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Endothelial Dysfunction


Endothelial dysfunction (ED) is a sign of underlying pathologies; threating the pathologies restores to normal the functions of the endothelial cell, just like curing a cold eliminates fever.  Pharma in shopping for conditions to be treated with their drugs has latched on to ED, and ignored the non-drug fixes.  At the end of this paper are those fixes pharma ignores and/or opposes.    Note:  the measurements for ED are measurements the effect of other conditions such as atherosclerosis. It is all part of a sales pitch.  Having said this my review of ED removes pharma’s spin and pointless complexity, and it adds to the understanding of AS, CVD and the role of Western diet.      

Endothelial dysfunction:  its role in the diseases of Western society, explained without pharma’s spin http://healthfully.org/rl/id11.html  12/27/15

  Pharma has researchers looking in the wrong places for the causes of cardiovascular disease.  Like pharma’s cholesterol myth, endothelial dysfunction has been modified for business ends.

Highly recommend is your reading the article on the role of pathogens and that of trans-and-rancid polyunsaturated fats in the development of atherosclerosis and its comorbidities. 

AS         Atherosclerosis


KOL      Key opinion leader

CVD      Cardiovascular disease


MeS      Metabolic syndrome

ECs         Endothelial cells


NALFD  Non-alcoholic fatty liver disease

ED         Endothelial dysfunction


T2D       Type 2 Diabetes

IR          Insulin resistance



Link to definitions of terms


Artery basics:  Endothelial Cells (ECs): “In a healthy vascular system the endothelium lines all blood-contacting surfaces, including arterioles, arteries, veins, capillaries, and heart chambers” Wiki.Endothelial Dysfunction[1](ED) is a major physiopathological mechanism that leads towards coronary artery disease, and other atherosclerotic diseases” Wiki.  While the illustrations and literature is on ED of the coronary arteries for CVD and the other arteries for atherosclerosis, a key role is played by the ECs in the blood vessels that nourishes the 3 layers of artery.  “The vasa vasorum (Latin, "the vessels of the vessels") is a network of small blood vessels that supply the walls of large blood vessels, such as elastic arteries (aorta) and large veins (vena cava).…  In smaller vessels it penetrates only the outer layer” Wiki. The main coronary arteries are sufficiently large as to require a network of blood vessels for oxygen, the vasa vasorum. 

Cardiovascular disease (CVD):  Thus far I have shown that pharma’s hypothesis as to the cause of CVD is not merely a minor causal factor, but totally false (the cholesterol-saturated fats myth).  I have answered the question what causes CVD by showing that pathogens and the subsequent immune response (including LDL mopping up bacterial toxins) play the key role in the development of atherosclerosis.  This still leaves the question of how does the Western diet figure into the much higher rate of CVD; thus  how does a diet high in sugar, refined carbs, and trans and polyunsaturated fats cause CVD?  Part of the answer is found in fatty liver and insulin resistance and their consequences among which is an increase in ED of the artery walls.  ECs are the gateway to atheroma (plaque) formation.[2] 

