Reduced exercise capacity, chronotropic incompetence, early systematic inflammation in cardiopulmonary phenotype Long COVID, 2023, Durstenfeld et al

[Andy]

Preprint.
Inflammation during early post-acute COVID-19 is associated with reduced exercise capacity and Long COVID symptoms after 1 year, 2022, Durstenfeld

Abstract

BACKGROUND Mechanisms 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.

METHODS We 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.

RESULTS Out 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-α) and SARS-CoV-2 antibody levels measured early in PASC were negatively correlated with peak VO2 more than 1 year later.

CONCLUSIONS Cardiopulmonary 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.

https://www.medrxiv.org/content/10.1101/2022.05.17.22275235v2

Now published: see later post for abstract

 

[rvallee]

Chronotropic incompetence was the primary abnormality among

This again. I can't say I understand much of it. But here it is again.

 

[SNT Gatchaman]

Now published as Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID (2023, J Infectious Diseases) and tagged as a major article.

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.

METHODS
We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in a post-COVID cohort, compared those with or without symptoms, and correlated findings with previously measured biomarkers.

RESULTS
Sixty participants (median age 53, 42% female, 87% non-hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted) compared to 3/19 (16%) without symptoms (p = 0.02). Adjusted peak VO2 was 5.2 ml/kg/min lower (95%CI 2.1-8.3; p = 0.001) or 16.9% lower percent predicted (95%CI 4.3-29.6; p = 0.02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias were absent.

CONCLUSIONS
Cardiopulmonary symptoms >1 year following COVID-19 were associated with reduced exercise capacity, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary Long COVID.

 

[SNT Gatchaman]

Open access, some liberal summary quotes on findings and hypotheses —

During clinical stress testing, failure to reach 85% of age-predicted maximum HR without ischemic electrocardiographic changes identifies chronotropic incompetence. With CPET, adjusted HR reserve (AHRR) <80% (which accounts for resting HR), lower than expected exercise capacity, maximal effort, and no other pattern of limitations is more specific for chronotropic incompetence.

Self-reported reduced exercise capacity was not included a priori but was added in sensitivity analyses.

A 5 ml/kg/min decrease in peak VO 2was associated with 2.75 times higher odds of symptoms (95%CI 1.39-5.44; p=0.004). Including EBV reactivation yielded a similar odds ratio (OR 3.04, 95%CI 1.31-6.93; p=0.01).

Among 56 maximal CPETs, 21 (37%) had peak VO2 <85% predicted; no participants had ventilatory limitation, 3 had cardiac limitation, and one had a hypertensive response. Four had findings most consistent with deconditioning/obesity, and one reached 84% predicted with no other abnormalities (possibly deconditioning).

Chronotropic incompetence was highly associated with symptoms (OR 17.6, 95%CI 1.43-216; p=0.03). [...] those with chronotropic incompetence had 49 beats per minute (bpm) lower peak HR (119 bpm vs 170; 95%CI 40-60; p<0.0001). [...] In absolute terms, those with chronotropic incompetence generated a mean peak VO 2 of 1.59 L/min compared to 2.35 L/min among those with normal exercise capacity (difference 0.76 L/min, 95%CI 0.23 to 1.28; p=0.007)

Of 52/56 with EBV antibodies assessed, all 11 individuals with chronotropic incompetence had evidence of EBV reactivation. This is driven by differences in early antigen IgG, a more specific marker of reactivation, with 81% with chronotropic incompetence positive compared to 55% with high nuclear antigen IgG. AHRR is 17% lower among those with early antigen IgG (95% CI 5.6-29.1; p=0.005), but no different by high nuclear antigen IgG (-1.6, 95%CI -14 to 11; p=0.80).

No participants had late gadolinium enhancement suggestive of replacement fibrosis, and markers of inflammation or interstitial fibrosis were not associated with symptoms. Some participants (10/43, 23%) had trace or small pericardial effusions with no difference by symptoms (p=0.59).

Our findings suggest that chronotropic incompetence contributes to exercise limitations in LC. [...] Evidence of EBV reactivation was found in all individuals with chronotropic incompetence. We did not find evidence of myocarditis, cardiac dysfunction, or clinically significant arrhythmias.

 

[SNT Gatchaman]

Animal models suggest inflammatory markers including IL-6 and TNF impair chronotropy and endothelial function. Chronic inflammation in other conditions is associated with adrenergic activation, chronotropic incompetence, and reduced exercise capacity. Reduced β-receptor responsiveness, a prominent feature of chronotropic incompetence, increases adrenergic activation which activates inflammatory pathways. Elevated sympathetic activation at rest occurs after SARSCoV-2 infection and is associated with reduced exercise capacity and vascular dysfunction in PASC. Coronary microvascular dysfunction occurs in early PASC, and endothelial dysfunction is associated with chronotropic incompetence and inflammation. Thus, chronic inflammation and adrenergic activation could blunt chronotropy, vascular function, and exercise capacity without autonomic nervous system or sinus node pathology.

To our knowledge, our study is the first to report evidence of EBV reactivation among those with chronotropic incompetence in PASC, a hypothesis-generating finding that needs replication. EBV reactivation may be associated with PASC, similar to early reports of elevated early antigen IgG in chronic fatigue syndrome/myalgic encephalitis where the role of EBV remains controversial over 3 decades later.

