Study: Cohort Study: 24 papers
Peer-reviewed work on the endothelial glycocalyx, microvascular health and the ingredients in our formulas, newest first. Abstracts are indexed here and every paper links to the journal.
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Published paper
Evaluation of Microvascular Rarefaction in Vascular Cognitive Impairment and Heart Failure (CRUCIAL): Study Protocol for an Observational Study
This is a study protocol (not results) for CRUCIAL, a consortium of four observational cohort studies investigating whether microvascular rarefaction \u2014 loss of perfused and structural microvessels \u2014 contributes to vascular cognitive impairment from cerebral small vessel disease and to heart failure with preserved ejection fraction. Investigators plan to compare advanced brain and cardiac MRI measures of microvascular density with easier surrogate measures, including sublingual capillary assessment, retinal optical coherence tomography angiography, and RNA from circulating extracellular vesicles. In the aortic stenosis surgical cohort, myocardial biopsies will provide histological validation of microvascular density.
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Published paper
Effects of a single aerobic exercise on perfused boundary region and microvascular perfusion: a field study
This observational field study measured sublingual microvascular glycocalyx dimensions (perfused boundary region, PBR) and red blood cell filling percentage using sidestream dark-field imaging with GlycoCheck software in 14 healthy adults immediately before and after a 10 km trail run. A single bout of aerobic exercise produced no significant change in PBR, RBC filling percentage, or capillary density. However, individual changes in PBR were inversely associated with changes in RBC filling percentage, suggesting that a thicker endothelial surface layer accompanies better microvascular perfusion.
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Published paper
Microcirculation, endothelium and glycocalyx changes associated with the use of milrinone in children with septic shock
This prospective single-center observational study used sublingual video microscopy (GlycoCheck) to compare microcirculation and glycocalyx measures in 140 children with septic shock, 81 of whom received milrinone infusions. Children given milrinone maintained functional capillary density and capillary blood volume recruitment capacity at 24 hours and showed less glycocalyx degradation (lower perfused boundary region) than those not given milrinone, with the effect most apparent in children under two years old. Higher PBR was associated with mortality in both groups.
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Published paper
Association between the lactate-albumin ratio and microcirculation changes in Pediatric Septic patients
This retrospective single-center study of 178 children with sepsis compared the lactate/albumin ratio (LAR) measured on PICU admission with sublingual video microscopy measures of the microcirculation taken at the same time. An elevated LAR (>0.5) was associated with reduced microvascular blood flow, lower small-capillary (4–6 µm) density, greater inflammation, more vasoactive support and higher mortality, but was not associated with glycocalyx thickness as measured by the perfused boundary region (PBR).
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Published paper
The association between prolonged capillary refill time and microcirculation changes in children with sepsis
This prospective single-center cohort study measured sublingual microcirculation with GlycoCheck sidestream dark-field video microscopy and blood biomarkers in 132 children with sepsis, comparing those with normal versus prolonged (>2 s) capillary refill time. Children with prolonged capillary refill had thinner glycocalyx (higher perfused boundary region) and fewer small capillaries recruited. Persistence of these abnormalities, especially with normal blood pressure ('hemodynamic incoherence'), was linked to higher mortality and longer stay.
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Published paper
The association between hypoalbuminemia and microcirculation, endothelium, and glycocalyx disorders in children with sepsis
This prospective observational PICU study measured sublingual microcirculation and glycocalyx thickness (perfused boundary region, PBR, by GlycoCheck) plus plasma endothelial biomarkers in 125 children with sepsis, comparing those with low serum albumin (<3.0 g/dL, n=48) to those with normal albumin. Children with hypoalbuminemia had thinner glycocalyx (higher flow-corrected PBR), greater small-capillary recruitment, and higher angiopoietin-2 and annexin A5, and more often required mechanical ventilation. In an observational subgroup analysis, children whose hypoalbuminemia was corrected with 20% albumin infusion had less abnormal PBR at 24 hours, shorter PICU stay, and lower mortality.
