Tag: exercise intolerance

Physiological underpinnings of long COVID: what have we learned?

In a review, Batta et al 2 , addressed the cardiovascular symptoms in COVID-19 patients with a focus on vascular dysfunction, arrhythmias, myocardial ischemia, and discussed the most updated recommendations for the treatment of COVID-19. We previously reported the presence of almost all the receptors of SARS-CoV-2 on cardiomyocytes which makes the heart a favorable target for this virus 3 . Batta et al 2 indicated that the vascular endothelial dysfunction is involved in the pathogenesis of SARS-CoV-2 and hence the activation of pro-inflammatory cytokines leading to increased vascular permeability and thrombosis in many organs.

Tachycardia was the most common cardiac presentation associated with SARS-CoV-2 infection, along with arrhythmias and conduction blocks, myocardial ischemia and injury, and hypertension. Interestingly, the authors reported that the elevated ACE-2 expression on endothelial cells of COVID -19 patients’ lungs indicates an elevated pro-hypertensive angiotensin II level leading to vasoconstriction and aldosterone-driven hypervolemia. Thus, the use of renin-angiotensin-aldosterone inhibitors in hypertension treatment of patients infected with SARS-CoV-2 was cautioned to avoid exacerbated cardiovascular clinical outcome.

An article from Gonzalez-Gonzalez et al. 4 reviewed the application of Virchow’s Triad in detail for the risk of developing stroke and related intravascular thrombotic diseases in the context of COVID-19 infection. The authors discussed each part of Virchow’s triad in detail, such as hypercoagulable state, vascular damage, and intravascular stasis of blood. They looked into literature on the effects of COVID-19 infection for the formation of intravascular and intracardiac clots (leading to stroke), formation of cardiac sequelae and autopsy studies reporting elevated markers in ventricular myocardium. The authors reviewed the risk factor for stroke development, differences between ischemic vs haemorrhagic stroke and frequent complications of COVID-19 patients such as pulmonary embolism. The authors also discussed the current treatment plans and recommended some differential treatment approaches for COVID-19 infection patients concerning known mechanisms of Virchow’s triad. Finally, the authors discussed the outcomes and long-term consequences of COVID-19 infection and the cardiovascular effects of COVID-19 vaccines.

The work from A. Mujalli and co-workers 5 investigated genetic pathways in patients with severe COVID-19 and comorbidities, by means of genome-wide transcriptomic datasets publicly available within the first year of the pandemic. Differential gene expression (DGE), gene ontology (GO), pathway enrichment, functional similarity, phenotypic analysis and drug target identification studies were conducted using a cohort of 120 COVID-19 patients, 281 patients with chronic comorbidities (153 CVD, 64 atherosclerosis, 33 diabetes, and 31 obesity), and 252 patients with different infectious diseases (145 respiratory syncytial virus, 95 influenza, and 12 MERS). In total, 29 genes were identified to contributing to the clinical severity of COVID-19 infection in patients with comorbidities. Remarkably, identified genes were found to be involved in immune cell homeostasis during innate immunity, mostly in monocyte and macrophage function. In addition, results from drug target identification studies show a mismatch between the currently used drugs in COVID-19 therapy and predicted drugs against identified genes.

Furtheremore, in this issue of the Journal, Chan et al 6 examined the association of COVID-19 with heart rate (HR) and blood pressure (BP) variability during exercise in a cohort of 18 patients with prior COVID-19 infection (equally split between symptomatic and asymptomatic), and a cohort of 9 controls who were never infected with COVID-19. Using a rigorous experimental design, the investigators measured HR and BP at regular intervals before, during, and after submaximal exercise, and quantified HR and BP variability on time and frequency domains. Baseline HR and BP were not significantly different between groups (symptomatic vs. asymptomatic vs. controls), nor were they different after completing a bout of submaximal exercise at a comparable workload. However, HR and BP variability was blunted only in individuals with prior symptomatic COVID-19 infection, but not in controls or those with a prior asymptomatic infection, suggesting an underlying degree of autonomic nervous system dysfunction in affected individuals.

