Vince
Super Moderator
The role of the endothelial glycocalyx in the pathogenesis of atherosclerosis: a new frontier in cardiovascular health Derrick DeSilva Jr, MD, Jeffrey Gladden, MD, FACC, Chen Chen, PhD, Jon Ward, MA
____________________________________________________________________________________ Much recent work on the pathogenesis of atherosclerosis has focused on the “response to injury theory”. In brief, the theory holds that atherosclerosis may be understood as an inflammatory response to insults occurring to the endothelium. 1 When the endothelium is healthy atherosclerosis does not occur. When the endothelium is damaged, it produces surface-adhesion molecules causing monocytes and t-lymphocytes to stick to its surface, which then penetrate the endothelium into intima. As low density lipoprotein (LDL) particles follow the path, they enter the intima and begin to oxidize. This sets the stage for foam cell formation and plaque development. The resulting plaque then builds up and, when internally inflamed or externally eroded, can be a threat to rupture its contents into the arterial flow, potentially triggering a blood clot that if large enough or not lysed quickly enough can occlude the artery to various degrees causing anything from mild to devastating downstream ischemia. Indeed, it is the clotting in response to plaque disruption, not the plaque accumulation in the arteries per se that poses the real threat. 75% of heart attacks occur at arteries that are less than 50% blocked, while mild plaquing escapes traditional stress tests 80% of the time. Needless to say, this means that merely measuring the serum levels of LDL and HDL is inadequate to assess event risk. To interrupt the cycle, clinicians need to be primarily concerned with the health of the endothelium. The injury-response theory is gaining widespread acceptance, but it begs an important question: What causes the injury to the endothelium in the first place? Multiple candidates have been cited such as: • Direct trauma causing physical injury • Turbulence in the blood flow, for example at artery bifurcations • Excessive blood glucose levels • Circulation of free radicals SA10420 Rev 2017-02-24 2 • TMAO (trimethylamine-N-oxide) • Higher than normal concentrations of LDL or VLDL • High blood pressure • Circulating toxins • Deterioration of the NO system All of these explanations have value, but they miss a critical factor in endothelial health which merits more attention than it has received in the current literature. That factor is the endothelial glycocalyx. The Endothelial Glycocalyx Popular accounts of the endothelium inaccurately describe it as “the inner lining” of the blood vessels. Here’s Wikipedia: “Endothelium is a type of epithelium that lines the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall.” What’s missing from these accounts is the glycocalyx, a slippery smooth gel coating of the endothelium that positions an additional layer between the endothelium and the circulating blood. This is the true interface. In other words, it’s the endothelial glycocalyx—not the endothelial cells themselves—that has (or should have) direct contact with the circulating fluids and particles. When we help doctors explain the endothelial glycocalyx to patients, we sometimes liken it to the non-stick surface of a frying pan. The analogy is useful because it highlights the protective function of this important structure. A healthy glycocalyx ensures that LDL particles “slip by” without contacting the endothelium. Conversely, when the endothelial glycocalyx is compromised (which happens very easily) the endothelium becomes susceptible to injury impairment and LDL penetration. Important clinical implications follow. To prevent atherosclerosis, we must protect the endothelium from injury and preserve its vital functions. To protect endothelial function, we must support its existing natural protection, the endothelial glycocalyx. In layman’s terms: if you want to stop food sticking to your saucepan, take care of the non-stick coating! If you want the infrastructure of the endothelium to work you need to protect its surface.
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____________________________________________________________________________________ Much recent work on the pathogenesis of atherosclerosis has focused on the “response to injury theory”. In brief, the theory holds that atherosclerosis may be understood as an inflammatory response to insults occurring to the endothelium. 1 When the endothelium is healthy atherosclerosis does not occur. When the endothelium is damaged, it produces surface-adhesion molecules causing monocytes and t-lymphocytes to stick to its surface, which then penetrate the endothelium into intima. As low density lipoprotein (LDL) particles follow the path, they enter the intima and begin to oxidize. This sets the stage for foam cell formation and plaque development. The resulting plaque then builds up and, when internally inflamed or externally eroded, can be a threat to rupture its contents into the arterial flow, potentially triggering a blood clot that if large enough or not lysed quickly enough can occlude the artery to various degrees causing anything from mild to devastating downstream ischemia. Indeed, it is the clotting in response to plaque disruption, not the plaque accumulation in the arteries per se that poses the real threat. 75% of heart attacks occur at arteries that are less than 50% blocked, while mild plaquing escapes traditional stress tests 80% of the time. Needless to say, this means that merely measuring the serum levels of LDL and HDL is inadequate to assess event risk. To interrupt the cycle, clinicians need to be primarily concerned with the health of the endothelium. The injury-response theory is gaining widespread acceptance, but it begs an important question: What causes the injury to the endothelium in the first place? Multiple candidates have been cited such as: • Direct trauma causing physical injury • Turbulence in the blood flow, for example at artery bifurcations • Excessive blood glucose levels • Circulation of free radicals SA10420 Rev 2017-02-24 2 • TMAO (trimethylamine-N-oxide) • Higher than normal concentrations of LDL or VLDL • High blood pressure • Circulating toxins • Deterioration of the NO system All of these explanations have value, but they miss a critical factor in endothelial health which merits more attention than it has received in the current literature. That factor is the endothelial glycocalyx. The Endothelial Glycocalyx Popular accounts of the endothelium inaccurately describe it as “the inner lining” of the blood vessels. Here’s Wikipedia: “Endothelium is a type of epithelium that lines the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall.” What’s missing from these accounts is the glycocalyx, a slippery smooth gel coating of the endothelium that positions an additional layer between the endothelium and the circulating blood. This is the true interface. In other words, it’s the endothelial glycocalyx—not the endothelial cells themselves—that has (or should have) direct contact with the circulating fluids and particles. When we help doctors explain the endothelial glycocalyx to patients, we sometimes liken it to the non-stick surface of a frying pan. The analogy is useful because it highlights the protective function of this important structure. A healthy glycocalyx ensures that LDL particles “slip by” without contacting the endothelium. Conversely, when the endothelial glycocalyx is compromised (which happens very easily) the endothelium becomes susceptible to injury impairment and LDL penetration. Important clinical implications follow. To prevent atherosclerosis, we must protect the endothelium from injury and preserve its vital functions. To protect endothelial function, we must support its existing natural protection, the endothelial glycocalyx. In layman’s terms: if you want to stop food sticking to your saucepan, take care of the non-stick coating! If you want the infrastructure of the endothelium to work you need to protect its surface.
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