Tag: preload

Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Introduction: Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are relatively common and disabling multisystem disorders that share overlapping features, including post-infectious onset and similar clinical manifestations such as brain fog, fatigue, muscle pain, and dysautonomia with orthostatic intolerance. These similarities suggest that Long COVID and ME/CFS may share common pathophysiological mechanisms, though the underlying mechanisms remain poorly understood, partly due to the difficulty in quantifying many of the symptoms.

Materials and methods: This retrospective study evaluated Long COVID and pre-COVID ME/CFS patients who completed autonomic testing between 2018 and 2023 at the Brigham and Women’s Faulkner Hospital Autonomic Laboratory. The evaluations included autonomic tests (Valsalva maneuver, deep breathing, tilt-table test, and sudomotor function) with capnography and transcranial Doppler monitoring of cerebral blood flow velocity (CBFv) in the middle cerebral artery, neuropathic assessment through skin biopsies for small fiber neuropathy (SFN), invasive cardiopulmonary exercise testing (ICPET), and laboratory analyses covering metabolic, inflammatory, autoimmune, and hormonal profiles.

Results: A total of 143 Long COVID and 170 ME/CFS patients were analyzed and compared to 73 healthy controls and 290 patients with hypermobile Ehlers-Danlos syndrome (hEDS). Tests revealed extensive similarities between Long COVID and ME/CFS, including reduced orthostatic CBFv (92%/88% in Long COVID/ME/CFS), mild-to-moderate widespread autonomic failure (95%/89%), presence of SFN (67%/53%), postural tachycardia syndrome (POTS) (22%/19%), neurogenic orthostatic hypotension (15%/15%) and preload failure (96%/92%, assessed in 25/66 Long COVID/ME/CFS). Patients with hEDS exhibited more severe peripheral neurodegeneration compared to the other groups. Laboratory tests did not distinguish between the conditions.

Conclusion: Both Long COVID and ME/CFS demonstrate dysregulation in cerebrovascular blood flow, autonomic reflexes, and small fiber neuropathy, suggesting that these conditions may share a common underlying pathophysiology. However, differing distributions of findings in patients with hEDS raise the question of whether these conditions represent distinct but overlapping syndromes or reflect a shared underlying pathway. Further research is required to clarify the relationship between these conditions and the potential underlying pathophysiological mechanisms.

Source: Novak P, Systrom DM, Witte A, Marciano SP, Felsenstein D, Milunsky JM, Milunsky A, Krier J, Fishman MC. Shared autonomic phenotype of long COVID and myalgic encephalomyelitis/chronic fatigue syndrome. PLoS One. 2026 Jan 23;21(1):e0341278. doi: 10.1371/journal.pone.0341278. PMID: 41576003. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0341278 (Full text)

Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing

Abstract:

Rationale: There is substantial overlap of exertional symptoms in Long COVID (LC) and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) including intractable fatigue, post-exertional malaise (PEM), and orthostatic intolerance, but very little objective data liking the two. This study compares exercise pathophysiology in the two disorders and normal controls using invasive cardiopulmonary exercise testing (iCPET).

Methods: Between January 2019 and December 2024, 1,518 patients underwent a clinical iCPET at Brigham and Women’s Hospital. Exclusion criteria included morbid obesity (BMI>40 kg/m2), severe anemia ([Hb]<9.0 g/dL), elite athletes (peak VO2 (pVO2)>120% predicted), sub-maximum effort (RER<1.05), a primary pulmonary mechanical limit (VE @ AT/MVV>0.7), and comorbidities such as active/treated cancer, interstitial lung disease, or other respiratory related diseases. iCPET results from 438 ME/CFS patients, 73 LC patients, and 43 symptomatic but otherwise normal controls were analyzed. pV02, peak cardiac output (pQc), peak right atrial pressure (pRAP), peak systemic oxygen extraction (pSOE; Ca-vO2/[Hb]), and ventilatory inefficiency (VE/VCO2 slope) were compared among groups. Statistical significance was determined using Kruskal-Wallis tests for global comparisons, with post-hoc Dunn tests for pairwise group comparisons. Holm-Bonferroni adjustments were applied to control for multiple comparisons.

