Dissertation
Targeting the endothelial glycocalyx to reduce cardiovascular disease
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2024
DOI: 10.25820/etd.007517
Abstract
Cardiovascular disease is the leading cause of death worldwide, in part, because of age-related vascular endothelial dysfunction. One potential cause of vascular endothelial dysfunction with advancing age is degradation of the endothelial glycocalyx. The endothelial glycocalyx is a dynamic, gel-like structure of glycoproteins, proteoglycans, and glycosaminoglycans that lines the luminal surface of the vascular endothelium and serves as the interface between circulating blood and the vascular wall. Additionally, preclinical research suggests that removal of the endothelial glycocalyx impairs vascular endothelial function and that restoring the endothelial glycocalyx improves vascular endothelial function. However, this idea has yet to be tested in humans. Thus, we attempted to address these critical gaps by completing the two following two aims: Aim 1) determine whether acute heparin administration degrades the endothelial glycocalyx and reduces vascular endothelial function in healthy young adults, and Aim 2) determine whether glycocalyx-target therapy increases endothelial glycocalyx thickness and vascular endothelial function in older adults.
In aim 1, healthy younger adults (n=19, aged 18-39 years, 53% female) underwent measurements of the endothelial glycocalyx and vascular endothelial function at baseline and after a single intravenous bolus 5000 U dose of heparin. Following acute heparin administration, there was no change in endothelial glycocalyx thickness or circulating glycocalyx components. Additionally, there was no difference in vascular endothelial function assessed via brachial artery flow-mediated dilation or plasma nitrite after heparin treatment. Our pilot study suggests that a single intravenous bolus dose of heparin does not result in acute endothelial glycocalyx degradation or vascular endothelial dysfunction in healthy younger adults.
In aim 2, we enrolled older men and postmenopausal women (n=23, aged 60-83 years, 52% female) in a randomized, double-blind, placebo-controlled, parallel-arms study to investigate the effect of 12-week Endocalyx Pro supplementation (3,712 mg/day) on endothelial glycocalyx thickness and vascular endothelial function. Compared with placebo, Endocalyx Pro did not significantly improve vascular endothelial function determined by flow-mediated dilation. Additionally, Endocalyx pro did not improve endothelial glycocalyx thickness significantly greater than placebo. However, compared with placebo, Endocalyx Pro did significantly improve flow-mediated dilation normalized to the shear stress stimulus and increase endothelial glycocalyx thickness in a select microvessel region. Overall, our pilot study suggests that Endocalyx Pro may be a promising therapy to improve endothelial glycocalyx thickness and vascular endothelial function in older adults. Larger clinical trials are needed to expand upon our pilot findings.
Taken together, this dissertation extended our knowledge on the endothelial glycocalyx’s relation with vascular endothelial function in humans. Future researchers should test alternative methods to assess the effect of experimental endothelial glycocalyx degradation on vascular endothelial function in humans. Additionally, larger clinical trials are needed to determine whether glycocalyx-targeted therapy is a viable treatment option to restore endothelial glycocalyx thickness and vascular endothelial function with aging and other chronic diseases in humans.
Details
- Title: Subtitle
- Targeting the endothelial glycocalyx to reduce cardiovascular disease
- Creators
- Colin J. Gimblet
- Contributors
- Gary Pierce (Advisor)Diana Jalal (Committee Member)Anna Stanhewicz (Committee Member)Darren Casey (Committee Member)Anthony Donato (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Health and Human Physiology
- Date degree season
- Spring 2024
- DOI
- 10.25820/etd.007517
- Publisher
- University of Iowa
- Number of pages
- xi, 95 pages
- Copyright
- Copyright 2024 Colin J. Gimblet
- Language
- English
- Date submitted
- 02/12/2024
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 82-95).
- Public Abstract (ETD)
Cardiovascular disease is the leading cause of death in the United States, accounting for 1 in every 5 deaths or roughly 1 person every 33 seconds. Additionally, cardiovascular disease poses a substantial burden on our economy, costing the United States an estimated $407 billion in 2018-2019 alone. Of note, the cost of cardiovascular disease has risen steadily for the past 20-years, partly because of the growing number of adults living past the age of 65. Importantly, the higher risk of cardiovascular disease with aging is largely because of a decline in our blood vessel health. Therefore, improving blood vessel health could reduce age-related cardiovascular disease and minimize its economic burden.
One way to improve blood vessel health with aging is by targeting the glycocalyx. The glycocalyx is a thick, gel-like structure that covers the inner layer of our blood vessels. With age, our glycocalyx thickness declines, and animal research suggests that a decline in glycocalyx thickness reduces blood vessel health. For this reason, we believe that lower glycocalyx thickness decreases blood vessel health in older adults. However, there is currently a lack of evidence in humans supporting this hypothesis. To test our hypothesis, we conducted two studies investigating the role of glycocalyx thickness on blood vessel health in humans.
Our first study aimed to test if acutely lowering glycocalyx thickness would decrease blood vessel health in young adults. To do this, we gave younger adults a single dose of heparin. Heparin is a drug that disrupts the glycocalyx. We found that glycocalyx thickness and blood vessel health were unchanged after administering heparin. Our findings suggest that heparin does not reduce glycocalyx thickness or lower blood vessel health in young adults. Additionally, our results indicate that a different experimental approach may needed to test whether lowering glycocalyx thickness decreases blood vessel health in humans.
Our second study aimed to test if Endocalyx Pro supplementation would increase glycocalyx thickness and improve blood vessel health in older adults. Endocalyx Pro is a supplement that helps build the glycocalyx. To answer our question, we conducted a clinical trial and randomly assigned people to receive either Endocalyx Pro or placebo for 12-weeks. We found that Endocalyx Pro increased glycocalyx thickness in certain blood vessel regions and improved specific markers of blood vessel health in older adults. However, larger clinical trials are needed to confirm our findings and to identify how Endocalyx Pro improves glycocalyx thickness and blood vessel health in older adults.
In conclusion, our studies indicate that targeting the glycocalyx with Endocalyx Pro could be a viable approach to improve blood vessel health and lower cardiovascular disease with aging, however additional clinical trials are needed. Furthermore, our studies highlight the need for more research on the glycocalyx’s role in age-related cardiovascular disease.
- Academic Unit
- Health, Sport, and Human Physiology
- Record Identifier
- 9984647257902771
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