GlycoCheck - Published research

Abstract

In this study, the effect of heterozygous germline mutations in the heparan sulfate (HS) glycosaminoglycan chain co-polymerases EXT1 and EXT2 on glomerular barrier function and the endothelial glycocalyx in humans is investigated. Heparan sulfate (HS) glycosaminoglycans are deemed essential to the glomerular filtration barrier, including the glomerular endothelial glycocalyx. Animal studies have shown that loss of HS results in a thinner glycocalyx. Also, decreased glomerular HS expression is observed in various proteinuric renal diseases in humans. A case report of a patient with an EXT1 mutation indicated that this could result in a specific renal phenotype. This patient suffered from multiple osteochondromas, an autosomal dominant disease caused by mono-allelic germline mutations in the EXT1 or EXT2 gene. These studies imply that HS is indeed essential to the glomerular filtration barrier. However, loss of HS did not lead to proteinuria in various animal models. We demonstrate that multiple osteochondroma patients do not have more microalbuminuria or altered glycocalyx properties compared to age-matched controls (n = 19). A search for all Dutch patients registered with both osteochondroma and kidney biopsy (n = 39) showed that an EXT1 or EXT2 mutation does not necessarily lead to specific glomerular morphological phenotypic changes. In conclusion, this study shows that a heterozygous mutation in the HS backbone elongating enzymes EXT1 and EXT2 in humans does not result in (micro)albuminuria, a specific renal phenotype or changes to the endothelial glycocalyx, adding to the growing knowledge on the role of EXT1 and EXT2 genes in pathophysiology.

Abstract

Capillary density rarefaction and endothelial dysfunction contribute to chronic hypoperfusion and cerebral small vessel disease. Previous animal experiments revealed spatiotemporal microvascular remodeling directing post-stroke brain reorganization. We hypothesized that microcirculatory changes during acute cerebrovascular events could be reflected systemically and visualized sublingually.

In a prospective observational trial in vivo sublingual sidestream darkfield videomicroscopy was performed in twenty-one patients with either acute stroke (n = 13 ischemic, n = 1 ischemic with hemorrhagic transformation and n = 2 hemorrhagic stroke) or transitory ischemic attacks (n = 5) within 24 h after hospital admission and compared to an age- and sex-matched control group. Repetitive measurements were performed on the third day and after one week.

Functional and perfused total capillary density was rarefied in the overall patient group (3060 vs 3717 μm/mm2, p = 0.001 and 5263 vs 6550 μm/mm2, p = 0.002, respectively) and in patients with ischemic strokes (2897 vs. 3717 μm/mm2, p < 0.001 and 5263 vs. 6550 μm/mm2, p = 0.006, respectively) when compared to healthy controls. The perfused boundary region (PBR), which was measured as an inverse indicator of glycocalyx thickness, was markedly related to red blood cell (RBC) filling percentage (regarded as an estimate of microvessel perfusion) in the overall patient group (r = −0.843, p < 0.001), in patients with ischemic strokes (r = −0.82, p = 0.001) as well as in healthy volunteers (r = −0.845, p < 0.001).

In addition, there were significant associations between platelet count or platelet aggregation values (as measured by whole blood impedance aggregometry) and microvascular parameters in the overall patient collective, as well as in patients with ischemic strokes.

In conclusion, cerebrovascular events are associated with altered systemic microvascular perfusion.

Abstract

Psoriatic disease is associated with vascular and myocardial dysfunction. We aimed to evaluate endothelial glycocalyx barrier properties and microvascular perfusion in psoriatic patients, as well as their correlation with carotid intima-media thickness (cIMT) and markers of left ventricular (LV) myocardial deformation. We examined 297 psoriatic patients and 150 controls, adjusted for age, sex, and atherosclerotic risk factors. The severity of psoriatic disease was estimated using the psoriasis area and severity index (PASI). Perfused boundary region (PBR), a marker of glycocalyx barrier function, was measured non-invasively in sublingual microvessels with a diameter 5–25 μm using Sidestream Dark Field camera (Microscan, GlycoCheck). Increased PBR indicates reduced glycocalyx thickness. Indexes of microvascular perfusion, including red blood cells filling (RBCF) and functional microvascular density, were also calculated. We measured cIMT, coronary flow reserve (CFR) and markers of myocardial deformation by speckle-tracking imaging, namely global longitudinal strain (GLS) and percentage changes between peak twisting and untwisting at mitral valve opening (%dpTw-UtwMVO). Compared to controls, psoriatic patients had higher PBR5-25μm (2.13 ± 0.29μm versus 1.78 ± 0.25μm, p < 0.001) and lower RBCF and functional microvascular density (p < 0.001). Increased PASI was associated with elevated PBR and more impaired cIMT and GLS (p < 0.05). There was an inverse association of PBR with RBCF and functional microvascular density (p < 0.001). In psoriatic population, increased PBR was related to increased cIMT, reduced CFR, impaired GLS and decreased %dpTw-UtwMVO (p < 0.001). Glycocalyx thickness is reduced in psoriatic patients, which in turn impairs microvascular perfusion, and is associated with carotid IMT and impaired coronary and myocardial function.

