Introduction

The SARS-CoV-2 pandemic is gradually transitioning to an endemic phase and almost one third of patients suffering from the acute infection may suffer from prolonged symptoms.¹ While over 100 symptoms have been reported among patients with post-acute sequelae of SARS-CoV-2 (PASC),² also known as "Long COVID," hallmark features of the syndrome include exercise intolerance and tachycardia out of proportion to perceived level of exertion, profound fatigue, and post-exertional malaise.³

Exercise Intolerance in PASC

Heart rate (HR) is typically determined by three key physiologic factors, including parasympathetic tone, sympathetic tone, and intrinsic HR. External factors that influence resting HR may include sleep quality, hydration, stress, and illness. Multiple factors contribute to exercise HR, including central command, arterial and cardiac baroreceptors, as well as peripheral feedback from group III (mechanoreceptors) and IV (metaboreceptors) afferents from skeletal muscle. Because resting and exertional HR – and cardiac output (Qc) – are so tightly controlled, compensatory tachycardia is rarely the result of an underlying dysautonomia.

Cardiac deconditioning contributes to symptoms commonly reported by patients suffering from Long COVID and may occur following as little as 20 hours of bedrest.⁴ In a study of five healthy men, 20 hours of bedrest led to an 8% reduction in total blood volume and 14% decline in central filling pressures leading to a 19% reduction in stroke volume (SV).⁴ During exercise, SV was approximately 20-40mL/beat lower and HR was approximately 40 bpm greater at any given workload when compared to pre-bedrest values obtained.⁴ The reduction in blood volume leads to a leftward shift in the left ventricle (LV) pressure-volume curve, reducing SV and contributing to a compensatory tachycardia.⁵ Thus, observed increases in HR among patients with Long COVID are not always an indication of dysautonomia. In the absence of other features, dysautonomia may not be the causative mechanism.⁶ Upright positioning introduces a gravitational load on the cardiovascular system, decreasing venous return and perpetuating the cardiovascular effects of cardiac deconditioning.⁷ This physiologic response to a gravitational load explains, at least in part, difficulties encountered with completion of routine activities of daily living and upright exercise, as well as many abnormalities observed on exercise testing in these patients.^7,8

Cardiopulmonary Exercise Testing (CPET) Among Patients with Long COVID

Several reports have emerged over the past 1-2 years describing cardiovascular and pulmonary abnormalities accounting for impairments in functional capacity among patients with Long COVID.^8,9 In an Italian study, 75 patients with Long COVID underwent CPET 3 months following hospitalization with critical (n=39), severe (n=18) and mild/moderate infection (n=18), of whom slightly over half (n=46, 61%) complained of persistent dyspnea on exertion. Peak oxygen uptake (VO₂) for the overall cohort was 20.0ml/kg/min (83±15% predicted) and ventilatory efficiency (slope of minute ventilation [V_E] to carbon dioxide production [VCO₂]) was 28.4±3.1. None of the patients demonstrated a ventilatory limitation to exercise, but abnormal HR reserve, suggestive of deconditioning, was a major limiting factor to exercise.⁷ Similarly, in a Norwegian study of 156 individuals with Long COVID evaluated 3 months after infection, peak VO₂ was 29±8mL/kg/min and V_E/VCO₂ slope was 28±5. Pulmonary function testing was normal (forced expiratory volume in 1 min [FEV1] 3.1±0.8 L) and impaired breathing reserve was rare. Deconditioning (defined by a peak VO₂ <80% predicted without evidence of ventilatory or circulatory limitations) was the major cause of impairments in exercise tolerance.¹⁰

Among 41 individuals (45±13 years) with Long COVID who completed CPET testing, peak VO₂ was 20.3±7ml/kg/min (77±21% predicted) and V_E/VCO₂ was 30±7.¹¹ Seven of the participants underwent invasive CPET with Swan-Ganz catheterization and had a low preload (right atrial pressure) resulting from reduced plasma volume.¹¹ Dysfunctional breathing (defined as resting tachypnea [>20 breaths/min] with continued rapid respiratory rate during exercise combined with delayed increase in tidal volume) was common (63% of participants).¹¹

Finally, in a cohort of 71 patients with history of COVID-19, those with persistent dyspnea (n=41) had greater impairments in functional capacity than asymptomatic participants.¹² Specifically, compared to the asymptomatic participants, those with dyspnea had a lower VO₂ (median [interquartile range]:17.8 [15.8-21.2] vs. 22.8 [18/8-27.7], P<0.01) and greater V_E/VCO₂ ratio (32.0 [28.1-37.4] vs. 29.4 [26.9-31.4], P=0.02) suggesting a hyperventilation syndrome in these patients (V_E/VCO₂ is considered normal when <30).¹³ Pulmonary function testing was similar between groups, with normal diffusion capacity for carbon monoxide, FEV1 and forced vital capacity.¹² Further data are necessary to determine whether dyspnea in this patient population may result from ventilation/perfusion mismatching.

