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Canadian Journal of Cardiology

Objective Hemodynamic Cardiovascular Autonomic Abnormalities in Post-Acute Sequelae of COVID-19

Published:December 09, 2022DOI:https://doi.org/10.1016/j.cjca.2022.12.002

      ABSTRACT

      Background

      Many COVID-19 patients are left with symptoms several months after resolution of the acute illness (“Post-Acute Sequalae of COVID-19” [PASC]). We aimed to determine the prevalence of objective hemodynamic cardiovascular autonomic abnormalities (CAA), explore sex differences, and assess the prevalence of CAA among hospitalized vs non-hospitalized PASC patients.

      Methods

      Patients with PASC (n=70; F=56; 42 years 95% CI [40,48]) completed standard autonomic tests, including an active stand test 399 days [338,455] after their COVID-19 infection. Clinical autonomic abnormalities were evaluated.

      Results

      Most patients with PASC met the criteria for at least one CAA (51; 73%; F=43). The Postural Orthostatic Tachycardia Syndrome hemodynamic criterion (POTSHR) of a heart rate increase of >30bpm within 5-10mins of standing was seen in 21 patients (30%; F=20; p=0.037 [by sex]). The Initial Orthostatic Hypotension hemodynamic criterion (IOH40) of a transient SBP change of >40mmHg in the first 15s of standing was seen in 43 (61%) patients and equally among females and males (63% vs. 57%; p=0.7). Only 9 (13%) patients were hospitalized; hospitalized vs. non-hospitalized patients had similar frequencies of abnormalities (67% vs. 74%; p=0.7).

      Conclusions

      Patients with PASC have evidence of CAA, most commonly IOH40, which will be missed unless an active stand test is used. Females have increased frequency of POTSHR, but IOH40 is equally prevalent between sexes. Finally, even non-hospitalized “mild” infections can result in long-term CAA.

      Graphical abstract

      KEYWORDS

      ABBREVIATIONS:

      BP (Blood Pressure), CASS (Composite Autonomic Severity Score), COMPASS-31 (Composite Autonomic Symptoms Scale – 31-items), CAA (Cardiovascular Autonomic Abnormalities), HR (Heart Rate), IOH (Initial Orthostatic Hypotension), IOH40 (Initial Orthostatic Hypotension Hemodynamic Criterion (transient SBP drop ≥40mmHg within 15 seconds of standing with recovery within 45 seconds)), IST (Inappropriate Sinus Tachycardia), IST100 (Inappropriate Sinus Tachycardia Hemodynamic Criterion (resting supine HR >100bpm)), OH (Orthostatic Hypotension), OH20 (Orthostatic Hypotension Hemodynamic Criterion (systolic BP (SBP) drop ≥20mmHg within 3 minutes of standing)), PASC (Post-Acute Sequelae of COVID-19), POTS (Postural Orthostatic Tachycardia Syndrome), POTSHR (Postural Orthostatic Tachycardia Syndrome Hemodynamic Criteria (HR increase ≥30 bpm within 10 minutes of standing in the absence of OH)), QSART (Quantitative Sudomotor Axon Reflex Testing)

      INTRODUCTION

      The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has impacted the health and economies of Canada and the world. Worldwide, there have been over 560 million cases and 6 million deaths attributed to COVID-19 (SARS-CoV-2 disease)

      World Health Organization. WHO Coronavirus (COVID-19) Dashboard | WHO Coronavirus (COVID-19) Dashboard With Vaccination Data. Accessed July 21, 2022. https://covid19.who.int/

      . While most patients recover, many are left with residual and sometimes disabling symptoms, several months after resolution of the acute illness.
      These ongoing symptoms have been termed "post-acute sequelae of COVID-19 syndrome" (PASC), defined as symptoms that develop during or after an infection consistent with COVID-19, continue for >12 weeks and are not explained by an alternative diagnosis

      National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. Published 2020. https://www.nice.org.uk/guidance/ng188

      . Common symptoms include exercise intolerance, dyspnea, fatigue, light-headedness, and tachycardia/palpitation

      National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. Published 2020. https://www.nice.org.uk/guidance/ng188

      ,
      • Paterson I.
      • Ramanathan K.
      • Aurora R.
      • et al.
      Long COVID-19: A Primer for Cardiovascular Health Professionals, on Behalf of the CCS Rapid Response Team.
      , which are common in cardiovascular autonomic abnormalities (CAA).
      Although studies have reported CAA in patients with PASC, including reports of new-onset postural orthostatic tachycardia syndrome (POTS)
      • Ståhlberg M.
      • Reistam U.
      • Fedorowski A.
      • et al.
      Post-COVID-19 Tachycardia Syndrome: A Distinct Phenotype of Post-Acute COVID-19 Syndrome.
      • Johansson M.
      • Ståhlberg M.
      • Runold M.
      • et al.
      Long-Haul Post–COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience.
      • Kanjwal K.
      • Jamal S.
      • Kichloo A.
      • Grubb B.P.
      New-onset Postural Orthostatic Tachycardia Syndrome Following Coronavirus Disease 2019 Infection.
      • Blitshteyn S.
      • Whitelaw S.
      Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients.

