Research & Studies

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GlycoCheck is being used by researchers in hospitals and universities in Africa, Asia, Australia, China, Europe, Japan, Russia, and the United States.

Examples of Diseases and Conditions Being Researched

The Crucial Consortium brings together 12 partners from multiple fields (clinicians, fundamental scientists, scientific SMEs, exploitation and dissemination SME, management SME, and a patient advocacy), representing 7 different countries.

The Crucial Consortium aims to address a difficult problem regarding how co-morbidities give rise both to mental disorders and non-mental disorders. In order to achieve this, they have assembled a consortium that has a balanced mix of skills on several levels.

It consists of fundamental scientists and clinicians. It consists of specialists in neuroscience (UM, Scannexus) and in cardiovascular science (UCL, UNAV, FIMA, GlycoCheck, KU Leuven, VIB).

The clinical scientists are strong leaders in the field of MRI (UCL, UM, UNAV, Scannexus), whereas the fundamental partners have strong skills in molecular biology and genetics that will allow them to develop new biomarkers and identify new pathways for pharmaceutical targeting (FIMA, KU Leuven, VIB). Beyond bridging fundamental research and clinical applications, the project also combines several state-of-the-art technical approaches to answer the research objective. This includes cell signalling, (single cell) RNA-Seq, metabolic assessments, microvesicle’s biomarker identification, GlycoCheck measurements, and advanced imaging (MRI, 2-photon and light sheet microscopy). Read more here.

Universities & Hospitals Researching the Glycocalyx

 

Reproducibility and Validity Studies

 

Clinical Papers

Bedside analysis of the sublingual microvascular glycocalyx in the emergency room and intensive care unit – the GlycoNurse study
Kuempers 2018: good intra-observer and excellent intra-class reproducibility of PBR measurements in ICU and ER patients; increased PBR in ICU patients compared with ER patients. PBR correlates with Mean Arterial Pressure (MAP) and with CRP and SOFA scores.

Early Onset Preeclampsia Is Associated With Glycocalyx Degradation and Reduced Microvascular Perfusion
Weissgerber 2019: reproducibility of PBR measurements in pre-eclampsia patients increases when taking average of 2 or 3 measurements.

Association of sublingual microcirculation parameters and endothelial glycocalyx dimensions in resuscitated sepsis
Kuempers 2019: PBR in patients correlates with plasma Syndecan-1 levels and with Atomic Force Microscope measurements of glycocalyx dimension on cultured endothelial cells exposed to patients' plasma.

Increase in perfused boundary region of endothelial glycocalyx is associated with higher prevalence of ischemic heart disease and lesions of microcirculation and vascular wall
Gorshkov 2018: Increase of PBR is associated with ischemic heart disease.

Experimental Papers

Rapid Insulin-Mediated Increase in Microvascular Glycocalyx Accessibility in Skeletal Muscle May Contribute to Insulin-Mediated Glucose Disposal in Rats
Eskens 2013:Insulin increases PBR, and hyaluronidase treatment of the glycocalyx abolishes the insulin effect

Early impairment of skeletal muscle endothelial glycocalyx barrier properties in diet-induced obesity in mice
Eskens 2014: PBR is increased in response to a High Fat Diet (figure 2D) and PBR correlates with increased duration and level of plasma glucose (area under the curve of glucose) after Glucose Tolerance Test.

Perturbed mechanotransduction by endothelial surface glycocalyx modification greatly impairs the arteriogenic process
Potter 2015: Inhibition of endothelial hyaluronan production increases PBR, which is associated with diminished glycocalyx dimension as measured with the Dextran 150kDa exclusion zone (figure 1).

Advanced age results in a diminished endothelial glycocalyx
Machin 2018: PBR increase in old mice is associated with decreased glycocalyx dimension, and increased PBR is associated with decreased glycocalyx dimension.

 

Current Ongoing Studies Using GlycoCheck and Endocalyx

 

Dietary Interventions on Glycocalyx Dimensions in South Asian Patients With Diabetic Nephropathy. (Glycotreat)

Sponsor:
Leiden University Medical Center

Collaborators:
Dutch Kidney Foundation
Health Holland
Radboud University

Subsidizing Party:
Health Holland (Dutch Top Sector Life Sciences & Health)
Laan van Nieuw Oost-Indië 334,
2593 CE Den Haag
The Netherlands

Dutch Kidney Foundation
Groot Hertoginnelaan 34
1405 EE, Bussum
The Netherlands

Laboratory Sites:
Leiden University Medical Center, The Netherlands
Radboud University Medical Center, The Netherlands

Objective:
To investigate whether intervention with the dietary supplement Endocalyx™ improves the
Microvascular Health Index between baseline and 3 months in type 2 diabetic South Asian patients with
microalbuminuria in comparison to the placebo group.

