Low-Density Lipoprotein (LDL) in Atherosclerosis and Heart Disease

The death rate from coronary artery disease (CAD) has declined considerably over the last three decades, mostly because of better control of risk factors and advances in therapy.

However, due to the aging of the population and better survival of those affected, the prevalence of the disease remains high. The current epidemic of obesity and type 2 diabetes will likely escalate the problem further.

Low Density Lipoprotein (LDL) in Atherosclerosis and Heart DiseaseAtherosclerosis, 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 an important role (1).

Atherosclerotic lesions or plaques may protrude into the lumen of the arteries, causing blockages which may limit blood flow to the heart muscle. Rupture of an atherosclerotic plaque may cause thrombosis (blood clotting) completely blocking blood flow in the artery. Atherosclerosis can affect all arteries in the body but seems to have a high affinity for the coronary arteries.

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 blood cholesterol and the extent of atherosclerosis (4). Furthermore, accumulation of cholesterol is found in human atherosclerotic plaques (5).



ecause 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. Lipoproteins that promote atherosclerosis are termed atherogenic. Apolipoprotein B (apoB) is an important component of atherogenic lipoproteins (6).

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).

Low-Density Lipoprotein (LDL) in Atherosclerosis and Heart Disease
The LDL particle has a core that is mostly composed of cholesterol esters and a coat containing phospholipids and unesterified cholesterol. ApoB, the major protein moiety encircles the equator of the particle. From Ballantyne, Clinical Lipidology, 2nd edition.

Although LDL is the lipoprotein most commonly associated with atherosclerosis, other lipoproteins, such as VLDL may also be atherogenic (7). On the other hand, HDL appears to play a protective role, and high levels of HDL particles are associated with less risk of coronary artery disease (8).

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 (9).

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LDL and Atherosclerosis

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.

Low-Density Lipoprotein (LDL) in Atherosclerosis and Heart DiseaseThe 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 appear to play an important role in this process.

LDL particles interact with particular constituents of the intima, particularly the extracellular matrix. Chondroitin sulphate proteoglycans (10) produced by smooth muscle cells in the arterial wall interact with apoB on the surface of lipoprotein particles, thereby increasing the retention of LDL.

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 endothelial barrier 1.7-fold more than large LDL particles (11).

Various fractions of LDL interact differently with the extracellular matrix. Small, dense LDL particles are more likely to bind to proteoglycans than large fluffy LDL particles (12). High numbers of small, dense LDL particles are associated with increased risk for CAD in prospective epidemiologic studies. (13).

Small LDL particles are associated with high triglycerides (14), low HDL cholesterol (15), 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 the 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 that unlatches 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 and that oxidized LDL (OxLDL) promotes the immune and inflammatory reactions that characterize atherosclerosis (17).

At the most basic level, oxidation is the loss of electrons. When a compound is oxidized, its properties change. For example, unoxidized iron is a strong structurally sound metal, while oxidized iron, because of the loss of electrons, is a brittle reddish powder.

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 which is a very complex biochemical process.

Circulating LDL is reasonably stable but the long dwelling time of LDL within the intima, a consequence of proteoglycan binding, 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 CAD events (19). One study found that plasma oxLDL was the strongest predictor of CAD events compared with a conventional lipoprotein profile and other traditional risk factors for CAD (20).

OxLDL particles may promote atherosclerosis through several mechanisms.  However, the inflammatory and immune response to LDL oxidation 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 the controlling action of an enzyme. 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).

LDL and Inflammation

Inflammation plays an important 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). Cytokines are released by cells and affect the behavior of other cells. 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 provoke vascular wall cells to produce cytokines (28). 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 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). 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 anti-oxidant mediators (30).

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 anti-oxidant 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 Vulnerable Plaque

Rupture of the plaque surface, often with blood clotting (thrombosis) superimposed, frequently occurs during the evolution of coronary atherosclerotic lesions. It is probably the most important mechanism underlying the sudden, rapid plaque progression responsible for acute coronary syndromes (32). Plaque rupture is an important mechanism underlying most cases of acute heart attack and sudden cardiac death.