      Jamal SM, Landers DB, Hollenberg SM, et al. Prospective Evaluation of Autonomic Dysfunction in Post-Acute Sequela of COVID-19. J Am Coll Cardiol. Published online 2022. doi:10.1016/j.jacc.2022.03.357

      • Addison D.
      • Kulkarni P.A.
      • Cohen M.G.
      AHA / ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19.
      • Gall N.
      • James S.
      • Kavi L.
      Observational case series of postural tachycardia syndrome (PoTS) in post-COVID-19 patients.
      , inappropriate sinus tachycardia (IST)
      • Addison D.
      • Kulkarni P.A.
      • Cohen M.G.
      AHA / ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19.
      ,
      • Aranyó J.
      • Bazan V.
      • Lladós G.
      • et al.
      Inappropriate sinus tachycardia in post-COVID-19 syndrome.
      , and orthostatic hypotension (OH)
      • Monaghan A.
      • Jennings G.
      • Xue F.
      • Byrne L.
      • Duggan E.
      • Romero-Ortuno R.
      Orthostatic Intolerance in Adults Reporting Long COVID Symptoms Was Not Associated With Postural Orthostatic Tachycardia Syndrome.
      , these studies have been retrospective
      • Blitshteyn S.
      • Whitelaw S.
      Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients.
      , had small patient sample sizes
      • Johansson M.
      • Ståhlberg M.
      • Runold M.
      • et al.
      Long-Haul Post–COVID-19 Symptoms Presenting as a Variant of Postural Orthostatic Tachycardia Syndrome: The Swedish Experience.
      • Kanjwal K.
      • Jamal S.
      • Kichloo A.
      • Grubb B.P.
      New-onset Postural Orthostatic Tachycardia Syndrome Following Coronavirus Disease 2019 Infection.
      • Blitshteyn S.
      • Whitelaw S.
      Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients.
      , and/or did not perform autonomic evaluations using standard tests of autonomic function
      • Ladlow P.
      • O’Sullivan O.
      • Houston A.
      • et al.
      Dysautonomia following COVID-19 is not associated with subjective limitations or symptoms but is associated with objective functional limitations.
      . Further, most studies used a tilt table test

      Jamal SM, Landers DB, Hollenberg SM, et al. Prospective Evaluation of Autonomic Dysfunction in Post-Acute Sequela of COVID-19. J Am Coll Cardiol. Published online 2022. doi:10.1016/j.jacc.2022.03.357

      ,
      • Eldokla A.M.
      • Ali S.T.
      Autonomic function testing in long-COVID syndrome patients with orthostatic intolerance.
      , and not an active stand test
      • Harms M.P.M.
      • Finucane C.
      • Pérez-Denia L.
      • et al.
      Systemic and cerebral circulatory adjustment within the first 60 s after active standing: An integrative physiological view.
      ; which, in conjunction with beat-to-beat hemodynamic monitoring, is required to diagnose initial orthostatic hypotension (IOH)
      • Harms M.P.M.
      • Finucane C.
      • Pérez-Denia L.
      • et al.
      Systemic and cerebral circulatory adjustment within the first 60 s after active standing: An integrative physiological view.
      ,
      • Finucane C.
      • van Wijnen V.K.
      • Fan C.W.
      • et al.
      A practical guide to active stand testing and analysis using continuous beat-to-beat non-invasive blood pressure monitoring.
      . As such, we currently do not know the prevalence of objective CAA in patients with PASC based on standard tests of autonomic function
      • Cheshire W.P.
      • Freeman R.
      • Gibbons C.H.
      • et al.
      Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology.
      .
      We determined the frequency of objective CAA in a cohort of patients with PASC and examined whether there was a sex dimorphism in the frequency of these abnormalities, and whether they were more frequent among patients hospitalized for their COVID-19 infections.

      METHODS

      Participants

      Patients with PASC between 18-80 years were recruited from the Calgary Autonomic Investigation and Management Clinic, the Alberta Health Services Calgary COVID Clinics, and through local advertising. All patients met the consensus statement criteria for PASC
      • Addison D.
      • Kulkarni P.A.
      • Cohen M.G.
      AHA / ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19.
      , including a positive SARS-CoV-2 polymerase chain reaction test and symptoms consistent with COVID-19 lasting >12 weeks following a COVID-19 infection

      World Health Organization. Coronavirus disease (COVID-19): Post COVID-19 condition. Published December 16, 2021. Accessed May 31, 2022. https://www.who.int/news-room/questions-and-answers/item/coronavirus-disease-(covid-19)-post-covid-19-condition

      . In our cohort, 80% of patients were not vaccinated before their initial COVID-19 infection. Participants were excluded if they were unable to provide informed consent or could not safely withdraw from medications affecting heart rate and blood pressure. The Conjoint Health Research Ethics Board at the University of Calgary (REB21-1188) provided ethical oversight and approval for this study. All participants provided written informed consent prior to study participation. Participants also completed the Composite Autonomic Symptom Score (COMPASS-31) questionnaire and a general autonomic symptoms questionnaire via RedCap
      • Harris P.A.
      • Taylor R.
      • Thielke R.
      • Payne J.
      • Gonzalez N.
      • Conde J.G.
      Research electronic data capture (REDCap) - a metadata-driven methodology and workflow process for providing translational research informatics support.
      .

      Instrumentation

      Studies were conducted in a post-void and post-absorptive state at least 2h after a meal. Continuous heart rate (HR) and blood pressure (BP) were recorded using a 5-lead ECG (IVY Biomedical Model 450C, Connecticut, USA) and non-invasive beat-to-beat finger cuff (BMEYE, Amsterdam, The Netherlands). Brachial BP measurements were obtained before, during, and after the tests to verify finger cuff BP recordings. Advanced hemodynamics, including stroke volume (SV), cardiac output (CO), and systemic vascular resistance (SVR), as well as indices corrected for body surface area (BSA) (i.e., SV index [SVI], cardiac index [CI], and SVR index [SVRI]) were calculated using waveform based Modelflow software (BMEYE, Amsterdam, The Netherlands). All analogue signals were sampled at 500 Hz (WinDaq, DATAQ Corporation) and stored digitally for off-line analysis using custom software written in MATLAB r2021b (December 2021, Mathworks, Natick, MA, USA).

