Optimizing Cardiometabolic Health Part 2: Endothelial And Blood Lipid Optimization
This article is part 2 of a 3 part series.
In part 1 of this series, an overview of the gravity of atherosclerotic cardiovascular disease and the fundamentals of plaque formation were reviewed. In part 2, the crucial role of endothelial function is presented.
Endothelial Dysfunction: The Platform for Athersclerotic Cardivascular Disease (ASCVD)
As noted in part 1 of this series, a dysfunctional endothelium lays the foundation for subsequent ASCVD. We’ll now look at how endothelial dysfunction develops, how to prevent and reverse it, and how to test for it.
Development of Endothelial Dysfunction
The endothelium is the largest organ in the body and located between the wall of blood vessels and the blood stream. It is made up of a single layer of endothelial cells that help the blood vessels contract and relax.
Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory state, and prothrombotic properties (1). This is known as a transition from a ‘calm’ to an activated state of the endothelium. Endothelial dysfunction reflects a vascular phenotype (observable characteristics) prone to atherogenesis and may therefore serve as a marker of the inherent atherosclerotic risk in an individual (2). Mechanisms that participate in the reduced vasodilatory responses in endothelial dysfunction include reduced nitric oxide generation, oxidative excess, and reduced production of hyperpolarizing factor (3). An additional component of a healthy endothelium is the endothelial glycocalyx, an often unacknowledged though important aspect of endothelial function.
Reduced nitric oxide production, oxidative stress, and a dysfunctional glycocalyx are primary factors in the process of endothelial dysfunction and are reviewed below as they are understood in terms of symptoms, causes, treatments, and testing. Hyperpolarizing factor and its impact on endothelial function is still being investigated and is less elucidated regarding pragmatic approaches to testing and treatment so will not be covered in this article.
Reduced Nitric Oxide Levels
Reduction of nitric oxide bioavailability is a characteristic hallmark of endothelial dysfunction.
Nitric oxide (NO) is a soluble gas continuously synthesized from the amino acid L-arginine in endothelial cells by the constitutive calcium-calmodulin-dependent enzyme nitric oxide synthase (NOS) (4). This substance has a wide range of biological properties that maintain vascular homeostasis, including modulation of vascular dilator tone, regulation of local cell growth, and protection of the vessel from injurious consequences of platelets and cells circulating in blood, playing in this way a crucial role in the normal endothelial function (5).
Symptoms of nitric oxide reduction include:
- Atherosclerosis
- Fatigue
- High blood pressure
- Poor vision
- Erectile dysfunction
Causes of nitric oxide reduction include
- Inflammation
- Toxin exposure
- Obesity
- Age
- Sedentary lifestyle
- Medications, such as proton pump inhibitors (PPIs)
- Low levels of arginine (a precursor to nitric oxide)
- A diet low in nitrates (a precursor to nitric oxide)
- Oral microbiome imbalance (healthy oral bacteria are needed to convert nitrates to nitric oxide)
- Smoking
Methods for increasing nitric oxide production
Ways to increase nitric oxide include:
- Exercise
- Nitrate-rich foods such as beets or nitrate supplementation such as beet powder
- Maintaining healthy weight
- Nitric oxide precursors such as l-arginine or l-citrulline (a precursor to l-arginine)
- Use of alcohol-free mouthwash to maintain a healthy oral microbiome
- Limiting toxin exposure
- Nitric oxide as a medication
Testing nitric oxide levels:
- Nitric oxide levels can be tested through use of salivary strips
Oxidative Excess
Oxidative stress is a phenomenon caused by an imbalance between production and accumulation of oxygen reactive species (ROS) in cells and tissues and the ability of a biological system to detoxify these reactive products (6). ROS can play, and in fact they do, several physiological roles (i.e., cell signaling), and they are normally generated as by-products of oxygen metabolism (7). Although there are physiological benefits to oxidants, the system can become overwhelmed due to various factors.