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 found pathological features of culprit lesions 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 (33).

One of the greatest challenges facing atherosclerotic research is identifying how and why plaques become vulnerable and how this may be translated into clinical practice. Currently available vascular imaging methods have a limited ability to assess plaque morphology and vulnerability.

Summary

An accumulation of LDL in the tunica intima is an important 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.

Low-Density Lipoprotein (LDL) in Atherosclerosis and Heart Disease

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 blood clotting (thrombosis) superimposed, 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.

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Practical Considerations

The figure below is based on data from the Framingham Study showing the distribution of blood cholesterol in people with and without CAD (34). Both curves are bell shaped with the top of the bell corresponding to the medium cholesterol level in each group.

Low Density Lipoprotein (LDL) in Atherosclerosis and Heart Disease
Castelli, William. The American Journal of Cardiology, 1998: 82:60T-65T

Those who have coronary artery disease have a 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.

Using LDL cholesterol to assess risk has several limitations (35). The measure accounts for the total amount of cholesterol carried by LDL particles. It doesn’t account for the number of LDL particles present in the circulation which is more important regarding risk (36). 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.

Endothelial dysfunction plays an important role. Increased permeability of the endothelium allows 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.

Modified lipoproteins such as glycated LDL and oxLDL are more liable to retention within the vessel wall intima. Hence, factors that promote glycation and oxidation of LDL are believed to enhance atherosclerosis.

Lately, metabolic syndrome, obesity, and type 2 diabetes have become increasingly common. These disorders are characterized by insulin resistance and increased risk of CAD. Insulin resistance is associated with low blood levels of HDL cholesterol and high levels of atherogenic triglyceride-rich lipoproteins such as VLDL (37).

Increased availability of small LDL particles is common in people with insulin resistance (38). Furthermore, insulin resistance is associated with higher levels of circulating oxLDL which may contribute to atherosclerosis and acute coronary events (39).

During the last 70 years, a simplified model of atherosclerosis and heart disease has been presented to health professionals and the lay public, highlighting cholesterol accumulation in the vessel wall as the main culprit. Consequently, lifestyle measures that lower cholesterol have been 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 recommended and 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.

This is not to say that cholesterol doesn’t matter. In fact, 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 or heightened risk due to other reasons. Denying the role of cholesterol in atherosclerosis is as naive as believing it explains everything.

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.

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Nigel Kinbrum
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Hi, What do you think about Subbotin’s neovascularisation hypothesis of atherosclerosis? See https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492120/ Subbotin is suggesting that the factors determining plaque formation are LDL-c and something else (which is why lowering LDL-c alone lowers the RR of CAD by an extremely variable amount). RE Triglycerides: Studies by Dreon D et al showing associations between increasing carbohydrate intake & reducing particle size had 50% of the carbs as sugars. I declare shenanigans. As Kitavans (~70%E from starchy carbohydrates) have high TG’s but virtually zero rates of CAD, it’s not TG’s that are the problem. It’s poor diet quality (high %E from… Read more »

Axel F Sigurdsson
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Axel F Sigurdsson

Noige.
I believe Subbotin’s suggesting that lipoproteins don’t enter the intima through the endothelium but through new vessel formation (neovascularisation) from the vasa vasorum in the adventitia. Haven’t studies his theories in detail though.

Nigel Kinbrum
Guest

Axel,

In https://jn.nutrition.org/content/134/11/3100.full , the upper tertile (~41ug/day) of Vitamin K2 intake had ~57% reduction in CHD mortality, compared to the lowest tertile (~15ug/day).

I don’t understand why a RCT on Vitamin K2 hasn’t been done, to test the hypothesis that Vitamin K2 drastically reduces atherosclerosis, by reversing calcification in the media. Do you know of any trials in the pipeline?

Suffice it to say, I supplement with Vitamin K2.

JDPatten
Guest
JDPatten

What form? MK-4? MK-7? Some say it makes a difference.