Read the full trial information here.

Dietary Glycocalyx Precursor Supplementation Ameliorates Age-Related Vascular Dysfunction


Daniel R Machin, Daniel Nguyen, R Colton Bramwell, Lisa A Lesniewski, and Anthony J Donator

Daniel Machin and Tony Donato published an abstract at the Experimental Biology 2019 meeting on the effect of Endocalyx on aging in mice:

Published in The FASEB Journal (volume 33, Issue 1_supplement, 01 April 2019):

Published Online: 1 Apr 2019 Abstract Number: 828.1

Abstract

Large elastic artery stiffening and endothelial dysfunction, and associated reductions in nitric oxide (NO) bioavailability, are central features of vascular aging. We have recently demonstrated that the glycocalyx, a gel-like structure that is bound to the luminal surface of the vascular endothelium, is dysfunctional in the aged vasculature. The glycocalyx has several functions that are critical for the maintenance of a healthy vasculature. We sought to determine if chronic dietary supplementation of glycocalyx precursors (glucosamine sulfate, fucoidan, superoxide dismutase, and high molecular weight hyaluronan) could restore glycocalyx function, while concomitantly ameliorating age-related vascular dysfunction. Young (Y: 7 mo) and old (O: 30 mo) male B6D2F1 mice consumed a control (C) or glycocalyx precursor (GP: 37 mg/kg encapsulated chow provided courtesy of MicroVascular Health Solutions, LLC [U.S. Patent Serial No. 9,943,572]) diet ad libitum for 10 weeks. Glycocalyx barrier function (perfused boundary region [PBR]) was evaluated in the mesenteric microcirculation using an intravital microscope equipped with an automated capture and analysis system. PBR was ~13% higher in OC compared to YC, suggestive of an age-related impairment in glycocalyx barrier function, and this was normalized in OGP mice (Both P<0.05; Figure 1). At baseline, aortic pulse wave velocity (PWV), a measure of large artery stiffness, was higher in OC and OGP compared with YC mice (Both P<0.05; Figure 2). However, after the dietary intervention, PWV decreased by ~13% in OGP (P<0.05), whereas, PWV was unchanged in OC and YC mice after the 10 week period (P>0.05). We assessed endothelial function by endothelium-dependent dilation (EDD, maximal response to acetylcholine [ACh]) in the carotid artery. Carotid artery EDD was higher in YC and OGP compared to OC mice (92.5±2.4 and 90.7±2.3 vs. 69.0±4.9%, respectively, P<0.05). EDD of OGP was similar to YC mice (P>0.05). After incubation with the nitric oxide (NO) synthase inhibitor, L-NAME, the dilatory response did not differ between groups (P>0.05). NO bioavailability (max ACh dilation - max ACh+L-NAME dilation) was ~10–14 fold higher in YC and OGP compared to OC mice (Both P<0.05; Figure 3). Endothelium-independent dilation (vasodilation to sodium nitroprusside) was not different between groups (P>0.05). In young mice, GP diet did not affect any of the aforementioned measurements (P>0.05). In conclusion, 10 weeks of dietary GP supplementation in old mice restores glycocalyx barrier function that is accompanied by reduced aortic stiffness and augmented EDD and NO bioavailability, suggesting that the glycocalyx may be an effective therapeutic target for vascular dysfunction in older adults.

Support or Funding Information

This study was funded in part by grants from the National Institute of Health (R01 AG040297, R01 AG048366, K02 AG045339, K99 AT010017) and US Department of Veterans Affairs (1I01BX002151).

Read the Abstract here.

Pilot Study in 13 Healthy Volunteers


Summary of Findings from Clinical Studies

6.3.2 Food supplement
A pilot study was conducted among 13 healthy volunteers receiving the Endocalyx food supplement. After 3 months, the Microvascular Health Index measured by SDF imaging improved by 31%. After 4 months, the Microvascular Health Index in the volunteers improved by 50%. This showed the beneficial effects of the food supplement on the microvasculature as it significantly increased capillary density and red blood cell filling percentage, and reduced the perfused boundary region (unpublished data, H. Vink).

