Chronic endothelial injury hypothesis
Encyclopedia
The chronic endothelial injury hypothesis is one of two major mechanisms postulated to explain the underlying cause of atherosclerosis
and coronary heart disease
(CHD), the other being the lipid hypothesis
. Although an ongoing debate involving connection between dietary lipids and CHD sometimes portrays the two hypotheses as being opposed, they are in no way mutually exclusive. Moreover, since the discovery of the role of LDL cholesterol
(LDL-C) in the pathogenesis of atherosclerosis
, the two hypotheses have become tightly linked by a number of molecular and cellular processes.
cell uncovering was the first step in the development of atherosclerosis
. Other hypotheses have associated the role of infectious agents (e.g. cytomegalovirus
, Chlamydia pneumoniae and Helicobacter pylori
) in inflammatory responses in the arterial wall. Currently, most research seems to focus on inflammatory processes which associate endothelial dysfunction with lipoprotein
accumulation.
and low-density lipoprotein (LDL) particles beneath the endothelium
. This is followed by the attachment of leukocytes, monocytes, and T-lymphocytes to the endothelial cell surface. Leukocytes migrate to the subendothelial space and aggregate within the intima.
In the presence of elevated levels of oxidized LDL (ox-LDL), monocytes are converted to activated macrophages. Macrophages accumulate modified lipid particles and become foam cells
. The formation of foam cells and their continued accumulation in the intima lead to the formation of fatty streaks. Continued cell migration and proliferation eventually result in the formation of a fibrous plaque.
Oxidized LDL promotes death of endothelial cells by augmenting apoptosis
. Also, through the activation of collagenases
, ox-LDL contributes to a process which may lead to the rupture of the fibrous plaque Oxidized LDL decreases the availability of endothelial nitric oxide (NO), which, in turn, increases the adhesion of monocytes to the endothelium. Moreover, NO is involved in paracrine signalling between the endothelium and the smooth muscle that maintains vascular tone; without it, the muscle will not relax, and the blood vessel remains constricted. Thus, oxidized LDL also contributes to the hypertension
often seen with atherosclerosis.
. A major breakthrough involved the discovery of statins, a class of drugs which help to clear LDL from the bloodstream. It has been demonstrated conclusively that elevated levels of LDL are associated with higher risk of mortality from coronary heart disease
(CHD); it has also been shown that statins substantially lower the risk of mortality in patients with high LDL.
A second approach would be to discourage the oxidation of LDL, thereby breaking the inflammatory cycle. Lipoproteins consist of a packaging of triglycerides and esterfied cholesterol
within a monolayer shell consisting of phospholipids and a class of proteins called apolipoproteins. The phospholipds are amphipathic, consisting of a hydrophobic tail which faces inwards, binding with the triglycerides and cholesterol, and a hydrophilic head which faces outwards, making the lipoproteins water soluble.
Polyunsaturated fatty acids (PUFA) contained in the outer shell make the lipoproteins especially susceptible to oxidation. However, lipoproteins also contain antioxidants which protect the components, vitamin E
and carotenoids being the two major naturally-occurring antioxidants in human lipoprotein.
Although some studies have shown positive results following anti-oxidant therapy with vitamin C
, vitamin E therapy has attracted the most public attention. There have been some positive results, though recent studies have shown no benefit for antioxidant therapy on mortality among patients at risk for CHD.,
which focused on hypercholesterolemia
lead to the suggestion that mortality from CHD might be reduced by controlling dietary input of cholesterol. Studies have demonstrated that increasing dietary cholesterol leads to an increase in both total cholesterol (TC) and LDL Cholesterol (LDL-C), however it also leads to increases in the level of high-density lipoprotein cholesterol (HDL-C), offsetting the effect of the increase in LDL-C. Epidemological studies which attempted to correlate dietary cholesterol with risk of mortality in CHD have produced mixed results.