Symptoms of excess oxidation include:
- Fatigue
- Cognitive dysfunction
- Joint aches
- Inflammatory disorders
Causative Factors of Oxidative Excess
Factors that may lead to excess oxidation include:
Exogenous (external) Factors (8):
- Ultraviolet light
- Ionizing radiation
- Environmental pollutants
- Heavy metals
- Cigarette smoke
- Overcooked foods, such as oils
Endogenous (internal) Factors (9):
- Immune cell activation
- Inflammation
- Low oxygen levels
- Stress
- Aging
Methods for reducing oxidative stress
Methods for reducing oxidative stress may include:
- Reducing exposure to the above exogenous oxidative stressors.
- Consume a diet rich in antioxidants foods, such as:
- Avocados
- Berries
- Cacao
- Cruciferous vegetables
- Green tea
- Olive oil
- Exercise regularly
- Take antioxidant supplements such as:
- Vitamin C
- Vitamin E (as tocopherols and tocotrienols with focus on tocotrienols)
- Selenium
- CoQ10 (as ubiquinol)
- Determine if you have excess levels of environmental toxins/heavy metals and undertake a detoxification program if they are elevated
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Testing Oxidation Levels:
Oxidation levels can be testing through the following:
- Oxidation-reduction (redox) testing
- Antioxidant status including glutathione levels
- 8-hydroxy-2’-deoxyguanosine (a significant product of DNA oxidation)
Endothelial Glycocalyx (eGCX) Dysfunction
The endothelial glycocalyx is a specialized extracellular matrix that covers the apical (inside of the vessel) side of vascular endothelial cells, projecting into the lumen (inner space) of blood vessels. The composition of the glycocalyx has been studied in great detail, and it is known to be composed of a mixture of proteoglycans, glycosaminoglycans, and glycoproteins (10). Although this structure was once believed to be a passive physical barrier, it is now recognized as a multifunctional and dynamic structure that participates in many vascular processes, including but not limited to vascular permeability, inflammation, thrombosis, mechanotransduction, and cytokine signaling (11).
These qualities of the glycocalyx are vital in the context of a healthy endothelium.
The level of vascular permeability is important as increased permeability may allow atherogenic particles to enter the tunica intima, which is the inner lining of the endothelium. This can begin the process of building a fatty streak, which is the initial stage of plaque formation, and a healthy glycocalyx can assist in the slowing or prevention of this process.
The disruption of the endothelial cell glycocalyx leads to cellular dysfunction, promoting inflammation and cardiovascular disease progression (12).
Thrombosis is the formation of a blood clot in a blood vessel and obstructs the flow of blood through the circulatory system. An atherosclerotic plaque that ruptures can form these clots and a healthy glycocalyx can assist in the prevention of plaque formation.
Cellular mechanotransduction, a critical regulator of numerous biological processes, is the conversion from mechanical signals to biochemical signals regarding cell activities and metabolism (13). The glycocalyx plays a significant role in the flow of blood through arteries by means of various signaling pathways in response to the endothelial cells and how blood vessels respond to mechanical force from blood flow.
Cytokines are physiological signaling molecules that act on the surface of cells. There are a variety of cytokines with both pro and anti-inflammatory properties. The glycocalyx can bind cytokines before they attach to endothelial cell surfaces, helping to mediate the inflammatory response and promote a healthy endothelium.
Due to the above mechanisms, a healthy glycocalyx is a crucial component of keeping the endothelium healthy.
Symptoms of glycocalyx dysfunction
Symptoms of glycocalyx dysfunction are generally associated with the various other diseases its dysfunction correlates with, so symptoms would map to those conditions.
Disruption or dysfunction of the eGCX has been associated with disease states such as diabetes, chronic kidney disease (CKD), inflammatory conditions, sepsis (a maladaptive response to infection), hypernatraemia (excess blood sodium) , hypervolaemia (excess fluid in the blood) and ischaemia/reperfusion injury (injury due to renewed blood flow) (14). As previously noted, eGCX dysfunction also plays a significant role in the development of ASCVD and subsequent symptoms and pathology.
Causes of glycocalyx dysfunction
Disruption of the glycocalyx can be caused by various factors and this becomes a vicious cycle as certain causes of a dysfunctional glycocalyx are then further exacerbated by the dysfunction of the glycocalyx itself.
