cjca.2022.12.002)
Hira R et al. Canadian Journal of Cardiology (2022) DOI: 10.1016/j.cjca.2022.12.002
POTS 21/70
Cardiovascular Autonomic Testing (CAT):
 Active stand test (beat-to-beat)
 Deep breathing test
 Valsalva maneuvre
 Quantitative sudomotor axon reflex testing
o Tilt testing
o Holter ECG
o 24h-ambulatory BP monitoring

18. Prevalence and clinical impact of Postural Orthostatic Tachycardia Syndrome in
non-hospitalised patients with post-acute COVID-19 syndrome (PACS)
 Non-hospitalised PACS-patients (n=365) recruited from the Long-COVID outpatient clinic at
Karolinska University Hospital 2020-2022
 117/365 diagnosed with POTS (32%) using active standing test or tilt testing
 PACS + POTS had shorter walking distance in the 6-minute-walk-test (-92m, p<0.001)
 PACS + POTS had lower self-assessed quality of life on the EuroQol-5D-Visual analogue scale (-9.8
points; p<0.001)
Björnson M, Ståhlberg M, Fedorowski A, Bruchfeld J, et al. Manuscript in preparation.

19. How to detect cardiovascular autonomic
dysfunction in PACS?

20. Mayuga K, Fedorowski A et al. Circulation: Arrhythmia and Electrophysiology. Sinus Tachycardia: a
Multidisciplinary Expert Focused Review. 2022; 15 (9): e007960, DOI: (10.1161/CIRCEP.121.007960)
20
Spahic JIM. 2023.Online.
https://doi.org/10.1111/joim.13566

21. ARTUR FEDOROWSKI, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
Common POTS Symptoms
0 Cardiovascular
 Palpitations
 Lightheadedness
 Chest discomfort/pain
 Shortness of breath
 Exercise intolerance
0 NeuroMuscular
 Mental clouding (brain
fog)
 Headaches (migraine)
 Sleep complaints
 Involuntary movements
Gastrointestinal
Nausea and vomiting
Constipation
Weight loss
Chronic Fatigue
Visceral and regional pain
Dysuria
Multiple symptoms associated with
orthostatic intolerance, fatigue and
postural tachycardia
Fedorowski A. JIM 2019;285(4):352-66.

22. ARTUR FEDOROWSKI, Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
How to understand and “measure” dysautonomic symptoms?
Spahic J et al. J Intern Med (2023);293:91-99.
 Although not always “visible”, the symptom
burden is significant, often debilitating.
 Cardiovascular and non-cardiovascular
symptoms may be equally distributed.
 Healthy controls differ from POTS patients
in every symptom category.

23. Mayuga K, Fedorowski A et al. Circulation: Arrhythmia and Electrophysiology. Sinus Tachycardia: a
Multidisciplinary Expert Focused Review. 2022; 15 (9): e007960, DOI: (10.1161/CIRCEP.121.007960)
23
Spahic JIM. 2023.Online.
https://doi.org/10.1111/joim.13566

24. www.escardio.org/guidelines
Basic cardiovascular autonomic function tests
 Active standing.
 Valsalva manoeuvre & deep breathing.
 Carotid sinus massage.
 Tilt testing.
 Ambulatory BP monitoring.
 ECG monitoring
Cardiovascular
Autonomic
Laboratory
2018 ESC Guidelines on Syncope – Michele Brignole & Angel Moya
European Heart Journal (2018) 39, 1883–1948

25. Active standing test
Woman, 20 yo, EDS and POTS, unexplained syncope
standing sitting
supine
Initial
Orthostatic
Hypotension
SBP⇣ >40mmHg
<30 sec

26. Valsalva test
Man, 37 yo, unexplained syncope
START STOP
sitting
Pathologic
reaction:
No overshoot
No HR reaction
ANS damage

27. Deep breathing test (1 min)
Woman, 31 yo, POTS
Normal respons
Woman, 27 yo, POTS
Pathologic response
(no oscillations)

28. Woman, 15 yo, orthostatic intolerance
1. Tilt testing for POTS/OH/VVS

29. Woman, 52y; prolonged post-COVID symptoms
“normal Holter ECG”
POTS with inappropriate sinus tachycardia
106 bpm
Heart rate ”spikes” and increased heart rate on average
2. Holter ECG for POTS/IST
Ståhlberg M et al. The American journal of medicine. 2021;134(12):1451-6.

