Tag: endothelial dysfunction

Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition that is characterized by unresolved fatigue, post-exertion symptom exacerbation (PESE), cognitive dysfunction, orthostatic intolerance, and other symptoms. ME/CFS lacks established clinical biomarkers and requires further elucidation of disease mechanisms.

A growing number of studies demonstrate signs of hematological and cardiovascular pathology in ME/CFS cohorts, including hyperactivated platelets, endothelial dysfunction, vascular dysregulation, and anomalous clotting processes. To build on these findings, and to identify potential biomarkers that can be related to pathophysiology, we measured differences in protein expression in platelet-poor plasma (PPP) samples from 15 ME/CFS study participants and 10 controls not previously infected with SARS-CoV-2, using DIA LC-MS/MS.

We identified 24 proteins that are significantly increased in the ME/CFS group compared to the controls, and 21 proteins that are significantly downregulated. Proteins related to clotting processes – thrombospondin-1 (important in platelet activation), platelet factor 4, and protein S – were differentially expressed in the ME/CFS group, suggestive of a dysregulated coagulation system and abnormal endothelial function. Complement machinery was also significantly downregulated, including C9 which forms part of the membrane attack complex. Additionally, we identified a significant upregulation of lactotransferrin, protein S100-A9, and an immunoglobulin variant.

The findings from this experiment further implicate the coagulation and immune system in ME/CFS, and bring to attention the pathology of or imposed on the endothelium. This study highlights potential systems and proteins that require further research with regards to their contribution to the pathogenesis of ME/CFS, symptom manifestation, and biomarker potential, and also gives insight into the hematological and cardiovascular risk for ME/CFS individuals affected by diabetes mellitus.

Source: Nunes, M., Vlok, M., Proal, A. et al. Data-independent LC-MS/MS analysis of ME/CFS plasma reveals a dysregulated coagulation system, endothelial dysfunction, downregulation of complement machinery. Cardiovasc Diabetol 23, 254 (2024). https://doi.org/10.1186/s12933-024-02315-x https://cardiab.biomedcentral.com/articles/10.1186/s12933-024-02315-x (Full text)

The Role of Heparin in Postural Orthostatic Tachycardia Syndrome and Other Post-Acute Sequelae of COVID-19

Abstract:

The therapeutic management and short-term consequences of the coronavirus disease 2019 (COVID-19) are well known. However, COVID-19 post-acute sequelae are less known and represent a public health problem worldwide. Patients with COVID-19 who present post-acute sequelae may display immune dysregulation, a procoagulant state, and persistent microvascular endotheliopathy that could trigger microvascular thrombosis. These elements have also been implicated in the physiopathology of postural orthostatic tachycardia syndrome, a frequent sequela in post-COVID-19 patients.
These mechanisms, directly associated with post-acute sequelae, might determine the thrombotic consequences of COVID-19 and the need for early anticoagulation therapy. In this context, heparin has several potential benefits, including immunomodulatory, anticoagulant, antiviral, pro-endothelial, and vascular effects, that could be helpful in the treatment of COVID-19 post-acute sequelae. In this article, we review the evidence surrounding the post-acute sequelae of COVID-19 and the potential benefits of the use of heparin, with a special focus on the treatment of postural orthostatic tachycardia syndrome.

Source: Gómez-Moyano E, Pavón-Morón J, Rodríguez-Capitán J, Bardán-Rebollar D, Ramos-Carrera T, Villalobos-Sánchez A, Pérez de Pedro I, Ruiz-García FJ, Mora-Robles J, López-Sampalo A, et al. The Role of Heparin in Postural Orthostatic Tachycardia Syndrome and Other Post-Acute Sequelae of COVID-19. Journal of Clinical Medicine. 2024; 13(8):2405. https://doi.org/10.3390/jcm13082405 https://www.mdpi.com/2077-0383/13/8/2405 (Full text)

Herpesvirus Infection as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Understanding the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is critical for advancing treatment options. This review explores the novel hypothesis that herpesviruses’ infection of endothelial cells (ECs) may underlie ME/CFS symptomatology.
We review evidence linking herpesviruses to persistent EC infection and the implications for endothelial dysfunction, encompassing blood flow regulation, coagulation, and cognitive impairment – symptoms consistent with ME/CFS and Long COVID. The paper provides a synthesis of current research on herpesvirus latency and reactivation, detailing the impact on ECs and subsequent systemic complications, including latent modulation and long-term maladaptation.
We suggest that the chronicity of ME/CFS symptoms and the multisystemic nature of the disease may be partly attributable to herpesvirus-induced endothelial maladaptation. Our conclusions underscore the necessity for further investigation into the prevalence and load of herpesvirus infection within ECs of ME/CFS patients.
This review offers a conceptual advance by proposing an endothelial infection model as a systemic mechanism contributing to ME/CFS, steering future research towards potentially unexplored avenues in understanding and treating this complex syndrome.
Source: Nunes, J.M.; Kell, D.B.; Pretorius, E. Herpesvirus Infection as a Systemic Pathological Axis in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints 2024, 2024011486. https://doi.org/10.20944/preprints202401.1486.v1 https://www.preprints.org/manuscript/202401.1486/v1 (Full text available as PDF file)

Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients

Abstract:

Background: Long COVID symptoms are widely diffused and have a poorly understood pathophysiology, with possible involvement of inflammatory cytokines.