Abstract

Introduction: Gestational diabetes mellitus (GDM) increases risk for cardiovascular disease (CVD). The subclinical cardiovascular structural and functional changes that contribute to long-term cardiovascular risk are unclear.

Hypothesis: We hypothesized that GDM is associated with adverse cardiovascular remodeling, diastolic function abnormalities, and endothelial dysfunction at approximately a decade after delivery, thereby increasing CVD risk.

Methods: We conducted a cross-sectional analysis of women from an existing cohort with abstracted clinical pregnancy data. Women attended a follow-up visit at a median of 9 years after delivery. Echocardiograms, Peripheral Arterial Tonometry (EndoPAT), glycocalyx analysis (GlycoCheck) and laboratory testing were conducted at the follow-up visit.

Results: Among 217 women who attended the follow-up visit, 53 (24%) had history of GDM. After adjusting for age, race, preeclampsia history or preterm delivery, women with prior Compared to women without GDM, women with prior GDM had higher interventricular septal and left ventricular (LV) posterior wall thickness and lower septal e’ velocity (Table; Model 2). They also had worse endothelial function with lower reactive hyperemia index (RHI) and adverse GlycoCheck parameters. Measures of hypertrophy were attenuated by additional adjustment for body mass index, hypertension, and diabetes (Model 3), but findings of adverse LV diastology, RHI and GlycoCheck parameters remained significant.

Conclusions: Women with GDM were more likely to have increased LV wall thickness, adverse diastology and endothelial dysfunction nearly a decade postpartum. Adjusting for traditional cardiovascular risk factors attenuated some but not all parameters. These findings suggest that subclinical structural and functional cardiac and vascular changes may be a mechanism by which GDM causes increased risk of CVD.

Abstract

We investigated whether disturbance of glycocalyx integrity is related with increased cardiovascular risk. In 600 healthy subjects, we measured perfused boundary region (PBR), a marker of glycocalyx integrity, in sublingual microvessels with diameter ranging 5–25 µm using a dedicated camera (Sideview Darkfield Imaging). Increased PBR indicates reduced glycocalyx thickness. We prospectively monitored the occurrence of cardiovascular events (MACE-death, myocardial infarction, and stroke) during a 6-year follow-up. Fifty-seven MACE were documented. Increased values of PBR5-25 predicted higher risk for MACE in a model including sex, age, hyperlipidemia, diabetes, hypertension, smoking, family history of coronary disease, treatment with ACEi/ARBs, or lipid-lowering agents (hazard ratio (HR), 6.44, p = 0.011; net reclassification improvement (NRI), 28%; C-statistic: 0.761). PBR5-25 was an independent and additive predictor of outcome when added in a model including the European Heart SCORE, diabetes, family history of CAD, and medication (HR, 4.71; NRI: 39.7%, C-statistic from 0.653 to 0.693; p < 0.01).Glycocalyx integrity is an independent and additive predictor to risk factors for MACE at 6-year follow-up in individuals without cardiovascular disease. ClinicalTrials.govIdentifier:NCT04646252.

Abstract

Background/Introduction

Psoriasis has been associated with vascular and myocardial dysfunction through mechanisms of inflammation and oxidative stress.

Purpose

We aimed to evaluate sublingual microvascular perfusion and glycocalyx barrier properties in psoriasis patients, as well as their correlation with coronary microcirculatory function and markers of myocardial deformation and atherosclerosis (carotid intima-media thickness, cIMT).

Methods

We examined 297 patients with psoriasis and 150 controls, adjusted for age, sex, and atherosclerotic risk factors. Perfusion boundary region (PBR), a marker of glycocalyx barrier function, was measured non-invasively in sublingual microvessels with a diameter ranging from 5–25μm using a dedicated camera (Sidestream Dark Field imaging, Microscan, GlycoCheck). Increased PBR indicates reduced glycocalyx thickness. Indexes of microvascular perfusion, including red blood cell (RBC) filling percentage and functional microvascular density, were also calculated. We measured coronary flow reserve (CFR), cIMT and markers of myocardial deformation by speckle tracking imaging utilizing echocardiography [peak twisting, the percentage changes between peak twisting, and untwisting at mitral valve opening (%dpTw-UtwMVO), at peak (%dpTw-UtwPEF), and the end of early LV diastolic filling (%dpTw-UtwEDF)].

Results

Psoriasis patients had higher PBR5–25 compared to controls (2.13±0.29 versus 1.78±0.25μm, p<0.05). There was an inverse association of PBR5–25 with perfused microvascular density (r=−0.42, p<0.001) and RBC fraction (r=−0.80, p<0.001). In psoriatic population, PBR5–25 was inversely correlated to CFR (r=−0.30, p=0.045). Increased values of PBR5–9 were associated with reduced untwisting at the end of the mitral inflow E wave (r=−0.24, p=0.006) and reduced %dpTw-UtwMVO (r=−0.35, p<0.001). Furthermore, decreased RBC filling percentage and perfused microvascular density were related to worse LV longitudinal strain and increased cIMT (p<0.05). Finally, a positive correlation between perfused microvascular density and %dpTw-UtwMVO was observed in patients with psoriasis (p<0.05).

Conclusion

Endothelial glycocalyx thickness is reduced in patients with psoriasis and is associated with impaired coronary and myocardial function, and vascular atherosclerosis.