Recent studies have focused more on the ratio of saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) in the diet. It has been demonstrated that intake of SFA raises TC in humans, whereas PUFA lowers TC; however SFA also increases the level of HDL-C, once more offsetting the effect of increased TC. Studies of individual fatty acids show that some SFAs, e.g. stearic acid
and palmitic acid
have little effect of LDL-C levels; stearic acid actually lowers the LDL/HDL ratio due to a greater increase of HDL-C levels relative to TC.
Epidemiological studies designed to test the relationship between high SFA/PUFA ratios and CHD mortality have tended to produce mixed results. Two recent studies provide an example of this lack of consensus: a study from Poland correlated a decline in CHD mortality with a decrease in the ratio of SFA to PUFA in the population's diet following the collapse of Communism. Yet a large population study from Sweden covering roughly the same time period showed no association between fat intake and CHD.
(AHA) to promulgate a set of dietary guidelines which included the recommendation to replace saturated fats found in dairy and meat products with polyunsaturated fats found in natural vegetable oils such as those derived from "corn, cottonseed, and soya". This first set of recommendations, published in the Journal Circulation in 1961, specifically sanctioned the use of products containing partially hydrogenated vegetable oils, i.e. margarine
and vegetable shortening
. Despite the lack of uncontrovertable epidemiological evidence of their effectiveness, these initial guidelines received widespread acceptance among the medical community in the US.
The suggestion to replace saturated animal fats with partially hydrogenated vegetable oils lead to a reaction which will be discussed below. However, is important to note that the AHA's dietary guidelines have undergone several revisions since the initial report. Although the most recent (2006) guidelines still recommend reducing the consumption of saturated fat, they no longer suggest switching to polyunsaturated fats. Moreover, the guidelines now recommend minimizing the intake of partially hydrogenated fats while increasing the consumption of fish and other sources rich in omega-3 fatty acids. Thus, the position of the AHA is now much closer to that of its critics.
This observation led some critics to invert the AHA guidelines. They stress the benefits of dietary SFA, citing the presence of natural antioxidants in animal fats, while encouraging people to avoid foods containing processed vegetable oils. They focus on the deleterious effect of dietary PUFA, often mentioning two factors: (1) the vulnerability of PUFA to oxidation and the formation of free radicals, and (2) the high ratio of omega-6 to omega-3 PUFA in the more common vegetable oils—those derived from “corn, cottonseed, and soya”. Their considerations are not limited to CHD, they point to an entire litany of inflammatory disorders which can be linked to diet and the consumption of processed vegetable oils. Some critics also question the safety of cholesterol-lowering drugs, suggesting that CHD is best controlled using a combination of diet and exercise.
This preoccupation with inflammatory processes has led some authors to popularize the chronic endothelial injury hypothesis. They also criticize the “Lipid Hypothesis”; however, for the most part, what is being criticized is not the lipid hypothesis itself, but a set of dietary guidelines that evolved from it. The debate is not (or should not be) about validity of the two hypothesis, but rather the relative benefits of two different therapeutic approaches: whether it is more productive to concentrate on lowering LDL levels or to focus on the underlying inflammatory mechanisms.
Many of these critics appeal to a popular, anti-establishment audience. At the most radical end of this spectrum, a number of books have been written which suggest the existence of a conspiracy between the “medical establishment” and “financial interests” , i.e. the food-processing industry and drug companies.
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
and coronary heart disease
Coronary heart disease
Coronary artery disease is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries that supply the myocardium with oxygen and nutrients. It is sometimes also called coronary heart disease...
(CHD), the other being the lipid hypothesis
Lipid hypothesis
The lipid hypothesis was one of two hypotheses developed in the 1850s to explain the pathogenesis of atherosclerosis...
. Although an ongoing debate involving connection between dietary lipids and CHD sometimes portrays the two hypotheses as being opposed, they are in no way mutually exclusive. Moreover, since the discovery of the role of LDL cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
(LDL-C) in the pathogenesis of atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, the two hypotheses have become tightly linked by a number of molecular and cellular processes.