Materials and methods: A prospective follow-up study involved 385 unvaccinated patients, started 1 month after SARS-CoV-2 infection and continued for up to 12 months. We compared circulating biomarkers of neutrophil degranulation, endothelial and metabolic dysfunction in subjects with long COVID symptoms and in asymptomatic post-COVID controls.

Results: The highest occurrence of symptoms (71%) was after 3 months from the infection, decreasing to 62.3% and 29.4% at 6 and 12 months, respectively. Compared to controls, long COVID patients had increased levels of the neutrophilic degranulation indices MMP-8 and MPO, of endothelial dysfunction indices L-selectin and P-selectin. Among indices of metabolic dysfunction, leptin levels were higher in long COVID patients than in controls.

Conclusion: In unvaccinated patients, symptoms may persist up to 1 year after acute COVID infection, with increased indices of neutrophil degranulation, endothelial and metabolic dysfunction. The clinical implications of specific inflammatory biomarkers require further attention, especially in individuals with fatigue and long COVID-linked cognitive dysfunctions.

Source: Di Ciaula A, Liberale L, Portincasa P, Khalil M, Galerati I, Farella I, Noto A, JohnBritto S, Moriero M, Michelauz C, Frè F, Olivero C, Bertolotto M, Montecucco F, Carbone F, Bonfrate L. Neutrophil degranulation, endothelial and metabolic dysfunction in unvaccinated long COVID patients. Eur J Clin Invest. 2024 Jan 16:e14155. doi: 10.1111/eci.14155. Epub ahead of print. PMID: 38226472. https://pubmed.ncbi.nlm.nih.gov/38226472/

Cardiovascular autonomic dysfunction in post-COVID-19 syndrome: a major health-care burden

Abstract:

Cardiovascular autonomic dysfunction (CVAD) is a malfunction of the cardiovascular system caused by deranged autonomic control of circulatory homeostasis. CVAD is an important component of post-COVID-19 syndrome, also termed long COVID, and might affect one-third of highly symptomatic patients with COVID-19. The effects of CVAD can be seen at both the whole-body level, with impairment of heart rate and blood pressure control, and in specific body regions, typically manifesting as microvascular dysfunction.

Many severely affected patients with long COVID meet the diagnostic criteria for two common presentations of CVAD: postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. CVAD can also manifest as disorders associated with hypotension, such as orthostatic or postprandial hypotension, and recurrent reflex syncope. Advances in research, accelerated by the COVID-19 pandemic, have identified new potential pathophysiological mechanisms, diagnostic methods and therapeutic targets in CVAD. For clinicians who daily see patients with CVAD, knowledge of its symptomatology, detection and appropriate management is more important than ever.

In this Review, we define CVAD and its major forms that are encountered in post-COVID-19 syndrome, describe possible CVAD aetiologies, and discuss how CVAD, as a component of post-COVID-19 syndrome, can be diagnosed and managed. Moreover, we outline directions for future research to discover more efficient ways to cope with this prevalent and long-lasting condition.

Key points:

  • Cardiovascular autonomic dysfunction (CVAD), in particular postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia, are among the most frequent and distinct phenotypes of post-COVID-19 syndrome; one-third of highly symptomatic patients can be affected.
  • CVAD arises from a malfunction of the autonomic control of the circulation, and can involve failure or inadequate or excessive activation of the sympathetic and parasympathetic components of the autonomic nervous system.
  • As well as global circulatory disturbances, CVAD in post-COVID-19 syndrome can manifest as microvascular and endothelial dysfunction, with local symptoms such as headache, brain fog, chest pain, dyspnoea and peripheral circulatory symptoms, including skin discolouration, oedema, Raynaud-like phenomena, and heat and cold intolerance.
  • A structured diagnostic work-up based on a detailed patient history, cardiovascular autonomic testing, long-term electrocardiogram and blood-pressure monitoring, and ancillary cardiac and peripheral vascular tests will lead to an appropriate diagnosis.
  • Management of CVAD in post-COVID-19 syndrome should involve a correct diagnosis, patient education, and both non-pharmacological and pharmacological methods; a tailored exercise training programme, blood volume expansion and compression garments are especially effective.
  • Pharmacological approaches target heart rate control, blood volume expansion, promotion of vasoconstriction and venoconstriction, and reduction of hyperadrenergic drive.

