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The death rate from coronary artery disease (CAD) has declined considerably over the last three decades. This is mainly due to better control of risk factors and advances in therapy.
However, the prevalence of CAD remains high due to the aging of the population and better survival of those affected.
The current epidemic of obesity and type 2 diabetes will likely escalate the problem further.
Atherosclerosis, the underlying cause of CAD, is characterized by an accumulation of lipids, white blood cells, and cell debris in the inner layers of the arterial wall. The immune system is involved in the process, and inflammation appears to play a critical role (1).
Atherosclerosis can affect all arteries in the body but seems to have a high affinity for the coronary arteries.
Atherosclerotic lesions or plaques may protrude into the lumen of the coronary arteries, causing blockages that may limit blood flow to the heart muscle.
Additionally, rupture of an atherosclerotic plaque may cause thrombosis (blood clotting), completely blocking blood flow in a coronary artery. The result may be an acute heart attack.
The Role of Cholesterol and Lipoproteins
There is abundant evidence linking lipids, cholesterol in particular, with atherosclerosis (2).
In 1913, Nikolai N. Anitschkow, a Russian pathologist in Saint Petersburg, demonstrated that when given to rabbits, cholesterol, extracted from the egg yolks, (purified, and dissolved in vegetable oil) produced arterial lesions that closely resembled those of human atherosclerosis (3).
Many autopsy studies have shown a relationship between the amount of blood cholesterol and the extent of atherosclerosis (4). Furthermore, accumulation of cholesterol is found in human atherosclerotic plaques (5).
Because fats are insoluble in water, cholesterol cannot be transported in blood on its own. Instead, cholesterol is attached to hydrophilic proteins that function as transport vehicles carrying different types of fats such as cholesterol, triglycerides, and phospholipids.
These combinations of fats and protein are termed lipoproteins. Lipoprotein particles vary in the primary lipoprotein present and the relative contents of the different lipid components.
There is strong evidence that lipoproteins play a fundamental role in atherosclerosis and their interaction with the arterial wall appears to initiate the cascade of events that leads to atherosclerosis.
There are five major types of lipoproteins; chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL).
Lately, the role of another lipoprotein, called lipoprotein(a) or Lp(a) has been highlighted (6).
Lipoproteins that promote atherosclerosis are termed atherogenic.
A specific protein, called Apolipoprotein B100 (ApoB), is an important component of all atherogenic lipoproteins (7).
Atherogenic lipoproteins such as LDL, VLDL, and Lp(a), all contain one ApoB molecule per particle. Hence, measurements of ApoB reflect the number of atherogenic particles.
On the other hand, HDL does not contain ApoB, and is not atherogenic. In fact, HDL appears to play a protective role and high levels of HDL particles are associated with less risk of coronary artery disease (9).
So, the atherogenicity of different lipoproteins is not determined by their cholesterol content. Instead, the lipoproteins’ molecular composition and the presence er absence of the ApoB molecule seem to be most important.
Lipoproteins are produced by the liver and their removal from the circulation is dependent on receptors found on the surface of cells, primarily in the liver. The LDL receptor plays a crucial role in the removal of LDL from the circulation.
Despite the proposed strengths of the associations between cholesterol, lipoproteins, and atherosclerosis, the underlying mechanisms have not been completely clarified.
Many people have high blood cholesterol throughout their lifetime without ever developing heart disease. Furthermore, a significant proportion of patients with coronary artery disease doesn’t have high blood cholesterol (10).
Retention of LDL in the Arterial Wall
The wall of an artery consists of three layers, the tunica intima, the tunica media, and the adventitia. Also, there is the endothelium, a thin cellular layer that lines the interior surface of the artery.
The intima and media consist of smooth muscle cells and extracellular matrix. The outermost layer, the adventitia, consists of looser connective tissue, nerve endings, mast cells, and vasa vasorum (a network of small blood vessels that supply the walls of larger arteries).
An accumulation of LDL in the arterial intima is an early step in atherosclerosis. Increased permeability of the endothelium and increased intimal retention of LDL are critical elements in the process.
