RESUMO
BACKGROUNDMechanisms underlying persistent cardiopulmonary symptoms following SARS-CoV-2 infection (post-acute sequelae of COVID-19 "PASC" or "Long COVID") remain unclear. The purpose of this study was to elucidate the pathophysiology of cardiopulmonary PASC using multimodality cardiovascular imaging including cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring. METHODSWe performed CMR, CPET, and ambulatory rhythm monitoring among adults > 1 year after PCR-confirmed SARS-CoV-2 infection in the UCSF Long-Term Impact of Infection with Novel Coronavirus cohort (LIINC; NCT04362150) and correlated findings with previously measured biomarkers. We used logistic regression to estimate associations with PASC symptoms (dyspnea, chest pain, palpitations, and fatigue) adjusted for confounders and linear regression to estimate differences between those with and without symptoms adjusted for confounders. RESULTSOut of 120 participants in the cohort, 46 participants (unselected for symptom status) had at least one advanced cardiac test performed at median 17 months following initial SARS-CoV-2 infection. Median age was 52 (IQR 42-61), 18 (39%) were female, and 6 (13%) were hospitalized for severe acute infection. On CMR (n=39), higher extracellular volume was associated with symptoms, but no evidence of late-gadolinium enhancement or differences in T1 or T2 mapping were demonstrated. We did not find arrhythmias on ambulatory monitoring. In contrast, on CPET (n=39), 13/23 (57%) with cardiopulmonary symptoms or fatigue had reduced exercise capacity (peak VO2<85% predicted) compared to 2/16 (13%) without symptoms (p=0.008). The adjusted difference in peak VO2 was 5.9 ml/kg/min lower (-9.6 to -2.3; p=0.002) or -21% predicted (-35 to -7; p=0.006) among those with symptoms. Chronotropic incompetence was the primary abnormality among 9/15 (60%) with reduced peak VO2. Adjusted heart rate reserve <80% was associated with reduced exercise capacity (OR 15.6, 95%CI 1.30-187; p=0.03). Inflammatory markers (hsCRP, IL-6, TNF-) and SARS-CoV-2 antibody levels measured early in PASC were negatively correlated with peak VO2 more than 1 year later. CONCLUSIONSCardiopulmonary symptoms and elevated inflammatory markers present early in PASC are associated with objectively reduced exercise capacity measured on cardiopulmonary exercise testing more than 1 year following COVID-19. Chronotropic incompetence may explain reduced exercise capacity among some individuals with PASC. Clinical PerspectiveWhat is New? O_LIElevated inflammatory markers in early post-acute COVID-19 are associated with reduced exercise capacity more than 1 year later. C_LIO_LIImpaired chronotropic response to exercise is associated with reduced exercise capacity and cardiopulmonary symptoms more than 1 year after SARS-CoV-2 infection. C_LIO_LIFindings on ambulatory rhythm monitoring point to perturbed autonomic function, while cardiac MRI findings argue against myocardial dysfunction and myocarditis. C_LI Clinical ImplicationsO_LICardiopulmonary testing to identify etiologies of persistent symptoms in post-acute sequalae of COVID-19 or "Long COVID" should be performed in a manner that allows for assessment of heart rate response to exercise. C_LIO_LITherapeutic trials of anti-inflammatory and exercise strategies in PASC are urgently needed and should include assessment of symptoms and objective testing with cardiopulmonary exercise testing. C_LI
RESUMO
BACKGROUNDShortness of breath, chest pain, and palpitations occur as post-acute sequelae of COVID-19 (PASC), but whether symptoms are associated with echocardiographic abnormalities, cardiac biomarkers, or markers of systemic inflammation remains unknown. METHODSIn a cross-sectional analysis, we assessed symptoms, performed echocardiograms, and measured biomarkers among adults >8 weeks after PCR-confirmed SARS-CoV-2 infection. We modeled associations between symptoms and baseline characteristics, echocardiographic findings, and biomarkers using logistic regression. RESULTSWe enrolled 102 participants at a median 7.2 months (IQR 4.1-9.1) following COVID-19 onset; 47 individuals reported dyspnea, chest pain, or palpitations. Median age was 52 years (range 24-86) and 41% were women. Female sex (OR 2.55, 95%CI 1.13-5.74) and hospitalization during acute infection (OR 3.25, 95%CI 1.08-9.82) were associated with symptoms. IgG antibody to SARS-CoV-2 receptor binding domain (OR 1.38 per doubling, 95%CI 1.38-1.84) and high-sensitivity C-reactive protein (OR 1.31 per doubling, 95%CI 1.00-1.71) were associated with symptoms. Regarding echocardiographic findings, 4/47 (9%) with symptoms had pericardial effusions compared to 0/55 without symptoms (p=0.038); those with pericardial effusions had a median 4 symptoms compared to 1 without (p<0.001). There was no strong evidence for a relationship between symptoms and echocardiographic functional parameters (including left ventricular ejection fraction and strain, right ventricular strain, pulmonary artery pressure) or high-sensitivity troponin, NT-pro-BNP, interleukin-10, interferon-gamma, or tumor necrosis factor-alpha. CONCLUSIONSAmong adults in the post-acute phase of SARS-CoV-2 infection, SARS-CoV-2 RBD antibodies, markers of inflammation and, possibly, pericardial effusions are associated with cardiopulmonary symptoms. Investigation into inflammation as a mechanism underlying PASC is warranted. FUNDINGThis work was supported by the UCSF Division of Cardiology at Zuckerberg San Francisco General, and the National Institutes of Health/National Heart Lung Blood Institute and National Institute of Allergy and Infectious Diseases. MSD is supported by NIH 5K12HL143961. MJP is supported on NIH T32 AI60530-12. JDK is supported by NIH K23AI135037. TJH is supported by NIH/NIAID 3R01A1141003-03S1. PYH is supported by NIH/NAID 2K24AI112393-06. This publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through UCSF-CTSI Grant Number UL1TR001872. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=169 HEIGHT=200 SRC="FIGDIR/small/21266834v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@7b2424org.highwire.dtl.DTLVardef@81d995org.highwire.dtl.DTLVardef@f3d6e5org.highwire.dtl.DTLVardef@a19373_HPS_FORMAT_FIGEXP M_FIG C_FIG