Source: Fedorowski, A., Fanciulli, A., Raj, S.R. et al. Cardiovascular autonomic dysfunction in post-COVID-19 syndrome: a major health-care burden. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-023-00962-3 https://www.nature.com/articles/s41569-023-00962-3

Sex differences in vascular endothelial function related to acute and long COVID-19

Abstract:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been at the forefront of health sciences research since its emergence in China in 2019 that quickly led to a global pandemic. As a result of this research, and the large numbers of infected patients globally, there were rapid enhancements made in our understanding of Coronavirus disease 2019 (COVID-19) pathology, including its role in the development of uncontrolled immune responses and its link to the development of endotheliitis and endothelial dysfunction.

There were also some noted differences in the rate and severity of infection between males and females with acute COVID. Some individuals infected with SARS-CoV-2 also experience long-COVID, an important hallmark symptom of this being Myalgic Encephalomyelitis-Chronic Fatigue Syndrome (ME-CFS), also experienced differently between males and females.

The purpose of this review is to discuss the impact of sex on the vasculature during acute and long COVID-19, present any link between ME-CFS and endothelial dysfunction, and provide evidence for the relationship between ME-CFS and the immune system. We also will delineate biological sex differences observed in other post viral infections and, assess if sex differences exist in how the immune system responds to viral infection causing ME-CFS.

Source: Kayla KA, Bédard-Matteau J, Rousseau S, Tabrizchi R, Noriko D. Sex differences in vascular endothelial function related to acute and long COVID-19. Vascul Pharmacol. 2023 Dec 1:107250. doi: 10.1016/j.vph.2023.107250. Epub ahead of print. PMID: 38043758. https://www.sciencedirect.com/science/article/abs/pii/S1537189123001106 (Full text)

Long COVID: Clinical Findings, Pathology, and Endothelial Molecular Mechanisms

Abstract:

Persistence of COVID-19 symptoms may follow SARS-CoV-2 infection. The incidence of long COVID increases with the severity of acute disease, but even mild disease can be associated with sequelae. The symptoms vary widely with fatigue, shortness of breath, and cognitive dysfunction being the most common. Abnormalities of multiple organs have been documented and histopathology has revealed widespread microthrombi. Elevated levels of complement are present in acute COVID-19 patients and may persist at lower levels in long COVID. Evidence supports complement activation with endotheliopathy associated disease as the molecular mechanism causing both acute and long COVID.

Section snippets

Prevalence and Definition: A review and meta-analysis of published results of long COVID studies suggest a global prevalence of the post COVID-19 condition of approximately 43% with a wide range of 9-81%.1 Using a population-representative survey epidemiologists have estimated the prevalence of long COVID in the United States to be 7.3%.2 In an effort to standardize the definition of long COVID the World Health Organization (WHO) established a Clinical Case Definition Working Group on the Post-COVID-19 Condition.3

Symptoms: The symptoms of long COVID are similar to those observed in patients following chronic critical illness and hospitalization in intensive care units.4 In the United Kingdom a retrospective matched cohort study was undertaken to determine symptoms beyond 12 weeks in non-hospitalized SARS-CoV-2 infected patients compared with uninfected patients.5 A cohort of 486,149 non-hospitalized adults with confirmed SARS-CoV-2 infection was compared to 1,944,580 propensity score-matched adults with no record

Evaluation and Testing: The previously referenced study of COVID patients 6 months after discharge from hospital in Wuhan, China enrolled patients in radiographic, pulmonary function, and blood testing.7 High resolution computerized tomography (HRCT) was performed on 390 patients and was abnormal in 52% not requiring supplemental oxygen and 54% of patients requiring supplemental oxygen. Lung diffusion impairment was noted in 22% of patients not requiring oxygen and up to 56% of patients requiring supplemental oxygen

Pathology and Histopathology: Autopsy data has contributed considerable information to our understanding of SARS-CoV-2 infection. A review of the histopathological findings in coronavirus disease 2019 reported diffuse alveolar damage (DAD), multiple organ microvasculitis, and lymphocytic infiltration with changes in immune organs and emphasized the observance of microthrombosis in numerous studies.18 An autopsy study from New York Presbyterian Hospital revealed macroscopic and/or microscopic thrombi in 84% patients.19

Complement, von Willebrand factor, and Endotheliopathy: A prospective study in the Netherlands was conducted to examine the role of complement as a component of the innate immune response to SARS-CoV-2 infection.29 Investigators found that complement factors C3a, C3c, and the terminal complement complex or membrane attack complex (MAC) were increased in COVID-19 patients compared to healthy controls. Furthermore, these complement factors were more increased in patients who were admitted to intensive care units, died, or experienced thromboembolic