CPETs may appear “normal” in previously athletic individuals even with lifealtering reductions in exercise capacity. "Normal” results may be due to pathologies not detectable with these techniques (e.g., viral persistence, microvascular, mitochondrial, or autonomic dysfunction, or non-cardiopulmonary etiologies). Cardiopulmonary PASC lacks a clear diagnostic signature and even advanced cardiopulmonary testing largely rules out diagnoses that were not present in our cohort.

Although exercise is unlikely to cure LC, exercise training is the only intervention demonstrated to improve exercise capacity in chronotropic incompetence separate from PASC and may improve symptoms and quality of life. [...] Reports of post-exertional malaise or symptom exacerbation in PASC overlapping with myalgic encephalitis/chronic fatigue syndrome mean that exercise-based interventions should be tested rigorously for safety and efficacy.

 

[Hutan]

From your excerpts @SNT Gatchaman, it doesn't look as though they are very aware of the results from repeat CPETS.

The finding of reactivated EBV is interesting, although perhaps it's just a downstream thing. I see that at least two organisations are making progress on an EBV vaccine; I hope it's not long before that is rolled out.

 

[SNT Gatchaman]

it doesn't look as though they are very aware of the results from repeat CPETS.

They are, but I think for this paper they were looking at mechanisms for baseline exertion intolerance, rather than mechanisms that might contribute to PEM. From their prior paper Use of Cardiopulmonary Exercise Testing to Evaluate Long COVID-19 Symptoms in Adults: A Systematic Review and Meta-analysis (2022) —

Careful postexertional symptom assessment, including after CPET and 2-day CPET protocols, may provide insights into PEM in individuals with LC symptoms. Correlative data with autonomical testing may provide mechanistic insights.

 

[marcjr]

How many times are they planning to repeat these same old CPET/ICPET studies that always return the same results? Isn't research supposed to be incremental?

 

[SNT Gatchaman]

How many times are they planning to repeat these same old CPET/ICPET studies that always return the same results? Isn't research supposed to be incremental?

To our knowledge, our study is the first to report evidence of EBV reactivation among those with chronotropic incompetence in PASC, a hypothesis-generating finding that needs replication.

 

[SNT Gatchaman]

See also Orthostatic chronotropic incompetence in patients with myalgic encephalomyelitis/chronic fatigue syndrome ME/CFS (2023)
and Orthostatic Intolerance and Chronotropic Incompetence in Patients With Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (2023)

ETA

and Chronotropic incompetence an overlooked determinant of symptoms and activity limitation in ME/CFS (2019, Frontiers in Pediatrics)
and Chronotropic Incompetence (2011, Circulation) as noted in that 2019 thread by @Snow Leopard.

 

[Tom Kindlon]

Free fulltext:
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiad131/7159960

JOURNAL ARTICLE ACCEPTED MANUSCRIPT

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

Matthew S Durstenfeld, Michael J Peluso, Punita Kaveti, Christopher Hill, Danny Li, Erica Sander, Shreya Swaminathan, Victor M Arechiga, Scott Lu, Sarah A Goldberg,
Rebecca Hoh, Ahmed Chenna, Brandon C Yee, John W Winslow, Christos J Petropoulos, J Daniel Kelly, David V Glidden, Timothy J Henrich, Jeffrey N Martin, Yoo Jin Lee, Mandar A Aras, Carlin S Long, Donald J Grandis, Steven G Deeks, Priscilla Y Hsue



The Journal of Infectious Diseases, jiad131, https://doi.org/10.1093/infdis/jiad131

Published:

11 May 2023




Abstract
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.

METHODS
We conducted cardiopulmonary exercise testing (CPET), cardiac magnetic resonance imaging (CMR) and ambulatory rhythm monitoring among adults > 1 year after confirmed SARS-CoV-2 infection in a post-COVID cohort, compared those with or without symptoms, and correlated findings with previously measured biomarkers.

RESULTS
Sixty participants (median age 53, 42% female, 87% non-hospitalized) were studied at median 17.6 months following SARS-CoV-2 infection. On CPET, 18/37 (49%) with symptoms had reduced exercise capacity (<85% predicted) compared to 3/19 (16%) without symptoms (p = 0.02). Adjusted peak VO2 was 5.2 ml/kg/min lower (95%CI 2.1-8.3; p = 0.001) or 16.9% lower percent predicted (95%CI 4.3-29.6; p = 0.02) among those with symptoms. Chronotropic incompetence was common. Inflammatory markers and antibody levels early in PASC were negatively correlated with peak VO2 more than 1 year later. Late-gadolinium enhancement on CMR and arrhythmias were absent.

CONCLUSIONS
Cardiopulmonary symptoms >1 year following COVID-19 were associated with reduced exercise capacity, which was associated with elevated inflammatory markers early in PASC. Chronotropic incompetence may explain exercise intolerance among some with cardiopulmonary Long COVID.

 

[Hutan]

I started, but realised I'm not up to looking properly into this today. But this interesting study does warrant careful consideration. Not just the CPET results, there's a lot of interesting positive and negative results.

On the blood testing:
(There's a copyright statement on the preprint, so I can't copy the charts.)
hsCPR, IL6, TNF-a
There are very persuasive linear negative relationships between the natural log of these measured around 6 months (3 to 9 months) after a Covid-19 infection and peak VO2 measured later.

A fairly small study, and the mixture of issues that make up Long Covid may be confounding things, but I'd definitely like to see replications of the investigations in larger samples.