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Published paper
Endothelial Glycocalyx Integrity in Treatment-Naïve People Living with HIV before and One Year after Antiretroviral Treatment Initiation
This prospective observational study measured sublingual endothelial glycocalyx thickness (via the perfused boundary region, PBR) in 66 treatment-naive people living with HIV before and at 24 and 48 weeks after starting combination antiretroviral therapy. PBR fell progressively (indicating thicker, healthier glycocalyx) over the first year, with no significant difference between integrase inhibitor- and protease inhibitor-based regimens. Final values remained above previously reported healthy-control values, suggesting only partial recovery.
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Published paper
Endothelial and Glycocalyx Biomarkers in Children With Sepsis After One Bolus of Unbalanced or Balanced Crystalloids
This single-center prospective cohort study followed 106 children with sepsis or septic shock who received a bolus of either balanced or unbalanced crystalloid fluid. Glycocalyx integrity was assessed by sublingual video microscopy (perfused boundary region) plus blood biomarkers. Children given unbalanced crystalloids showed more glycocalyx degradation at 6 hours, along with markers of vascular permeability and apoptosis, and higher odds of metabolic acidosis and acute kidney injury; the perfused boundary region normalized by 24 hours.
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Published paper
Evaluation of miCRovascular rarefaction in vascUlar Cognitive Impairment and heArt faiLure (CRUCIAL): Study protocol for an observational study
This is a published study protocol (no results yet) for CRUCIAL, a multicenter observational program investigating whether microvascular rarefaction - loss of perfused small vessels - is a shared mechanism in vascular cognitive impairment and heart failure with preserved ejection fraction. Participants across four cohorts (75 VCI, 60 HFpEF, 60 aortic stenosis, 200 aging controls) undergo advanced brain and cardiac MRI, cognitive testing, echocardiography, retinal OCT angiography, sublingual videomicroscopy with the GlycoCheck system, blood biomarkers, and (in the surgical cohort) myocardial biopsy. The aim is to validate cheaper non-invasive surrogate markers of microvascular density against imaging and histology.
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Published paper
Microvascular rarefaction in patients with cerebrovascular events
This prospective observational study used sublingual sidestream darkfield videomicroscopy to assess microcirculation in 21 patients within 24 hours of an acute stroke or transient ischemic attack, with repeat measurements on day 3 and after one week, compared with age- and sex-matched healthy controls. Patients showed substantially lower capillary density than controls, and the perfused boundary region (an inverse marker of glycocalyx thickness) correlated strongly with red blood cell filling of capillaries. The authors conclude that cerebrovascular events are accompanied by measurable systemic microvascular changes detectable under the tongue.
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Published paper
Perfused boundary region as biomarker for endothelial integrity in former preterms in adolescence
In the Belgian PREMATCH cohort, researchers measured sublingual perfused boundary region (PBR, an inverse index of glycocalyx thickness) by sidestream dark-field imaging in 93 adolescents born at extremely low birth weight (ELBW) and 87 healthy controls, alongside blood pressure, cystatin-C-based eGFR, and retinal vessel imaging. PBR did not differ between the groups even though ELBW survivors had higher blood pressure, lower eGFR, and altered retinal vessel width and tortuosity. The authors provide reference PBR values for adolescents but conclude that PBR correlates too weakly with other microvascular markers to serve as a stand-alone marker of endothelial integrity in this group.
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Published paper
Impaired Endothelial Glycocalyx Predicts Adverse Outcome in Subjects Without Overt Cardiovascular Disease: a 6-Year Follow-up Study
In 600 subjects free of overt cardiovascular disease, researchers measured the perfused boundary region (PBR) in sublingual microvessels using sidestream dark-field imaging as an index of endothelial glycocalyx integrity, then followed them for 6 years. Higher PBR (indicating a thinner glycocalyx) independently predicted major adverse cardiovascular events beyond conventional risk factors and the European Heart SCORE.