Results: LC and ME/CFS displayed reduced pVO2 % predicted compared to controls (LC: 78.4 ± 18%, ME/CFS: 78.1 ± 17%, Controls: 97.5 ± 10%, P≤0.0001). Reduced pQc % predicted was also observed compared to controls (LC: 91.1 ± 18%, ME/CFS: 96.3%, Controls: 101 ± 11%, P≤0.001). pRAP were significantly less compared to controls (LC: 1.1 ± 3.1 mmHg, ME/CFS: 1.3 ± 2.8 mmHg, Controls: 3.6 ± 3.4 mmHg, P≤0.001). Significant reductions in pSOE were seen for LC and ME/CFS (LC: 0.81 ± 0.1, ME/CFS: 0.81 ± 0.1, Controls, 0.91 ± 0.1, P≤0.0001). The only measure with no significant difference between disease and control was VE/VCO2 slope (LC: 31.4 ± 8.4, ME/CFS: 31.6 ± 6.9, Controls: 32.0 ± 6.7, P≥0.261). Most interestingly, no significant differences were seen between the two diseases for any of the analyzed measures (P≥0.245).

Conclusions: We report the largest cohort of ME/CFS and LC investigated with iCPET to date. ME/CFS and LC share symptomatic, reduced aerobic capacity at peak exercise, which is driven by preload insufficiency and impaired systemic O2 extraction, the latter compatible with peripheral left-to-right shunting and/or limb skeletal muscle dysfunction. These findings should drive future diagnostics and personalized medicine in both diseases. We hope these data inform the pending prospective NIH RECOVER iCPET study of LC.

Source: J. Squires, S. Palwayi, P. Li, W. Xiao, K. LeWine, S.W. Johnson, D. Felsenstein, A.B. Waxman, and D.M. Systrom. Exercise Pathophysiology in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID: Commonalities Detected by Invasive Cardiopulmonary Exercise Testing [abstract]. Am J Respir Crit Care Med 2025;211:A7881. https://www.atsjournals.org/doi/​10.1164/ajrccm.2025.211.Abstracts.A7881

Head-down tilt reduces the heart rate in postural tachycardia syndrome in acute setting: a pilot study

Abstract:

Background: Reduced preload and thoracic blood volume accompany postural tachycardia syndrome (POTS). Head-down tilt (HDT) increases both preload and intrathoracic blood volume. The objective of this study was to assess the safety and efficacy of HDT in POTS in acute settings.

Methods: This retrospective study evaluated POTS patients. Analyzed data included heart rate, blood pressure, cerebral blood flow velocity (CBFv) in the middle cerebral artery, and capnography. The baseline supine hemodynamic data were compared with the data obtained at the second minute of the -10° HDT. A linear mixed-effects model was used to assess the effect of HDT on hemodynamic variables.

Results: The HDT was explored in seven POTS patients and an additional seven POTS patients without HDT served as controls. In the HDT arm, four POTS patients had overlapping diagnoses of myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) and one patient had comorbidity of post-acute sequelae of SARS-CoV-2 infection (PASC). HDT lowered heart rate by 10% and increased end-tidal CO2 by 8%. There was no change in other cardiovascular variables.

Conclusions: In the acute setting, HDT is safe. HDT reduces the heart rate presumably by modulating baroreflex by enhancing preload and stroke volume, which in turn increases thoracic blood volume with a net effect of parasympathetic cardiovagal activation and/or sympathetic withdrawal. This pilot study provides a foundation to proceed with longitudinal studies exploring the long-term effect of repetitive HDT in conditions associated with preload failure such as POTS, ME/CSF, and PASC.

Source: Novak P. Head-down tilt reduces the heart rate in postural tachycardia syndrome in acute setting: a pilot study. Neurol Sci. 2023 Nov 3. doi: 10.1007/s10072-023-07153-5. Epub ahead of print. PMID: 37919442. https://pubmed.ncbi.nlm.nih.gov/37919442/

Cardiovascular risk factors predict who should have echocardiographic evaluation in long COVID

Abstract:

