Atherosclerosis and Aging — Insights Into the Role of the Endothelial Glycocalyx in Cardiovascular Health
By Joel Kahn, MD
The development of atherosclerosis can result from multiple factors that influence the health and function of arteries supplying vital organs in the body. The risk of atherosclerosis rises with age, and aging is a dominant risk factor for the development of clinically relevant atherosclerotic plaques.1,2 This perspective may play a critical role in improving health outcomes because coronary artery disease, which results from the development of atherosclerotic plaques within the vessels that supply the heart with blood, is the leading cause of death worldwide and in the United States.3,4 Cerebrovascular stroke, which occurs when these plaques form in the carotid arteries or other vessels that supply blood to the brain, is the fifth leading cause of deaths in the United States.5
Recent findings demonstrate that the most potent factors in the progression of atherosclerosis are the various mechanisms that repair the endothelium lining of the blood vessels in response to endothelial damage and dysfunction.1 Despite being only one cell thick, the vascular endothelium is the body’s largest organ—it would cover six tennis courts. It plays a critical role in regulating blood pressure, immunity, and clotting and also in inhibiting plaque development. The progression of atherosclerosis appears to correlate with loss of endothelial function rather than the onset of high lipid levels.1 A decline in the integrity and function of the arterial endothelium, which occurs with aging over time, allows the formation of atherosclerotic plaques.
The Endothelial Glycocalyx: A Critical Mediator
For many years, it was believed that atherosclerotic plaques lead to cardiovascular complications, such as coronary artery disease and stroke, by narrowing the arteries and limiting blood flow to the heart, brain, and other organs.6 While this can happen in some patients, it’s become evident that the rupture of vulnerable plaque—plaque that has a large necrotic lipid core and thin fibrous cap—is responsible for 60% to 70% of acute coronary syndromes. The blood clots and inflammatory processes that result from plaque rupture are significant contributors to morbidity and mortality due to acute cardiovascular events.7,8
The increased focus on the physiology and function of the vascular endothelium has provided new insights into the critical role that the endothelial glycocalyx (EG) plays in arterial health. The EG, a slippery lining composed of a polysaccharide-proteoglycan matrix, protects and regulates several critical endothelial functions. As such, it’s the first line of defense against atherogenesis. Because it’s located between the bloodstream and the endothelium, the EG affects vascular permeability and limits the ability of certain molecules to reach the endothelium.9 Recent data show that the EG plays a key role in arterial health by regulating the accumulation of cholesterol within the endothelial lining as well as other vascular properties, including permeability, nitric oxide (NO) production, and adhesion of cells and other molecules.9,10
Additionally, a broad array of biologic molecules requires interaction with the EG to function properly.9 These include pro- and anticoagulation factors such as antithrombin III, heparin cofactor II, and tissue factor pathway inhibitor; growth factors such as vascular endothelial growth factor, transforming growth factor-, and fibroblast growth factor; mediators of cholesterol transport and metabolism such as lipoprotein lipase and LDL; and multiple interleukins that mediate chemotaxis of leukocytes into the subendothelium.9
The EG is extraordinarily dynamic and, while it collapses rapidly in response to high-glycemic diets, diabetes, hypertension, smoking, inflammation, stress, air pollution, and a variety of disease conditions, it takes longer to rebuild. EG damage is associated with a variety of pathologies, including atherosclerosis, stroke, diabetes, kidney disease, hypertension, and pulmonary edema.9,11 Results of a 2007 study suggest that LDL cholesterol accumulates in regions of the blood vessel in which the thickness of the EG is reduced.9
In vitro studies conducted under conditions that degrade the EG and reduce EG coverage of endothelial cells found that a lack of EG was apparent in the majority of cells that had increased uptake of oxidized LDLs.10 These findings suggest that degradation of the EG can initiate proatherosclerotic activity with endothelial cells. Additional in vitro studies also show that the EG plays critical roles in NO production as well as in determining the composition of the gap junctions through which endothelial cells communicate with each other—activities that are both relevant to vascular health and atherosclerosis.10
Assessing and Promoting Vascular Endothelial Health
As noted above, there’s a growing body of data underscoring the importance of maintaining a healthy vascular endothelium throughout our lives but especially as we age. Despite the potential benefits of targeting vascular endothelial health as a mechanism for reducing the risk of coronary artery disease and stroke, this approach is not widely pursued in today’s clinical practice. I believe a key reason for this gap is the mistaken belief that arterial health cannot be assessed or managed. In my clinical practice, however, we pursue an integrative approach to cardiac longevity that takes advantage of new approaches to assessing arterial health as well as foods and nutraceuticals that can promote vascular endothelial health.