LDL particles interact with particular constituents of the intima, notably the extracellular matrix. Here, the presence of ApoB may be a key factor.
Chondroitin sulphate proteoglycans (11) produced by smooth muscle cells in the arterial wall interact with ApoB on the surface of lipoprotein particles, thereby increasing the retention of LDL.
Endothelial dysfunction may also be a key factor. It may cause increased permeability of the endothelium allowing atherogenic lipoproteins to enter the vessel wall.
However, if lipoproteins are not retained in the intima, atherosclerosis is less likely to occur. Therefore, factors that promote lipoprotein retention are likely to induce atherosclerosis.
LDL Particle Size and Atherosclerosis
The size of the LDL particles may influence how readily LDL penetrates the endothelial barrier. Small LDL particles appear to penetrate the the endothelium and reach the intima 1.7-fold more than large LDL particles (12).
Also, small, dense LDL particles are more likely to bind to proteoglycans than large fluffy LDL particles (13).
High numbers of small, dense LDL particles are associated with increased risk for CAD in prospective epidemiologic studies. (14).
Small LDL particles are associated with high triglycerides (15), low HDL cholesterol (9), insulin resistance, metabolic syndrome (16), and type 2 diabetes.
The propensity of small LDL particles to be retained within the intima may explain why patients with metabolic syndrome and type 2 diabetes are at heightened risk of coronary artery disease in the face of normal or average blood levels of LDL cholesterol.
Modified LDL (Glycated LDL and OxLDL) and Atherosclerosis
Evidence suggests that to initiate atherosclerosis, LDL has to undergo chemical modification. Otherwise, it can not unlatch the typical cellular and inflammatory reactions typical of the disorder.
The oxidation hypothesis of atherosclerosis, summarized in 1989 by Steinberg, Whitman, and colleagues, suggests that oxidative modification of LDL plays a crucial role (17).
At the most basic level, oxidation is the loss of electrons. When a compound is oxidized, its properties change.
Because of its complex composition, the LDL particle is very sensitive to oxidized damage.
Each LDL particle contains approximately 700 molecules of phospholipids, 600 molecules of free cholesterol, 1600 molecules of cholesterol esters, 185 molecules of triglycerides, and one molecule of apoB. Both the protein and lipid moieties can undergo oxidative modification.
Whereas circulating LDL is reasonably stable, the long dwelling time of LDL within the intima provides a greater opportunity for oxidative modification.
Recent findings suggest that oxLDL begins to deposit in human coronary arteries before plaque formation and increasingly deposits with plaque growth (18).
Plasma concentration of oxLDL is associated with the risk of acute coronary heart disease events (19). One study found that plasma oxLDL was the strongest predictor of such events compared with a conventional lipoprotein profile and other traditional risk factors (20).
Oxidized LDL (OxLDL) promotes the immune and inflammatory reactions that characterize atherosclerosis. Evidence suggests that these reactions may be genetically determined (21).
Glycation is another type of atherogenic modification of LDL that may contribute to atherosclerosis (22).
Glycation is the result of bonding of a protein or lipid molecule with a sugar molecule, such as fructose or glucose, without an enzyme’s controlling action.
Small, dense LDL is more susceptible to glycation than more buoyant LDL (23).
Glycation and oxidation of LDL appear to be intimately linked and glycated LDL is more likely to be oxidized than non-glycated LDL (24).
Inflammation and Atherosclerosis
Inflammation plays a vital role in the formation of atherosclerotic lesions and the subsequent clinical complications (25).
Popular theories on the initiation of atherosclerosis suggest that modified lipoproteins, such as oxLDL, may play a central role in promoting the inflammatory reactions that characterize and drive atherosclerosis.
Cytokines are small proteins that are important in cell signaling (26).
Common cytokines include interferons, adipokines, interleukins, and tumor necrosis factor.
The discovery that vascular wall cells themselves can produce cytokines provided an important insight into the initiation of atherosclerosis.
According to the original concept, cytokines function to signal between leukocytes (white blood cells), hence the name “interleukin” (27).
