FALL 2017 DIGITAL EDITION REDEFINING MEDICINE FALL 2017 DIGITAL EDITION ARTICLES The role of the endothelial glycocalyx in the pathogenesis of atherosclerosis: a new frontier in cardiovascular health 4 By Derrick DeSilva Jr, MD, Jeffrey Gladden, MD, FACC, Chen Chen, PhD, Jon Ward, MA A nutritional formula produces a favorable glycemic response in healthy volunteers with prediabetes in a randomized, crossover evaluation 16 By Jyh-Lurn Chang, PhD (Scientific and Editorial Manager) and Kirti Salunkhe, MD (Senior Director of Medical Affairs) First Randomized, Double-Blind, Placebo-Controlled Study to 28 Show Telomeres Getting Longer in Humans Sermorelin & associated peptides: Restoring growth hormone in aging 35 By Anthony J. Campbell, PharmD Modulation of Metabolic Detoxification Pathways Using Foods and Food- Derived Components: A Scientific Review with Clinical Application 43 By Romilly E. Hodges And Deanna M. 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ASHEVILLE • ATLANTA • LONDON 800.522.4762 • www.gdx.net A4M_Winter-FullPageAd_GIFX_0717.indd 1 7/27/17 10:28 AM The role of the endothelial glycocalyx in the pathogenesis of atherosclerosis: a new frontier in cardiovascular health By Derrick DeSilva Jr, MD, Jeffrey Gladden, MD, FACC, Chen Chen, PhD, Jon Ward, MA The following article is not endorsed and/or supported by The American Academy of Anti-Aging Medicine. The purposes of this publication do not imply endorsement and/or support of any author, company or theme related to this article. Much recent work on the pathogenesis of atherosclerosis has focused on the “re- sponse to injury theory”. In brief, the theory holds that atherosclerosis may be un- derstood as an inflammatory response to insults occurring to the endothelium. 1 When the endothelium is healthy athero- of heart attacks occur at arteries that are sclerosis does not occur. When the endothe- less than 50% blocked, while mild plaqu- lium is damaged, it produces surface-ad- ing escapes traditional stress tests 80% of hesion molecules causing monocytes and the time t-lymphocytes to stick to its surface, which then penetrate the endothelium into in- Needless to say, this means that merely tima. As low density lipoprotein (LDL) measuring the serum levels of LDL and particles follow the path, they enter the HDL is inadequate to assess event risk. To intima and begin to oxidize. This sets the interrupt the cycle, clinicians need to be stage for foam cell formation and plaque primarily concerned with the health of the development. The resulting plaque then endothelium. builds up and, when internally inflamed or externally eroded, can be a threat to The injury-response theory is gaining wide- rupture its contents into the arterial flow, spread acceptance, but it begs an import- potentially triggering a blood clot that if ant question: What causes the injury to large enough or not lysed quickly enough the endothelium in the first place? Mul- can occlude the artery to various degrees tiple candidates have been cited such as: causing anything from mild to devastat- ing downstream ischemia. Indeed, it is the • Direct trauma causing physical injury clotting in response to plaque disruption, not the plaque accumulation in the arter- • Turbulence in the blood flow, for exam- ies per se that poses the real threat. 75% ple at artery bifurcations 4 ANTI-AGING MEDICAL NEWS | FALL 2017 • Excessive blood glucose levels When we help doctors explain the endo- • Circulation of free radicals thelial glycocalyx to patients, we some- times liken it to the non-stick surface of a • TMAO (trimethylamine-N-oxide) frying pan. The analogy is useful because • Higher than normal concentrations of it highlights the protective function of this LDL or VLDL important structure. A healthy glycocalyx • High blood pressure ensures that LDL particles “slip by” with- out contacting the endothelium. Con- • Circulating toxins versely, when the endothelial glycocalyx is • Deterioration of the NO system compromised (which happens very easily) the endothelium becomes susceptible to All of these explanations have value, but injury impairment and LDL penetration. they miss a critical factor in endothelial health which merits more attention than Important clinical implications follow. To it has received in the current literature. prevent atherosclerosis, we must protect That factor is the endothelial glycocalyx. the endothelium from injury and preserve its vital functions. To