Two biomarker blood tests measure levels of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine. Elevations in these biomarkers can be indicative of damage to the endothelium. ADMA competitively inhibits the production of NO, a key mediator of endothelial homeostasis.12 A prospective study conducted in more than 1,900 patients with coronary artery disease found that high levels of baseline AMDA independently predict future cardiovascular risk.13
There’s also EndoPAT, a device cleared by the FDA in 2003 for assessment of endothelial function. EndoPAT measures a NO-mediated endothelial response and has been shown in clinical studies to be predictive of future major adverse cardiac events, even in patients with normal Framingham Risk Scores.14
Rather than waiting for patients to exhibit symptoms of cardiovascular disease, the ADMA and EndoPAT tests improve physicians’ ability to predict which patients are at risk of future major adverse cardiac events. These tests can enable physicians and patients to work together to establish nutrition and lifestyle programs that can protect or improve their vascular endothelial health.
Nutrition can play a key role in how we help our patients achieve and maintain healthy vascular endothelium. Given the importance of NO in vascular endothelial function, we counsel our patients to eat foods high in arginine and citrulline, both of which are amino acids used in the production of NO.15 These foods include legumes, nuts, and watermelon. We also recommend foods rich in dietary nitrates, such as arugula, chard, other leafy greens, and beets. Patients in my practice are also counseled about the need for adequate sleep and exercise and the benefits of avoiding fast foods, processed carbohydrates, and excess sugar.
Given that endothelial dysfunction is the starting point for most cardiovascular disease and the EG is the primary protector and regulator of the endothelium, maintaining a healthy EG may be one of the most important approaches to reducing cardiovascular risk and preventing cardiovascular disease. While there are no pharmaceutical products that directly target the EG, promising early data from a small study suggest that certain glycocalyx regenerating compounds (GRCs) may provide cardiovascular benefits. These GRCs mimic the building blocks the body requires to restore and maintain a healthy EG.
Research has shown that there’s an increase in the adhesion of leukocytes to the vascular endothelium following enzymatic removal of the EG.16 Data from a recent presentation demonstrate that this increase is normalized within minutes of exposure to certain GRCs. Promising early data from a small study using the same GRCs show a dramatic reduction in vulnerable plaque within 60 days.17 In this study, adults with carotid artery plaques confirmed by MRI-PlaqueView, the only FDA-approved software program used with MRI devices to analyze carotid plaque, received a GRC-containing nutraceutical, Arterosil, daily for two months and then underwent a second MRI. Preliminary data from the study demonstrate a 56% average reduction in the lipid-rich necrotic core of the assessed plaque, with a significant increase in lumen size.
Based on the growing body of data supporting the cardiovascular benefits of these GRCs and the fact that Arterosil is a natural product, we recommend it to patients in my practice as part of an integrative approach to enhancing their cardiac longevity. Combined with a diet rich in arginine, citrulline, and dietary nitrates; a healthy lifestyle that provides adequate sleep and exercise; and periodic ADMA or EndoPAT testing, physicians now have tangible ways to help patients achieve or maintain good EG and vascular endothelial health, which will help reduce their risk of future adverse cardiac events.
Aging may be inevitable; atherosclerosis isn’t.
— Joel Kahn, MD, is founder of the Kahn Center for Cardiac Longevity.
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