Nigel Kinbrum
Guest

MK-4. It disappears from circulation into adipocytes much faster than MK-7. Other than that, I don’t think that there’s much difference.

It definitely works! See https://bit.ly/1PJFeel

Joern M. Vikse
Guest
Joern M. Vikse

All ldl’s begin their life as vldl’s don’t they ? And vldl’s are created in the liver and filled with trigs converted from carbs in the liver. Apparently in the process also polyunsaturated fats are packed in the vldl’s (Ralf Sundberg youtube video)
Reducing the amount of carbs converted in the liver should make the ldl’s fewer and bigger (less trigs, more cholesterol) ?
Reducing the amount of polyunsaturated fat should make the ldl’s less prone to oxidation ?
Why…..og why is saturated fat always convicted as the bad guy ?

Axel F Sigurdsson
Guest
Axel F Sigurdsson

You’re right Joern.
It is believed that most LDL is produced from VLDL.
Once in circulation, VLDL comes in contact with lipoprotein lipase in the capillary beds. Lipoprotein lipase catalyzes the breakdown of VLDL, releasing triglycerides for energy production or storage in adipose tissue. After the removal of triglycerides from VLDL, the composition of the lipoprotein changes and it becomes intermediate-density lipoprotein (IDL). Later, when the amount of cholesterol increases, IDL becomes low-density lipoprotein (LDL).

Joern M. Vikse
Guest
Joern M. Vikse

Thx for a brilliant summary by the way

bessary
Guest
bessary

I don’t think the “healthcare professionals” have figured out which came first… the inflammation or the cholesterol. I think when they figure out that the inflammation is first, and concentrate on what is causing the inflammation and that it could be a combination of different factors in different people they will solve the problem.

Joern M. Vikse
Guest
Joern M. Vikse

The big question might be: Do anybody want to «really» solve it, and more specifically: Who should fund the proper research.
Unless it will result in a drug there probably isn’t funding for it. And the statin business out of patent, but still a considerable industry will plummet, as will the new pcsk9 inhibitors industry not yet off the ground.
Almost 100 years of research and we have the current situation ?

tannngl
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tannngl

Doc, I had a question while reading this analysis.

In my reading on VLC diets, there have been looks at North American Eskimos (pre-Western influence) and the Masai in Africa.

Most of the Masai all had atherosclerosis but the incidence of coronary infarct seemed almost nil.

Is it possible that atherosclerosis does not necessarily lead to heart attack? Perhaps it’s a normal part of aging?

Axel F Sigurdsson
Guest
Axel F Sigurdsson

Tanngl
Myocardial infarction (MI) usually doesn’t occur unless there is plaque rupture with superimposed thrombosis. So, you can have widespread atherosclerosis without MI occurring.

In many ways atherosclerosis can be regarded as a normal part of aging. We will all have it if we live long enough. So basically, it is premature atherosclerosis that we should regard as disease.

Joern M. Vikse
Guest
Joern M. Vikse

The lipoprotein transport system might not have been evolution’s greatest moment.
But evolution is primarily concerned with the survival of the species, not prolonged life expectancy

George
Guest
George

The LDL lipoprotein transport system prolongs life expectancy in the elderly, when infections are a major cause of death, whatever it might do in middle age.

Joern M. Vikse
Guest
Joern M. Vikse

I was referring to the mechanical construction of the lipoproteins. No doubt do they play an important and benificial role.
Evolution often deems things to be «good enough»
It can hardly foresee our deliberate attempt to destroy it….sugar, inflammation, Linoleic acid in excess etc

tannngl
Guest
tannngl

Thanks!

Mie
Guest
Mie

“So, of course, high blood cholesterol is not enough to cause atherosclerosis.”

I thought high LDL alone is sufficient. FH patients, anyone? That, of course, doesn’t mean that other factors aren’t involved or that a multifactorial approach (not just about lowering LDL) isn’t the best.

