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

Abstract

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.METHODSIn the Long-Term Impact of Infection with Novel Coronavirus (LIINC) Cohort, we performed CMR, CPET, and ambulatory rhythm monitoring among adults > 1 year after PCR-confirmed SARS-CoV-2 infection. We used logistic and linear regression to compare those with and without cardiopulmonary symptoms (dyspnea, chest pain, palpitations) adjusting for confounders.RESULTSOne hundred twenty individuals were studied, among whom 46 participants (unselected for symptom status) had at least one advanced test performed at median 17 months (IQR 15-18). Median age was 52 (IQR 42-61), 18 (39%) were female, and 6 (13%) were hospitalized for severe acute infection. On CMR (n=39), smaller RV volume and stroke volume and higher extracellular volume were present among those 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), 13/15 (87%) participants with reduced exercise capacity (<85% predicted) reported cardiopulmonary symptoms or fatigue (p=0.008). Adjusted peak VO2 was 2.7 ml/kg/min lower among those with cardiopulmonary symptoms (95%CI −6.9 to 1.5; p=0.20) or −11% predicted (95%CI −27 to 5, p=0.17). Including fatigue along with cardiopulmonary symptoms, the adjusted difference in peak VO2 was −5.9 ml/kg/min (−9.6 to −2.3; p=0.002) or −21% predicted (−35 to −7; p=0.006). Chronotropic incompetence was the primary abnormality among 9/15 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). Those with chronotropic incompetence had higher hsCRP, lower heart rate recovery, and lower heart rate variability suggestive of autonomic dysfunction.CONCLUSIONSReduced exercise capacity and reduced heart rate response to exercise, and hsCRP are associated with persistent cardiopulmonary symptoms more than 1 year following COVID-19. Chronic inflammation and autonomic dysfunction may underlie cardiopulmonary PASC.Clinical PerspectiveWhat is New?Impaired chronotropic response to exercise is associated with reduced exercise capacity and cardiopulmonary symptoms more than 1 year after SARS-CoV-2 infection.Findings on ambulatory rhythm monitoring point to perturbed autonomic function, while cardiac MRIfindings argue against myocardial dysfunction and myocarditis.Clinical ImplicationsCardiopulmonary 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.Therapeutic trials of antiviral, anti-inflammatory, and exercise strategies in PASC are urgently needed and should include assessment of symptoms and objective testing with cardiopulmonary exercise testing.

Impact of Pre-Existing Chronic Viral Infection and Reactivation on the Development of Long COVID

“…We and others have previously reported associations between several of these markers ( e.g . IL-6, TNFα) and LC symptoms (Durstenfeld et al, 2022a, 2022b; Peluso et al, 2021a, 2022a; Phetsouphanh et al, 2022). The lack of association between EBV serology and these markers suggest that there are additional important etiological factors driving PASC and LC symptoms that are not directly related to EBV reactivation.…”

Cardiopulmonary exercise testing to evaluate post-acute sequelae of COVID-19 (“Long COVID”): a systematic review and meta-analysis

“…Most studies performed CPET 3-6 months after infection; only one study investigated individuals > 1 year after infection. 25 Nearly half of the studies (16/39, 41%) only included hospitalized individuals (median 73% hospitalized, range 0-100%), and most predominantly included symptomatic individuals (median 89% symptomatic, range 38-100%).…”

“…27,58,60 Cardiac limitations were uncommon, but Mancini reported attenuations in preload augmentation 52 and Brown and Szekely reported reduced stroke volume augmentation. 30,33 Five studies reported chronotropic incompetence to be a major cause of reduced exercise capacity, 25,30,44,63,64 and most studies reported a lower peak heart rate among individuals with reduced exercise capacity. One study each specifically reported pulmonary fibrosis, 65 pulmonary vascular limitation, 66 impaired microcirculation, 61 endothelial dysfunction, 67 dysautonomia, 64 and loss of mechanical efficiency 28 as the primary etiology of reduced exercise capacity.…”

“…Only two studies (including our own) presented an adjusted difference in peak VO 2 between those with and without LC. 25,45…”

“…Only two studies (including our own) presented an adjusted difference in peak VO2 between those with and without LC. 25,45 Therefore, our confidence in the meta-analysis effect estimate of SARS-CoV-2 on exercise capacity is low. Our estimate likely exaggerates the true average causal effect, but the studies provide evidence that exercise capacity is reduced 3-6 months after hospitalization for COVID-19 and in LC compared to healthy controls.…”