Tag: blood flow

Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations

Abstract:

Background: Post-exertional malaise (PEM), the hallmark symptom of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), represents a constellation of abnormal responses to physical, cognitive, and/or emotional exertion including profound fatigue, cognitive dysfunction, and exertion intolerance, among numerous other maladies. Two sequential cardiopulmonary exercise tests (2-d CPET) provide objective evidence of abnormal responses to exertion in ME/CFS but validated only in studies with small sample sizes. Further, translation of results to impairment status and approaches to symptom reduction are lacking.

Methods: Participants with ME/CFS (Canadian Criteria; n = 84) and sedentary controls (CTL; n = 71) completed two CPETs on a cycle ergometer separated by 24 h. Two-way repeated measures ANOVA compared CPET measures at rest, ventilatory/anaerobic threshold (VAT), and peak effort between phenotypes and CPETs. Intraclass correlations described stability of CPET measures across tests, and relevant objective CPET data indicated impairment status. A subset of case–control pairs (n = 55) matched for aerobic capacity, age, and sex, were also analyzed.

Results: Unlike CTL, ME/CFS failed to reproduce CPET-1 measures during CPET-2 with significant declines at peak exertion in work, exercise time, V˙e, V˙O2, V˙CO2, V˙ T, HR, O2pulse, DBP, and RPP. Likewise, CPET-2 declines were observed at VAT for V˙e/V˙CO2, PetCO2, O2pulse, work, V˙O2 and SBP. Perception of effort (RPE) exceeded maximum effort criteria for ME/CFS and CTL on both CPETs. Results were similar in matched pairs. Intraclass correlations revealed greater stability in CPET variables across test days in CTL compared to ME/CFS owing to CPET-2 declines in ME/CFS. Lastly, CPET-2 data signaled more severe impairment status for ME/CFS compared to CPET-1.

Conclusions: Presently, this is the largest 2-d CPET study of ME/CFS to substantiate impaired recovery in ME/CFS following an exertional stressor. Abnormal post-exertional CPET responses persisted compared to CTL matched for aerobic capacity, indicating that fitness level does not predispose to exertion intolerance in ME/CFS. Moreover, contributions to exertion intolerance in ME/CFS by disrupted cardiac, pulmonary, and metabolic factors implicates autonomic nervous system dysregulation of blood flow and oxygen delivery for energy metabolism. The observable declines in post-exertional energy metabolism translate notably to a worsening of impairment status. Treatment considerations to address tangible reductions in physiological function are proffered.

Trial registration number: ClinicalTrials.gov, retrospectively registered, ID# NCT04026425, date of registration: 2019-07-17.

Source: Keller, B., Receno, C.N., Franconi, C.J. et al. Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations. J Transl Med 22, 627 (2024). https://doi.org/10.1186/s12967-024-05410-5 https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05410-5#Abs1 (Full text)

 

Coronary microvascular health in symptomatic patients with prior COVID-19 infection: an updated analysis

Abstract:

Aims: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with endothelial dysfunction. We aimed to determine the effects of prior coronavirus disease 2019 (COVID-19) on the coronary microvasculature accounting for time from COVID-19, disease severity, SARS-CoV-2 variants, and in subgroups of patients with diabetes and those with no known coronary artery disease.

Methods and results: Cases consisted of patients with previous COVID-19 who had clinically indicated positron emission tomography (PET) imaging and were matched 1:3 on clinical and cardiovascular risk factors to controls having no prior infection. Myocardial flow reserve (MFR) was calculated as the ratio of stress to rest myocardial blood flow (MBF) in mL/min/g of the left ventricle. Comparisons between cases and controls were made for the odds and prevalence of impaired MFR (MFR < 2). We included 271 cases matched to 815 controls (mean ± SD age 65 ± 12 years, 52% men). The median (inter-quartile range) number of days between COVID-19 infection and PET imaging was 174 (58-338) days. Patients with prior COVID-19 had a statistically significant higher odds of MFR <2 (adjusted odds ratio 3.1, 95% confidence interval 2.8-4.25 P < 0.001). Results were similar in clinically meaningful subgroups. The proportion of cases with MFR <2 peaked 6-9 months from imaging with a statistically non-significant downtrend afterwards and was comparable across SARS-CoV-2 variants but increased with increasing severity of infection.

Conclusion: The prevalence of impaired MFR is similar by duration of time from infection up to 1 year and SARS-CoV-2 variants, but significantly differs by severity of infection.

