At 600,000 fatalities a year, CVD accounts for 25% of American deaths. Stroke kills another 130,000.1 The precursor to most of these deaths is atherosclerosis: the development of plaque in the arterial wall. While some plaque is relatively stable, it is the unstable plaque that causes most events.2 This more vulnerable plaque is liable to erupt and deposit its contents into the bloodstream, causing dangerous clots.
Atherosclerosis can be understood as an inflammatory process of the endothelium. Endothelial dysfunction through injury or some other disturbance can trigger an inflammatory response. This attracts monocytes that may leak into the subendothelial space, along with LDL which can become oxidized. Inside the intima, the monocytes absorb oxidized LDL and form macrophages. These in turn may grow to become foam cells. When the foam cells die, they contribute to the formation of plaque with a lipid rich necrotic core. A fibrous cap forms to cover this core, but it may be fragile. If the cap is thin or ulcerated, it is susceptible to rupture. When the cap breaks, the accumulated lipid contents of the necrotic core spill into the bloodstream, forming a clot that may recruit circulating platelets and block vessels, triggering either a myocardial infarction or stroke.3
The Role of the Endothelial Glycocalyx
Classically, treatment for atherosclerosis is by statins to reduce the lipids in the blood. Statins have also been shown to lower the lipid content of vulnerable plaque.4 However, a completely different pathway is possible, based on an essential structural component of the endothelium, the endothelial glycocalyx (EGX).
The EGX is a semipermeable barrier, rich in polysaccharides, attached to the layer of endothelial cells. The EGX is the only surface directly exposed to the contents of the blood.
The EGX has three specific functions which all have bearing on atherogenesis:
- It provides a semi-permeable barrier that allows small molecules to enter the subendothelial space, but inhibits large molecules such as LDL.5
- It plays an active role in communications between the endothelial cells, which affects how they tighten or loosen their junctions in response to the flow and contents of the blood.6
- It mediates vascular tone, by triggering the production of nitric oxide (NO), a primary vasodilator.7
A compromise of any one of these functions can increase the opportunity for atherogenesis, so it’s not surprising that a deficiency of the EGX has been associated with the development atherosclerosis.8
Clinical Interest in the EGX
The importance of the EGX to endothelial function has emerged in recent years through a massive expansion of human, animal, and in vitro studies. It is increasingly seen as an opportunity for therapeutic intervention, both for prevention and for treatment.
One way to look at the EGX is as a gatekeeper, managing the exchange of cholesterol between the lumen and the intima.
Plaque can only develop if the endothelial surface allows an excess of LDL to penetrate and remain in the intima. Some back-and-forth passage of this material is physiological: problems arise when more of it remains than needed and is not removed quickly. This indicates a failure of the EGX: the gatekeeper isn’t doing its job. A healthy EGX therefore plays an important role in the prevention of atherosclerosis. It inhibits the excessive accumulation of LDL in the subendothelial space.
Once plaque develops, a restored EGX may play a role in reducing its lipid contents. Because the EGX plays an active role in the traffic of material between the lumen and the intima, it can block further accumulation of cholesterol and also may facilitate the removal of plaque components via other mechanisms.
For both prevention and treatment of atherosclerosis, strengthening the protective and mediating functions of the EGX might be as effective, or more effective, than attempting to change the lipid contents of the blood.
How the Endothelial Glycocalyx is Compromised
The EGX is inherently dynamic: it grows and diminishes in response to a variety of conditions, in particular the flow of blood. This makes it vulnerable to degradation, especially at the junctions where arteries bifurcate. At these points, the flow becomes turbulent and may reverse itself, potentially causing a reduction of EGX. Significantly, atherosclerotic plaque is far more common at these points than along straight segments of the artery where blood flows smoothly.9
There are many other factors that can compromise the EGX and contribute to pathology. Hyperglycemia is a particular hazard: high levels of glucose in the blood have been associated with EGX dysfunction.10 Inflammation, stress, and various disease conditions can also undermine the EGX. Simple aging has been shown to reduce the thickness of the EGX.11
Whatever the cause, EGX dysfunction is a necessary precursor for atherogenesis.8
The Case for Clinical Restoration of the EGX
So what are the clinical implications? Practitioners now have a new approach to supporting healthy arterial function, beyond lipid management. They can directly shore up the body’s own first line of defense, the EGX.
Curious about how this might work in clinical practice? In this presentation, Kristine Burke, MD, reviews a case series where EGX restoration led to plaque regression in especially stubborn cases.
- Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Committee American Heart Association statistics, and subcommittee stroke statistics, heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146–e603.
- Falk, Erling. “Pathogenesis of Atherosclerosis.” Journal of the American College of Cardiology, vol. 47, no. 8 Suppl, Apr. 2006, pp. C7-12, doi:10.1016/j.jacc.2005.09.068.
- Mitra, Ronodeep, et al. “Glycocalyx in Atherosclerosis-Relevant Endothelium Function and as a Therapeutic Target.” Current Atherosclerosis Reports, vol. 19, no. 12, 2017, doi:10.1007/s11883-017-0691-9.
- Crisby M, Nordin-Fredriksson G, Shah PK, Yano J, Zhu J, Nilsson J. Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization. Circulation. 2001;103(7):926–933
- Cheng MJ, Kumar R, Sridhar S, Webster TJ, Ebong EE. Endothelial glycocalyx conditions influence nanoparticle uptake for passive targeting. Int J Nanomedicine. 2016;11:3305–3315.
- Ebong EE, Depaola N. Specificity in the participation of connexin proteins in flow-induced endothelial gap junction communication. Pflugers Arch. 2013;465(9):1293–1302.
- Ebong EE, Lopez-Quintero SV, Rizzo V, Spray DC, Tarbell JM. Shear-induced endothelial NOS activation and remodeling via heparan sulfate, glypican-1, and syndecan-1. Integr Biol (Camb) 2014;6(3):338–347
- Nieuwdorp M, Meuwese MC, Vink H, Hoekstra JB, Kastelein JJ, Stroes ES. The endothelial glycocalyx: a potential barrier between health and vascular disease. Curr Opin Lipidol. 2005;16(5):507–11
- Warboys CM, Amini N, de Luca A, Evans PC. The role of blood flow in determining the sites of atherosclerotic plaques. F1000 Med Rep. 2011;3:5
- Nieuwdorp, Max, et al. “Loss of Endothelial Glycocalyx During Acute Hyperglycemia Coincides With Endothelial Dysfunction and Coagulation Activation In Vivo.” Diabetes, vol. 55, no. 2, Feb. 2006, pp. 480–86, doi:10.2337/diabetes.55.02.06.db05-1103.
- Machin, Daniel R., et al. “Advanced Age Results in a Diminished Endothelial Glycocalyx.” American Journal of Physiology-Heart and Circulatory Physiology, vol. 315, no. 3, May 2018, pp. H531–39, doi:10.1152/ajpheart.00104.2018.
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