Reduced Exercise Capacity, Chronotropic Incompetence, and Early Systemic Inflammation in Cardiopulmonary Phenotype Long Coronavirus Disease 2019

  1. Matthew S Durstenfeld
  2. Michael J Peluso
  3. Punita Kaveti
  4. Christopher Hill
  5. Danny Li
  6. Erica Sander
  7. Shreya Swaminathan
  8. Victor M Arechiga
  9. Scott Lu
  10. Sarah A Goldberg
  11. Rebecca Hoh
  12. Ahmed Chenna
  13. Brandon C Yee
  14. John W Winslow
  15. Christos J Petropoulos
  16. J Daniel Kelly
  17. David V Glidden
  18. Timothy J Henrich
  19. Jeffrey N Martin
  20. Yoo Jin Lee
  21. Mandar A Aras
  22. Carlin S Long
  23. Donald J Grandis
  24. Steven G Deeks
  25. Priscilla Y Hsue

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Abstract

Background

Mechanisms underlying persistent cardiopulmonary symptoms after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (postacute sequelae of coronavirus disease 2019 [COVID-19; PASC] or “long COVID”) remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity.

Methods

We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults >1 year after SARS-CoV-2 infection, compared those with and those without symptoms, and correlated findings with previously measured biomarkers.

Results

Sixty participants (median age, 53 years; 42% female; 87% nonhospitalized; median 17.6 months after infection) were studied. At CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted), compared with 3/19 (16%) without symptoms (P = .02). The adjusted peak oxygen consumption (VO2) was 5.2 mL/kg/min lower (95% confidence interval, 2.1–8.3; P = .001) or 16.9% lower percent predicted (4.3%-29.6%; P = .02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2. Late-gadolinium enhancement on CMR and arrhythmias were absent.

Conclusions

Cardiopulmonary symptoms >1 year after COVID-19 were associated with reduced exercise capacity, which was associated with earlier inflammatory markers. Chronotropic incompetence may explain exercise intolerance among some with “long COVID.”

Article activity feed

  1. Version published to 10.1093/infdis/jiad131
  2. Version published to 10.1101/2022.05.17.22275235v3 on medRxiv
  3. Version published to 10.1101/2022.05.17.22275235v2 on medRxiv
  4. ScreenIT

    SciScore for 10.1101/2022.05.17.22275235: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: The study was approved by the UCSF Committee on Human Research (IRB 20-33000) and all participants provided written informed consent.
    Consent: The study was approved by the UCSF Committee on Human Research (IRB 20-33000) and all participants provided written informed consent.
    Sex as a biological variableParticipants were excluded who were pregnant (to reduce confounding due to expected changes during pregnancy) or had significant cardiopulmonary disease including congenital heart disease, heart failure, myocardial infarction, or heart surgery.
    Randomizationnot detected.
    BlindingSamples were assayed blinded with respect to patient and clinical information, and assay performance was consistent with the manufacturer’s specifications.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Statistical Design: As we have previously reported, we defined a composite symptom variable for cardiopulmonary PASC including chest pain, dyspnea, or palpitations in the preceding 2 weeks prior to the study visit;7 all participants had new symptoms, were more than 3 months after SARS-CoV-2 infection, and did not have alternative cardiac disease to explain their symptoms, consistent with the WHO definition of PASC.
    PASC
    suggested: (PASC , RRID:SCR_016642)
    REDCap was used for data entry.
    REDCap
    suggested: (REDCap, RRID:SCR_003445)
    Statistical analyses were performed using STATA version 17.1 and additional visualization was done using R version 4.2.0 using the ggplot2 package.
    STATA
    suggested: (Stata, RRID:SCR_012763)
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Others have attributed exercise limitations to ventilatory inefficiency from pulmonary vasculopathy,18 respiratory abnormalities,19 obesity and differences in cardiorespiratory fitness29 and deconditioning.20, 21 Impaired oxygen extraction at the peripheral level (assessed using invasive CPET) has also been suggested to explain reduced exercise capacity among those with PASC at 11 months after infection by Singh et al.31 However, they describe stopping CPETs once RER was greater than 1.10 or heart rate was >85% predicted, which is below maximal exercise for most individuals and does not allow evaluation of chronotropic incompetence. They hypothesize that autonomic regulation of microcirculatory function may be one mechanism by which SARS-CoV-2 may alter oxygen extraction during exercise.32 Others have hypothesized that IL-6 (which may be elevated in PASC)33 functions as a myokine that regulates energy allocation during exercise.34 We did not find differences in the VO2 work slope, a noninvasive correlate of peripheral oxygen extraction, but we did not measure peripheral oxygen extraction since we did not perform invasive CPET. Mancini et al and others have found that dysfunctional (rapid, erratic) breathing or exercise hyperventilation may contribute to symptoms of persistent dyspnea in PASC.35–37 In contrast, we did not observe dysfunctional breathing in any participant. Although not a universal finding, several other groups have also reported chronotropic incompetence in PA...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04362150RecruitingLong-term Impact of Infection With Novel Coronavirus (COVID-…

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  5. Version published to 10.1101/2022.05.17.22275235v1 on medRxiv