Source: Ahmed AI, Al Rifai M, Alahdab F, Saad JM, Han Y, Alfawara MS, Nayfeh M, Malahfji M, Nabi F, Mahmarian JJ, Cooke JP, Zoghbi WA, Al-Mallah MH. Coronary microvascular health in symptomatic patients with prior COVID-19 infection: an updated analysis. Eur Heart J Cardiovasc Imaging. 2023 May 31:jead118. doi: 10.1093/ehjci/jead118. Epub ahead of print. PMID: 37254693. https://pubmed.ncbi.nlm.nih.gov/37254693/

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/

Letter: Could endothelial dysfunction and vascular damage contribute to pain, inflammation and post-exertional malaise in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)?

To the Editor,

In their hypothesis paper, Wirth, Scheibenbogen, and Paul describe how endothelial dysfunction could produce a wide range of neurological symptoms in people with ME/CFS [1]. As they and others work to refine their understanding of ME/CFS and the related Long COVID syndrome, I would encourage consideration of the possibility that endothelial dysfunction and vascular damage could also explain other symptoms, including widespread pain and inflammation and post-exertional malaise.

For the past four years, my wife and I have been caregivers for our teenage daughter, who has ME/CFS, hypermobile Ehlers-Danlos syndrome, craniocervical instability, Chiari malformation and several other comorbid conditions. Through observation and trial and error, I have developed a number of hypotheses on these matters that I offer here in the hope they might prompt formal research into how to effectively treat these conditions [2].

Widespread pain and inflammation

Discussion of endothelial dysfunction and vascular damage in ME/CFS and Long COVID generally focuses on how leakages from dysfunctional blood vessels lead to reduced blood flow, which has many consequences, including reduced oxygenation of muscles and reduced cerebral brain flow. As researchers study this phenomenon, I would encourage consideration of the additional possibility that the leaking fluid causes independent damage. Lipedema researchers have found that leakages from microangiopathic blood vessels cause an excess of interstitial fluid that stimulates the formation of subcutaneous adipose tissue [3], which generates hypoxic conditions and becomes fibrotic, contributing to pain and inflammation [4].

I hypothesize that a similar process happens when fluid leaks from faulty blood vessels in ME/CFS, possibly exacerbated by endothelial dysfunction in lymphatic vessels that inhibit the fluid’s removal, causing widespread pain and inflammation. This mechanism appears most pronounced among people with hypermobility or other connective tissue disorders, a common trait among people with both ME/CFS and lipedema.

My daughter experiences pain from fibrotic adipose tissue as well as what appears to be nerve compression from accumulated interstitial / lymphatic fluid. Manual lymphatic drainage, the squeezing of affected tissue, and the manual break-up of fibrotic adipose tissue have helped to ameliorate these symptoms.

In my daughter, I have also observed impaired drainage of fluid from the glymphatic system, both at the cribriform plate and down her spine. Could this be related to damaged lymphatic vessels or blockages from fibrotic adipose tissue?

Post-exertional malaise

Like many people with moderate or severe ME/CFS, my daughter struggles to recover from even small amounts of physical exertion. In addition to mitigating her pain, manual lymphatic drainage and the squeezing of affected tissue greatly accelerates this recovery process. We have observed a direct dose–response relationship: the more exercise, the more fluid is present in her tissues, and the more manual draining / squeezing is necessary for her to recover.

Based on this experience, I hypothesize that excess interstitial fluid resulting from dysfunctional blood and lymphatic vessels contributes to the experience of post-exertional malaise, with fluid literally drowning affected tissue, leading to hypoxic conditions and inflammation. Possible explanations for the increased interstitial fluid are increases in blood pressure during physical exertion, hypermobile joints going out of place, prompting localized increases in interstitial fluid, and increases in cortisol that generate an increase in fluid and blood volume. Increases in fluid leakage due to elevated cortisol levels may also explain why some people with ME/CFS feel worse when stressed or anxious. The role of cortisol (or another mediator with fluid retaining properties) may explain why cognitive exertion can also generate post-exertional malaise. When present, elevated estrogen levels may exacerbate leakage by increasing fluid volume.

I am not sure why there is typically a delay between physical exertion and the experience of the most acute symptoms of post-exertional malaise. One possibility is that it takes time for the tissue inundated with fluid to feel the full effects of the hypoxic conditions. Another possibility is that a biphasic reaction triggered during physical exertion leads to the release of a mediator that causes heightened endothelial dysfunction and fluid release.

Further research is needed into the causes of endothelial dysfunction and damage (in addition to initial infection and inflammatory overreaction, consider major “crashes,” mast cell activations, surgeries and microclots as additional contributors) and appropriate treatment.

References

1. Wirth KJ, Scheibenbogen C, Paul F. An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Transl Med. 2021;19:471. https://doi.org/10.1186/s12967-021-03143-3.

