Tag: microcirculation

Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent, debilitating and still enigmatic disease. There is a broad overlap in the symptomatology of ME/CFS and the Post-COVID Syndrome (PCS). A fraction of the PCS patients develops the full clinical picture of ME/CFS.
New observations in microvessels and blood from patients suffering from PCS have appeared and include microclots and malformed pathological blood cells. Capillary blood flow is impaired not only by pathological blood components but also by prothrombotic changes in the vascular wall, endothelial dysfunction, and expression of adhesion molecules in the capillaries. These disturbances can finally cause a low capillary flow and even capillary stasis. A low cardiac stroke volume due to hypovolemia and the inability of the capacitance vessels to adequately constrict to deliver the necessary cardiac preload generate an unfavorable low precapillary perfusion pressure.
Furthermore, a predominance of vasoconstrictor over vasodilator influences exists, in which sympathetic hyperactivity and endothelial dysfunction play a strong role, causing constriction of resistance vessels and of precapillary sphincters which leads to a fall in capillary pressure behind the sphincters. The interaction of these two precapillary cardiovascular mechanisms causing a low capillary perfusion pressure is hemodynamically highly unfavorable in the presence of a primary capillary stasis already caused by the pathological blood components and their interaction with the capillary wall, to severely impair organ perfusion.
The detrimental coincidence of the microcirculatory with the precapillary cardiovascular disturbances may constitute the key disturbance of the Post-COVID-19 syndrome and finally lead to ME/CFS in pre-disposed patients because the interaction causes a particular kind of perfusion disturbance – capillary ischemia-reperfusion – which has a high potential of causing mitochondrial dysfunction by inducing sodium- and calcium-overload in skeletal muscles. The latter in turns worsens the vascular situation by the generation of reactive oxygen species to close a vicious cycle from which the patient can hardly escape.
Source: Wirth, K.J.; Löhn, M. Microvascular Capillary and Precapillary Cardiovascular Disturbances Strongly Interact to Severely Affect Tissue Perfusion and Mitochondrial Function in ME/CFS Evolving from the Post COVID-19 Syndrome. Preprints 2023, 2023120791. https://doi.org/10.20944/preprints202312.0791.v1  https://www.preprints.org/manuscript/202312.0791/v1 (Full text available as PDF file)

Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation

Abstract:

Background: Post-COVID-19 syndrome (PCS) is a lingering disease with ongoing symptoms such as fatigue and cognitive impairment resulting in a high impact on the daily life of patients. Understanding the pathophysiology of PCS is a public health priority, as it still poses a diagnostic and treatment challenge for physicians.

Methods: In this prospective observational cohort study, we analyzed the retinal microcirculation using Retinal Vessel Analysis (RVA) in a cohort of patients with PCS and compared it to an age- and gender-matched healthy cohort (n=41, matched out of n = 204).

Measurements and main results: PCS patients exhibit persistent endothelial dysfunction (ED), as indicated by significantly lower venular flicker-induced dilation (vmax; 3.42% ± 1.77% vs. 4.64 % ± 2.59%; p = 0.02), narrower central retinal artery equivalent (CRAE; 178.1 [167.5 – 190.2] vs. 189.1 [179.4 – 197.2], p = 0.01) and lower arteriolar-venular ratio (AVR; (0.84 [0.8 – 0.9] vs. 0.88 [0.8 – 0.9], p = 0.007). When combining AVR and vmax, predicted scores reached good ability to discriminate groups (area under the curve: 0.75). Higher PCS severity scores correlated with lower AVR (R= -0.37 p = 0.017). The association of microvascular changes with PCS severity were amplified in PCS patients exhibiting higher levels of inflammatory parameters.

Conclusion: Our results demonstrate that prolonged endothelial dysfunction is a hallmark of PCS, and impairments of the microcirculation seem to explain ongoing symptoms in patients. As potential therapies for PCS emerge, RVA parameters may become relevant as clinical biomarkers for diagnosis and therapy management.

Source: Timon Kuchler, Roman Günthner, Andrea Ribeiro et al. Persistent endothelial dysfunction in post-COVID-19 syndrome and its associations with symptom severity and chronic inflammation, 22 May 2023, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-2952588/v1 (Full text)

Pulmonary circulation abnormalities in post-acute COVID-19 syndrome: dual-energy CT angiographic findings in 79 patients

Abstract:

Objectives: To evaluate the frequency and pattern of pulmonary vascular abnormalities in the year following COVID-19.