Axel F Sigurdsson
Guest
Axel F Sigurdsson

High LDL alone probably isn’t sufficient. Many individuals with very high LDL’s don’t develop CAD, including patients with FH. Of course, those with high LDL’s are at higher risk.

Mie
Guest
Mie

Axel, many individuals who smoke on a regular basis don’t get lunc cancer. Does that mean that smoking doesn’t cause lung cancer? 🙂

FH patients differ from others in one respect and yet their risk of getting CAD is much, much higher. So yes, high LDL alone is sufficient.

Axel F Sigurdsson
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Axel F Sigurdsson

Ok Mie. Fair enough.. or maybe not. You can’t really compare LDL with smoking. Smoking is an external/environmental factor that can hardly be compared to a biological substance, a lipoprotein that is necessary for normal physiological/biochemical equilibrium. If you’re going to use the smoking analogy you would have to say that something that causes elevation of LDL causes atherosclerosis (for example some types of saturated fat). I agree that there is abundant evidence and no doubt that smoking causes lung cancer. However, there is no clear evidence that external factors that raise LDL (such as some saturated fats) alone cause… Read more »

Mie
Guest
Mie

“You can’t really compare LDL with smoking. Smoking is an external/environmental factor that can hardly be compared to a biological substance, a lipoprotein that is necessary for normal physiological/biochemical equilibrium.” True. But, of course, irrelevant in this case. Of course, LDL per se is not the issue but abnormal levels of it. As for the elevation point, isn’t that a bit like splitting hairs? You might as well argue that it’s not smoking but something that CAUSES people to smoke, right? “However, there is no clear evidence that external factors that raise LDL (such as some saturated fats) alone cause… Read more »

George
Guest
George

The FH patients may be the equivalent of the cholesterol-fed rabbits. The rabbits were fed cholesterol well above their threshold of tolerance. FH patients may have LDL above a threshold of tolerance (total cholesterol levels of 650-1000 mg/dL are typical of homozygous FH), but that doesn’t prove that variations in the range below that threshold are meaningful.

Mie
Guest
Mie

The “may” there is misguided: the risk increases in a pretty much linear fashion among us “regular folk” too and is just as strongly a sufficient (and necessary) factor.

George
Guest
George

My understanding is that the linear association of LDL-C with CHD risk is weak and contingent in the normal range. For example, in Hooper et al (2015), a meta-analysis of saturated fat reduced diet trials, lowering LDL-C by substituting PUFA (an essential nutrient(s) that is associated with vitamin E, another essential nutrient) for SFA (an inessential nutrient) was associated with a reduction in non-fatal CHD events (not including heart attacks). Whereas lowering LDL-C by substituting carbohydrate (an inessential nutrient) for SFA (an inessential nutrient) was not associated with any change in risk. This is a weak association of LDL-C with… Read more »

Mie
Guest
Mie

“My understanding is that the linear association of LDL-C with CHD risk is weak and contingent in the normal range.” Your understanding is … well, wrong. Or then you’re going for a semantic “argument” than a real one? “Normal” in western population is not really the same as “optimal”, you do know that? “For example, in Hooper et al (2015) …” The problem with this – and many other meta-analyses is that it doesn’t take into account the size of the effect. In RCT evidence, large trials like WHI which had statistically significant but clinically insignificant results tend to bias… Read more »

George
Guest
George

By “normal” I meant “not homozygous FH” for a start. Normal is a genetic judgement in this context. Secondly, when you read the Hooper paper, you will find that the associations I reported come from the subgroup analysis of cholesterol lowering, which was only associated with benefit (events but not MI or mortality) if due to PUFA substitution. This specifically excluded the WHI study. In all the diet-heart studies, food quality and carbohydrate quality was improved in the intervention arms compared to the control arms. The reason is obvious – biscuits, cakes and other baked goods, and deep fried foods… Read more »

