. 2023 Aug 31;228(5):542-554.

doi: 10.1093/infdis/jiad131.

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

Matthew S Durstenfeld^{1

2}, Michael J Peluso^{1

3}, Punita Kaveti^{1

4}, Christopher Hill⁵, Danny Li², Erica Sander⁴, Shreya Swaminathan², Victor M Arechiga², Scott Lu³, Sarah A Goldberg⁵, Rebecca Hoh², Ahmed Chenna⁶, Brandon C Yee⁶, John W Winslow⁶, Christos J Petropoulos⁶, J Daniel Kelly^{7

8

9}, David V Glidden¹⁰, Timothy J Henrich^{1

9}, Jeffrey N Martin¹⁰, Yoo Jin Lee¹¹, Mandar A Aras^{1

4}, Carlin S Long^{1

4}, Donald J Grandis^{1

4}, Steven G Deeks^{1

3}, Priscilla Y Hsue^{1

2}

Affiliations

¹ Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
² Division of Cardiology, Zuckerberg San Francisco General, University of California, San Francisco, San Francisco, California, USA.
³ Division of HIV, Infectious Diseases, and Global Medicine, Zuckerberg San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA.
⁴ Division of Cardiology, UCSF Health, San Francisco, California, USA.
⁵ School of Medicine, University of California, San Francisco, San Francisco, California, USA.
⁶ Monogram Biosciences, LabCorp, University of California, San Francisco, California, USA.
⁷ Institute of Global Health Sciences, University of California, San Francisco, San Francisco, California, USA.
⁸ F.I. Proctor Foundation, University of California, San Francisco, San Francisco, California, USA.
⁹ Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA.
¹⁰ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
¹¹ Cardiac and Pulmonary Imaging, Department of Radiology, University of California, San Francisco, San Francisco, California, USA.

PMID: 37166076
PMCID: PMC10686699
DOI: 10.1093/infdis/jiad131

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

Matthew S Durstenfeld et al. J Infect Dis. 2023.

. 2023 Aug 31;228(5):542-554.

doi: 10.1093/infdis/jiad131.

Authors

Affiliations

¹ Department of Medicine, University of California, San Francisco, San Francisco, California, USA.
² Division of Cardiology, Zuckerberg San Francisco General, University of California, San Francisco, San Francisco, California, USA.
³ Division of HIV, Infectious Diseases, and Global Medicine, Zuckerberg San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA.
⁴ Division of Cardiology, UCSF Health, San Francisco, California, USA.
⁵ School of Medicine, University of California, San Francisco, San Francisco, California, USA.
⁶ Monogram Biosciences, LabCorp, University of California, San Francisco, California, USA.
⁷ Institute of Global Health Sciences, University of California, San Francisco, San Francisco, California, USA.
⁸ F.I. Proctor Foundation, University of California, San Francisco, San Francisco, California, USA.
⁹ Division of Experimental Medicine, University of California, San Francisco, San Francisco, California, USA.
¹⁰ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
¹¹ Cardiac and Pulmonary Imaging, Department of Radiology, University of California, San Francisco, San Francisco, California, USA.

PMID: 37166076
PMCID: PMC10686699
DOI: 10.1093/infdis/jiad131

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."

Keywords: SARS-CoV-2; cardiac magnetic resonance imaging; cardiopulmonary exercise testing; chronotropic incompetence; postacute sequelae of COVID-19.