protect endotheli- al function, we must support its existing The Endothelial Glycocalyx natural protection, the endothelial glyco- calyx. In layman’s terms: if you want to Popular accounts of the endothelium in- stop food sticking to your saucepan, take accurately describe it as “the inner lining” care of the non-stick coating! If you want of the blood vessels. Here’s Wikipedia: the infrastructure of the endothelium to work you need to protect its surface. “Endothelium is a type of epithelium that lines the interior surface of blood vessels A Closer Look at the Glycocalyx and lymphatic vessels, forming an inter- face between circulating blood or lymph The endothelial glycocalyx is a thin gel-like in the lumen and the rest of the vessel layer that coats the entire luminal side of wall.” the vascular endothelium. It is a meshwork mainly of glycoproteins, proteoglycans What’s missing from these accounts is the and glycosaminoglycans at a thickness of glycocalyx, a slippery smooth gel coating approximately 1 µm magnitude.2-4 Syn- of the endothelium that positions an ad- decans and glypicans are the core proteins ditional layer between the endothelium of heparan sulfate (a glycosaminoglycan) and the circulating blood. This is the true proteoglycans bound to endothelial cells interface. In other words, it’s the endo- identified in the glycocalyx. Glycoproteins thelial glycocalyx—not the endotheli- such as selectins and integrins are also an- al cells themselves—that has (or should chored on endothelial cells while some have) direct contact with the circulating other soluble proteins and proteoglycans fluids and particles. simply dock in glycocalyx.5 5 ANTI-AGING MEDICAL NEWS | FALL 2017 Extensive research has revealed the impor- via heparan sulfate in the glycocalyx to ei- tance of glycocalyx-mediated endothelial ther up- or down-regulate the synthesis of function in vascular and microvascular nitric oxide (NO) in response to the blood health. flow.9,10 For example, the endothelial glycocalyx: Figure 1 below illustrates the chemical structure of the endothelial glycocalyx • Regulates vascular permeability and and its signal transduction to eNOS and fluid balance due to the large size and subsequently sGC (soluble guanynyl cy- negative charge of glycosaminogly- clase) to induce smooth muscle relaxation cans.6,7 via shear stress. • Provides a physical barrier against in- advertent adhesion of platelets and 8 leukocytes to the vascular wall. Figure 1. Structure of the endothelial glycocalyx • Regulates coagulation as many of me- and its activation of vascular muscle relaxation via diators of coagulation pathway are NO in response to increased shear force buried inside the glycocalyx under normal physiological condition.5 Most intriguingly, the glycocalyx is found to be a mechano-sensor and -transducer of the shear-force inside blood vessels.3 The signal is believed to be transduced to endothelial nitric oxide synthase (eNOS) Damage to the Endothelial Glycocalyx The endothelial glycocalyx is a delicate Hyperglycemia is a major cause for dis- structure and can be damaged by sever- ruption of the endothelial glycocalyx.11,13 al common mechanisms involved in the In fact individuals with hyperglycemia pathogenesis of atherosclerosis. These and diabetes are known to have less include high blood glucose, 11 oxidative endothelial glycocalyx.14 Such a change stress, 12 and inflammation. 4 It is known may explain the endothelial dysfunction that high-sugar diets, cigarette smok- and increased microvascular permeabil- ing, stress, and aging can all degrade ity that lead to major complications in the glycocalyx. the diabetic population.15,16 6 ANTI-AGING MEDICAL NEWS | FALL 2017 There are several other disease conditions identified so far to be associated with a compromised endothelial glycocalyx: • Coronary heart disease17 • Renal diseases18 • Lacunar stroke (a small vessel disease)19 • Severe trauma20 These electron-microscope images show the deterioration of the endothelial glycocalyx: Clinical Interventions Given the vital role the endothelial glycoc- measuring recovery of RHI (reactive hyper- alyx plays in the pathology of many vascu- emia index) in 20 healthy human subjects lar and micro-vascular related diseases, it following a high-sugar, high-fat meal. Re- has naturally become a target for pharma- sults were compared with and without ceutical intervention.21,22 However, glycoc- consumption of ArterosilHP. The study