Summary of Known and Potential Risks and Benefits

6.4.2 Food supplement
In the pilot study with Endocalyx, no serious adverse effects were reported. One side effect that was reported was dizziness, as the Endocalyx supplement lowered the systolic blood pressure. The supplement is already used in general practitioners’ offices in the United States and to date; no one reported any major side effects. Studies conducted with the individual ingredients also did not report any serious adverse effects. A possible side effect may be an unknown allergic reaction to one of the ingredients of the supplement. Benefits of the Endocalyx food supplement in diabetic patients remain to be established but are mainly improving the microvascular health by supporting endothelial glycocalyx function.

 

Most Recent Published Papers Using GlycoCheck

 

Effects of Glucagon‐Like Peptide‐1 Receptor Agonists, Sodium‐Glucose Cotransporter‐2 Inhibitors, and Their Combination on Endothelial Glycocalyx, Arterial Function, and Myocardial Work Index in Patients With Type 2 Diabetes Mellitus After 12‐Month Treatment
Journal of the American Heart Association 2020 Apr 24

Uncoupling of Microvascular Blood Flow and Capillary Density in Vascular Cognitive Impairment
Frontiers in Neurology 2019 Dec 3

Derangement of the endothelial glycocalyx in sepsis
Wiley Online Library, 2018 December

Alterations of conjunctival glycocalyx and microcirculation in non-septic critically ill patients
Microvasc Res. 2018 Jul;118:44-48. doi: 10.1016/j.mvr.2018.02.004. Epub 2018 Feb 17.

Automated Measurement of Microvascular Function Reveals Dysfunction in Systemic Sclerosis: A Cross-sectional Study.
J Rheumatol. 2017 Nov;44(11):1603-1611. doi: 10.3899/jrheum.170120. Epub 2017 Sep 15.

Advanced age results in a diminished endothelial glycocalyx.
Am J Physiol Heart Circ Physiol. 2018 Sep 1;315(3):H531-H539. doi: 10.1152/ajpheart.00104.2018. Epub 2018 May 11.

Induced Trf2 deletion leads to aging vascular phenotype in mice associated with arterial telomere uncapping, senescence signaling, and oxidative stress.
J Mol Cell Cardiol. 2019 Feb;127:74-82. doi: 10.1016/j.yjmcc.2018.11.014. Epub 2018 Nov 29.

Impact of Intravenous Fluid Challenge Infusion Time on Macrocirculation and Endothelial Glycocalyx in Surgical and Critically Ill Patients.
Biomed Res Int. 2018 Nov 1;2018:8925345. doi: 10.1155/2018/8925345. eCollection 2018.

Neuraxial anesthesia is less harmful to the endothelial glycocalyx during elective joint surgery compared to general anesthesia1,2.
Clin Hemorheol Microcirc. 2018 Nov 29. doi: 10.3233/CH-180428. [Epub ahead of print]

Effect of acute hypernatremia induced by hypertonic saline administration on endothelial glycocalyx in rabbits.
Clin Hemorheol Microcirc. 2018 Nov 2. doi: 10.3233/CH-189907. [Epub ahead of print]

The Effect of Fluid Loading and Hypertonic Saline Solution on Cortical Cerebral Microcirculation and Glycocalyx Integrity.
J Neurosurg Anesthesiol. 2018 Jul 13. doi: 10.1097/ANA.0000000000000528. [Epub ahead of print]

Increase in perfused boundary region of endothelial glycocalyx is associated with higher prevalence of ischemic heart disease and lesions of microcirculation and vascular wall.
Microcirculation. 2018 May;25(4):e12454. doi: 10.1111/micc.12454.

In vivo assessment of the human cerebral microcirculation and its glycocalyx: A technical report.
J Neurosci Methods. 2018 Jun 1;303:114-125. doi: 10.1016/j.jneumeth.2018.03.009. Epub 2018 Mar 22.

HDL cholesterol levels and endothelial glycocalyx integrity in treated hypertensive patients.
J Clin Hypertens (Greenwich). 2018 Nov;20(11):1615-1623. doi: 10.1111/jch.13404. Epub 2018 Oct 13.

Association of impaired endothelial glycocalyx with arterial stiffness, coronary microcirculatory dysfunction, and abnormal myocardial deformation in untreated hypertensives.
J Clin Hypertens (Greenwich). 2018 Apr;20(4):672-679. doi: 10.1111/jch.13236. Epub 2018 Mar 2.

Sublingual functional capillary rarefaction in chronic heart failure.
Eur J Clin Invest. 2018 Feb;48(2). doi: 10.1111/eci.12869. Epub 2017 Dec 14.

Bedside analysis of the sublingual microvascular glycocalyx in the emergency room and intensive care unit - the GlycoNurse study.
Scand J Trauma Resusc Emerg Med. 2018 Feb 14;26(1):16. doi: 10.1186/s13049-018-0483-4.