Endothelial dysfunction, a causal factor for CVD:  The ECs that line the inner walls of arteries are the gatekeepers for what enters the underlying tissues in the arteries.  Thus damage to these cells promotes atherogenesis (development of atherosclerosis).  Endothelial dysfunction has 5 major causes, of which 3 are associated with the Western diet.[3]  1) diet and lifestyle that causes high level of blood sugar, especially the 7 times more reactive fructose (compared to glucose), through the process of glycation[4]  damages the ECs.  2) Fructose is converted to fat in the liver.  The level of glucose which controls insulin affects the rate of conversion of fructose to fat and its storage.  Thus the combination of a diet high in sugar and refined carbs (high insulin) when consumed long-term results in a fatty liver.[5]  A fatty liver mucks up the metabolic regulatory system to cause insulin resistance, which slows the clearance of sugars from the blood.  These causes increase the rate of glycation which damages ECs.  3) A diet high in trans-fats and polyunsaturated fats (polyunsaturated fats are subject to a process of rancidification in the body, in deep fryers, and on the shelf).  Their abnormal shapes adversely affect the cell walls of the ECs (and all other cells) and thus their function as gatekeeper to the underlying tissue.  The compromised cell walls of ECs permit bacterial and viruses to pass through and enter the underlying tissue of the arteries.  Pathogens in the artery wall cause the development of AS and their associated pathologies.   The abnormal shaped fats affect every cell in the body since they accumulate in cells because they can’t be metabolized.  They adversely affecting cellular functions; for a review of the evidence click on link.  4) Carbon monoxide (mostly from tobacco) and other reactive chemical in the blood bond to the ECs (similar to glycation).  Thus significant exposure to high levels of blood borne reactive chemicals promotes atherosclerosis.  5) Infectious agents through their toxins circulating in the blood damage the ECs (certain chronic infections are associated with CVD).  In summation:  these causes of damage to ECs which compromise their function as the gatekeeper that selectively permits chemicals and cells to enter the underlying layers of the artery; thus so damaged the ECs permit the penetration of pathogens into the tissue within the arteries.  Infectious agents in the artery walls have been convincingly shown to be the major cause of plaque formation through an immune response to their presence.[6]  In conclusion, the five processes which damage the ECs are atherogenic.  6) Elevated homocysteine is causally associated with ED through reactive chemicals (the details of this mechanism are sketchy at best) and also by causing LDL aggregation (clumping) following LDL’s reaction with pathogens or their toxins.  Such clumps it is theorized hinder the flow of oxygen from the vasa vasorum (Uffe Ravnskov How the Cholesterol Myths are Kept Alive, 210). 7) The damaged ECs are more likely to leak the underlying young plaque and thereby cause an ischemic event that could result in myocardial fraction, stroke, or kidney damage-- depending on location of leak. 


The Western diet with its fructose, refined carbs, and unnatural fats has caused the CVD, T2D, and obesity pandemics.  These conditions along with strokes, heart attacks, arthritis, macular degeneration, osteoporosis, and dementia are collectively called “the diseases of Western society/civilization”.  Tragically the food manufacturers have successfully exported this diet to Asia and the underdeveloped world—watch Globesity.  These manufacturers have followed the same path as the tobacco industry has done to increase their bottom line.   This is compounded through the active support of the pharmaceutical industry which profits from the illnesses associated with the Western diet. 



Trans & rancid fats


The cause of CVD from a 2006 review article on trans-fats:   “In addition incorporation of trans-isomers into membrane phospholipids may influence the physical properties of the membrane as well as the activities of the membrane-associated enzymes.  Several studies suggest that trans-fats cause ECs affects wall of arteries and other tissues]… soluble vascular-cell adhesion factor…reflected by ruction in brachial artery flow-mediated vasodilation by 29 percent [raises blood pressure], as compared with intake of saturated-fats.”  The 1986 ADA review article states the same.  Both list the effects of rancid polyunsaturated fats. Polyunsaturated fats are subjected to oxidation through reactive products of metabolisms (ROS), and as rancid fats, like transfats the body lacks enzymes for their metabolism.  They both accumulate in the body and muck up various systems.  Rancidification can produce potentially toxic compounds associated with long-term harmful health effects concerning advanced aging, neurological disorders, heart disease, and cancer. A combination of water-soluble and fat-soluble antioxidants is ideal” Wiki.  “Under such conditions [of commercial frying] both thermal and oxidative decomposition of the oil may take place.  Such unavoidable chemical reactions cause formation of both volatile and nonvolatile decomposition products…. Various symptoms of toxicity, including irritation of the digestive tract, organ enlargement, growth depression, and even death have been observed when highly abused (oxidized and heated) fats were fed to laboratory animals”… and the article goes on Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage.  It most often affects polyunsaturated fatty acids, because they contain multiple double bonds in between which lie methylene bridges (-CH2-) that possess especially reactive hydrogens.  If not terminated fast enough, there will be damage to the cell membrane…” for more on rancid fats.

[1] I must caution the reader that Wikipedia articles on issues affecting pharma are written by pharma’s KOLs and those accepting their tobacco science.  A case in point is the definition of endothelia dysfunction:  In vascular diseases, EC is a systemic pathological state of the endothelium (the inner lining of blood vessels) ….  Normal functions of EC include mediation of coagulation, platelet adhesion, immune function and control of volume and electrolyte content of the intravascular and extravascular spaces. ”  The EC act as a gatekeeper as to what can penetrate the tissue that make up the arteries, which includes both pathogens, white blood cells, LDL, and nutrients necessary for the health of the tissue that makes up the arteries.  See bottom of page for a discussion of what is wrong with pharma’s description of endothelial dysfunction, including what I edited out. 