      Assessment of Hemodynamic Criteria for Cardiovascular Autonomic Abnormalities

      Following a 10-minute baseline in the supine position, participants completed an active stand test
      • Harms M.P.M.
      • Finucane C.
      • Pérez-Denia L.
      • et al.
      Systemic and cerebral circulatory adjustment within the first 60 s after active standing: An integrative physiological view.
      where they were instructed to stand as quickly as possible, and remain standing for 10 minutes.
      Hemodynamic criteria for cardiovascular autonomic disorders were determined using HR and BP changes during the active stand test. The hemodynamic criterion for orthostatic hypotension (OH) was defined as a systolic BP (SBP) drop ≥20mmHg within 3 minutes of standing (OH20)

      Fedorowski A, Hamrefors V, Sutton R, et al. Do we need to evaluate diastolic blood pressure in patients with suspected orthostatic hypotension? Clin Auton Res. 27. doi:10.1007/s10286-017-0409-7

      • Arnold A.C.
      • Ng J.
      • Lei L.
      • Raj S.R.
      Autonomic Dysfunction in Cardiology: Pathophysiology, Investigation, and Management.
      • Freeman R.
      • Wieling W.
      • Axelrod F.B.
      • et al.
      Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome.
      . The hemodynamic criterion for postural orthostatic tachycardia syndrome (POTS) was defined as a HR increase ≥30 bpm within 10 minutes of standing in the absence of OH (POTSHR)
      • Arnold A.C.
      • Ng J.
      • Lei L.
      • Raj S.R.
      Autonomic Dysfunction in Cardiology: Pathophysiology, Investigation, and Management.
      ,
      • Raj S.R.
      • Guzman J.C.
      • Harvey P.
      • et al.
      Canadian Cardiovascular Society Position Statement on Postural Orthostatic Tachycardia Syndrome (POTS) and Related Disorders of Chronic Orthostatic Intolerance.
      . Initial orthostatic hypotension (IOH) was defined as a transient SBP drop ≥40mmHg within 15 seconds of standing with recovery within 45 seconds (IOH40)
      • Sheikh N.
      • Phillips A.A.
      • Ranada S.
      • et al.
      Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation.
      . Inappropriate sinus tachycardia (IST) was assessed as a resting supine HR >100bpm (IST100)

      Sheldon RS, Grubb BP, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Sheldon RS, ed. Hear Rhythm. 2015;12(6):e41-e63. Accessed April 12, 2022. http://dx.doi.org/10.1016/j.hrthm.2015.03.029

      .

      Autonomic Function Testing

      Participants completed the following standard tests of autonomic function: quantitative sudomotor axon reflex testing (QSART), deep breathing, and Valsalva maneuver. QSART (QSWEAT, WR Medical Electronics Co., Stillwater, Minnesota, USA) was used to evaluate post-ganglionic peripheral sympathetic nerve integrity. Axon terminals were transdermally iontophoresed at a constant current (2mA) for 5-minutes with 10% acetylcholine at four standard sites (left forearm, left proximal leg, left distal leg, and left foot)
      • Novak P.
      Quantitative Autonomic Testing.
      , followed by a 5-minute post-stimulation period. Total sweat volumes were calculated as the area under the curve over 10 minutes.
      Cardiovagal function was assessed using deep breathing and the Valsalva maneuver. During deep breathing
      • Cheshire W.P.
      • Freeman R.
      • Gibbons C.H.
      • et al.
      Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology.
      , participants were instructed to breathe at a rate of 6 breaths/min for 90s. The peak to trough difference over five consecutive breaths was averaged to provide an average HR response to deep breathing (ΔHRDB). For the Valsalva maneuver
      • Cheshire W.P.
      • Freeman R.
      • Gibbons C.H.
      • et al.
      Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology.
      , participants were instructed to blow into a tube with an air leak (to ensure an open glottis) and to maintain an expiratory pressure of 40mmHg for 15s. A Valsalva ratio was calculated by dividing the maximum HR obtained during the maneuver by the minimum HR in the 30s immediately following release.
      The CASS was calculated for each participant to quantify the severity and distribution of autonomic dysfunction normalized for age and sex
      • Cheshire W.P.
      • Freeman R.
      • Gibbons C.H.
      • et al.
      Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology.
      . This 10-point scale evaluates autonomic dysfunction across three functional domains: sudomotor, adrenergic, and cardiovagal
      • Cheshire W.P.
      • Freeman R.
      • Gibbons C.H.
      • et al.
      Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the International Federation of Clinical Neurophysiology.
      .

      Autonomic Symptom Assessment

      Prior to their visit, all participants completed the COMPASS-31 Autonomic Symptom Score questionnaire
      • Sletten D.M.
      • Suarez G.A.
      • Low P.A.
      • Mandrekar J.
      • Singer W.
      COMPASS 31: A Refined and Abbreviated Composite Autonomic Symptom Score.
      . The COMPASS-31, comprised of 31 self-reported questions with a total score of 100, quantifies symptoms associated with autonomic dysfunction in the following domains: orthostatic intolerance (max. score of 40), vasomotor (max. score of 5), secretomotor (max. score of 15), gastrointestinal (max. score of 25), bladder (max. score of 10), and pupillomotor (max. score of 5).
      Participants also completed a questionnaire pertaining to common clinical symptoms in PASC
      • Addison D.
      • Kulkarni P.A.
      • Cohen M.G.
      AHA / ACC Key Data Elements and Definitions for Cardiovascular and Noncardiovascular Complications of COVID-19.
      (Supplemental Table S1).