Causes may include:
- Inflammation
- TNF-α (an inflammatory molecule)
- Trauma
- Viral infections
- Elevated blood pressure
- Nutrient deficiencies, such as Vitamin D and omega-3 fatty acids
- Advanced glycation end products (AGEs)
- Haemorrhagic shock
- Hypovolemia (low blood volume)
- Ischaemia-reperfusion
Methods for maintaining or restoring a healthy glycocalyx
Methods may include:
- An anti-inflammatory nutrition plan such as a modified Mediterranean diet
- Optimal levels of nutrients such Vitamin D and omega-3 fatty acids
- Resolution of chronic viral infections
- Optimized blood pressure
- A reduction in AGEs
- Sulfur consumption, such as from cruciferous vegetables
- Maintaining healthy weight
- Glycocalyx targeted supplements, such as Arterosil HP®
Testing for glycocalyx dysfunction
The field of glycocalyx research and applications are unfolding rapidly, though the majority of testing of glycocalyx structure and function has been done in laboratory settings. Fortunately, there is now a test available for patients called the GlycoCheck.
Additional Testing for Endothelial Function
Coronary Reactivity Testing is the gold standard for diagnosing coronary microvascular disease and endothelial wall dysfunction. It is an angiography procedure specifically designed to examine the blood vessels in the heart and how they respond to different medications. Physicians can use these images to distinguish different types of blood vessel reactivity dysfunction.
The Coronary Reactivity Test is an invasive procedure and must be performed in a medical facility. An additional and non-invasive test that can be performed in a doctor’s office is the EndoPAT®️, an FDA approved device for accurate testing of the endothelium.
Additionally, there are a variety of blood tests that can indirectly test the endothelium to paint a picture of endothelial inflammation and dysfunction.
Blood testing for endothelial function includes:
- Homocysteine
- Blood glucose
- Fibrinogen
- Testosterone
- Iron
- Ferritin
- Lp-PLA2
- Oxidized LDL
- Asymmetric Dimethylarginine (ADMA)
- Myeloperoxidase (MPO)
- Omega 3 index
Low nitric oxide levels, excess oxidation, and a dysfunctional glycocalyx are critical components leading to endothelial dysfunction. Once the endothelium is in an ‘activated’ rather than calm state, the foundation for atherosclerotic plaque is present. At this point, the opportunity for atherogenic (plaque forming) particles to infiltrate the endothelial lining of arteries is present, potentially leading to fatty streak and subsequent plaque formation. Fortunately, taking steps to reduce or reverse low nitric oxide levels, excess oxidation, and a dysfunctional glycocalyx is viable and testing and protocols are available to do so.
Conclusion
In this article, what the endothelium and glycocalyx are have been reviewed. Maintaining a healthy endothelium and glycocalyx is an essential component of reducing risk of atherosclerotic cardiovascular disease. By understanding what the endothelium and glycocalyx are and taking steps to ensure these are healthy is a significant component of maintaining cardiovascular health and reducing ASCVD risk.
In this article, the following aspects of this process have been reviewed:
- What the endothelium is
- Endothelial dysfunction
- The role of nitric oxide in health
- Symptoms of low nitric oxide
- How to increase nitric oxide levels
- How to test nitric oxide levels
- The role of oxidative stress in endothelial health
- Symptoms of oxidative stress
- Causes of oxidative stress
- How to reduce oxidative stress
- How to test oxidative stress levels
- What the glycocalyx is
- Symptoms of glycocalyx dysfunction
- Causes of glycocalyx dysfunction
- How to maintain a healthy glycocalyx or reverse glycocalyx dysfunction
- How to test glycocalyx health
We are fortunate to have a wide range of tools to diagnose and treat atherosclerotic cardiovascular disease. By utilizing these tools, a serious outcome (such as heart attack and stroke) of this largely silent and asymptomatic process can frequently be avoided. Diagnosing this disease as early as possible is a key factor in avoiding the world’s number one killer as there are many ways to treat it before it reaches a critical stage of development.
Functional medicine can play an important role in addressing ASCVD as it continuously looks to find root-causes, and there are many root-causes to address in the process of atherosclerotic plaque development. Ideally, the process can be avoided altogether by ensuring optimal physiological state is maintained continuously.
At Medicine with Heart and through our patient journey, we seek to optimize all aspects of the body for maximal healthspan and fulfillment in life.
In part 3 of this series, the role of atherogenic lipids will be reviewed.