Article PubMed PubMed Central Google Scholar

2. For background, see Lubell, J. To speed progress in treating chronic conditions, engage patients and caregivers as research partners. 2021 Sept.20 In: BMJ Opinion. https://blogs.bmj.com/bmj/2021/09/20/to-speed-progress-in-treating-chronic-conditions-engage-patients-and-caregivers-as-research-partners/

3. Allen M, Schwartz M, Herbst KL. Interstitial Fluid in Lipedema and Control Skin. Womens Health Rep (New Rochelle). 2020;1(1):480–7. https://doi.org/10.1089/whr.2020.0086.PMID:33786515;PMCID:PMC7784769.

Article Google Scholar

4. Herbst KL. Subcutaneous Adipose Tissue Diseases: Dercum Disease, Lipedema, Familial Multiple Lipomatosis, and Madelung Disease. [Updated 2019 Dec 14]. In: Feingold KR, Anawalt B, Boyce A, et al., editors. South Dartmouth (MA).

Source: Lubell J. Letter: Could endothelial dysfunction and vascular damage contribute to pain, inflammation and post-exertional malaise in individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)? J Transl Med. 2022 Jan 24;20(1):40. doi: 10.1186/s12967-022-03244-7. PMID: 35073915. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03244-7

ME/CFS may be linked to failure in energy supply to the cells

By Elise Kjørstad

Researchers at the University of Bergen and Haukeland University Hospital were part of a research team for a new study that found differences in blood samples between ME/CFS patients and healthy people.

Patients with myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS, had different levels of some substances that affect energy metabolism in the cells.

“What we think might be an explanation is that restricted blood flow during activity means the cells are receiving too little oxygen, and this leaves metabolic traces over time,” says Karl Johan Tronstad.

In the new study, the researchers performed an analysis of metabolites and other substances in blood samples from ME/CFS patients. Metabolites are metabolic products that are created when the cells convert different substances in the body.

The researchers analysed blood samples from 83 individuals with ME/CFS and 35 healthy controls.

The researchers measured about 1700 substances in the blood samples they took.

In the ME/CFS patients, they found an altered level of over 300 substances. Many of them involved the conversion of amino acids, which build up proteins, and lipids (fats).

Read the rest of this article HERE.

 

 

Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: a quantitative, controlled study using Doppler echography

Abstract:

Objective: The underlying hypothesis in orthostatic intolerance (OI) syndromes is that symptoms are associated with cerebral blood flow (CBF) reduction. Indirect CBF measurements (transcranial Doppler flow velocities), provide inconsistent support of this hypothesis. The aim of the study was to measure CBF during a 30 min head-up tilt test (HUT), using Doppler flow imaging of carotid and vertebral arteries, in individuals with chronic fatigue syndrome/myalgic encephalomyelitis (ME/CFS), a condition with a high prevalence of OI.

Methods: 429 ME/CFS patients were studied: 247 had a normal heart rate (HR) and blood pressure (BP) response to HUT, 62 had delayed orthostatic hypotension (dOH), and 120 had postural orthostatic tachycardia syndrome (POTS). We also studied 44 healthy controls (HC). CBF measurements were made at mid-tilt and end-tilt. Before mid-tilt, we administered a verbal questionnaire to ascertain for 15 OI symptoms.

Results: End-tilt CBF reduction was 7% in HC versus 26% in the overall ME/CFS group, 24% in patients with a normal HR/BP response, 28% in those with dOH, and 29% in POTS patients (all P<.0005). Using a lower limit of normal of 2SD of CBF reduction in HC (13% reduction), 82% of patients with normal HR/BP response, 98% with dOH and 100% with POTS showed an abnormal CBF reduction. There was a linear correlation of summed OI symptoms with the degree of CBF reduction at mid-tilt (P<.0005).

Conclusions: During HUT, extracranial Doppler measurements demonstrate that CBF is reduced in ME/CFS patients with POTS, dOH, and even in those without HR/BP abnormalities.

Significance: This study shows that orthostatic intolerance symptoms are related to CBF reduction, and that the majority of ME/CFS patients (90%) show an abnormal cerebral flow reduction during orthostatic stress testing. This may have implications for the diagnosis and treatment of ME/CFS patients.

Source: C. (Linda) M.C.van Campen, Freek W.A. Verheugt, Peter C. Rowe, Frans C.Visser. Cerebral blood flow is reduced in ME/CFS during head-up tilt testing even in the absence of hypotension or tachycardia: a quantitative, controlled study using Doppler echography. Clinical Neurophysiology Practice. Available online 8 February 2020. https://doi.org/10.1016/j.cnp.2020.01.003 https://www.sciencedirect.com/science/article/pii/S2467981X20300044 (Full text)

Visible and near-infrared spectral changes in the thumb of patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) patients show a persistent fatigue condition with muscle pain and impairment of concentration, memory, and sleep. Presently, the physiological basis of CFS remains unclear. In this study, spectroscopic differences in the thumb were compared between 103 CFS patients and 122 healthy controls to examine possible changes of levels of oxygenated or deoxygenated hemoglobin.