The authors are to be lauded for their elegant and clinically relevant work, despite the obvious limitation of small sample size, since it provides much needed insight into COVID-19-induced abnormalities in cardiac physiology. The current findings provide a potential explanation for exercise intolerance, a frequently reported long-term symptom among survivors of COVID-19, since blunting of HR and BP variability are markers of impaired parasympathetic nervous system and poor cardiovascular health.In conclusion, the COVID-19 pandemic affected millions around the globe before it started abating with the advent of the emergent vaccines that were approved for use on emergency basis.

The WHO declared the end of the pandemic after three years of its surge. While millions succumbed to this deadly respiratory infection, survivors from this illness, particularity those who were severely sick, are reporting cardiac and nervous abnormalities. We hope that this series provides a new perspectives on the manifestations of COVID-19 in the heart, the brain, and the vasculature with the hope to guide therapeutic interventions for patients suffering from long term sequelae of SARS-CoV-2 infection.

Source: Moni Nader1, Georges E. Haddad, Jacobo Elies, Sriharsha Kantamneni and Firas Albadarin. Physiological underpinnings of long COVID: what have we learned? Front. Physiol. Sec. Clinical and Translational Physiology. Volume 14 – 2023 | doi: 10.3389/fphys.2023.122455 https://www.frontiersin.org/articles/10.3389/fphys.2023.1224550/full (Full text)

Cardiopulmonary testing in long COVID-19 versus non-COVID-19 patients with undifferentiated Dyspnea on exertion

Abstract:

Background: Dyspnea and fatigue are characteristics of long SARS-CoV-2 (COVID)-19. Cardiopulmonary exercise testing (CPET) can be used to better evaluate such patients.

Research question: How significantly and by what mechanisms is exercise capacity impaired in patients with long COVID who are coming to a specialized clinic for evaluation?

Study design and methods: We performed a cohort study using the Mayo Clinic exercise testing database. Subjects included consecutive long COVID patients without prior history of heart or lung disease sent from the Post-COVID Care Clinic for CPET. They were compared to a historical group of non-COVID patients with undifferentiated dyspnea also without known cardiac or pulmonary disease. Statistical comparisons were performed by t-test or Pearson’s chi2 test controlling for age, sex, and beta blocker use where appropriate.

Results: We found 77 patients with long COVID and 766 control patients. Long COVID patients were younger (47 ± 15 vs 50 ± 10 years, P < .01) and more likely female (70% vs 58%, P < .01). The most prominent difference on CPETs was lower percent predicted peak V̇O2 (73 ± 18 vs 85 ± 23%, p < .0001). Autonomic abnormalities (resting tachycardia, CNS changes, low systolic blood pressure) were seen during CPET more commonly in long COVID patients (34 vs 23%, P < .04), while mild pulmonary abnormalities (mild desaturation, limited breathing reserve, elevated V̇E/V̇CO2) during CPET were similar (19% in both groups) with only 1 long COVID patient showing severe impairment.

Interpretation: We identified severe exercise limitation among long COVID patients. Young women may be at higher risk for these complications. Though mild pulmonary and autonomic impairment were common in long COVID patients, marked limitations were uncommon. We hope our observations help to untangle the physiologic abnormalities responsible for the symptomatology of long COVID.

Source: Contreras AM, Newman DB, Cappelloni L, Niven AS, Mueller MR, Ganesh R, Squires RW, Bonikowske AR, Allison TG. Cardiopulmonary testing in long COVID-19 versus non-COVID-19 patients with undifferentiated Dyspnea on exertion. Prog Cardiovasc Dis. 2023 May 19:S0033-0620(23)00053-1. doi: 10.1016/j.pcad.2023.05.005. Epub ahead of print. PMID: 37211198; PMCID: PMC10198738. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10198738/ (Full text)

Musculoskeletal involvement: COVID-19 and post COVID 19

Abstract:

The worldwide pandemic of coronavirus disease 2019 (COVID-19) was known to predominantly affect the lungs, but it was realized that COVID-19 had a large variety of clinical involvement. Cardiovascular, gastrointestinal, neurological, and musculoskeletal systems are involved by direct or indirect mechanisms with various manifestations.