Background: The need for echocardiograms among patients with long COVID is debatable. Our aim was to evaluate the prevalence of left ventricular (LV) dysfunction and identify predictors.
Methods: We conducted a cross-sectional study and included all consecutive patients enrolled in our post-COVID clinic. We included patients who had an echocardiogram and had no previous known heart disease. We defined LV dysfunction as a low ejection fraction or grade II to grade III diastolic dysfunction on an echocardiogram with evidence of elevated filling pressures. We calculated the prevalence of heart disease and predictors of heart disease using logistic regression.
Results: We included 217 post-COVID patients enrolled in the clinic. The prevalence of LV dysfunction is 24%;95% CI 18-30. Predictors of heart disease include older age and a previous history of hypertension and diabetes or having a intermediate or high ASCVD score. Patients with low ASCVD score did not have low ejection fraction on the screening echocardiograms.
Conclusion: Our study found a considerable number of patients with LV dysfunction. Older patients with cardiovascular risk factors are at risk of long COVID associated heart disease.
Source: Leonardo Tamariz, Mathew Ryan, George Marzouka R, et al. Cardiovascular risk factors predict who should have echocardiographic evaluation in long COVID. Authorea. August 23, 2023. https://www.authorea.com/doi/full/10.22541/au.169277562.22633945 (Full text available as download)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators?

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is often associated with various other syndromes or conditions including mast cell activation (MCA), dysmenorrhea and endometriosis, postural tachycardia (POTS) and small fiber neuropathy (SFN). The causes of these syndromes and the reason for their frequent association are not yet fully understood.

We previously published a comprehensive hypothesis of the ME/CFS pathophysiology that explains the majority of symptoms, findings and chronicity of the disease. We wondered whether some of the identified key pathomechanisms in ME/CFS are also operative in MCA, endometriosis and dysmenorrhea, POTS, decreased cerebral blood flow and SFN, and possibly may provide clues on their causes and frequent co-occurrence.

Our analysis indeed provides strong arguments in favor of this assumption, and we conclude that the main pathomechanisms responsible for this association are excessive generation and spillover into the systemic circulation of inflammatory and vasoactive tissue mediators, dysfunctional β2AdR, and the mutual triggering of symptomatology and disease initiation. Overall, vascular dysfunction appears to be a strong common denominator in these linkages.

Source: Wirth KJ, Löhn M. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Comorbidities: Linked by Vascular Pathomechanisms and Vasoactive Mediators? Medicina. 2023; 59(5):978. https://doi.org/10.3390/medicina59050978  https://www.mdpi.com/1648-9144/59/5/978 (Full text)

ME/CFS Pathophysiology Investigated by Invasive Cardiopulmonary Exercise Testing and Autonomic Function Testing

Abstract

Introduction: Mechanisms underlying exercise and orthostatic intolerance in myalgic encephalomyelitis/chronic
fatigue syndrome (ME/CFS) have been uncovered by invasive cardiopulmonary exercise testing (iCPET) and
autonomic function testing (AFT), but the relationships between the two are not known. This study aims to determine
if there is overlap of cardiovascular and respiratory pathophysiology in patients who have undergone both
tests.

Methods: Between January 2017 and April 2022, 62 patients were identified with a contemporary iCPET and
AFT. Key variables from the iCPET included peak oxygen uptake (pVO2), cardiac output (pQc), right atrial pressure
(pRAP), and systemic oxygen extraction (Ca-vOy/Hgb) at peak exercise. Key variables from the autonomic testing
included epidermal and sweat gland small fiber neurite density, electrochemical skin conductance, and change in
heart rate (AH) and end tidal carbon dioxide (AETCO2) from supine to upright during the tilt table test
(TTT).

Results: All 62 patients demonstrated preload failure (pRAP < 6.5mmHg). Of this group, 54 patients (87.1%) fulfilled NAM criteria for ME/CFS, with 32 testing positive (59.3%) for small fiber neuropathy (SFN) using either morphological and/or functional testing. Significant correlations were found between pVOg and both AH (r=-0.439. P<0.05) and AETCO, (r=0.474, P<0.05) during TTT. The same tilt table variables were found to be significantly correlated with pQc (r=-0.365, P<0.05 and r=0.351, P<0.05) from the iCPET. It should be noted that 8 of the ME/CFS SFN patients (25%) fulfilled diagnostic criteria for postural orthostatic tachycardia syndrome (POTS) based on the tilt table test.

Conclusion: Decreased oxygen uptake and cardiac output at peak exercise during iCPET correlated with a greater change in heart rate and ETCO from supine to upright during TTT. There appears to be significant overlap of cardiopulmonary pathophysiology in ME/CFS underlying exercise and orthostatic symptoms.