      Active Stand Symptom Assessment

      Participants were asked to report symptoms they experienced during the active stand test. Specifically, participants were asked to report if they experienced symptoms within the first 60-seconds of the active stand. At the end of each stand, orthostatic symptoms were also assessed using the Vanderbilt Orthostatic Symptoms Score (VOSS)
      • Kpaeyeh A.
      • Mar P.
      • Raj V.
      • et al.
      Hemodynamic Profiles and Tolerability of Modafinil in the Treatment of POTS: a randomized placebo-controlled trial.
      • Raj S.R.
      • Black B.K.
      • Biaggioni I.
      • Harris P.A.
      • Robertson D.
      Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome.
      • Green E.
      • Black B.
      • Biaggioni I.
      • et al.
      Melatonin reduces tachycardia in Postural Tachycardia Syndrome (POTS): A Randomized, Crossover Trial.
      . In brief, the VOSS assesses nine orthostatic symptoms, with scores ranging from 0 (no symptoms) to 10 (worst symptoms), with higher scores indicating worse orthostatic intolerance.

      Statistical Analyses

      Continuous data are presented as median [95% Confidence Interval]. Categorical data are presented as number (%). A Fisher’s exact test was used to compare categorical variables, while continuous variables were compared using Mann-Whitney U tests. A 2-tailed p-value of <0.05 was deemed to be statistically significant.
      Sub-group analyses were conducted to evaluate (1) sex (male vs. female) differences; and (2) hospitalization (hospitalized vs. non-hospitalized) differences. Statistical analyses were performed using SPSS statistical software for Windows version 28 (SPSS, Inc., IBM, Armonk, NY). Figures were created using GraphPad Prism (version 8.0.0 for Windows, GraphPad Software, San Diego, California USA, www.graphpad.com).