Mie
Guest
Mie

“Secondly, when you read the Hooper paper, you will find that the associations I reported come from the subgroup analysis of cholesterol lowering, which was only associated with benefit (events but not MI or mortality) if due to PUFA substitution. This specifically excluded the WHI study.” So a) “only” events? 🙂 And b) the abovementioned points concerning the effect sizes, underpowered studies etc.? If I don’t remember wrong, the absolute effect size (LDL lowering) in studies included by Hooper was 0,21 mmol/L. In comparison, in LA Veterans the reduction in the experimental group was around 20% of starting point of… Read more »

George
Guest
George

HDL raising doesn’t work because the means are the wrong drugs.
If studies are underpowered, you’re looking for a weak effect. Plenty of effects (eg low carb for weight loss) are significant in small studies.
Modern epidemiology corrects for vit E specifically

George
Guest
George

Your vitamin E meta-analysis is a review of supplementation, not of induced deficiencies, of vitamin E, which seems to be what was produced in the LA veterans study. To me this discussion sums up everything that is wrong with the lipid hypothesis. It may well be true for people with CAD, in the contingent fashion laid out brilliantly by Axel. This seems likely. But when people arguing for LDL as a measurement from a nutritional perspective try to argue away vitamin deficiency, this seems to me wholly typical of the way the LDL hypothesis has distorted nutritional advice, so that… Read more »

oehaut
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oehaut

“so that advising the entire population of the USA, and by extension the world, to avoid saturated fat as completely as possible becomes more of a priority for the DGAC, AHA etc than finding nutritious food to eat” I’d say this is not true. The DGAC recommends a variety of whole, fresh food mostly from plant. They don’t put that much emphasize on reducing SFAs per se. And, why would anyone want to eat SFAs? (the long-chain one that is, the one from animal food). I’m not away of any evidence that they are beneficial to health. Quite the contrary.… Read more »

George
Guest
George

The latest DGA specifically advises people undereating iron, choline, and vitamin D to get these nutrients from foods that are poor sources, such as wholegrains, and avoids mentioning the fatty animal foods which are the best sources of these nutrients. That is a nutritional failure, and it is solely due to a belief in the harms of saturated fat on the part of the DGAC. Where are these harms in two large recent epidemiological studies, the EPIC-Netherlands study, or the Malmo Diet and Cancer study? In the former, saturated fat is associated with less CVD, in the latter (using a… Read more »

oehaut
Guest
oehaut

“t is solely due to a belief in the harms of saturated fat on the part of the DGAC” Not quite. The link between red meat and colorectal cancer still require caution on a population level. And they don’t say to not eat red meat but to simply reduce its consumption. They don’t advice against eating poultry and fish either. I think the evidence clearly points in the direction of a plant-based diet with some animal product as being optimal. My own diet is between 70-80% plant and 20-30% animal product (mainly whole, unprocessed food) and I believe this to… Read more »

George
Guest
George

(Apologies for not seeing your citation style) “the link between red meat and colorectal cancer still require caution on a population level. And they don’t say to not eat red meat but to simply reduce its consumption.” The US Dietary Guidelines tell pre-menopausal women are at risk of an iron deficiency and don’t eat enough red meat to eat anything “healthy” other than red meat; nothing they do list is a good source of iron. I shouldn’t have to explain why this is harmful nonsense. They also consistently say to use low-fat dairy products and lean meat and avoid tropical… Read more »

Mie
Guest
Mie

“The latest DGA specifically advises people undereating iron, choline, and vitamin D to get these nutrients from foods that are poor sources, such as wholegrains, and avoids mentioning the fatty animal foods which are the best sources of these nutrients. That is a nutritional failure, and it is solely due to a belief in the harms of saturated fat on the part of the DGAC.” Please provide evidence that following the guidelines results in getting too little nutrients. “Why would you want to eat SFA? Because if you don’t, if you try to avoid it, you overlook some nutritious foods… Read more »