The musculoskeletal involvement can manifest during COVID-19 infection, due to medications used for the treatment of COVID-19, and in the post/long COVID-19 syndrome. The major symptoms are fatigue, myalgia/arthralgia, back pain, low back pain, and chest pain. During the last two years, musculoskeletal involvement increased, but no clear consensus was obtained about the pathogenesis. However, there is valuable data that supports the hypothesis of angiotensinconverting enzyme 2, inflammation, hypoxia, and muscle catabolism. Additionally, medications that were used for treatment also have musculoskeletal adverse effects, such as corticosteroid-induced myopathy and osteoporosis. Therefore, while deciding the drugs, priorities and benefits should be taken into consideration.

Symptoms that begin three months from the onset of the COVID-19 infection, continue for at least two months, and cannot be explained by another diagnosis is accepted as post/long COVID-19 syndrome. Prior symptoms may persist and fluctuate, or new symptoms may manifest. In addition, there must be at least one symptom of infection. Most common musculoskeletal symptoms are myalgia, arthralgia, fatigue, back pain, muscle weakness, sarcopenia, impaired exercise capacity, and physical performance. In addition, the female sex, obesity, elderly patients, hospitalization, prolonged immobility, having mechanical ventilation, not having vaccination, and comorbid disorders can be accepted as clinical predictors for post/long COVID-19 syndrome.

Musculoskeletal pain is also a major problem and tends to be in chronic form. There is no consensus on the mechanism, but inflammation and angiotensin-converting enzyme 2 seem to play an important role. Localized and generalized pain may occur after COVID-19, and general pain is at least as common as localized pain. An accurate diagnosis allows physicians to initiate pain management and proper rehabilitation programs.

Source: Evcik D. Musculoskeletal involvement: COVID-19 and post COVID 19. Turk J Phys Med Rehabil. 2023 Feb 28;69(1):1-7. doi: 10.5606/tftrd.2023.12521. PMID: 37201006; PMCID: PMC10186015.

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

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.

Source: Durstenfeld MS, Peluso MJ, Kaveti P, Hill C, Li D, Sander E, Swaminathan S, Arechiga VM, Lu S, Goldberg SA, Hoh R, Chenna A, Yee BC, Winslow JW, Petropoulos CJ, Kelly JD, Glidden DV, Henrich TJ, Martin JN, Lee YJ, Aras MA, Long CS, Grandis DJ, Deeks SG, Hsue PY. Reduced exercise capacity, chronotropic incompetence, and early systemic inflammation in cardiopulmonary phenotype Long COVID. J Infect Dis. 2023 May 11:jiad131. doi: 10.1093/infdis/jiad131. Epub ahead of print. PMID: 37166076. https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiad131/7159960 (Full text available as PDF file)

Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation

Abstract:

Abstract available online: https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

Source: S. Jothi, G. Claessen, M. Insel, S. Kubba, E. Howden, S.-R. Carmona, F.P. Rischard. Post-acute Sequelae of SARS Co-V2 and Chronic Fatigue/Myalgic Encephalitis Share Similar Pathophysiologic Mechanisms of Exercise Limitation. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A6470

Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome

Abstract:

Approximately 50% of patients who recover from the acute SARS-CoV-2 experience Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. The pathophysiological hallmark of PASC is characterized by impaired system oxygen extraction (EO2) on invasive cardiopulmonary exercise test (iCPET). However, the mechanistic insights into impaired EO2 remain unclear.

We studied 21 consecutive iCPET in PASC patients with unexplained exertional intolerance. PASC patients were dichotomized into mildly reduced (EO2peak-mild) and severely reduced (EO2peak-severe) EO2 groups according to the median peak EO2 value. Proteomic profiling was performed on mixed venous blood plasma obtained at peak exercise during iCPET.

PASC patients as a group exhibited depressed peak exercise aerobic capacity (peak VO2; 85 ± 18 vs. 131 ± 45% predicted; p = 0.0002) with normal systemic oxygen delivery, DO2 (37 ± 9 vs. 42 ± 15 mL/kg/min; p = 0.43) and reduced EO2 (0.4 ± 0.1 vs. 0.8 ± 0.1; p < 0.0001). PASC patients with EO2peak-mild exhibited greater DO2 compared to those with EO2peak-severe [42.9 (34.2-41.2) vs. 32.1 (26.8-38.0) mL/kg/min; p = 0.01]. The proteins with increased expression in the EO2peak-severe group were involved in inflammatory and fibrotic processes. In the EO2peak-mild group, proteins associated with oxidative phosphorylation and glycogen metabolism were elevated.