Origins of the hypothesis
Ross and Glomset initially proposed that endothelialEndothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
cell uncovering was the first step in the development of atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
. Other hypotheses have associated the role of infectious agents (e.g. cytomegalovirus
Cytomegalovirus
Cytomegalovirus is a viral genus of the viral group known as Herpesviridae or herpesviruses. It is typically abbreviated as CMV: The species that infects humans is commonly known as human CMV or human herpesvirus-5 , and is the most studied of all cytomegaloviruses...
, Chlamydia pneumoniae and Helicobacter pylori
Helicobacter pylori
Helicobacter pylori , previously named Campylobacter pyloridis, is a Gram-negative, microaerophilic bacterium found in the stomach. It was identified in 1982 by Barry Marshall and Robin Warren, who found that it was present in patients with chronic gastritis and gastric ulcers, conditions that were...
) in inflammatory responses in the arterial wall. Currently, most research seems to focus on inflammatory processes which associate endothelial dysfunction with lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
accumulation.
The inflammatory process
The first phase of the inflammatory process is marked by the accumulation of lipidLipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
and low-density lipoprotein (LDL) particles beneath the endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
. This is followed by the attachment of leukocytes, monocytes, and T-lymphocytes to the endothelial cell surface. Leukocytes migrate to the subendothelial space and aggregate within the intima.
In the presence of elevated levels of oxidized LDL (ox-LDL), monocytes are converted to activated macrophages. Macrophages accumulate modified lipid particles and become foam cells
Foam cells
Foam cells are cells in an atheroma derived from both macrophages and smooth muscle. In chronic hyperlipidemia, lipoproteins aggregate within the intima of blood vessels and become oxidized by the action of oxygen free radicals generated either by macrophages or endothelial cells...
. The formation of foam cells and their continued accumulation in the intima lead to the formation of fatty streaks. Continued cell migration and proliferation eventually result in the formation of a fibrous plaque.
The role of oxidized LDL
Once LDL accumulates in the subendothelial space, it tends to become modified or oxidized. This oxidized LDL plays several key roles in furthering the course of the inflammatory process. It is chemotactic to monocytes; oxidized LDL causes endothelial cells to secrete molecules that cause monocytes to penetrate between the endothelial cells and accumulate in the intima.Oxidized LDL promotes death of endothelial cells by augmenting apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Also, through the activation of collagenases
Collagenases
Collagenases are enzymes that break the peptide bonds in collagen.They assist in destroying extracellular structures in pathogenesis of bacteria such as Clostridium. They are an exotoxin and help to facilitate the spread of gas gangrene...
, ox-LDL contributes to a process which may lead to the rupture of the fibrous plaque Oxidized LDL decreases the availability of endothelial nitric oxide (NO), which, in turn, increases the adhesion of monocytes to the endothelium. Moreover, NO is involved in paracrine signalling between the endothelium and the smooth muscle that maintains vascular tone; without it, the muscle will not relax, and the blood vessel remains constricted. Thus, oxidized LDL also contributes to the hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
often seen with atherosclerosis.
Implications for the treatment and prevention of arteriosclerosis
The role LDL plays suggests two different approaches to treatment and prevention. The first approach involves discouraging the accumulation of LDL by lowering the levels of serum LDL, an idea more closely associated with the lipid hypothesisLipid hypothesis
The lipid hypothesis was one of two hypotheses developed in the 1850s to explain the pathogenesis of atherosclerosis...
. A major breakthrough involved the discovery of statins, a class of drugs which help to clear LDL from the bloodstream. It has been demonstrated conclusively that elevated levels of LDL are associated with higher risk of mortality from coronary heart disease
Coronary disease
Coronary disease refers to the failure of coronary circulation to supply adequate circulation to cardiac muscle and surrounding tissue. It is already the most common form of disease affecting the heart and an important cause of premature death in Europe, the Baltic states, Russia, North and South...