Mie
Guest
Mie

“HDL raising doesn’t work because the means are the wrong drugs.” Could be, but YOU need to show it. It seems that the means are as right as any other possible means (diet, exercise) but when LDL is already low, raising HDL-C offers very little additional benefit. “If studies are underpowered, you’re looking for a weak effect. Plenty of effects (eg low carb for weight loss) are significant in small studies.” Apples and oranges. There are NO hard end-point low carb studies in CVD reduction, they’re all risk marker studies. Showing benefit in CVD events and deaths is very different… Read more »

George
Guest
George

Let’s go back to the LA veterans study shall we? That was the study where the control group was deficient in vitamin E. Is there evidence that a deficiency of vitamin E is a factor in heart disease? Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. “Essential antioxidants were determined in plasma of middle-aged men representing 16 European study populations, which differed sixfold in age-specific mortality from ischemic heart disease (IHD). In 12 populations with “common” plasma cholesterol (5.7-6.2 mmol/L) and blood pressure, both classical risk factors lacked significant correlations to IHD mortality,… Read more »

Mie
Guest
Mie

“Let’s go back to the LA veterans study shall we?” Let’s not, as you simply cannot admit to being wrong. Simple: if vitamin E was the factor confounding the results, you’d expect that there’d be consistent and solid evidence from trials focusing SOLELY on vitamin E. There isn’t. “Have Americans followed dietary guidelines? Their SFA intake has declined to within a % of that recommended. I’d say mission achieved.” If reducing SFA intake was a) the ONLY factor and if b) it was achieved by replacing SFA with vegetable oils, nuts, fruits, veggies and whole grains while c) not increasing… Read more »

George
Guest
George

Yes, let’s not go back. Your vitamin E argument may be fallacious, but it probably has little relation to the failure of LA veterans to reduce mortality due to an increase in non-CHD mortality in those fed PUFA. The dietary guidelines have influenced the diets of Americans. This is not deniable. But as you haven’t read the various guidelines, you wouldn’t know that they haven’t recommended “healthy diet patterns” until very recently. For decades the thrust was on replacing SFA with CHO and PUFA. This was definitely done. People ate more as a consequence. The guidelines are a moving target,… Read more »

Mie
Guest
Mie

“Your vitamin E argument may be fallacious, but it probably has little relation to the failure of LA veterans to reduce mortality due to an increase in non-CHD mortality in those fed PUFA.” MY argument? Err George, FYI: you made the argument that vitamin E was a key player here. I pointed out that there’s no evidence to back that up. As far as tot. mortality is concerned, it’s useless in trials of this scope, field and magnitude – far too crude a tool. “The dietary guidelines have influenced the diets of Americans. This is not deniable.” Semantic play on… Read more »

George
Guest
George

“The focus was NEVER to replace SFA with Western carbs.” I must have missed the bit where it said to only replace SFA with rice. If they didn’t want people to replace SFA with sugar and refined grains, they should have listed those as “nutrients of concern” as well and recommended limits. That’s the way guidelines work. In fact they assumed that any substitution of CHO for SFA, because it would lower LDL, would improve the health of the population. That was the thinking; that was the important point of the original DGA; to reduce heart disease by lowering LDL… Read more »

Mary949
Guest
Mary949

my aunt smoked all her life. died of something else at age 80. my friend smoked, died at 60.

Frank
Guest
Frank

George, I will reply here because I can’t directly reply under your post in this thread. I’d like to ask a different question : Why do you think we should emphasize saturated fat? I’m not aware of a any evidences showing SFAs (the long chained one, from animal product) to be beneficial to health. If anything, they are neutral, but there is other lines of evidences which clearly makes them seem bad health wise. See Overfeeding polyunsaturated and saturated fat causes distinct effects on liver and visceral fat accumulation in humans. “Both groups gained similar weight. SFAs, however, markedly increased… Read more »

George
Guest
George

Why does the rupture of a plaque always cause a blood clot? What is the clotting mechanism by which platelets are affected by the contents of the plaque?
One of the earliest treatments was warfarin; though superceded as a sole treatment, it must have worked, and no doubt helps to account for part of the drop in CHD mortality during the 1970s, along with reductions in smoking, improvements in workplace and environmental safety standards, and more varied diet due to increased transport and cultivation of non-seasonal or non-regional foods.