In PASC patients with impaired EO2, there exist a spectrum of PASC phenotype related to differential aberrant protein expression and cardio-pulmonary physiologic response. PASC patients with EO2peak-severe exhibit a maladaptive physiologic and proteomic signature consistent with persistent inflammatory state and endothelial dysfunction, while in the EO2peak-mild group, there is enhanced expression of proteins involved in oxidative phosphorylation-mediated ATP synthesis along with an enhanced cardiopulmonary physiological response.

Source: Singh I, Leitner BP, Wang Y, Zhang H, Joseph P, Lutchmansingh DD, Gulati M, Possick JD, Damsky W, Hwa J, Heerdt PM, Chun HJ. Proteomic profiling demonstrates inflammatory and endotheliopathy signatures associated with impaired cardiopulmonary exercise hemodynamic profile in Post Acute Sequelae of SARS-CoV-2 infection (PASC) syndrome. Pulm Circ. 2023 Apr 1;13(2):e12220. doi: 10.1002/pul2.12220. PMID: 37091121; PMCID: PMC10113513. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10113513/ (Full text)

Exercise Intolerance Associated with Impaired Oxygen Extraction in Patients with Long COVID

Abstract:

Objective: Chronic mental and physical fatigue and post-exertional malaise are the more debilitating symptoms of long COVID-19. The study objective was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies. Exercise capacity data of patients referred for a cardiopulmonary exercise test (CPET) and included in a COVID-19 Survivorship Registry at one urban health center were retrospectively analyzed.

Results: Most subjects did not meet normative criteria for a maximal test, consistent with suboptimal effort and early exercise termination. Mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced, supporting impaired energy metabolism as a mechanism of exercise intolerance in long COVID, n=59. We further identified blunted rise in heart rate peak during maximal CPET. Our preliminary analyses support therapies that optimize bioenergetics and improve oxygen utilization for treating long COVID-19.

Source: Norweg A, Yao L, Barbuto S, Nordvig AS, Tarpey T, Collins E, Whiteson J, Sweeney G, Haas F, Leddy J. Exercise Intolerance Associated with Impaired Oxygen Extraction in Patients with Long COVID. Respir Physiol Neurobiol. 2023 Apr 17;313:104062. doi: 10.1016/j.resp.2023.104062. Epub ahead of print. PMID: 37076024; PMCID: PMC10108551. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10108551/ (Full text)

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not?

Abstract:

Topic importance: Post-Acute Sequelae of SARS-CoV-2 (PASC) is a long-term consequence of acute infection from coronavirus disease 2019 (COVID-19). Clinical overlap between PASC and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has been observed, with shared symptoms including intractable fatigue, postexertional malaise, and orthostatic intolerance. The mechanistic underpinnings of such symptoms are poorly understood.

Review findings: Early studies suggest deconditioning as the primary explanation for exertional intolerance in PASC. Cardiopulmonary exercise testing (CPET) reveals perturbations related to systemic blood flow and ventilatory control associated with acute exercise intolerance in PASC, which are not typical of simple detraining. Hemodynamic and gas exchange derangements in PASC have substantial overlap with those observed with ME/CFS, suggestive of shared mechanisms.

Summary: This review aims to illustrate exercise pathophysiologic commonalities between PASC and ME/CFS that will help guide future diagnostics and treatment.