[2]  A second entrance to the tissue is the vasa vasorum a network of small blood vessels in the arteries that supply oxygen and nutrients.  The research on their role in CVD is thin.  They too are lined with endothelial cells.  They are involved in atherogenesis, though probably that which causes EC is also operative in the vasa vasorum.  Given both the lack of consensus and that a discussion of this system adds little to the topic of atherogenesis, for the sake of simplicity, I am forgoing further discussion of the vasa vasorum’s role.  Though not mentioned, 1-5 above applies also to the vasa vasorum.      

[3] There is very strong epidemiological evidence, for example, Orientals on traditional diets have a much lower incident of metabolic syndrome (MeS) consisting of obesity, CVD, T2D, and IR.  Once on a Western diet, they and others populations who once were on a traditional diet, they now all manifest all the chronic conditions associated with Western civilization.  The common factor is the combination of fructose and refined carbohydrates.  The traditional oriental diet is high in refined carbs, but only 14 grams of fructose.             Traditional diets are also very low in the unhealthful trans-and-polyunsaturated fats.   

[4]  Glycation is the non-enzymatic bonding (random bonding) of sugars to lipids and proteins.  This bonding is damaging to the EC that line the arteries—glycation is more damaging to them than the short-lived red and white blood cells.  Thus part of the reason why diabetes rate has over doubled the risk for MI lies with the higher serum glucose level.  Some AGEs are benign, but others are more reactive than the sugars they are derived from, and are implicated in many age-related chronic diseases such as cardiovascular diseases (the endothelium, fibrinogen, and collagen are damaged)” Wiki.

[5] Other factors contribute or reduce risk; most important are the rate of metabolism, lifestyle, fasting, and genetics. 

[6] Pharma with their tobacco science claims that atherosclerosis is caused by an immune response to oxidized LDL which results in plaque consisting of cholesterol, macrophages, and LDL.  These are far-fetched (see Ravnskov supra) or click on link, and   are found in plaque.  Numerous journal articles make both points; click on this link and for a few of the published journal articles.  Thus we have 2 distortions, that concerning pathogens and that on the function of LDL.”  The same finding with much greater detail is in the 1984 thorough review by the Department of Agriculture. 

Why in primitive societies are obesity virtually unknown and the diseases of Western societies much lower?

Even among those primitive societies that consume a significant amount of fruit and carbs there are several differences all of which work towards remaining slim and not developing atherosclerosis:  1) lack of steady food supply.  Fruits are seasonal, and during dry season the diet is much different than during the rainy seasons.  And even during times of plenty, daily foods varied more; thus these people do not prior to farming have a steady diet high in sugars and refined carbs.  2)  Wild varieties of fruits have only a fraction of the sugar of domestic varieties.  3) Grains are not processed to remove the cereal germ and the bran, and most tubers contain a significant portion of fiber; thus they have a lower glycemic and insulin index.   4) Periodic periods of scarcity results in energy restricted diets.  5) Physical excursion entails a lower insulin spike following a high carb meal.   6) The literature and old photos confirm that obesity was virtually unknown and medical records once contact with civilization occurred before lifestyle was changed indicate that the diseases of civilization (heart attacks, strokes, dementia, arthritis, and cancer) were very rare if recorded at all.  Infectious diseases and violence were their principle cause of death.  The daily high sugar (fructose) Western diet has no equivalent among paleo societies.      



Fix for ED

What is to be done:  The fix is simple to get off the Western diet and exercise.  For detail recommendations on supplements and on 3 diets depending on state of health 

Evidence for the fix is scattered throughout the above material.  In short to avoid the Western diet with its unhealthy combination of sugar (fructose) and refined carbs and the trans-and-polyunsaturated fats.