30. Woman, 47y; post-COVID syndrome and syncope
POTS with spontaneous hypotensive tendency
76 mmHg
Unexpected BP drops that are easily interpreted
as artefacts or erroneous BP measurements
Rivasi et al. Eur Heart J 2022; https://doi.org/10.1093/eurheartj/ehac347.
3. 24h ABPM for POTS/OH/VVS
 Low-BP phenotype
 Hypotensive tendency
 Disruption of circadian rhythm

31. ARTUR FEDOROWSKI Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
Mahdi A et al Nov 5-7 2022 AHA Sessions Abstract Oral Presentation
Endothelial and microvascular dysfunction in post-COVID POTS
No MVD in cMRI in control group
4. In the pipeline …

32. ARTUR FEDOROWSKI Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
Tissue responses to activation of specific adrenergic receptor subtypes
Gerald W. Dorn II Physiol Rev 2010;90:1013-1062
©2010 by American Physiological Society
➡️ stimulation
➡️ inhibition
➡️ transformation
POTS:
autoimmune disease?

33. ARTUR FEDOROWSKI Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
How to detect autoantibodies directed to GPCRs?
Serum/Ig from POTS/controls
Available detection methods
ELISA
Protein/receptor only
(Aab presence yes/not)
Cell-based assays
Functional receptor
(activation/inhibition)
Biological models
(living cells)
Whole biological target
system (cardiomyocytes)
Hall J et al Circulation (2022);146:613–622

34. ARTUR FEDOROWSKI Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
How to detect autoantibodies directed to GPCRs?
Serum/Ig from POTS/controls
Available detection methods
ELISA
Protein/receptor only
(Aab presence yes/not)
Cell-based assays
Functional receptor
(activation/inhibition)
Biological models
(living cells)
Whole biological target
system (cardiomyocytes)

35. ARTUR FEDOROWSKI Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
Fedorowski et al. Europace 2017;19(7):1211-1219
Detection of antiadrenergic
activating autoantibodies
in POTS plasma
using CHO-K1 cells
Significant GPCR activation
blocked by specific antagonist

36. Non-
pharmacological
POTS treatment
Stop exacarbating medicines (blood
volume ⬇️; heart rate ⬆️ )
Increase water/fluid intake up to 2-3
l/daily
Increase salt intake/ smaller food
portions
Lower body compression garments (20-40
mmHg)

37. Beta blockers
Ivabradine
CCBs
Midodrine
Droxidopa
Pseudoephedrine
Fludrocortisone
Pirydostygmine
GI Symptoms
Muscle fatigue
Dexamphetamine
“Brain fog”
What drugs for POTS?
Fedorowski A. JIM 2019;285(4):352-66.
Raj S, Fedorowski A, Sheldon RS. CMAJ 2022;194(10):E378-E385.
Heart rate
Blood pressure

38. Summary
 Between 10 and 15% of COVID-19 convalescents develop Long COVID. One third of highly-
symptomatic patients have POTS and other forms of CV dysautonomia.
 CV autonomic dysfunction in Long COVID affects global (sinus tachycardia, hyper- and hypotensive
tendency) and local circulation (chest pain, migraine, oedema) with a wide spectrum of non-specific
symptoms such as fatigue and dyspnoea.
 Tilt testing/ active standing test, prolonged (Holter) ECG monitoring, and 24-h ABPM are useful in
diagnosis and therapy. Additional autonomic tests (deep breathing, Valsalva) may be useful but are not
necessary for treatment.
 Non-pharmacological measures (fluids and salt, tailored training, lifestyle changes, compression
garments, counterpressure manoeuvres) and heart-rate regulating plus blood pressure stabilizing drugs
are the cornerstone of therapy. Causal therapy is still waiting round the corner …
38

39. ARTUR FEDOROWSKI Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden
Thank you for your attention!
artur.fedorowski@ki.se
@ArturFedorowski