METHODS: Visible and near-infrared (Vis-NIR) spectroscopy was used to examine possible changes in the region of 600-1100 nm.

RESULTS: Vis-NIR spectra showed sharp peaks at 694, 970 and 1060 nm and broad peaks in the regions of 740-760 and 830-850 nm. As these peaks are possibly related to oxyhemoglobin, cytochrome c oxidase and water, levels of these factors were compared between the two groups. Statistical analysis of the absorbance of Vis-NIR spectra showed a significant decrease in water content, a significant increase in oxyhemoglobin content, and a significant increase in the oxidation of heme a+a(3) and copper in cytochrome c oxidase in CFS patients.

CONCLUSIONS: These changes imply accelerated blood flow and energy metabolism in the thumbs of CFS patients.

 

Source: Sakudo A, Kato YH, Tajima S, Kuratsune H, Ikuta K. Visible and near-infrared spectral changes in the thumb of patients with chronic fatigue syndrome. Clin Chim Acta. 2009 May;403(1-2):163-6. doi: 10.1016/j.cca.2009.02.010. Epub 2009 Feb 25. https://www.ncbi.nlm.nih.gov/pubmed/19248775

 

Muscle metabolism with blood flow restriction in chronic fatigue syndrome

Abstract:

The purpose of this study was to determine whether chronic fatigue syndrome (CFS) is associated with reduced blood flow and muscle oxidative metabolism. Patients with CFS according to Centers for Disease Control criteria (n = 19) were compared with normal sedentary subjects (n = 11).

Muscle blood flow was measured in the femoral artery with Doppler ultrasound after exercise. Muscle metabolism was measured in the medial gastrocnemius muscle with (31)P-magnetic resonance spectroscopy. Muscle oxygen saturation and blood volume were measured using near-infrared spectroscopy. CFS and controls were not different in hyperemic blood flow or phosphocreatine recovery rate. Cuff pressures of 50, 60, 70, 80, and 90 mmHg were used to partially restrict blood flow during recovery. All pressures reduced blood flow and oxidative metabolism, with 90 mmHg reducing blood flow by 46% and oxidative metabolism by 30.7% in CFS patients.

Hyperemic blood flow during partial cuff occlusion was significantly reduced in CFS patients (P < 0.01), and recovery of oxygen saturation was slower (P < 0.05). No differences were seen in the amount of reduction in metabolism with partially reduced blood flow.

In conclusion, CFS patients showed evidence of reduced hyperemic flow and reduced oxygen delivery but no evidence that this impaired muscle metabolism. Thus CFS patients might have altered control of blood flow, but this is unlikely to influence muscle metabolism. Furthermore, abnormalities in muscle metabolism do not appear to be responsible for the CFS symptoms.

 

Source: McCully KK, Smith S, Rajaei S, Leigh JS Jr, Natelson BH. Muscle metabolism with blood flow restriction in chronic fatigue syndrome. J Appl Physiol (1985). 2004 Mar;96(3):871-8. Epub 2003 Oct 24. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680353/ (Full article)

 

Blood flow and muscle metabolism in chronic fatigue syndrome

Abstract:

The purpose of this study was to determine if chronic fatigue syndrome (CFS) is associated with reduced blood flow and oxidative delivery to skeletal muscle. Patients with CFS according to CDC (Center for Disease Control) criteria ( n =19) were compared with normal sedentary subjects ( n =11). Muscle blood flow was measured with Doppler ultrasound after cuff ischaemia and exercise. Muscle oxygen delivery was measured as the rate of post-exercise and post-ischaemic oxygen-haem resaturation. Oxygen-haem resaturation was measured in the medial gastrocnemius muscle using continuous wavelength near-IR spectroscopy. Muscle metabolism was measured using (31)P magnetic resonance spectroscopy. CFS patients and controls were not different in the peak blood flow after cuff ischaemia, the rate of recovery of phosphocreatine after submaximal exercise, and the rate of recovery of oxygen saturation after cuff ischaemia. In conclusion, CFS patients showed no deficit in blood flow or oxidative metabolism. This suggests that CFS symptoms do not require abnormal peripheral function.

 

Source: McCully KK, Smith S, Rajaei S, Leigh JS Jr, Natelson BH. Blood flow and muscle metabolism in chronic fatigue syndrome.  Clin Sci (Lond). 2003 Jun;104(6):641-7. http://www.ncbi.nlm.nih.gov/pubmed/12589704