      RESULTS

      Demographics

      Patients with PASC (n=70; 42 years [40,48]) were evaluated for CAA a median of 399 days (338,455) following an acute infection with COVID-19 (Table 1).
      Table 1Participant characteristics, hemodynamics, and symptoms in patients with PASC with and without hemodynamic autonomic abnormalities
      CharacteristicPatients with PASC: Overall (n=70)Patients with PASC with CAA (n=51)Patients with PASC without CAA (n=19)p-value
      Age, years42 (40, 48)44 (40, 49)41 (36, 49)0.409
      Female56 (80%)43 (84%)13 (68%)0.139
      Height, cm168 (165, 170)167 (165, 170)170 (161, 173)0.979
      Weight, kg77 (71, 88)78 (71, 90)73 (60, 88)0.222
      BMI, kg/m227.2 (24.7, 28.7)27.8 (25.2, 31.5)26.1 (22.7, 28.5)0.237
      BSA, m21.92 (1.82, 2.02)1.92 (1.83, 2.07)1.85 (1.69, 2.08)0.202
      Race0.727
      Caucasians64 (91.4%)46 (90.2%)18 (94.7%)
      South Asians2 (2.9%)2 (3.8%)0 (0%)
      Indigenous Canadians1 (1.4%)1 (2.0%)0 (0%)
      West Asians1 (1.4%)1 (2.0%)0 (0%)
      ≥1 race2 (2.9%)1 (2.0%)1 (5.3%)
      Duration since Initial COVID infection, days399 (338, 455)418 (341, 456)344 (319, 477)0.989
      Hospitalized with COVID-19 infection9 (13%)6 (12%)3 (16%)0.655
      Autonomic Function Testing
      Sympathetic Nerve Integrity (Total Sweat Volumes)
      Forearm, μL0.51 (0.39, 0.74)0.48 (0.35, 0.64)0.86 (0.39, 1.47)0.093
      Proximal leg, μL0.39 (0.32, 0.66)0.38 (0.30, 0.54)0.70 (0.12, 1.23)0.276
      Distal leg, μL0.49 (0.40, 0.67)0.46 (0.36, 0.54)0.74 (0.20, 0.167)0.063
      Foot, μL0.45 (0.30, 0.55)0.44 (0.29, 0.55)0.48 (0.22, 0.81)0.663
      Cardiovagal function
      ΔHRDB (bpm)15 (12, 18)15 (12, 18)15 (10, 20)0.769
      VR1.75 (1.67, 1.91)1.74 (1.64, 1.92)1.82 (1.55, 2.11)0.840
      Composite Autonomic Severity Score (CASS)
      Overall CASS1 (1, 2)1 (1, 2)1 (0, 2)0.163
      Sudomotor0 (0, 0)0 (0, 0)0 (0, 1)0.701
      Cardiovagal0 (0, 0)0 (0, 0)0 (0, 1)0.702
      Adrenergic1 (1, 1)1 (1, 1)0 (0, 1)0.06
      Autonomic Symptom Assessment
      COMPASS-31 Domains
      Orthostatic Intolerance20 (16, 20)20 (16, 24)16 (12, 20)0.038
      Vasomotor0 (0, 0)0 (0, 0)0 (0, 0.33)0.578
      Secretomotor6.43 (4.29, 6.43)6.43 (4.29, 6.43)6.43 (4.29, 8.57)0.757
      Gastrointestinal7.14 (6.25, 8.92)8.04 (6.25, 9.82)7.14 (4.46, 10.7)0.736
      Bladder1.11 (0, 1.11)1.11 (0, 1.11)1.11 (0, 2.22)0.693
      Pupillomotor2.33 (2.0, 2.67)2.33 (2.0, 2.67)2.33 (1.67, 3.0)0.873
      Total36 (31, 40)37 (31, 40)32 (23, 40)0.288
      PASC Symptoms
      Light-headedness55 (79%)40 (78%)15 (79%)0.963
      Shortness of breath51 (74%)37 (74%)14 (74%)0.979
      Palpitations49 (70%)37 (73%)12 (63%)0.446
      Fatigue64 (91%)48 (94%)16 (84%)0.188
      Headache41 (59%)30 (60%)11 (58%)0.874
      Loss/change in taste21 (31%)16 (33%)5 (26%)0.612
      Constipation20 (29%)16 (32%)4 (21%)0.371
      Problems with sleeping51 (75%)38 (76%)13 (72%)0.751
      Values are expressed as Median (95% Confidence Interval [CI]). P-values were generated from Mann-Whitney U test for continuous variables and Fischer’s Exact test for categorical variables. BMI – Body Mass Index; BSA – Body Surface Area; CASS – Composite Autonomic Severity Score; COMPASS-31 - Composite Autonomic Symptom Score; ΔHRDB – Delta HR in Deep Breathing; PASC – Post-Acute Sequelae of COVID-19; VR – Valsalva Ratio; HR – Heart Rate.
      Sex-based analysis: Fifty-six female (80%; 42 years [40,47]), and fourteen male (20%; 50 years [31,63]) patients were evaluated a median of 427 days (357,461) and 324 days (285,475) after a COVID-19 infection (Table 2).
      Table 2Participant characteristics, hemodynamics, and symptoms in male vs. female patients with PASC
      CharacteristicFemale Patients with PASC (n=56)Male Patients with PASC (n=14)p-value
      Age, years42 (40, 47)50 (31, 63)0.577
      Height, cm167 (163, 168)179 (172, 183)<0.001
      Weight, kg72 (67, 83)89 (78, 109)0.015
      BMI, kg/m226.3 (23.7, 29.1)27.9 (26.1, 33.6)0.322
      BSA, m21.84 (1.77, 1.92)2.1 (2.0, 2.33)0.004
      Race0.060
      Caucasians52 (92.8%)12 (85.8%)
      South Asians2 (3.6%)0 (0%)
      West Asians0 (0%)1 (7.1%)
      Indigenous Canadian0 (0%)1 (7.1%)
      ≥1 race2 (3.6%)0 (0%)
      Duration since Initial COVID infection, days427 (357, 461)324 (285, 475)0.083
      Hospitalized with COVID-19 infection6 (10.7%)3 (4.3%)0.284
      Autonomic Function Testing
      Sympathetic Nerve Integrity (Total Sweat Volumes)
      Forearm, μL0.47 (0.37, 0.59)1.08 (0.28, 1.84)0.01
      Proximal leg, μL0.38 (0.27, 0.55)0.72 (0.10, 1.41)0.093
      Distal leg, μL0.48 (0.38, 0.57)0.75 (0, 1.77)0.277
      Foot, μL0.39 (0.28, 0.50)1.18 (0, 2.04)0.028
      Cardiovagal function
      ΔHRDB (bpm)15 (12, 18)14 (11, 24)0.489
      VR1.82 (1.67, 1.94)1.73 (1.38, 2.11)0.146
      Composite Autonomic Severity Score (CASS)
      Overall CASS1 (1, 2)2 (1, 3)0.468
      Sudomotor0 (0, 0)0 (0, 2)0.245
      Cardiovagal0 (0, 0)0 (0, 1)0.972
      Adrenergic1 (1, 1)1 (0, 1)0.960
      Autonomic Symptom Assessment
      COMPASS-31 Domains
      Orthostatic Intolerance20 (16, 24)16 (0, 20)0.163
      Vasomotor0 (0, 0)0 (0, 0)0.172
      Secretomotor6.43 (4.29, 6.43)5.36 (2.14, 6.43)0.468
      Gastrointestinal8.04 (7.14, 9.82)4.91 (3.57, 10.7)0.032
      Bladder1.11 (0, 1.11)0 (0, 2.22)0.742
      Pupillomotor2.33 (2.0, 2.67)1.83 (0.67, 2.67)0.065
      Total37 (32, 40)28 (12, 40)0.083
      PASC Symptoms
      Light-headedness45 (80%)10 (71%)0.466
      Shortness of breath40 (73%)11 (79%)0.657
      Palpitations43 (77%)6 (43%)0.013
      Fatigue53 (95%)11 (79%)0.055
      Headache37 (67%)4 (29%)0.008
      Loss/change in taste20 (37%)1 (7.1%)0.031
      Constipation19 (35%)1 (7.1%)0.044
      Problems with sleeping43 (78%)8 (62%)0.213
      Values are expressed as Median (95% Confidence Interval [CI]). P-values were generated from Mann-Whitney U test for continuous variables and Fischer’s Exact test for categorical variables. BMI – Body Mass Index; BSA – Body Surface Area; CASS – Composite Autonomic Severity Score; COMPASS-31 - Composite Autonomic Symptom Score; ΔHRDB – Delta HR in Deep Breathing; PASC – Post-Acute Sequelae of COVID-19; VR – Valsalva Ratio; HR – Heart Rate.
      Hospitalization-based analysis: A minority of patients were hospitalized during their initial COVID-19 infection (13%; Supplemental Table S2). Hospitalized patients trended older (53 years [41,59] vs. 41 years [39,46]; p=0.051). Hospitalization frequency did not differ between sexes (p=0.3).