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Published paper
Links between Endothelial Glycocalyx Changes and Microcirculatory Parameters in Septic Patients
In this single-center prospective observational study, sublingual microcirculation (Cytocam incident dark field imaging) and glycocalyx perfused boundary region (PBR, GlycoCheck) were compared between adults with sepsis or septic shock and healthy age-matched volunteers. Septic patients had significantly increased PBR (indicating thinner glycocalyx) across all vessel diameter classes, and PBR in the smallest capillaries correlated inversely with capillary density measures. The authors conclude there may be a functional link between glycocalyx damage in the smallest capillaries and sepsis-related microcirculatory alterations.
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Published paper
Non-invasive evaluation of macro- and microhemodynamic changes during induction of general anesthesia – A prospective observational single-blinded trial
In 150 women undergoing gynecologic surgery, non-invasive bioimpedance monitoring showed that induction of general anesthesia caused a larger fall in cardiac output (~40%) than in mean arterial pressure (~26%). Patients who later needed norepinephrine already had lower baseline cardiac output, stroke volume and contractility, and norepinephrine raised blood pressure without restoring cardiac performance. Sidestream dark-field imaging in a subset showed a 6.4% rise in perfused boundary region by the end of surgery, consistent with glycocalyx impairment.
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Published paper
Effect of gestational age and postnatal age on the endothelial glycocalyx in neonates
This prospective observational study used sidestream dark-field imaging with GlycoCheck software to measure the perfused boundary region (PBR, an inverse marker of endothelial glycocalyx thickness) in the skin microcirculation of 85 term and 39 preterm newborns. Preterm infants, especially those born before 30 weeks, had lower PBR (i.e., larger glycocalyx dimensions) than term infants, and PBR rose (glycocalyx thinned) with increasing postnatal age. Extremely preterm infants reached higher PBR values by 6-7 weeks of life than moderately preterm or term babies measured at the same corrected gestational age.
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Published paper
Visual and Biochemical Evidence of Glycocalyx Disruption in Human Dengue Infection, and Association With Plasma Leakage Severity
This prospective observational study in Vietnam re-analyzed stored sublingual sidestream dark-field videos with GlycoCheck software and measured plasma syndecan-1 and endocan in 75 patients with confirmed dengue and 12 outpatients with other febrile illness. Patients with the most severe grade of plasma leakage showed a thinner, more degraded glycocalyx (higher perfused boundary region) and much higher plasma levels of shed glycocalyx proteoglycans during the critical illness phase. There were no significant glycocalyx differences between mild outpatient dengue and other febrile illnesses.
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Published paper
Immediate effects of whole blood donation on the endothelial surface layer and glycocalyx shedding
Researchers measured the sublingual microcirculation and blood markers of glycocalyx shedding in healthy volunteers immediately before and after donating 500 mL of whole blood. Using sidestream dark-field imaging with GlycoCheck software, they found no significant immediate change in the perfused boundary region (PBR) or red blood cell filling percentage. Plasma heparan sulfate and hyaluronan fell slightly while syndecan-1 was unchanged, suggesting the endothelial surface layer remains structurally stable after a standard donation.
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Published paper
Decreased endothelial glycocalyx thickness is an early predictor of mortality in sepsis
Researchers measured sublingual glycocalyx thickness (as the perfused boundary region, PBR) with sidestream dark-field imaging and GlycoCheck software within 24 hours of ICU admission in 21 septic patients, and compared results with plasma markers and survival. Patients who did not survive to hospital discharge had a thinner glycocalyx (higher PBR) than survivors, and admission PBR discriminated survivors from non-survivors moderately well. PBR correlated with angiopoietin-2 but not with syndecan-1 or severity scores.