Source: Joseph P, Singh I, Oliveira R, Capone CA, Mullen MP, Cook DB, Stovall MC, Squires J, Madsen K, Waxman AB, Systrom DM. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of SARS-CoV-2: More in Common Than Not? Chest. 2023 Apr 11:S0012-3692(23)00502-0. doi: 10.1016/j.chest.2023.03.049. Epub ahead of print. PMID: 37054777; PMCID: PMC10088277. https://pubmed.ncbi.nlm.nih.gov/37054777/

Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome

Abstract:

Primary mitochondrial myopathies (PMM) are a clinically and genetically highly heterogeneous group that, in some cases, may manifest exclusively as fatigue and exercise intolerance, with minimal or no signs on examination. On these occasions, the symptoms can be confused with the much more common chronic fatigue syndrome (CFS).
Nonetheless, other possibilities must be excluded for the final diagnosis of CFS, with PMM being one of the primary differential diagnoses. For this reason, many patients with CFS undergo extensive studies, including extensive genetic testing and muscle biopsies, to rule out this possibility.
This study evaluated the diagnostic performance of growth differentiation factor-15 (GDF-15) as a potential biomarker to distinguish which patient with chronic fatigue has a mitochondrial disorder. We studied 34 adult patients with symptoms of fatigue and exercise intolerance with a definitive diagnosis of PMM (7), CFS (22), or other non-mitochondrial disorders (5).
The results indicate that GDF-15 can accurately discriminate between patients with PMM and CFS (AUC = 0.95) and between PMM and patients with fatigue due to other non-mitochondrial disorders (AUC = 0.94). Therefore, GDF-15 emerges as a promising biomarker to select which patients with fatigue should undergo further studies to exclude mitochondrial disease.
Source: Bermejo-Guerrero L, de Fuenmayor-Fernández de la Hoz CP, Guerrero-Molina MP, Martín-Jiménez P, Blázquez A, Serrano-Lorenzo P, Lora D, Morales-Conejo M, González-Martínez I, López-Jiménez EA, Martín MA, Domínguez-González C. Serum GDF-15 Levels Accurately Differentiate Patients with Primary Mitochondrial Myopathy, Manifesting with Exercise Intolerance and Fatigue, from Patients with Chronic Fatigue Syndrome. Journal of Clinical Medicine. 2023; 12(6):2435. https://doi.org/10.3390/jcm12062435 (Full text)

Left atrial longitudinal strain analysis in long Covid-19 syndrome

Abstract:

It is known that during the active course of Coronavirus disease 2019 (COVID-19), myocardial injury has an established pathological base, while its myocardial injury post-recovery is still obscured.

The aim of this study was to evaluate the longitudinal left atrial strain (LAS) using speckle tracking echocardiography (STE) in COVID-19-recovered patients who are previously healthy without confounder comorbidities to detect the potential cardiac dysfunction. 200 patients were prospectively included and examined 4?12 weeks after recovery from COVID-19 infection. 137 participants with comorbidities or previous history of cardiopulmonary disease were excluded from the analysis. A total of 63 patients who fulfilled our inclusion criteria were recruited into two groups according to the presence or absence of persistent dyspnoea and exercise intolerance. Clinical, laboratory & comprehensive echocardiographic examinations were done for all.

We observed that 31.7% of the previously healthy individuals developed dyspnoea & exercise intolerance post-COVID-19 infection. There were significantly impaired LAS parameters in the symptomatic group (LA reservoir, contraction & conduit strain, 22.7%, -6.6% & -16.1% versus 40%, -12%, and ? 27% in the asymptomatic group with P < 0.000).

Only LA reservoir strain and LA stiffness can independently predict the development of dyspnoea & exercise intolerance post-COVID-19 at cut-off values of 30% & 24.5% respectively with a sensitivity of 90% and a specificity of 91%, P < 0.001. These impaired LAS parameters could explain the developed symptoms post-COVID-19 recovery, even before disturbed conventional diastolic echocardiographic parameters. LAS parameters are significantly associated with the developed exertional dyspnoea & exercise intolerance post-COVID-19. LA reservoir strain & LA stiffness could provide a simple, easily available tool that points to early LV diastolic dysfunction and may direct the therapy in this subset of the population.

Source: ZeinElabdeen SG, Sherif A, Kandil NT, Altabib AMO, Abdelrashid MA. Left atrial longitudinal strain analysis in long Covid-19 syndrome. Int J Cardiovasc Imaging. 2023 Feb 14:1–6. doi: 10.1007/s10554-023-02801-5. Epub ahead of print. PMID: 36786877; PMCID: PMC9927057. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9927057/ (Full text)