      Prevalence of Hemodynamic Criteria for Cardiovascular Autonomic Disorders

      Most patients with PASC (73%) met the criteria for at least one CAA (Figure 1). Among the CAA group, 16 (31%) patients met the hemodynamic criteria for >1 abnormality. The POTSHR criterion was met in 21 (30%) patients with PASC (40 years [35,45]) with a median ΔHR of +41bpm (+34,+59) from supine to standing. IST100 was seen in one (1.4%; 18-year-old) patient (supine HR: 136bpm). Sustained OH20 was evident in two (2.9%) patients with PASC (ΔSBP: -21mmHg [-21,-35]) with an average age of 52 years [46,58]. In contrast, the IOH40 criterion was evident in 43 (61%) patients (45 years [39,51]) with PASC with a median ΔSBP of -52mmHg (-61,-46) in the first 15 seconds of an active stand.
      Figure thumbnail gr1
      Figure 1Proportions of Hemodynamic Cardiovascular Autonomic Abnormalities (CAA) in Patients with Post-Acute Sequelae of COVID-19 (PASC), including sex-based and hospitalization status-based differences. Caption: (a) CAA were evaluated using hemodynamic criteria from an active stand test, which assessed for hemodynamic criteria for Postural Orthostatic Tachycardia Syndrome (POTS), Inappropriate Sinus Tachycardia (IST), Orthostatic Hypotension (OH), and Initial Orthostatic Hypotension (IOH); (b) Proportions of PASC patients meeting hemodynamic criteria for a CAA, broken down by patient sex. (c) Proportions of PASC patients meeting hemodynamic criteria for a CAA, broken down by patient hospitalization status during initial COVID-19 infection.
      Sex-based analysis: The POTSHR criterion was evident in 36% females vs. 7.1% males (p=0.037; Figure 1). In contrast, IOH40 criterion was equally prevalent in females and males (63% vs. 57%; p=0.7). The OH20 (p=0.5) and IST100 criterion (p=0.6) were only met in females. Overall, the increased estimates of females vs. males meeting any CAA criteria were not significant (77% vs. 51%; p=0.14).
      Hospitalization-based analysis: The overall prevalence of CAA was not different (67% vs. 74%; p=0.7). IOH40 was similar between the groups (67% vs. 61%; p=0.7), There was not a significant difference in the prevalence of patients with POTSHR who were hospitalized (11% vs. 33%; p=0.18). The OH20 and IST100 patients were not hospitalized (Figure 1).

      Autonomic Function Testing

      Post-ganglionic sympathetic nerve integrity: Reduced nerve integrity was evident in 15 patients with CAA and in 4 patients without (p=0.5). There was a trend for sympathetic nerve function to be attenuated in the forearm and distal leg for patients with CAA (Table 1). Between sexes, reduced nerve integrity was present in 13 females and 6 males (p=0.14). Sympathetic nerve function was reduced in females at the forearm and foot (Table 2). Abnormal nerve function was observed in both hospitalized and non-hospitalized patients (p=0.2). The forearm had worse sympathetic nerve integrity in non-hospitalized patients (Supplemental Table S2).
      Cardiovagal: HR responses to deep breathing and Valsalva maneuver were not different between patient groups (Table 1; Table 2; Supplemental Table S2).
      CASS: Hospitalized patients had higher cardiovagal scores (Supplemental Table S2; p=0.022).

      Autonomic Symptom Assessment

      All patients reported at least one symptom on the COMPASS-31 with an overall median score of 36/100 (31,40). Patients with CAA had higher COMPASS-31 scores in the orthostatic intolerance domain vs. patients without CAA (p=0.038; Table 1). Among all patients, females had higher gastrointestinal scores compared to males (p=0.032; Table 2) on the COMPASS-31. On the PASC-symptom questionnaire, more females than males reported a loss/change in taste (p=0.031), constipation (p=0.044), palpitations (p=0.013), and headache (p=0.008), and a trend toward more fatigue (p=0.055) (Table 2). Supplemental Table S1 provides an assessment of all symptoms in the general PASC symptom questionnaire.

      Active Stand Symptom Assessment

      In our cohort, 71% of patients reported symptoms in the first 60s of standing and 100% of patients reported a score of ≥1 on the VOSS. Among patients with symptom assessments, 74% of IOH patients reported symptoms within the first 60s of standing and 84% reported symptoms of new onset orthostatic intolerance (OI), including light-headedness or palpitations. Additionally, 100% of patients meeting POTS criteria reported a score of ≥ 1 on the VOSS and 91% reported new onset OI symptoms of light-headedness or palpitations following their COVID-19 infection in the PASC questionnaire. Finally, 50% of patients meeting OH criterion reported symptoms while standing, and the single IST patients (100%) did not complete a symptom assessment during the active stand. Notably, with the IOH sub-group, the change in BP in the first 60s of stand was negatively correlated with higher OI scores (rs=-0.328; p=0.006). Similarly, patients with higher orthostatic tachycardia also reported higher OI symptoms (rs=0.284; p=0.017).

      DISCUSSION

      In this study we report one of the largest PASC cohorts that have undergone autonomic testing. Here, we report that: 1) many patients with PASC have objective evidence of CAA; 2) the most common abnormality is IOH, followed by POTS; 3) both males and females with PASC meet the IOH criterion with a similar frequency, but POTS skewed heavily toward female patients; and 4) hospitalized patients with PASC did not have increased rates of CAA compared to non-hospitalized patients, suggesting even mild, non-hospitalized COVID-19 infections can result in long-term CAA.