Products of oxLDL may stimulate vascular wall cells to produce cytokines (28). These cytokines are believed to be mediators of inflammation and immune reactions in the atherosclerotic process.
Leukocytes, the type of white blood cells which is typically involved in most inflammatory reactions in the body, appear to play a significant role in atherosclerosis.
Leukocyte recruitment to the arterial wall is an important initial step in the formation of atherosclerotic lesions. The circulating leukocytes that enter the vessel wall are called monocytes, but within tissues, they are termed macrophages.
Typically, the endothelium resists the adhesion of leukocytes derived from blood. However, when stimulated by pro-inflammatory cytokines, adhesion molecules on the surface of endothelial cells may capture leukocytes (29). Hence, cytokines may play a key role in recruiting inflammatory cells in the vascular wall.
Failure of counter-regulatory mechanisms may also promote inflammation and oxidation in atherosclerosis. For example, HDL particles may function as carriers for anti-inflammatory and antioxidant mediators (30). In fact, HDL is an effective antioxidant.
HDL may also inhibit the expression of adhesion molecules in endothelial cells, thus reducing the recruitment of leucocytes into the artery wall.
Furthermore, HDL can inhibit the oxidative modification of LDL and thereby reduce the atherogenic potential of LDL.
Hence, low HDL levels may aggravate atherosclerosis because of blunted anti-inflammatory and antioxidant actions.
After reaching the intima, leukocytes (macrophages) take up modified lipoproteins. These-lipid laden white blood cells are called foam cells. Foam cells comprise the bulk of early atherosclerotic lesions, often termed fatty streaks (31).
Foam cells play a critical role in the occurrence and development of atherosclerosis.
The Stable Plaque and the Vulnerable Plaque
Rupture of the plaque surface, often with superimposed blood clotting (thrombosis), frequently occurs during the evolution of coronary atherosclerotic lesions.
Actually, plaque rupture is an important mechanism underlying most cases of acute heart attack and sudden cardiac death (32).
The concept of plaque rupture was first reported at the autopsy of the celebrated neoclassical Danish artist Bertel Thorvaldsen, who died of sudden cardiac death in the Royal Theater in Copenhagen in 1844 (33).
However, it was not until the next century that researchers described the features of plaques responsible for acute coronary syndrome and sudden cardiac death.
Atherosclerotic plaques may become large over time and bulge into the lumen of the artery, limiting blood flow to tissues and organs. However, these plaques are not necessarily prone to rupture because the risk of plaque rupture depends on plaque type (composition) rather than plaque size (volume).
An atherosclerotic plaque that is prone to rupture is defined as a vulnerable plaque, whereas a plaque that is not prone to rupture is considered a stable plaque.
A vulnerable plaque is characterized by a thin fibrous cap, large lipid-rich necrotic core, plaque inflammation, increased vasa-vasorum vascularization, and intra-plaque bleeding (34).
One of the most significant challenges facing atherosclerotic research is identifying how and why plaques become vulnerable and how this may be translated into clinical practice.
The Role of Metabolic Syndrome and Insulin Resistance
Lately, metabolic syndrome, obesity, and type 2 diabetes have become increasingly common. These disorders are characterized by insulin resistance and an increased risk of CAD (16).
Insulin resistance is associated with low blood levels of HDL-cholesterol and high levels of atherogenic triglyceride-rich lipoproteins such as VLDL (35).
Increased availability of small LDL particles is common in people with insulin resistance (36).
Furthermore, insulin resistance is associated with higher levels of circulating oxLDL, which may contribute to atherosclerosis and acute coronary events (39).
The Limitations of Using LDL-Cholesterol to Assess Risk
The figure below is based on data from the Framingham Study showing the distribution of blood cholesterol in people with and without CAD (37). Both curves are bell-shaped with the top of the bell corresponding to the medium cholesterol level in each group.
Notice that those who have coronary artery disease have slightly higher medium levels of blood cholesterol, but the difference is small.
Interestingly, a substantial number of people with normal cholesterol levels (<200 mg/dL) develop coronary artery disease. Furthermore, a significant number of individuals with elevated cholesterol (225-300 mg/dL) don’t have coronary artery disease.