Acute ischemic injury to the renal microvasculature in human kidney transplantation.
Am J Physiol Renal Physiol. 2010 Nov;299(5):F1134-40

Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus.
Diabetologia. 2010 Dec;53(12):2646-55

Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation.
Eur J Cardiovasc PrevRehabil. 2011 Dec;18(6):775-89

Damage of the endothelial glycocalyx in dialysis patients.
J Am SocNephrol. 2012 Nov;23(11):1900-8

Sublingual microvascular glycocalyx dimensions in lacunar stroke patients.
Cerebrovasc Dis. 2013;35(5):451-4

Non-invasive assessment of microvascular dysfunction in families with premature coronary artery disease.
Int J Cardiol. 2013 Oct 12;168(5):5026-8

Alteration of the sublingual microvascular glycocalyx in critically ill patients.
Microvasc Res. 2013 Nov;90:86-9

Association of kidney function with changes in the endothelial surface layer.
Clin J Am SocNephrol. 2014 Apr;9(4):698-704

Microcirculatory effects of the transfusion of leukodepleted or non-leukodepleted red blood cells in patients with sepsis: a pilot study.
Crit Care. 2014 Feb 17;18(1):R33

Skeletal muscle capillary density and microvascular function are compromised with aging and type 2 diabetes.
J ApplPhysiol (1985). 2014 Apr 15;116(8):998-1005 

Deeper penetration of erythrocytes into the endothelial glycocalyx is associated with impaired microvascular perfusion.
PLoS One. 2014 May 9;9(5):e96477

Is the systemic microvascular endothelial glycocalyx in peritoneal dialysis patients related to peritoneal transport?
Nephron ClinPract. 2014;128(1-2):159-65

Effects of ultrapure hemodialysis and low molecular weight heparin on the endothelial surface layer.
Blood Purif. 2014;38(3-4):203-10

Characteristics and determinants of the sublingual microcirculation in populations of different ethnicity.
Hypertension. 2015 May;65(5):993-1001

Plasma free hemoglobin and microcirculatory response to fresh or old blood transfusions in sepsis.
PLoS One. 2015 May 1;10(5):e0122655

Effect of an acute and chronic slat load on microvascular permeability in healthy subjects.
JHypertens. 2015 Jun;33 Suppl 1

Perturbation of the microvascular glycocalyx and perfusion in infants after cardiopulmonary bypass.
J Thorac Cardiovasc Surg. 2015 Dec;150(6):1474-81.

Side-by-Side Alterations in Glycocalyx Thickness and Perfused Microvascular Density During Acute Microcirculatory Alterations in Cardiac Surgery.
Microcirculation. 2016 Jan;23(1):69-74.

The impact of periodontal disease treatment on endothelium of sublingual microvessels.
Stomatologiia (Mosk). 2016;95(4):9-12. Russian.

Protocol for intraoperative assessment of the human cerebrovascular glycocalyx.
BMJ Open. 2017 Jan 5;7(1)

Early detection of left ventricular dysfunction in first-degree relatives of diabetic patients by myocardial deformation imaging: The role of endothelial glycocalyx damage.
Int J Cardiol. 2017 Apr 15;233:105-112.

Improvement of arterial stiffness and myocardial deformation in patients with poorly controlled diabetes mellitus type 2 after optimization of antidiabetic medication.
Eur Heart J Cardiovasc Imaging. 2016 Dec 1;17(suppl_2)

Effects of varenicline and nicotine replacement therapy on arterial elasticity, endothelial glycocalyx and oxidative stress during a 3-month smoking cessation program.
Atherosclerosis. 2017 May 13;262:123-130.

Sublingual microvascular glycocalyx dimensions in lacunar stroke patients.
Cerebrovasc Dis. 2013;35(5):451-4

Non-invasive assessment of microvascular dysfunction in patients with microvascular angina.
Int J Cardiol. 2017 Dec 1;248:433-439. doi: 10.1016/j.ijcard.2017.05.010. Epub 2017 Jul 18.

Automated Measurement of Microvascular Function Reveals Dysfunction in Systemic Sclerosis: A Cross-sectional Study.
J Rheumatol. 2017 Nov;44(11):1603-1611. doi: 10.3899/jrheum.170120. Epub 2017 Sep 15.

The Measurement of the Endothelial Glycocalyx as a New Biomarker of Endothelial Derangement in Systemic Sclerosis: A Challenge for the Future.
J Rheumatol. 2017 Nov;44(11):1572-1574. doi: 10.3899/jrheum.170958. Epub 2017 Nov 1. No abstract available.

 

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