      Prevalence of cardiovascular autonomic abnormalities (CAA)

      Within our cohort, IOH was the most prevalent hemodynamic abnormality (61%). Previous studies have observed IOH ranging from 15-30% in the general population
      • Finucane C.
      • O’Connell M.D.L.
      • Fan C.W.
      • et al.
      Age-related normative changes in phasic orthostatic blood pressure in a large population study: Findings from the Irish longitudinal study on ageing (TILDA).
      , suggesting IOH may be more prevalent among patients with PASC. IOH requires an active stand with beat-to-beat hemodynamics for accurate detection
      • Harms M.P.M.
      • Finucane C.
      • Pérez-Denia L.
      • et al.
      Systemic and cerebral circulatory adjustment within the first 60 s after active standing: An integrative physiological view.
      ,
      • Sheikh N.
      • Phillips A.A.
      • Ranada S.
      • et al.
      Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation.
      ,
      • Wieling W.
      • Krediet C.T.P.
      • Van Dijk N.
      • Linzer M.
      • Tschakovsky M.E.
      Initial orthostatic hypotension: Review of a forgotten condition.
      . Few studies have employed these methods, suggesting underdiagnosis of IOH is likely in patients with PASC. This is important as there are targeted non-pharmacological treatments that can help patients with IOH
      • Eldokla A.M.
      • Ali S.T.
      Autonomic function testing in long-COVID syndrome patients with orthostatic intolerance.
      ,
      • Sheikh N.
      • Phillips A.A.
      • Ranada S.
      • et al.
      Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation.
      ,
      • Sheikh N.A.
      • Ranada S.
      • Lloyd M.
      • et al.
      Lower body muscle preactivation and tensing mitigate symptoms of initial orthostatic hypotension in young females.
      . The POTS hemodynamic criterion was met in 30% of patients with PASC, which is consistent with prior reports
      • Eldokla A.M.
      • Ali S.T.
      Autonomic function testing in long-COVID syndrome patients with orthostatic intolerance.
      ,

      Shouman K, Vanichkachorn G, William ·, et al. Autonomic dysfunction following COVID-19 infection: an early experience. Clin Auton Res. 2021;31:385-394. doi:10.1007/s10286-021-00803-8

      , but higher than the prevalence seen in the general population (0.2%)

      Sheldon RS, Grubb BP, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Sheldon RS, ed. Hear Rhythm. 2015;12(6):e41-e63. Accessed April 12, 2022. http://dx.doi.org/10.1016/j.hrthm.2015.03.029

      , and specifically within females aged 20-40 years. For example, in a Croatian cohort, the prevalence of POTS in females 20-40 years ranged from 3-21%
      • Adamec I.
      • Crnošija L.
      • Ruška B.
      • et al.
      The incidence of postural orthostatic tachycardia syndrome in the population of Zagreb, Croatia.
      . Finally, IST and OH were relatively uncommon in our PASC cohort.
      In addition to abnormal orthostatic hemodynamics, CAA patients also had higher OI scores, and these scores were related to orthostatic hemodynamic abnormalities. For example, IOH patients with larger BP drops and POTS patients with higher HRs both reported higher OI scores. These findings further emphasize the need to incorporate an active stand and beat-to-beat hemodynamics when evaluating patients presenting with chronic PASC symptoms, especially symptoms of OI (e.g., light-headedness or palpitations).

      Sex-based differences

      There was a trend toward increased frequency of a CAA among females compared to males. These findings are consistent with many disorders of the ANS, including POTS
      • Raj S.R.
      • Guzman J.C.
      • Harvey P.
      • et al.
      Canadian Cardiovascular Society Position Statement on Postural Orthostatic Tachycardia Syndrome (POTS) and Related Disorders of Chronic Orthostatic Intolerance.
      , which predominantly affects pre-menopausal Caucasian females (5-fold female predominance)
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • et al.
      The Face of Postural Tachycardia Syndrome - Insights from a Large Cross-Sectional Online Community-Based Survey.
      . It is important, however, to acknowledge that our PASC cohort was predominantly comprised of Caucasian females. It is hard to know if this represents the broader PASC population or if this reflects our sampling and recruitment. Despite a strong overall female predominance, we found that individuals meeting the cardiovascular criteria for IOH was equally prevalent among males and females. IOH can be a common cause of syncope in individuals with unexplained syncope
      • Sheikh N.A.
      • Ranada S.
      • Lloyd M.
      • et al.
      Lower body muscle preactivation and tensing mitigate symptoms of initial orthostatic hypotension in young females.
      ,
      • van Twist D.J.L.
      • Dinh T.
      • Bouwmans E.M.E.
      • Kroon A.A.
      Initial orthostatic hypotension among patients with unexplained syncope: An overlooked diagnosis?.
      , suggesting both males and females are at an equal risk of experiencing a syncopal episode related to PASC.
      From a symptom perspective, there were several symptoms that were more prevalent among females, including reports of headache, loss/change in taste, gastrointestinal (e.g., constipation), fatigue, and palpitations. Many of these symptoms are reported among patients with POTS, which was also female dominated in our PASC cohort. Palpitations is a common cardiac symptoms of POTS
      • Raj S.R.
      Postural tachycardia syndrome (POTS).
      , however, what might be less appreciated is that many POTS patients also experience several non-cardiac symptoms including significant, debilitating fatigue
      • Raj S.R.
      Postural tachycardia syndrome (POTS).
      • Bagai K.
      • Song Y.
      • Ling J.F.
      • et al.
      Sleep disturbances and diminished quality of life in postural tachycardia syndrome.