Discussion: Long COVID or post acute sequelae of COVID-19 (PASC) is a frequent occurrence in patients recovering from acute SARS-CoV-2 infection. Estimates of the incidence vary widely with the more recent estimates trending below 10% in the United States. Changes in definition, increasing population immunity, treatment with antivirals and monoclonal antibodies, and newer variants may all play a role in the downward trend. The symptoms of long COVID are numerous and reflect the multi-organ nature of both…

Conclusion: The pathology and histopathology of COVID-19 patients has demonstrated the presence of widespread multi-organ microthrombi as a central feature of SARS-CoV-2 infection. Elevated levels of complement factors and von Willebrand factor have been found in COVID-19 patients and the degree of increases are directly related to the severity of disease and persistent high levels correlate with long COVID symptoms.39 Persisting symptoms following acute COVID-19 occur more often and are more debilitating

Source: Hawley HB. Long COVID: Clinical Findings, Pathology, and Endothelial Molecular Mechanisms. Am J Med. 2023 Sep 11:S0002-9343(23)00539-9. doi: 10.1016/j.amjmed.2023.08.008. Epub ahead of print. PMID: 37704072. https://www.sciencedirect.com/science/article/abs/pii/S0002934323005399

Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations

Abstract:

Individuals with SARS-CoV-2 infection can develop symptoms that persist well beyond the acute phase of COVID-19 or emerge after the acute phase, lasting for weeks or months after the initial acute illness. The post-acute sequelae of COVID-19, which include physical, cognitive, and mental health impairments, are known collectively as long COVID or post-COVID-19 condition.

The substantial burden of this multisystem condition is felt at individual, health-care system, and socioeconomic levels, on an unprecedented scale. Survivors of COVID-19-related critical illness are at risk of the well known sequelae of acute respiratory distress syndrome, sepsis, and chronic critical illness, and these multidimensional morbidities might be difficult to differentiate from the specific effects of SARS-CoV-2 and COVID-19.

We provide an overview of the manifestations of post-COVID-19 condition after critical illness in adults. We explore the effects on various organ systems, describe potential pathophysiological mechanisms, and consider the challenges of providing clinical care and support for survivors of critical illness with multisystem manifestations.

Research is needed to reduce the incidence of post-acute sequelae of COVID-19-related critical illness and to optimise therapeutic and rehabilitative care and support for patients.

Source: Parotto M, Gyöngyösi M, Howe K, Myatra SN, Ranzani O, Shankar-Hari M, Herridge MS. Post-acute sequelae of COVID-19: understanding and addressing the burden of multisystem manifestations. Lancet Respir Med. 2023 Jul 17:S2213-2600(23)00239-4. doi: 10.1016/S2213-2600(23)00239-4. Epub ahead of print. PMID: 37475125. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(23)00239-4/fulltext (Full text)

Circulating Reelin promotes inflammation and modulates disease activity in acute and long COVID-19 cases

Abstract:

Thromboembolic complications and excessive inflammation are frequent in severe COVID-19, potentially leading to long COVID. In non-COVID studies, we and others demonstrated that circulating Reelin promotes leukocyte infiltration and thrombosis. Thus, we hypothesized that Reelin participates in endothelial dysfunction and hyperinflammation during COVID-19.

We showed that Reelin was increased in COVID-19 patients and correlated with the disease activity. In the severe COVID-19 group, we observed a hyperinflammatory state, as judged by increased concentration of cytokines (IL-1α, IL-4, IL-6, IL-10 and IL-17A), chemokines (IP-10 and MIP-1β), and adhesion markers (E-selectin and ICAM-1).

Reelin level was correlated with IL-1α, IL-4, IP-10, MIP-1β, and ICAM-1, suggesting a specific role for Reelin in COVID-19 progression. Furthermore, Reelin and all of the inflammatory markers aforementioned returned to normal in a long COVID cohort, showing that the hyperinflammatory state was resolved. Finally, we tested Reelin inhibition with the anti-Reelin antibody CR-50 in hACE2 transgenic mice infected with SARS-CoV-2. CR-50 prophylactic treatment decreased mortality and disease severity in this model.

These results demonstrate a direct proinflammatory function for Reelin in COVID-19 and identify it as a drug target. This work opens translational clinical applications in severe SARS-CoV-2 infection and beyond in auto-inflammatory diseases.

Source: Calvier L, Drelich A, Hsu J, Tseng CT, Mina Y, Nath A, Kounnas MZ, Herz J. Circulating Reelin promotes inflammation and modulates disease activity in acute and long COVID-19 cases. Front Immunol. 2023 Jun 27;14:1185748. doi: 10.3389/fimmu.2023.1185748. PMID: 37441066; PMCID: PMC10333573. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10333573/ (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/