Methods: The study population included 79 patients remaining symptomatic more than 6 months after hospitalization for SARS-CoV-2 pneumonia who had been evaluated with dual-energy CT angiography.

Results: Morphologic images showed CT features of (a) acute (2/79; 2.5%) and focal chronic (4/79; 5%) PE; and (b) residual post COVID-19 lung infiltration (67/79; 85%). Lung perfusion was abnormal in 69 patients (87.4%). Perfusion abnormalities included (a) perfusion defects of 3 types: patchy defects (n = 60; 76%); areas of non-systematized hypoperfusion (n = 27; 34.2%); and/or PE-type defects (n = 14; 17.7%) seen with (2/14) and without (12/14) endoluminal filling defects; and (b) areas of increased perfusion in 59 patients (74.9%), superimposed on ground-glass opacities (58/59) and vascular tree-in-bud (5/59). PFTs were available in 10 patients with normal perfusion and in 55 patients with abnormal perfusion. The mean values of functional variables did not differ between the two subgroups with a trend toward lower DLCO in patients with abnormal perfusion (74.8 ± 16.7% vs 85.0 ± 8.1).

Conclusion: Delayed follow-up showed CT features of acute and chronic PE but also two types of perfusion abnormalities suggestive of persistent hypercoagulability as well as unresolved/sequelae of microangiopathy.

Clinical relevance statement: Despite dramatic resolution of lung abnormalities seen during the acute phase of the disease, acute pulmonary embolism and alterations at the level of lung microcirculation can be identified in patients remaining symptomatic in the year following COVID-19.

Key points: • This study demonstrates newly developed proximal acute PE/thrombosis in the year following SARS-CoV-2 pneumonia. • Dual-energy CT lung perfusion identified perfusion defects and areas of increased iodine uptake abnormalities, suggestive of unresolved damage to lung microcirculation. • This study suggests a complementarity between HRCT and spectral imaging for proper understanding of post COVID-19 lung sequelae.

Source: Mohamed I, de Broucker V, Duhamel A, Giordano J, Ego A, Fonne N, Chenivesse C, Remy J, Remy-Jardin M. Pulmonary circulation abnormalities in post-acute COVID-19 syndrome: dual-energy CT angiographic findings in 79 patients. Eur Radiol. 2023 Apr 25:1–13. doi: 10.1007/s00330-023-09618-9. Epub ahead of print. PMID: 37145145; PMCID: PMC10129318. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10129318/ (Full text)

Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect?

Abstract:

Following COVID-19 infection, a substantial proportion of patients suffer from persistent symptoms known as Long COVID. Among the main symptoms are fatigue, cognitive dysfunction, muscle weakness and orthostatic intolerance (OI). These symptoms also occur in myalgic encephalomyelitis/chronic fatigue (ME/CFS).
OI is highly prevalent in ME/CFS and develops early during or after acute COVID-19 infection. The causes for OI are unknown and autonomic dysfunction is hypothetically assumed to be the primary cause, presumably as a consequence of neuroinflammation. Here, we propose an alternative, primary vascular mechanism as the underlying cause of OI in Long COVID.
We assume that the capacitance vessel system, which plays a key role in physiologic orthostatic regulation, becomes dysfunctional due to a disturbance of the microvessels and the vasa vasorum, which supply large parts of the wall of those large vessels. We assume that the known microcirculatory disturbance found after COVID-19 infection, resulting from endothelial dysfunction, microthrombus formation and rheological disturbances of blood cells (altered deformability ), also affects the vasa vasorum to impair the function of the capacitance vessels.
In an attempt to compensate for the vascular deficit, sympathetic activity overshoots to further worsen OI, resulting in a vicious circle that maintains OI. The resulting orthostatic stress, in turn, plays a key role in autonomic dysfunction and the pathophysiology of ME/CFS.
Source: Wirth KJ, Löhn M. Orthostatic Intolerance after COVID-19 Infection: Is Disturbed Microcirculation of the Vasa Vasorum of Capacitance Vessels the Primary Defect? Medicina. 2022; 58(12):1807. https://doi.org/10.3390/medicina58121807 https://www.mdpi.com/1648-9144/58/12/1807 (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground?

Abstract:

A Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease of unknown aetiology under growing interest now in view of the increasingly recognized post-COVID syndrome as a new entity with similar clinical presentation.

We performed the first cross-sectional study of ME/CFS in community population in Russia and then described and compared some clinical and pathophysiological characteristics of ME/CFS and post-COVID syndrome as neuroimmune disorders.

Of the cohort of 76 individuals who suggested themselves suffering from ME/CFS 56 subsequently were confirmed as having CFS/ME according to ≥1 of the 4 most commonly used case definition.