A recent systematic review and meta-analysis of 38 studies detailing CPET data on patients (n=2160, 1228 with Long COVID symptoms, 3-18 months following SARS-CoV-2 infection) found that peak VO₂ was 4.9 (95% confidence interval [CI]: 3.4 to 6.4) ml/kg/min lower among patients with persistent symptoms compared to those who had fully recovered.⁹ Major factors contributing to reduced functional capacity included deconditioning and chronotropic incompetence, as well as dysfunctional breathing and reduced peripheral oxygen extraction.⁹

Summary Thoughts and Future Directions

Available reports describing CPET among patients with Long COVID demonstrates that this is a heterogeneous syndrome. However, some general principles are apparent. For example, peak VO₂ is frequently mild-moderately reduced and ventilatory efficiency is either normal or mildly impaired. Some individuals may have dysfunctional breathing (a disorder that is not clearly defined¹¹) but pulmonary function testing is frequently normal. Persistent, severe reductions in diffusing capacity for carbon monoxide (DLCO) are more likely among patients who required mechanical ventilation. Among those with a less-severe index infection, DLCO is typically normal or only mildly impaired.^14-16 Deconditioning has emerged as a central theme and a major contributor to development of symptoms characteristic of this syndrome.¹⁷ However, there may also be abnormalities at other points in the oxygen cascade that, in conjunction with deconditioning, contribute to exercise tolerance.⁹

These findings may inform effective treatment strategies.^3,17 Given the severity of symptoms associated with Long COVID and profound impairments in quality-of-life, effective treatment strategies are essential. Emerging evidence suggests that exercise training, which is highly effective for other populations suffering from deconditioning, such as postural orthostatic tachycardia syndrome¹⁸ and bedrest,¹⁹ is also effective when applied to patients with Long COVID.^3,17 Data derived from CPET analyses in these patients are critical for further developing therapeutic strategies to improve/alleviate symptoms associated with this condition.

References

1. Logue JK, Franko NM, McCulloch DJ, et al. Sequelae in adults at 6 months after COVID-19 infection. JAMA Netw Open 2021;4:e210830.
2. Hayes LD, Ingram J, Sculthorpe NF. More than 100 persistent symptoms of SARS-CoV-2 (Long COVID): a scoping review. Front Med (Lausanne) 2021;8:750378.
3. Gluckman TJ, Bhave NM, Allen LA, et al. 2022 ACC expert consensus decision pathway on cardiovascular sequelae of COVID-19 in adults: myocarditis and other myocardial involvement, post-acute sequelae of SARS-CoV-2 infection, and return to play. J Am Coll Cardiol 2022;79:1717-56.
4. Gaffney FA, Nixon JV, Karlsson ES, Campbell W, Dowdey AB, Blomqvist CG. Cardiovascular deconditioning produced by 20 hours of bedrest with head-down tilt (-5 degrees) in middle-aged healthy men. Am J Cardiol 1985;56:634-38.
5. Levine BD, Zuckerman JH, Pawelczyk JA. Cardiac atrophy after bed-rest deconditioing: a nonneural mechanism for orthostatic intolerance. Circulation 1997;96:517-25.
6. Benarroch EE. "Dysautonomia": a plea for precision. Clin Auton Res 2021;31:27-29.
7. Rinaldo RF, Mondoni M, Parazzini EM, et al. Deconditioning as main mechanism of impaired exercise response in COVID-19 survivors. Eur Respir J 2021;58:2100870.
8. Naeije R, Caravita S. Phenotyping long COVID. Eur Respir J 2021;58:2101763.
9. Durstenfeld MS, Sun K, Tahir P, et al. Use of cardiopulmonary exercise testing to evaluate Long COVID-19 symptoms in adults: a systematic review and meta-analysis. JAMA Netw Open 2022;5:e2236057.
10. Skjorten I, Ankerstjerne OAW, Trebinjac D, et al. Cardiopulmonary exercise capacity and limitations 3 months after COVID-19 hospitalisation. Eur Respir J 2021;58:2100996.
11. Mancini DM, Brunjes DL, Lala A, Trivieri MG, Contreras JP, Natelson BH. Use of cardiopulmonary stress testing for patients with unexplained dyspnea post–coronavirus disease. JACC Heart Fail 2021;9:927-37.
12. Aparisi A, Ybarra-Falcon C, Garcia-Gomez M, et al. Exercise ventilatory inefficiency in post-COVID-19 syndrome: insights from a prospective evaluation. J Clin Med 2021;10:2591.
13. Balady GJ, Arena R, Sietsema K, et al. Clinician's guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation 2010;122:191-225.
14. Cornwell WK III, Levine BD. Altitude Travel Following COVID-19 Infection. http://www.acc.org. Oct 25, 2021. Accessed 10/01/2022. https://www.acc.org/latest-in-cardiology/articles/2021/10/25/13/49/altitude-travel-following-covid-19-infection.
15. Daher A, Balfanz P, Cornelissen C, et al. Follow up of patients with severe coronavirus disease 2019 (COVID-19): pulmonary and extrapulmonary disease sequelae. Respir Med 2020;174:106197.
16. Finney LJ, Doughty R, Lovage S, et al. Lung function deficits and symptom burden in survivors of COVID-19 requiring mechanical ventilation. Ann Am Thorac Soc 2021;18:1740-43.
17. Rudofker E, Parker H, Cornwell WK 3rd. An exercise prescription as a novel management strategy for treatment of Long COVID. JACC Case Rep 2022;4:1344-47.
18. Fu Q, Vangundy TB, Shibata S, Auchus RJ, Williams GH, Levine BD. Exercise training versus propranolol in the treatment of the postural orthostatic tachycardia syndrome. Hypertension 2011;58:167-75.
19. Saltin B, Blomqvist G, Mitchell JH, Johnson RL Jr, Wildenthal K, Chapman CB. Response to exercise after bed rest and after training. Circulation 1968;38:VII1-VII78.

Clinical Topics: Arrhythmias and Clinical EP, COVID-19 Hub, Heart Failure and Cardiomyopathies, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Sports and Exercise Cardiology

Keywords: Activities of Daily Living, Exercise Test, COVID-19, SARS-CoV-2, Pandemics, Pressoreceptors, Dyspnea, Tachycardia, Primary Dysautonomias, Hospitalization, Fatigue, Forced Expiratory Volume, Physical Exertion, Bed Rest

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