(CHD); it has also been shown that statins substantially lower the risk of mortality in patients with high LDL.
A second approach would be to discourage the oxidation of LDL, thereby breaking the inflammatory cycle. Lipoproteins consist of a packaging of triglycerides and esterfied cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
within a monolayer shell consisting of phospholipids and a class of proteins called apolipoproteins. The phospholipds are amphipathic, consisting of a hydrophobic tail which faces inwards, binding with the triglycerides and cholesterol, and a hydrophilic head which faces outwards, making the lipoproteins water soluble.
Polyunsaturated fatty acids (PUFA) contained in the outer shell make the lipoproteins especially susceptible to oxidation. However, lipoproteins also contain antioxidants which protect the components, vitamin E
Vitamin E
Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...
and carotenoids being the two major naturally-occurring antioxidants in human lipoprotein.
Although some studies have shown positive results following anti-oxidant therapy with vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...
, vitamin E therapy has attracted the most public attention. There have been some positive results, though recent studies have shown no benefit for antioxidant therapy on mortality among patients at risk for CHD.,
Implications for diet: Dietary lipids and LDL levels
An early incarnation of the lipid hypothesisLipid hypothesis
The lipid hypothesis was one of two hypotheses developed in the 1850s to explain the pathogenesis of atherosclerosis...
which focused on hypercholesterolemia
Hypercholesterolemia
Hypercholesterolemia is the presence of high levels of cholesterol in the blood. It is not a disease but a metabolic derangement that can be caused by many diseases, notably cardiovascular disease...
lead to the suggestion that mortality from CHD might be reduced by controlling dietary input of cholesterol. Studies have demonstrated that increasing dietary cholesterol leads to an increase in both total cholesterol (TC) and LDL Cholesterol (LDL-C), however it also leads to increases in the level of high-density lipoprotein cholesterol (HDL-C), offsetting the effect of the increase in LDL-C. Epidemological studies which attempted to correlate dietary cholesterol with risk of mortality in CHD have produced mixed results.
Recent studies have focused more on the ratio of saturated fatty acids (SFAs) and polyunsaturated fatty acids (PUFAs) in the diet. It has been demonstrated that intake of SFA raises TC in humans, whereas PUFA lowers TC; however SFA also increases the level of HDL-C, once more offsetting the effect of increased TC. Studies of individual fatty acids show that some SFAs, e.g. stearic acid
Stearic acid
Stearic acid is the saturated fatty acid with an 18 carbon chain and has the IUPAC name octadecanoic acid. It is a waxy solid, and its chemical formula is CH316CO2H. Its name comes from the Greek word στέαρ "stéatos", which means tallow. The salts and esters of stearic acid are called stearates...
and palmitic acid
Palmitic acid
Palmitic acid, or hexadecanoic acid in IUPAC nomenclature, is one of the most common saturated fatty acids found in animals and plants. Its molecular formula is CH314CO2H. As its name indicates, it is a major component of the oil from palm trees . Palmitate is a term for the salts and esters of...
have little effect of LDL-C levels; stearic acid actually lowers the LDL/HDL ratio due to a greater increase of HDL-C levels relative to TC.
Epidemiological studies designed to test the relationship between high SFA/PUFA ratios and CHD mortality have tended to produce mixed results. Two recent studies provide an example of this lack of consensus: a study from Poland correlated a decline in CHD mortality with a decrease in the ratio of SFA to PUFA in the population's diet following the collapse of Communism. Yet a large population study from Sweden covering roughly the same time period showed no association between fat intake and CHD.