Of the cohort of 14 individuals with post-COVID-19 syndrome 14 met diagnostic criteria for ME/CFS. The prevalence of clinically expressed and subclinical anxiety and depression in ME / CFS and post-COVID ME/CFS did not differ significantly from that in healthy individuals.

Severity of anxiety / depressive symptoms did not correlate with the severity of fatigue neigther in ME / CFS nor in post-COVID ME/CFS, but the positive correlation was found between the severity of fatigue and 20 other symptoms of ME / CFS related to the domains of “post-exertional exhaustion”, “immune dysfunction”, “sleep disturbances”, “dysfunction of the autonomic nervous system”, “neurological sensory / motor disorders” and “pain syndromes”.

Immunological abnormalities were identified in 12/12 patients with ME / CFS according to the results of laboratory testing.

The prevalence of postural orthostatic tachycardia assessed by the active standing test was 37.5% in ME / CFS and 75.0% in post-COVID ME/CFS (the latter was higher than in healthy controls, p = 0.02).  There was a more pronounced increase in heart rate starting from the 6th minute of the test in post-COVID ME/CFS compared with the control group.

Assessment of the functional characteristics of microcirculation by laser doppler flowmetry revealed obvious and very similar changes in ME/CFS and post-COVID ME/CFS compared to the healthy controls.  The identified pattern corresponded to the hyperemic form of microcirculation disorders, usually observed in acute inflammatory processes or in deficiency of systemic vasoconstriction influences.

Source: Ryabkova, V.A.; Gavrilova, N.Y.; Fedotkina, T.V.; Churilov, L.P.; Shoenfeld, Y. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-COVID Syndrome: A Common Neuroimmune Ground?. Preprints 2022, 2022090289 (doi: 10.20944/preprints202209.0289.v1) https://www.preprints.org/manuscript/202209.0289/v1 (Full study available as PDF file)

Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue

Abstract:

Post-COVID-19 syndrome (PCS) summarizes persisting sequelae after infection with the severe-acute-respiratory-syndrome-Coronavirus-2 (SARS-CoV-2). PCS can affect patients of all covid-19 disease severities. As previous studies revealed impaired blood flow as a provoking factor for triggering PCS, it was the aim of the present study to investigate a potential association of self-reported chronic fatigue and retinal microcirculation in patients with PCS, potentially indicating an objective biomarker.

A prospective study was performed, including 201 subjects: 173 patients with PCS and 28 controls. Retinal microcirculation was visualized by OCT-Angiography (OCT-A) and quantified by the Erlangen-Angio-Tool as macula and peripapillary vessel density (VD). Chronic Fatigue (CF) was assessed with the variables ‘Bell score’, age and gender. The VD in the superficial vascular plexus (SVP), intermediate capillary plexus (ICP) and deep capillary plexus (DCP) were analyzed considering the repetitions (12 times). Taking in account of such repetitions a mixed model was performed to detect possible differences in the least square means between different groups of analysis.

An age effect on VD was observed between patients and controls (p<0.0001). Gender analysis yielded that women with PCS showed lower VD levels in SVP compared to male patients (p=0.0015). The PCS patients showed significantly lower VD of ICP as compared to the controls (p=0.0001, [CI: 0.32; 1]). Moreover, considering PCS patients, the mixed model reveals a significant difference between chronic fatigue (CF) and without CF in VD of SVP (p=0.0033, [CI: -4.5; -0.92]). The model included age, gender and the variable ‘Bell score’, representing a subjective marker for CF. Consequently, the retinal microcirculation might be an objective biomarker in subjective-reported chronic fatigue of patients with PCS.

Source: Sarah Schlick, Marianna Lucio, Alexander Bartsch, Adam Skornia, Jakob Hoffmanns, Charlotte Szewczykowski, Thora Schröder, Franziska Raith, Lennart Rogge, Felix Heltmann, Michael Moritz, Lorenz Beitlich, Julia Schottenhamml, Martin Herrmann, Thomas Harrer, Marion Ganslmayer, Friedrich E. Kruse, Robert Lämmer, Christian Mardin, Bettina Hohberger. Post-COVID-19 syndrome: retinal microcirculation as a potential marker for chronic fatigue. medRxiv 2022.09.23.22280264; doi: https://doi.org/10.1101/2022.09.23.22280264 https://www.medrxiv.org/content/10.1101/2022.09.23.22280264v1.full-text (Full text)

Chronic Fatigue Associated with Post-COVID Syndrome versus Transient Fatigue Caused by High-Intensity Exercise: Are They Comparable in Terms of Vascular Effects?