Given the wide variation in the readers’ health, I have an article, Concise Diet, that covers all situations, at  In addition that are some worthy supplements (from bottom of Concise Diet):  Besides the healthful diet describe above and exercise, several supplements have significant health benefits.  Best are aspirin 325 mg, CoQ10, vitamin C, & omega-3 fatty acids fish oil—in that order.  All 4 reduce very significantly the risk for CVD & other chronic conditions.  In sufficient dose Natural hormone replacement therapy (NHRT) estradiol for women and for elderly men testosterone; they slow down the aging process and reduce the risk of chronic conditions.  These hormones ALSO promote weight control and the motivation to exercise.  For more info on statins, cholesterol myth, CVD, carbs, fats, and a video library click on links.   The video page has documentaries and books that confirm my claims.   Click on Junk treatments to find out how pharma manipulates the practice of medicine.   You ought to take better care of your body than your car.


Bad Pharma on Endothelia Dysfunction:

I must caution the reader that Wikipedia articles on issues affecting pharma are written by pharma’s KOLs and others who accept pharma’s tobacco science.  A case in point is the definition of endothelia dysfunction:  In vascular diseases, EC is a systemic pathological state of the endothelium (the inner lining of blood vessels) and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium.[1] Normal functions of ECs include mediation of coagulation, platelet adhesion, immune function and control of volume and electrolyte content of the intravascular and extravascular spaces.”  The article Wikipedia article states:   ”Endothelial dysfunction is thought to be a key event in the development of atherosclerosis” thus implying that hypertension causes AS, rather than AS causes hypertension.   Thus the treatment for ED so as to prevent AS is to lower blood pressure.  Pharma makes billions treating hypertension, thus the reference to imbalance, which they correct with drugs. Unfortunately treating symptoms is not treating the cause and thus patients do not significantly benefit from treating hypertension with drugs, except for the population with malignant hypertension (above 180 over 110).   Pharma makes billions treating those who don’t benefit from hypertension drugs.[1]  Hypertension is a sign of atherosclerosis, like fever is of influenza, thus treating it only reduces the discomfort caused by elevated blood pressure (if there is any), it doesn’t affect the underlying cause atherosclerosis and the risk for ischemic events. 


Given that there is no reliable test that measures ED.  Current test measure factors associated with AS.  This entails that pharma is creating another condition, ED, that promotes drug sales.  

[1] Again I must caution that the Wikipedia article is grossly distorted by leaving out the role of atherosclerosis, hard, swollen, stiff arteries.  Most of the pathological developments associated from malignant hypertension result from thrombolysis, the leaking of young, unstable plaque from atherosclerotic arteries.    

^^^^^^^^^^^^^  supplemental journal article  ^^^^^^^^^^^^^

Except for parts in courier new all that is below is taken from the journal article. 

http://diabesity.ejournals.ca/index.php/diabesity/article/view/19    Online First: October 15, 2015  abstract

Hyperinsulinemia: A unifying theory of chronic disease?


Globally, there is an increasing prevalence of non-communicable diseases. The morbidity and mortality from these conditions confer a greater Economic societal burden. Epidemiological research associates insulin resistance in the etiology of these diseases, but there is limited evidence for the mechanism of damage. Emerging research suggests that hyperinsulinemia, a symptom of insulin resistance, may cause these pathological changes, and therefore be an independent contributor to these diseases. This review shows that hyperinsulinemia, or excessive insulin secretion, should be considered independently to insulin resistance, defined as glucose uptake rate, even though the two conditions are intertwined and will co-exist under normal conditions. Hyperinsulinemia directly and indirectly contributes to a vast array of metabolic diseases including all inflammatory conditions, all vascular diseases, gestational and type-2 diabetes, non-alcoholic fatty liver disease, obesity and certain cancers and dementias. The mechanisms include increased production of: insulin growth factor-1; reactive oxidative species and advanced glycation end-products; and triglyceride and fatty acids. Hyperinsulinemia also directly and indirectly affects many other hormones and cytokine mechanisms including leptin, adiponectin and estrogen. There is limited research standardizing the hyperinsulinemia diagnostic process. Methodological concerns and lack of standardized reference ranges preclude the use of fasting insulin. Most research has also focused on insulin resistance and it is unknown whether these methods translate to hyperinsulinemia.

