Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID

medRxiv. 2023 Mar 21;2022.05.17.22275235. doi: 10.1101/2022.05.17.22275235. Preprint


Background: Mechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 "PASC" or "Long COVID") remain unclear. This study sought to elucidate mechanisms of cardiopulmonary symptoms and reduced exercise capacity using advanced cardiac testing.

Methods: We performed cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in Long-Term Impact of Infection with Novel Coronavirus cohort (LIINC; substudy of NCT04362150 ). Adults who completed a research echocardiogram (at a median 6 months after SARS-CoV-2 infection) without evidence of heart failure or pulmonary hypertension were asked to complete additional cardiopulmonary testing approximately 1 year later. Although participants were recruited as a prospective cohort, to account for selection bias, the primary analyses were as a case-control study comparing those with and without persistent cardiopulmonary symptoms. We also correlated findings with previously measured biomarkers. We used logistic regression and linear regression models to adjust for potential confounders including age, sex, body mass index, time since SARS-CoV-2 infection, and hospitalization for acute SARS-CoV-2 infection, with sensitivity analyses adjusting for medical history.

Results: Sixty participants (unselected for symptoms, median age 53, 42% female, 87% non- hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On maximal CPET, 18/37 (49%) with symptoms had reduced exercise capacity (peak VO 2 <85% predicted) compared to 3/19 (16%) without symptoms (p=0.02). The adjusted peak VO 2 was 5.2 ml/kg/min (95%CI 2.1-8.3; p=0.001) or 16.9% lower actual compared to predicted (95%CI 4.3- 29.6; p=0.02) among those with symptoms compared to those without symptoms. Chronotropic incompetence was present among 12/21 (57%) with reduced VO 2 including 11/37 (30%) with symptoms and 1/19 (5%) without (p=0.04). Inflammatory markers (hsCRP, IL-6, TNF-α) and SARS-CoV-2 antibody levels measured early in PASC were negatively correlated with peak VO 2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias on ambulatory monitoring were not present.

Conclusions: We found evidence of objectively reduced exercise capacity among those with cardiopulmonary symptoms more than 1 year following COVID-19, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary phenotype Long COVID.

Key points: Long COVID symptoms were associated with reduced exercise capacity on cardiopulmonary exercise testing more than 1 year after SARS-CoV-2 infection. The most common abnormal finding was chronotropic incompetence. Reduced exercise capacity was associated with early elevations in inflammatory markers.

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