Abstract:

Purpose: The pathophysiology of chronic fatigue associated with post-COVID syndrome is not well recognized. It is assumed that this condition is partly due to vascular dysfunction developed during an acute phase of infection. There is great demand for a diagnostic tool that is able to clinically assess post-COVID syndrome and monitor the rehabilitation process.

Patients and methods: The Flow Mediated Skin Fluorescence (FMSF) technique appears uniquely suitable for the analysis of basal microcirculatory oscillations and reactive hyperemia induced by transient ischemia. The FMSF was used to measure vascular circulation in 45 patients with post-COVID syndrome. The results were compared with those for a group of 26 amateur runners before and after high-intensity exercise as well as for a control group of 32 healthy age-matched individuals.

Results: Based on the observed changes in the NOI (Normoxia Oscillatory Index) and RHR (Reactive Hyperemia Response) parameters measured with the FMSF technique, it was found that chronic fatigue associated with post-COVID syndrome is comparable with transient fatigue caused by high-intensity exercise in terms of vascular effects, which are associated with vascular stress in the macrocirculation and microcirculation. Acute and chronic fatigue symptomatology shared similarly altered changes in the NOI and RHR parameters and both can be linked to calcium homeostasis modification.

Conclusion: The NOI and RHR parameters measured with the FMSF technique can be used for non-invasive clinical assessment of post-COVID syndrome as well as for monitoring the rehabilitation process.

Source: Chudzik M, Cender A, Mordaka R, Zielinski J, Katarzynska J, Marcinek A, Gebicki J. Chronic Fatigue Associated with Post-COVID Syndrome versus Transient Fatigue Caused by High-Intensity Exercise: Are They Comparable in Terms of Vascular Effects? Vasc Health Risk Manag. 2022 Sep 6;18:711-719. doi: 10.2147/VHRM.S371468. PMID: 36097586; PMCID: PMC9464031.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9464031/ (Full text)

Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation

Abstract:

Long COVID (LC) describes the clinical phenotype of symptoms after infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Diagnostic and therapeutic options are limited, as the pathomechanism of LC is elusive. As the number of acute SARS-CoV-2 infections was and is large, LC will be a challenge for the healthcare system. Previous studies revealed an impaired blood flow, the formation of microclots, and autoimmune mechanisms as potential factors in this complex interplay. Since functionally active autoantibodies against G-protein-coupled receptors (GPCR-AAbs) were observed in patients after SARS-CoV-2 infection, this study aimed to correlate the appearance of GPCR-AAbs with capillary microcirculation.

The seropositivity of GPCR-AAbs was measured by an established cardiomyocyte bioassay in 42 patients with LC and 6 controls. Retinal microcirculation was measured by OCT-angiography and quantified as macula and peripapillary vessel density (VD) by the Erlangen-Angio Tool. A statistical analysis yielded impaired VD in patients with LC compared to the controls, which was accentuated in female persons. A significant decrease in macula and peripapillary VD for AAbs targeting adrenergic β2-receptor, MAS-receptor angiotensin-II-type-1 receptor, and adrenergic α1-receptor were observed. The present study might suggest that a seropositivity of GPCR-AAbs can be linked to an impaired retinal capillary microcirculation, potentially mirroring the systemic microcirculation with consecutive clinical symptoms.

Source: Szewczykowski C, Mardin C, Lucio M, Wallukat G, Hoffmanns J, Schröder T, Raith F, Rogge L, Heltmann F, Moritz M, Beitlich L, Schottenhamml J, Herrmann M, Harrer T, Ganslmayer M, Kruse FE, Kräter M, Guck J, Lämmer R, Zenkel M, Gießl A, Hohberger B. Long COVID: Association of Functional Autoantibodies against G-Protein-Coupled Receptors with an Impaired Retinal Microcirculation. Int J Mol Sci. 2022 Jun 29;23(13):7209. doi: 10.3390/ijms23137209. PMID: 35806214. https://www.mdpi.com/1422-0067/23/13/7209/htm (Full text)

Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study

Abstract:

Objective: Non-respiratory long-coronavirus disease 2019 (COVID-19) symptoms are mainly related to a long-lasting endothelial dysfunction and microcirculation impairment. We hypothesized that Sulodexide, a purified glycosaminoglycan mixture with a beneficial endothelial effect in arterial and venous peripheral diseases, may be effective in a subset of patients with long COVID-19.