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Conflict of interest statement

Potential conflicts of interest. A. C., B. C. Y., J. W. W., and C. J. P. are employees of Monogram Biosciences, a division of LabCorp. They performed biomarker measurements blinded to participant data. P. Y. H. has received modest honoraria from Gilead and Merck and a research grant from Novartis, unrelated to the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

**Figure 1.**
Exercise capacity by symptoms and chronotropic response to exercise. Box and whisker plots represent peak oxygen consumption (VO₂) among those without (*left*) or with (*right*) symptoms 17.6 months after severe acute respiratory syndrome coronavirus 2 infection (top). *A, B,* The mean peak VO₂ (standard deviation) was 22.7 ( 8.1) and 29.6 (7.0) mL/kg/min among those with and those without symptoms (A), respectively, a difference of 6.9 mL/kg/min (95% confidence interval, 2.5–11.3; P = .003) and 92% versus 107% percent predicted, respectively (B), a 15% difference (P = .02). C, Peak VO₂ plotted by adjusted heart rate reserve (AHRR) to demonstrate the cluster of symptomatic individuals with low peak VO₂ and chronotropic incompetence (*bottom left, circles = symptoms, squares = no symptoms*). D, Cardiopulmonary exercise testing (CPET) patterns among participants with long coronavirus disease 2019 symptoms: half achieved ≥85% predicted peak VO₂, and chronotropic incompetence was the most common pattern among those with reduced exercise capacity.

**Figure 2.**
Heart rate (HR) during exercise by chronotropic response to exercise. The mean HR is plotted as a function of exercise time normalized to the percent of predicted peak oxygen consumption (VO₂). The top line represents participants with normal exercise capacity (peak VO₂ ≥85% predicted) and normal HR response (n = 16); middle line, those with normal exercise capacity (peak VO₂ ≥85%) and blunted HR response (adjusted HR response <80%) (n = 8); bottom line, those with chronotropic incompetence (n = 9), as described in Supplementary Table 4.

**Figure 3.**
Correlation between peak oxygen consumption (VO₂) and previously measured inflammatory markers and antibody levels. Scatterplots and linear trend lines represent peak VO₂ (measured at about 18 months) by natural log of selected biomarker levels, with unadjusted Pearson’s ρ correlations and P values listed. High-sensitivity C-reactive protein (hsCRP) was measured a median of 6 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; interleukin 6 (IL-6), tumor necrosis factor (TNF), and SARS-CoV-2 receptor binding domain (RBD) immunoglobulin G (IgG) were measured a median of 4 months after infection. Prior hsCRP, IL-6, TNF, and SARS-CoV-2 antibody levels were correlated with subsequent peak VO₂. Additional biomarkers are plotted in Supplementary Figure 2.

**Figure 4.**
Hypothesized mechanisms of cardiopulmonary symptoms and reduced exercise capacity. We found that higher inflammatory markers (high-sensitivity C-reactive protein, interleukin 6 [IL-6], and tumor necrosis factor [TNF]) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G antibody levels measured within the first 6 months after infection are associated with reduced exercise capacity measured with cardiopulmonary exercise testing >1 year after infection. We also found that evidence of Epstein-Barr virus (EBV) reactivation was common, including among all individuals with chronotropic incompetence. We propose that persistent immune activation and systemic inflammation, possibly related to EBV reactivation, may cause a dysregulated response to autonomic signaling that may manifest as chronotropic incompetence, reduced exercise capacity, and symptoms of long coronavirus disease 2019 (“long COVID”). Abbreviation: HR, heart rate. (Figure created with BioRender.com.)

See this image and copyright information in PMC

Update of

Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID.
Durstenfeld MS, Peluso MJ, Kaveti P, Hill C, Li D, Sander E, Swaminathan S, Arechiga VM, Lu S, Goldberg SA, Hoh R, Chenna A, Yee BC, Winslow JW, Petropoulos CJ, Kelly JD, Glidden DV, Henrich TJ, Martin JN, Lee YJ, Aras MA, Long CS, Grandis DJ, Deeks SG, Hsue PY. Durstenfeld MS, et al. medRxiv [Preprint]. 2023 Mar 21:2022.05.17.22275235. doi: 10.1101/2022.05.17.22275235. medRxiv. 2023. Update in: J Infect Dis. 2023 Aug 31;228(5):542-554. doi: 10.1093/infdis/jiad131. PMID: 35677073 Free PMC article. Updated. Preprint.

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

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

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