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Published paper
Effects of Different Antidiabetic Medications on Endothelial Glycocalyx, Myocardial Function, and Vascular Function in Type 2 Diabetic Patients: One Year Follow-Up Study
One hundred people with poorly controlled type 2 diabetes were assessed before and 12 months after intensifying their antidiabetic treatment, with measurements of arterial stiffness, brachial artery flow-mediated dilation, sublingual endothelial glycocalyx (perfused boundary region by GlycoCheck), heart muscle deformation on echocardiography, and blood markers of oxidative stress. Average HbA1c fell from 8.9% to 7.1%, and this was accompanied by lower arterial stiffness, a smaller perfused boundary region (suggesting a thicker/less penetrable glycocalyx), better endothelial and left ventricular function, and lower oxidative stress markers. In multivariable analysis, incretin-based drugs (GLP-1 receptor agonists and DPP-4 inhibitors) were associated with these improvements over and above the fall in HbA1c.
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Published paper
Neuraxial anesthesia is less harmful to the endothelial glycocalyx during elective joint surgery compared to general anesthesia1,2.
This prospective observational study used sidestream dark-field imaging of the sublingual microcirculation to measure the perfused boundary region (PBR), an inverse marker of endothelial glycocalyx thickness, before and 2 hours after elective hip or knee replacement. PBR increased significantly after surgery in both anesthesia groups, indicating glycocalyx perturbation. The increase was greater in patients receiving general anesthesia than in those receiving neuraxial anesthesia.
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Published paper
Inflammatory and Angiogenic Factors Linked to Longitudinal Microvascular Changes in Hemodialysis Patients Irrespective of Treatment Dose Intensity
This 6-month prospective analysis of the multicenter INTHEMO study compared macro- and microvascular measures in hemodialysis patients receiving more than 12 hours per week of dialysis versus conventional regimens. Dialysis intensity did not predict changes in pulse wave velocity, ambulatory blood pressure, or sublingual glycocalyx measures. Instead, baseline inflammatory and angiogenic biomarkers predicted 6-month change in the perfused boundary region (PBR), a marker of glycocalyx integrity.
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Published paper
Improvement of arterial stiffness and myocardial deformation in patients with poorly controlled diabetes mellitus type 2 after optimization of antidiabetic medication
This study compared arterial stiffness, heart muscle deformation, endothelial function, and sublingual microvascular glycocalyx thickness in 50 patients with poorly controlled type 2 diabetes versus 25 healthy controls, then reassessed the diabetic patients 6 months after their antidiabetic medication was optimized. At baseline, diabetic patients had stiffer arteries, worse left ventricular strain and diastolic indices, and a higher perfusion boundary region (indicating a thinner endothelial glycocalyx). After achieving glycemic control, carotid-femoral pulse wave velocity fell and untwisting velocity and flow-mediated dilatation improved.
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Published paper
Side-by-Side Alterations in Glycocalyx Thickness and Perfused Microvascular Density During Acute Microcirculatory Alterations in Cardiac Surgery
This observational study of 36 coronary bypass patients used sublingual sidestream dark-field imaging (GlycoCheck) to track perfused vessel density and perfused boundary region (PBR, an inverse index of glycocalyx thickness) before, during, and after surgery. Onset of cardiopulmonary bypass was accompanied by a fall in perfused vessel density and a rise in PBR, while off-pump surgery showed no such deterioration. Postoperative recovery of both measures occurred with pulsatile but not nonpulsatile bypass flow.
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Published paper
Acute ischemic injury to the renal microvasculature in human kidney transplantation
During transplant surgery, researchers used sidestream darkfield imaging to observe peritubular capillaries in kidneys from donors after cardiac death (DCD, substantial ischemia) and from living donors (minimal ischemia). DCD kidneys showed markedly poorer microvascular perfusion and biochemical and imaging signs of endothelial glycocalyx degradation, despite similar overall renovascular resistance. The authors conclude that ischemia-reperfusion in kidney grafts involves impaired capillary flow and loss of glycocalyx integrity.
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