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

Charfeddine, S.; Ibnhadjamor, Hassen; Jdidi, J.; Torjmen, Slim; Kraiem, Salma; Bahloul, A.; Makni, Ahmed; Kallel, N.; Moussa, N.; Boudaya, M.; Touil, I.; Ghrab, Aiman; Meddeb, Z.; Thabet, Yamina; Salem, Kais Ben; Addad, Faouzi; Bouslama, K.; Milouchi, Sami; Hammami, R.; Abdessalem, Salem; Abid, Leïla

doi:10.3389/fcvm.2022.866113

Cited by 28 publications

(25 citation statements)

References 42 publications

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“…Specifically, long COVID individuals showed a higher endothelial quality index and a slower response to the reperfusion phase. This finding was partially reversed after oral intake of sulodexide, a highly purified mixture of glycosaminoglycans, that includes fast-moving heparin and dermatan sulfate [ 15 ]. Indeed, our data imply that long COVID individuals respond inadequately to local variations of tissue metabolic demand.…”

Section: Discussionmentioning

confidence: 99%

Persistent capillary rarefication in long COVID syndrome

et al. 2022

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Background Recent studies have highlighted Coronavirus disease 2019 (COVID-19) as a multisystemic vascular disease. Up to 60% of the patients suffer from long-term sequelae and persistent symptoms even 6 months after the initial infection. Methods This prospective, observational study included 58 participants, 27 of whom were long COVID patients with persistent symptoms > 12 weeks after recovery from PCR-confirmed SARS-CoV-2 infection. Fifteen healthy volunteers and a historical cohort of critically ill COVID-19 patients (n = 16) served as controls. All participants underwent sublingual videomicroscopy using sidestream dark field imaging. A newly developed version of Glycocheck™ software was used to quantify vascular density, perfused boundary region (PBR-an inverse variable of endothelial glycocalyx dimensions), red blood cell velocity (VRBC) and the microvascular health score (MVHS™) in sublingual microvessels with diameters 4–25 µm. Measurements and main results Although dimensions of the glycocalyx were comparable to those of healthy controls, a µm-precise analysis showed a significant decrease of vascular density, that exclusively affected very small capillaries (D5: − 45.16%; D6: − 35.60%; D7: − 22.79%). Plotting VRBC of capillaries and feed vessels showed that the number of capillaries perfused in long COVID patients was comparable to that of critically ill COVID-19 patients and did not respond adequately to local variations of tissue metabolic demand. MVHS was markedly reduced in the long COVID cohort (healthy 3.87 vs. long COVID 2.72 points; p = 0.002). Conclusions Our current data strongly suggest that COVID-19 leaves a persistent capillary rarefication even 18 months after infection. Whether, to what extent, and when the observed damage might be reversible remains unclear.

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Section: Discussionmentioning

confidence: 99%

Persistent capillary rarefication in long COVID syndrome

et al. 2022

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“…In addition to the above drugs discussed, there are several other reports showing that serine protease inhibitors (camostat mesylate), KLF2 activators [ 120 ], RIPK3 inhibitors [ 166 ], spironolactone [ 77 ], glycocalyx repairing drugs [ 67 ], purified glycosaminoglycan mixture sulodexide [ 167 ], CCR5 blockers (Maraviroc), anti-VEGF (bevacizumab [ 168 ]), adrecizumab [ 169 ], mesenchymal stem cell therapy [ 170 ], estrogen [ 171 ], melatonin [ 172 ] and NO donor [ 173 ] could also be beneficial (Fig. 6 ).…”

Section: Therapeutic Agents Targeting Endothelial Dysfunction In Covi...mentioning

confidence: 99%

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

2022

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The fight against coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is still raging. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19) is understudied. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. SARS-CoV-2 infection primarily affects the pulmonary system, but accumulating evidence suggests that it also affects the pan-vasculature in the extrapulmonary systems by directly (via virus infection) or indirectly (via cytokine storm), causing endothelial dysfunction (endotheliitis, endothelialitis and endotheliopathy) and multi-organ injury. Mounting evidence suggests that SARS-CoV-2 infection leads to multiple instances of endothelial dysfunction, including reduced nitric oxide (NO) bioavailability, oxidative stress, endothelial injury, glycocalyx/barrier disruption, hyperpermeability, inflammation/leukocyte adhesion, senescence, endothelial-to-mesenchymal transition (EndoMT), hypercoagulability, thrombosis and many others. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Of translational relevance, several candidate drugs which are endothelial protective have been shown to improve clinical manifestations of COVID-19 patients. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. We envisage further development of cellular models and suitable animal models mimicking endothelial dysfunction aspect of COVID-19 being able to accelerate the discovery of new drugs targeting endothelial dysfunction in pan-vasculature from COVID-19 patients.

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“…There were six published trials 25 , 26 , 27 , 28 , 29 , 30 on long COVID interventions conducted in the following countries: Tunisia, India, Italy, and Saudi Arabia. Four of these trials were randomized 27 , 28 , 29 , 30 and only two were double‐blind.…”

Section: Resultsmentioning

confidence: 99%

“…Two trials included only premorbid healthy participants, 26 , 30 while another three trials included participants with at least one comorbidity such as hypertension and diabetes mellitus. 25 , 27 , 29 The diagnosis of SARS‐CoV‐2 infection was made via positive polymerase chain reaction (PCR) test or SARS‐CoV‐2 antigen test in all six trials. None of the trials stratified participants according to vaccination status or SARS‐CoV‐2 variant.…”

Section: Resultsmentioning

confidence: 99%

“…The recently published TUN‐EndCOV study recruited 290 patients with long COVID symptoms and proven endothelial dysfunction. 25 Approximately one‐quarter of the participants had diabetes mellitus, and one‐third had hypertension. After receiving oral sulodexide for 3 weeks, there was a significant improvement in endothelial function (measured as postocclusive reactive hyperemia) and this was associated with the alleviation of chest pain and palpitations.…”

Section: Resultsmentioning

confidence: 99%

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Clinical trials on the pharmacological treatment of long COVID: A systematic review

Chee

Fan

Young

et al. 2022

Journal of Medical Virology

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The postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection (PASC), also known as post‐acute coronavirus disease 19 (COVID‐19) or the long COVID syndrome (long COVID) is an emerging public health concern. A substantial proportion of individuals may remain symptomatic months after initial recovery. An updated review of published and ongoing trials focusing on managing long COVID will help identify gaps and address the unmet needs of patients suffering from this potentially debilitating syndrome. A comprehensive literature search was conducted on the international databases and clinical trial registries from inception to 31 July 2022. This review included 6 published trials and 54 trial registration records. There is significant heterogeneity in the characterization of long COVID and ascertainment of primary outcomes. Most of the trials are focused on individual symptoms of long COVID or isolated organ dysfunction, classified according to cardiovascular, respiratory and functional capacity, neurological and psychological, fatigue, and olfactory dysfunction. Most of the interventions are related to the mechanisms causing the individual symptoms. Although the six published trials showed significant improvement in the symptoms or organ dysfunction studied, these initial studies lack internal and external validity limiting the generalizability. This review provides an update of the pharmacological agents that could be used to treat long COVID. Further standardization of the diagnostic criteria, inclusion of participants with concomitant chronic cardiometabolic diseases and standardization of outcomes will be essential in future clinical trials.

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

Cited by 28 publications

References 42 publications

Persistent capillary rarefication in long COVID syndrome

Persistent capillary rarefication in long COVID syndrome

Endothelial dysfunction in COVID-19: an overview of evidence, biomarkers, mechanisms and potential therapies

Clinical trials on the pharmacological treatment of long COVID: A systematic review

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