      Wu REY, Khan FM, Hockin BCD, Lobban TCA, Sanatani S, Claydon VE. Faintly tired: a systematic review of fatigue in patients with orthostatic syncope. Clin Auton Res. Published online June 10, 2022. doi:10.1007/S10286-022-00868-Z

      , which has important implications in all facets of life, including increased absences from school, work and loss of productivity
      • Ricci J.A.
      • Chee E.
      • Lorandeau A.L.
      • Berger J.
      Fatigue in the U . S . Workforce : Prevalence and Implications for Lost Productive Work Time.
      . Other non-cardiac symptoms reported in patients with POTS include headache and GI issues
      • Raj S.R.
      Postural tachycardia syndrome (POTS).
      , which are also consistent with our findings. Conversely, shortness of breath, light-headedness and sleep difficulties were not different between females and males within our cohort. Light-headedness is commonly reported in patients with autonomic disorders
      • Sheikh N.
      • Phillips A.A.
      • Ranada S.
      • et al.
      Mitigating Initial Orthostatic Hypotension: Mechanistic Roles of Muscle Contraction Versus Sympathetic Activation.
      ,
      • Raj S.R.
      Postural tachycardia syndrome (POTS).
      . Given that IOH was equally prevalent among males and females and was frequently reported within the first 60s of standing, it is not surprising that light-headedness was not different between sexes.

      Hospitalization Status

      Contrary to our hypothesis, patients with PASC hospitalized due to their COVID-19 infections did not have increased rates of CAA compared to non-hospitalized patients. Similarly, reported symptoms did not differ between groups. These findings suggest that even “mild” COVID-19 infections may result in CAA with significant symptomatology.
      Although we cannot infer causation from the current study, viral infections are commonly reported triggers of altered autonomic control, and have been reported in various disorders of orthostatic intolerance
      • Shaw B.H.
      • Stiles L.E.
      • Bourne K.
      • et al.
      The Face of Postural Tachycardia Syndrome - Insights from a Large Cross-Sectional Online Community-Based Survey.
      ,
      • Carod-Artal F.J.
      Infectious diseases causing autonomic dysfunction.
      . Additionally, autoantibodies have been reported in patients with OH
      • Li H.
      • Kem D.C.
      • Reim S.
      • et al.
      Agonistic autoantibodies as vasodilators in orthostatic hypotension: A new mechanism.
      and POTS
      • Li H.
      • Yu X.
      • Liles C.
      • et al.
      Autoimmune basis for postural tachycardia syndrome.
      ,
      • Fedorowski A.
      • Li H.
      • Yu X.
      • et al.
      Antiadrenergic autoimmunity in postural tachycardia syndrome.
      . Recently, Blitshteyn et al., reported that ∼20% of their PASC patient cohort had abnormal autoimmune or inflammatory biomarkers
      • Blitshteyn S.
      • Whitelaw S.
      Postural orthostatic tachycardia syndrome (POTS) and other autonomic disorders after COVID-19 infection: a case series of 20 patients.
      . These findings lend to the possibility that the observed CAA may result from an underlying autoimmune/inflammatory response. However, further studies including inclusion of a healthy control group are needed to explore whether these findings are related to PASC, and to explore the relationship between autoimmune/inflammatory biomarkers and severity of autonomic dysfunction and/or symptoms.

      Limitations

      Our study highlighted the importance of testing autonomic function in patients with PASC, but there were some limitations. First, this was a descriptive study and lacked a proper control group to determine what is truly abnormal with PASC physiology. Our initial focus was to recruit and study patients with PASC, and there are plans to study a matched control group going forward. Despite this limitation, due to the societal impact of the COVID-19 related health crisis, we felt it was important to report these data quickly. Second, our cohort may not represent the full PASC patient population. We recruited through local advertising and “Long-COVID” clinics, but it is possible that some patients found our study based on knowledge of our interest and expertise in CAA. This could lead to an overestimation of the prevalence of CAA in the broader PASC population. Additionally, we acknowledge that the low number of male patients and hospitalized patients may have an impact on statistical power. Finally, we focussed on the hemodynamic criteria that could be identified with autonomic testing. Some of these disorders (such as POTS and IOH) also require a specific symptoms constellation during a clinical evaluation. Therefore, it is more correct for us to speak about the hemodynamics of these disorders being present, rather than the disorders being present. Finally, a 24-hour Holter monitor can also be used to diagnose IST. As a single-day study, we opted to assess IST as a resting supine HR >100bpm

      Sheldon RS, Grubb BP, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Sheldon RS, ed. Hear Rhythm. 2015;12(6):e41-e63. Accessed April 12, 2022. http://dx.doi.org/10.1016/j.hrthm.2015.03.029

      . However, the use of a 24-h Holter may provide additional insights that may not have been captured with the timeframe of our study potentially result in a underdiagnosis within our cohort.

      CONCLUSION

      Given the high prevalence of CAA among patients with PASC, these patients should have cardiovascular autonomic function testing, especially if they report symptoms of orthostatic intolerance. Ideally, this evaluation will include beat-to-beat BP and HR monitoring with an active stand test to evaluate for criteria consistent with IOH, in addition to POTS, OH & IST. While IOH was common in both sexes, POTS was seen primarily in females. Hemodynamic cardiovascular autonomic abnormalities were common even in patients who were not hospitalized with their COVID-19 infections, suggesting even ‘mild’ infections can results in CAA.

      Acknowledgements

      The authors would like to acknowledge the patients who took the time to participate in our study.

      Supplementary Material

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      Linked Article

      • Cardiovascular autonomic abnormalities in patients with Post-acute Sequalae of COVID-19: don’t miss that target!
        Canadian Journal of Cardiology
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          A massive and sustained world-wide spread of the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has triggered a pandemic that has lasted for three years now and generated > 600 million reported cases around the globe. It has been increasingly evident that a substantial portion of patients who develop Corona Virus Disease 2019 (COVID-19) do not recover completely but rather experience lingering symptoms for months to years. This novel clinical syndrome is has been termed Long COVID or Post-acute Sequalae of COVID-19 (PASC), and has been defined by the World Health Organization as ongoing symptoms beyond three months from the acute illness due to confirmed or suspected SARS-CoV-2 infection that cannot be explained by other diseases1.
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