Approach and results: We conducted a multicenter prospective quasi-experimental study. A total of 290 patients from the TUN-EndCOV study with long-COVID-19 symptoms and endothelial dysfunction were included. The endothelial function was clinically assessed using a post-occlusive reactive hyperemia protocol with finger thermal monitoring device. Endothelial quality index (EQI) was assessed at inclusion and at 21 days later. The study population was assigned to a sulodexide group (144 patients) or a no-medical treatment group (146 patients). Clinical characteristics were similar at inclusion in the two groups. Fatigue, shortness of breath, and chest pain were the most common symptoms, respectively, 54.5, 53.8, and 28.3%. At 21 days, the sulodexide group improved significantly better than the no-medical treatment group in chest pain (83.7 vs. 43.6%, p < 10-3), palpitations (85.2 vs. 52.9%, p = 0.009), and endothelial function [median delta-EQI 0.66 (0.6) vs. 0.18 (0.3); p < 10-3]. Endothelial function improvement was significantly correlated with chest pain and palpitations recovery (AUC, i.e., area under the curve = 0.66, CI [0.57- 0.75], p = 0.001 and AUC = 0.60, CI [0.51- 0.69], p = 0.03, respectively).

Conclusion: Sulodexide significantly improves long-lasting post-COVID-19 endothelial dysfunction and alleviates chest pain and palpitations.

Source: Charfeddine S, Ibnhadjamor H, Jdidi J, Torjmen S, Kraiem S, Bahloul A, Makni A, Kallel N, Moussa N, Boudaya M, Touil I, Ghrab A, Elghoul J, Meddeb Z, Thabet Y, Ben Salem K, Addad F, Bouslama K, Milouchi S, Hammami R, Abdessalem S, Abid L. Sulodexide Significantly Improves Endothelial Dysfunction and Alleviates Chest Pain and Palpitations in Patients With Long-COVID-19: Insights From TUN-EndCOV Study. Front Cardiovasc Med. 2022 May 12;9:866113. doi: 10.3389/fcvm.2022.866113. PMID: 35647070; PMCID: PMC9133483. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9133483/ (Full text)

Red blood cell deformability is diminished in patients with Chronic Fatigue Syndrome

[Editor’s comment: Conspicuously absent from the reference section in this paper is the pioneering work of L. O. Simpson. In 1989 Dr. Leslie O. Simpson, a New Zealand pathologist, discovered that the blood of people with ME/CFS tends to have a higher proportion of cup-shaped red blood cells. (Simpson, L.O. “Nondiscocyte Erythrocytes in Myalgic Encephalomyelitis.” New Zealand Medical Journal 2(864):126-127,1989.) Cup-shaped cells are more difficult to squeeze through small capillaries than disc-shaped cells, making it harder for blood to oxygenate capillary-dependent tissues. In further investigations, Dr. Simpson also observed similar changes in red blood cell morphology in other diseases. He noted that red blood cell shape can change from minute to minute. A summary of Dr. Simpson’s work on red blood cell morphology in ME/CFS can be found HERE.]

Abstract:

BACKGROUND: Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a poorly understood disease. Amongst others symptoms, the disease is associated with profound fatigue, cognitive dysfunction, sleep abnormalities, and other symptoms that are made worse by physical or mental exertion. While the etiology of the disease is still debated, evidence suggests oxidative damage to immune and hematological systems as one of the pathophysiological mechanisms of the disease. Since red blood cells (RBCs) are well-known scavengers of oxidative stress, and are critical in microvascular perfusion and tissue oxygenation, we hypothesized that RBC deformability is adversely affected in ME/CFS.

METHODS: We used a custom microfluidic platform and high-speed microscopy to assess the difference in deformability of RBCs obtained from ME/CFS patients and age-matched healthy controls.

RESULTS AND CONCLUSION: We observed from various measures of deformability that the RBCs isolated from ME/CFS patients were significantly stiffer than those from healthy controls. Our observations suggest that RBC transport through microcapillaries may explain, at least in part, the ME/CFS phenotype, and promises to be a novel first-pass diagnostic test

Source: Saha KA, Schmidt RB, Wilhelmy J, Nguyen V, Abugherir A, Do KJ, Nemat-Gorgani M, Davis WR, Ramasubramanian KA. Red blood cell deformability is diminished in patients with Chronic Fatigue Syndrome.Clin Hemorheol Microcirc. 2018 Dec 28. doi: 10.3233/CH-180469. [Epub ahead of print]  https://content.iospress.com/articles/clinical-hemorheology-and-microcirculation/ch180469 (Full article)