Complete article sections thereof.  Comments by JK are in Courier New and/or brackets

http://docs.google.com/viewer?url=http://diabesity.ejournals.ca/index.php/diabesity/article/viewFile/19/61 Long

The mechanisms include increased production of: insulin growth factor-1; reactive oxidative species and advanced glycation end-products; and triglyceride and fatty acids.  Hyperinsulinemia also directly and indirectly affects many other hormones and cytokine mechanisms including leptin, adiponectin and estrogen. There is limited research standardizing the hyperinsulinemia diagnostic process. Methodological concerns and lack of standardized reference ranges preclude the use of fasting insulin. Most research has also focused on insulin resistance and it is unknown whether these methods translate to hyperinsulinemia [p 34].

From this article Fructose: Fructose is metabolized in liver into ATP and/or triglycerides in a process that is competitive with, and preferential to, glucose. If excessive fructose is consumed, glucose will not be metabolized causing hyperglycemia and subsequent hyperinsulinemia.20, 21   Excessive fructose also results in hyperuricemia which is associated with reduced endothelial nitric oxide causing vasoconstriction, endothelial dysfunction and insulin resistance 21 [p 35-36].

Medication-induced: There are a number of medications known or suspected to cause hyperinsulinemia and/or contribute to insulin resistance. Exogenous corticosteroids (prednisone) and exogenous insulin and insulin ecretagogues (sulphonylureas) have had their mechanisms discussed. Other medications include the antipsychotics (e.g. clozapine), and statins.27  [Thus the use of statins has been found to significantly increase the risk for T-2-D].  The mechanisms for these medications  causing hyperinsulinemia are currently unknown.  Due to the nature of insulin receptor regulation, it is also plausible that insulin sensitivity of the cells can be restored. This would require the absence of both hyperinsulinemia and hyperglycemia. Case studies indicate that a carbohydrate restricted diet may facilitate this effect.10   Overall, it should be recognized that hyperinsulinemia is independent to insulin resistance:  Hyperinsulinemia is excessive insulin secretion, while insulin resistance is impaired glucose uptake, p 36. 

As shown in Table 1, hyperinsulinemia can be  mechanistically and epidemiologically linked to metabolic syndrome, gestational and type 2 diabetes and therefore, cardiovascular and other diseases with an increased prevalence in those with metabolic syndrome.2-4, 28 It is also an independent risk factor for a number of other diverse conditions including diet-induced obesity, steoarthritis, certain cancers, especially breast and colon/rectum, disease and other dementias.5, 6, 29-32  Hyperinsulinemia affects the body via five main mechanisms: Increased reactive oxidative species and advanced glycation end-products; increased insulin-like growth factor-1 (IGF-1); hyperglycemia; increased fatty acid/triglyceride production; and by affecting different hormones and cytokines p 36.

On page 37-8 is a table of conditions associated with ED and the mechanism of causation with references to journal articles divided into mechanical (modus operandi) and epidemiological (population studies). 





Breast, ovarian, colon, bladder, pancreas, liver


Atherosclerosis, cardiomyopathy, endothelial dysfunction, thrombosis


Chronic inflammation, obesity


Diabetes type 2 and gestational, hyper-triglyceridemia, non-alcoholic fatty liver disease


Alzheimer’s and vascular dementia, peripheral neuropathy, retinopathy


Osteoporosis (caused by collagen breakdown and menserchymal cell compromise


Nephropathy (microvascular diseases, microaneurysm formations, etc.). 




Polyunsaturated fatty acids are considered very susceptible to reactive oxidative species damage, triggering lipid peroxidation, which can affect cell membrane fluidity and integrity, potentially being the mechanism for endothelial damage.  Amino acids such as cysteine and methionine are very susceptible to reactive oxidative species damage. Changes to these amino acids are implicated in the development of Alzheimer’s disease.  Insulin, IGF-1 and other substances such as vascular endothelial growth factor (VEGF) can stimulate the growth and division of many cells… cancer cell proliferation and metastasis29 [p 38].  

Hyperinsulinemia is also believed to elevate plasminogen activator inhibitor type-1 (PAL-1) levels, with associated increased fibrinolysis and increased risk of thrombosis. When combined with the increased coagulation from hyperglycemia, this may explain why over 80% of people with type 2 diabetes have a thrombotic death [p 39].

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