Blood levels of LDL-cholesterol are commonly used to assess the risk of heart disease. However, using LDL-cholesterol to assess risk has several limitations (38).
The LDL-cholesterol value accounts for the total amount of cholesterol carried by LDL particles. Importantly, it doesn’t account for the number of LDL particles present in the circulation, which is more important when it comes to risk assessment (39).
Furthermore, LDL-cholesterol does not provide information about the size of LDL particles, which is important because small particles are more strongly associated with atherosclerosis than large particles.
So, of course, high blood cholesterol is not enough to cause atherosclerosis. But, if the availability of atherogenic lipoproteins such as LDL and VLDL is high, atherosclerosis is more likely to occur. However, for that to happen, other factors have to be present as well.
Lately, metabolic syndrome, obesity, and type 2 diabetes have become increasingly common. These disorders are characterized by insulin resistance and an increased risk of CAD.
A Few Practical Considerations
During the last 75 years, a simplified model of atherosclerosis and heart disease has been presented to health professionals and the lay public.
The model higlights cholesterol accumulation in the vessel wall as the main culprit. Consequently, lifestyle measures that lower cholesterol are emphasized.
Clinical and dietary guidelines have pinnacled LDL-cholesterol as an important target to prevent the occurrence of CAD.
Recommendations to limit the intake of saturated fats and cholesterol are based on the assumption that these types of fats will raise LDL-cholesterol and thereby increase risk. Hence, low-fat food products have been marketed with the aim of reducing the burden of cardiovascular disease.
Nonetheless, compared with low-fat diets, low-carbohydrate diets provide greater improvements in parameters associated with insulin resistance, such as HDL cholesterol, VLDL, LDL particle size, and particle number (40).
Moreover, low-carbohydrate diets provide greater reductions in inflammatory markers than low-fat diets (41).
There is no reason to believe that food products that elevate HDL cholesterol, lower triglycerides, reduce the availability of atherogenic LDL particles, and reduce insulin resistance and inflammatory markers, would be less effective in fighting heart disease than food that lowers LDL cholesterol.
That’s not to say that cholesterol doesn’t matter.
Lowering the availability of cholesterol-rich lipoproteins such as LDL and VLDL may be crucial in patients with coronary artery disease and individuals prone to atherosclerosis, such as those with familial hypercholesterolemia.
Denying the role of cholesterol in atherosclerosis is as naive as believing it explains everything.
Summary
An accumulation of LDL in the arterial wall is an essential step in the initiation of atherosclerosis.
Increased permeability of the endothelium and increased retention of LDL particles within the intima are important underlying mechanisms.
Small LDL particles are more likely to be retained in the intima than large buoyant LDL particles.
LDL particles may undergo chemical modification within the intima and become oxidized. OxLDL may enter white blood cells (leukocytes) called macrophages, which subsequently transform into foam cells. Foam cells are commonly found in atherosclerotic plaques.
Products of oxLDL may provoke vascular wall cells to produce cytokines, which promote recruitment of inflammatory cells into the vascular wall. Immune reactions and low-grade inflammation play a crucial role in the formation and progression of atherosclerotic plaques.
Rupture of the plaque surface, often with superimposed blood clotting (thrombosis), frequently occurs during the evolution of coronary atherosclerotic lesions. Plaque rupture is an important mechanism underlying most cases of acute heart attack and sudden cardiac death. Plaques that are prone to rupture are termed vulnerable plaques.
Currently, atherosclerosis is viewed as a complex multifactorial disorder involving the vessel wall, endothelial function, lipoproteins, lipoprotein modification such as glycation and oxidation, immune reactions, inflammation, and blood clotting (thrombosis).
It is the responsibility of experts in the field to educate health professionals and the general public about the complexity of atherosclerosis.
Unfortunately, the deep-rooted and oversimplified cholesterol-model of atherosclerosis has skewed recommendations on dietary interventions and other lifestyle measures to prevent coronary artery disease.
The article was initially published in 2016.
It was revised, updated and republished on February 13th, 2021.