The AHA guidelines and the beginning of a controversy
The early studies associating the ratio of dietary SFA and PUFA with TC levels led the American Heart AssociationAmerican Heart Association
The American Heart Association is a non-profit organization in the United States that fosters appropriate cardiac care in an effort to reduce disability and deaths caused by cardiovascular disease and stroke. It is headquartered in Dallas, Texas...
(AHA) to promulgate a set of dietary guidelines which included the recommendation to replace saturated fats found in dairy and meat products with polyunsaturated fats found in natural vegetable oils such as those derived from "corn, cottonseed, and soya". This first set of recommendations, published in the Journal Circulation in 1961, specifically sanctioned the use of products containing partially hydrogenated vegetable oils, i.e. margarine
Margarine
Margarine , as a generic term, can indicate any of a wide range of butter substitutes, typically composed of vegetable oils. In many parts of the world, the market share of margarine and spreads has overtaken that of butter...
and vegetable shortening
Shortening
Shortening is any fat that is solid at room temperature and used to make crumbly pastry. The reason it is called shortening is because it prevents cross-linkage between gluten molecules. Cross linking is what causes doughs to be sticky. Seeing as cake is not meant to be sticky, shortening is used...
. Despite the lack of uncontrovertable epidemiological evidence of their effectiveness, these initial guidelines received widespread acceptance among the medical community in the US.
The suggestion to replace saturated animal fats with partially hydrogenated vegetable oils lead to a reaction which will be discussed below. However, is important to note that the AHA's dietary guidelines have undergone several revisions since the initial report. Although the most recent (2006) guidelines still recommend reducing the consumption of saturated fat, they no longer suggest switching to polyunsaturated fats. Moreover, the guidelines now recommend minimizing the intake of partially hydrogenated fats while increasing the consumption of fish and other sources rich in omega-3 fatty acids. Thus, the position of the AHA is now much closer to that of its critics.
Criticism of the AHA guidelines: the “Cholesterol Skeptics”
Critics of the AHA dietary guidelines point out that incidence of CHD in the US increased markedly during a 60 year period beginning in 1910. During the same period, consumption of saturated fat fell, while consumption of processed vegetable oils rose more than 400%. (Much of the evidence presented to support this claim of a large increase in incidence of CHD in the early part of the century is anecdotal. Statistics covering the period from 1950 to 1980 show that mortality from CHD in the US, although much higher than in most other countries, began to decline slowly after 1966 (mortality in the UK, although initially much lower than in the US, rose continuously during this period). These are mortality figures; the downward trend in the US probably reflects improvements in survival rate and not a decrease in incidence.)This observation led some critics to invert the AHA guidelines. They stress the benefits of dietary SFA, citing the presence of natural antioxidants in animal fats, while encouraging people to avoid foods containing processed vegetable oils. They focus on the deleterious effect of dietary PUFA, often mentioning two factors: (1) the vulnerability of PUFA to oxidation and the formation of free radicals, and (2) the high ratio of omega-6 to omega-3 PUFA in the more common vegetable oils—those derived from “corn, cottonseed, and soya”. Their considerations are not limited to CHD, they point to an entire litany of inflammatory disorders which can be linked to diet and the consumption of processed vegetable oils. Some critics also question the safety of cholesterol-lowering drugs, suggesting that CHD is best controlled using a combination of diet and exercise.
This preoccupation with inflammatory processes has led some authors to popularize the chronic endothelial injury hypothesis. They also criticize the “Lipid Hypothesis”; however, for the most part, what is being criticized is not the lipid hypothesis itself, but a set of dietary guidelines that evolved from it. The debate is not (or should not be) about validity of the two hypothesis, but rather the relative benefits of two different therapeutic approaches: whether it is more productive to concentrate on lowering LDL levels or to focus on the underlying inflammatory mechanisms.
Many of these critics appeal to a popular, anti-establishment audience. At the most radical end of this spectrum, a number of books have been written which suggest the existence of a conspiracy between the “medical establishment” and “financial interests” , i.e. the food-processing industry and drug companies.