References
- Endemann, D. H., & Schiffrin, E. L. (2004). Endothelial dysfunction. Journal of the American Society of Nephrology : JASN, 15(8), 1983–1992. https://doi.org/10.1097/01.ASN.0000132474.50966.DA
- Bonetti, P. O., Lerman, L.O., Lerman, A. (2003). Endothelial Dysfunction: A Marker of Atherosclerotic Risk. Arteriosclerosis, Thrombosis, and Vascular Biology : AHA Journals, 168-175, 23, 2. https://www.ahajournals.org/doi/abs/10.1161/01.ATV.0000051384.43104.FC
- Endemann, D. H., & Schiffrin, E. L. (2004). Endothelial dysfunction. Journal of the American Society of Nephrology : JASN, 15(8), 1983–1992. https://doi.org/10.1097/01.ASN.0000132474.50966.DA
- Tousoulis Dimitris, Kampoli Anna-Maria, Tentolouris Nikolaos Papageorgiou Costas and Stefanadis Christodoulos (2012). The Role of Nitric Oxide on Endothelial Function, Current Vascular Pharmacology, 2012. https://dx.doi.org/10.2174/157016112798829760
- Tousoulis Dimitris, Kampoli Anna-Maria, Tentolouris Nikolaos Papageorgiou Costas and Stefanadis Christodoulos (2012). The Role of Nitric Oxide on Endothelial Function, Current Vascular Pharmacology, 2012. https://dx.doi.org/10.2174/157016112798829760
- Pizzino, G., Irrera, N., Cucinotta, M., Pallio, G., Mannino, F., Arcoraci, V., Squadrito, F., Altavilla, D., & Bitto, A. (2017). Oxidative Stress: Harms and Benefits for Human Health. Oxidative medicine and cellular longevity, 2017, 8416763. https://doi.org/10.1155/2017/8416763
- Pizzino, G., Irrera, N., Cucinotta, M., Pallio, G., Mannino, F., Arcoraci, V., Squadrito, F., Altavilla, D., & Bitto, A. (2017). Oxidative Stress: Harms and Benefits for Human Health. Oxidative medicine and cellular longevity, 2017, 8416763. https://doi.org/10.1155/2017/8416763
- Pizzino, G., Irrera, N., Cucinotta, M., Pallio, G., Mannino, F., Arcoraci, V., Squadrito, F., Altavilla, D., & Bitto, A. (2017). Oxidative Stress: Harms and Benefits for Human Health. Oxidative medicine and cellular longevity, 2017, 8416763. https://doi.org/10.1155/2017/8416763
- Pizzino, G., Irrera, N., Cucinotta, M., Pallio, G., Mannino, F., Arcoraci, V., Squadrito, F., Altavilla, D., & Bitto, A. (2017). Oxidative Stress: Harms and Benefits for Human Health. Oxidative medicine and cellular longevity, 2017, 8416763. https://doi.org/10.1155/2017/8416763
- Moore, Kyle H., Murphy, Hayley A., George, Eric M. (2021). The glycocalyx: a central regulator of vascular function. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2021. https://journals.physiology.org/doi/abs/10.1152/ajpregu.00340.2020
- Moore, Kyle H., Murphy, Hayley A., George, Eric M. (2021). The glycocalyx: a central regulator of vascular function. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2021. https://journals.physiology.org/doi/abs/10.1152/ajpregu.00340.2020
- Campeau, MA., Leask, R.L. Empagliflozin mitigates endothelial inflammation and attenuates endoplasmic reticulum stress signaling caused by sustained glycocalyx disruption. Sci Rep 12, 12681 (2022). https://doi.org/10.1038/s41598-022-16763-6
- Di, X., Gao, X., Peng, L. et al. Cellular mechanotransduction in health and diseases: from molecular mechanism to therapeutic targets. Sig Transduct Target Ther 8, 282 (2023). https://doi.org/10.1038/s41392-023-01501-9
- Onur Yilmaz, Baris Afsar, Alberto Ortiz, Mehmet Kanbay, The role of endothelial glycocalyx in health and disease, Clinical Kidney Journal, Volume 12, Issue 5, October 2019, Pages 611–619, https://doi.org/10.1093/ckj/sfz042