Axel F Sigurdsson
Guest
Axel F Sigurdsson

George
Many plaque ruptures don’t cause blood clotting. In fact, many plaques appear to heal without any serious consequences. It’s a balance between factors that increase or decrease clotting activity. If the anti-clotting mechanisms are stronger the plaque will just heal and probably go unnoticed.
The anti-platelet activity of aspirin leads to less risk of blood clotting which is probably the main reason why the drug improves prognosis in CAD.

George
Guest
George

Thank you. I guess the blood clots for the same reason it would with an external rupture like a cut?

George
Guest
George

The statement “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.” is ambiguous – though I’m sure you didn’t intend it, this could be read as saying that the idea that lipoproteins initiate the cascade is based on strong evidence. Whereas it seems to me that no-one has good evidence of an initiating process. The idea that failure of eNOS is an early occurrence in endothelial dysfunction preceding plaque formation is consistent with some facts and can be demonstrated… Read more »

Axel F Sigurdsson
Guest
Axel F Sigurdsson

I guess you’re right George. What initiates atherosclerosis is not entirely clear and there are many factors involved. Maybe it would be more correct to say that lipoproteins are found within the vessel wall early in the atherosclerotic process.

Russell
Guest
Russell

Dr. Greger has stated that indigenous populations in Africa (excepting the Masai) had LDLs between 50-70 and virtually zero incidence of heart disease. He suggests that one can almost be bulletproof, heart-wise, by maintaining ultra-low LDLs while following a plant-based diet that results in similar LDLs. Do you agree? Is there controversy over this, or is this pretty well established?

And on a personal note, how can VLDL-3 be reduced though diet or lifestyle? I’m vegan and don’t drink, but yet I struggle to get below 14 (but other lipids are fine).

Thanks much.

Axel F Sigurdsson
Guest
Axel F Sigurdsson

Russell
There is evidence suggesting that exposing someone to low LDL-C through a lifetime reduces CVD risk. For example, nonsense mutations in a specific gene located on chromosome 1 have beens shown to cause low levels of PCSK9. Low PCSK9 will lead to less breakdown of LDL-receptors causing these people to have very low levels of LDL-C. At the same time these individuals have a very low risk of CVD. https://www.docsopinion.com/2012/11/08/pcsk9-a-new-target-for-the-treatment-of-heart-disease/

Russell
Guest
Russell

That’s very helpful thank you.

Also any thoughts on how to reduce VLDL-3?

Ted63
Guest
Ted63

Age 53, only RF is age/ gender. I had a CT calcium score 2.5 years ago of 41 putting me at the 80th %tile. Then a CT cor angio with small soft plaque at the proximal LAD about 20%, but I’m RCA dominant. My LDL was 131 and TG 181 and started statins, since then LDL to 73. Weight down by 30 lbs. Waist from 36 to 32.8 inches. Now after 6 weeks of LCHF diet (P100/ C 20/ F 210), Labs–> TC 137–> 204 LDL ( 127 bad HDL (> 40) 54–> 59 good TG about same at 87.… Read more »

Mary949
Guest
Mary949

Low carb moderate fat. Why the high-fat? Eat more fish and soluble fiber. I have high LDL and my spouse has low LDL, eating red meat, etc. while I struggle. You can’t overturn your genetics, I am trying and it’s a challenge.

Ken McMurtrie
Guest

Axel F. Sigurdsson MD Thanks for a great informative article.
Without getting into professional conflicts, hopefully, I wish to present your article to my GP and Cardiologist who believe that “LDL is simply LDL”.
Without the list of references you refer to in your article, they may disregard your information as unsupported.
Firstly, is it reasonable and acceptable to you, to go ahead with my proposal?
Secondly, would you please publish your list of references?
Respectfully, Ken McMurtrie

Ken McMurtrie
Guest

Hoping for the reference list to be published to strengthen approach to my GP and Cardiologist with your information.
Would that be appropriate?

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