Source: J. Squires, K. Wichmann Madsen, M.C. Stovall, S. Al-Zayer, W. Xiao, C.-J. Chang, P. Novak, D.M. Systrom. ME/CFS Pathophysiology Investigated by Invasive Cardiopulmonary Exercise Testing and Autonomic Function Testing. American Journal of Respiratory and Critical Care Medicine 2023;207:A2996. https://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2023.207.1_MeetingAbstracts.A2996

Down-regulation of renin-aldosterone and antidiuretic hormone systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Central nervous system dysfunction associated with myalgic encephalomyelitis (ME) has been postulated as the cause of chronic fatigue syndrome (CFS). A small heart or reduced left ventricular volume with reduced cardiac output has been reported to be common in patients with ME. The main circulatory blood volume regulators may be down-regulated.

METHODS: Plasma levels of the neurohumoral factors that regulate circulatory blood volume were determined in 18 patients with ME and 15 healthy subjects (Controls).

RESULTS: The echocardiographic examination revealed that the mean values for the left ventricular end-diastolic diameters, stroke volume index, and cardiac index as well as the mean blood pressure were all significantly smaller in the ME group than in the Controls. The mean plasma renin activity (1.6±1.0ng/ml/h vs. 2.5±1.5ng/ml/h, p=0.06) was considerably lower in the ME group than in the Controls. Both the mean plasma aldosterone (104±37pg/ml vs. 157±67pg/ml, p=0.004) and antidiuretic hormone (ADH) (2.2±1.0pg/ml vs. 3.3±1.5pg/ml, p=0.02) concentrations were significantly lower in the ME group than in the Controls.

Desmopressin (120μg), a synthetic version of arginine vasopressin, was orally administered for five successive days to 10 patients with ME. In five patients (50%), the symptoms of orthostatic intolerance during a 10min active standing test were ameliorated in association with a significant increase in urinary osmotic pressure and decrease in heart rate. Furthermore, in five patients (50%), the performance status scores for the activities of daily living were improved.

CONCLUSIONS: Both the renin-aldosterone and ADH systems were down-regulated despite the existence of reduction in cardiac preload and output in patients with ME. Desmopressin improved symptoms in half of the patients.

Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

 

Source: Miwa K. Down-regulation of renin-aldosterone and antidiuretic hormone systems in patients with myalgic encephalomyelitis/chronic fatigue syndrome. J Cardiol. 2016 Jul 8. pii: S0914-5087(16)30120-4. doi: 10.1016/j.jjcc.2016.06.003. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27401397

 

Variability of postural orthostatic tachycardia in patients with myalgic encephalomyelitis and orthostatic intolerance

Abstract:

Central nervous system dysfunction with myalgic encephalomyelitis (ME) has been suggested as the main cause of chronic fatigue syndrome. Fluctuation of the symptom severity and hierarchy is a characteristic feature in ME patients. The characteristics of the sympathetic activation may differ between the “good days” and “bad days” in them.

Twenty-four ME patients with orthostatic intolerance underwent a conventional 10-min active standing test and echocardiography both on a “good day” and a “bad day”, defined according to the severity of their symptoms. The mean heart rate at rest was significantly higher on the “bad days” than on the “good days”. During the standing test on a “bad day”, 5 patients (21 %) failed to maintain an upright posture for 10 min, whereas on a “good day” all the 24 patients maintained it.

Postural orthostatic tachycardia (POT) (increase in heart rate ≥30 beats/min) or severe POT (heart rate ≥120 beats/min) was observed on the “bad days” in 10 patients (43 %) who did not suffer from the severe tachycardia on the “good days”, suggesting the exaggerated sympathetic nervous activation.

In contrast, POT did not occur or severe POT was attenuated on the “bad days” in 5 patients (21 %) who developed POT or severe POT on the “good days”, suggesting the impaired sympathetic activation. Echocardiography revealed significantly lower mean values of both the left ventricular end-diastolic diameter and stroke volume index on the “bad days” compared with the “good days”.

In conclusion, in ME patients with orthostatic intolerance, the exaggerated activation of the sympathetic nervous system while standing appears to switch to the impaired sympathetic activation after the system is loaded with the additional accentuated stimuli associated with the preload reduction.

 

Source: Miwa K. Variability of postural orthostatic tachycardia in patients with myalgic encephalomyelitis and orthostatic intolerance. Heart Vessels. 2016 Sep;31(9):1522-8. doi: 10.1007/s00380-015-0744-3. Epub 2015 Sep 15. https://www.ncbi.nlm.nih.gov/pubmed/26374335