Atherosclerosis: Challenging Conventional Wisdom on Heart Disease

The Misconceptions About LDL Cholesterol and Heart Disease

For decades, we've been told that high levels of LDL (low-density lipoprotein) cholesterol are the primary culprit behind atherosclerosis and heart disease. The conventional wisdom suggests that LDL particles coat the sides of blood vessels, much like fat clogging a drain. However, this simplistic view is not only inaccurate but potentially harmful to our understanding of cardiovascular health.

In fact, research has shown that higher LDL cholesterol levels are associated with longevity. A systematic review of 19 cohort studies, involving over 68,000 participants, found that the higher the LDL cholesterol level, the lower the chance of death. This finding directly contradicts the notion that LDL cholesterol is inherently harmful.

Understanding LDL Particles

To grasp why the traditional view of LDL cholesterol is flawed, we need to understand what LDL actually is. LDL is a complex molecule comprised of both lipids and proteins. It's not just pure cholesterol floating around in the bloodstream. The LDL particle contains cholesterol as cargo internally, and it's also dotted throughout the outer membrane. Cholesterol is only one component of many within an LDL particle.

While it's true that LDL particles can be found in atherosclerotic plaques, this doesn't necessarily mean they cause atherosclerosis. Correlation does not imply causation. In fact, research has shown that 75% of patients hospitalized for heart attacks do not have higher LDL levels. This statistic alone should make us question the role of LDL in heart disease.

The True Culprit: Blood Clots and Thrombosis

If LDL cholesterol isn't the primary cause of atherosclerosis, what is? Compelling evidence points to blood clots, or more specifically, thrombosis, as the root cause of heart disease. Atherosclerosis appears to be the result of blood clots forming inside blood vessels.

Evidence from Atherosclerotic Plaques

Scientists have found several key components within atherosclerotic plaques that support the thrombosis theory:

1. Red Blood Cells: Using a special stain, researchers have detected glycophorin A, a chemical unique to red blood cells, deep inside atherosclerotic plaques. This proves the presence of red blood cells within these plaques.

2. Platelets and Fibrin: Blood clots are not just made of blood cells; they also contain platelets and fibrin, which forms fibrous strands binding the clot together. Both of these components have been found buried deep inside atherosclerotic plaques.

3. Layered Formation: Interestingly, these clots can occur episodically over time, one on top of another. This leads to the prediction that atherosclerotic plaques would form in layers, which is exactly what we observe. Some plaques show a single layer with a lipid-rich core covered by a fibrous connective tissue cap, while others display multiple distinct layers with separate fibrous caps.

The presence of these blood components deep within atherosclerotic plaques cannot be explained by the traditional lipid hypothesis of heart disease.

Cholesterol Crystals: Not What They Seem

One of the arguments often used to support the lipid hypothesis is the presence of cholesterol-like crystals in atherosclerotic plaques. However, the origin of these crystals is not what many assume.

The Role of Red Blood Cells

The cholesterol found in atherosclerosis primarily comes from red blood cells, not LDL particles. Red blood cells have outer membranes that contain more cholesterol than any other cell in the body. Research has shown that there's a central accumulation of red blood cell membranes within atherosclerotic plaques.

In animal studies, injecting red blood cells into subjects produced atherosclerotic plaques containing both cholesterol crystals and LDL-laden foam cells. This demonstrates that the presence of cholesterol crystals in plaques can be explained by the thrombosis theory, without needing to implicate LDL as the primary cause.

Phytosterols: A Hidden Culprit

Interestingly, what we often identify as "cholesterol crystals" in atherosclerotic plaques may not always be cholesterol. Phytosterols, which are plant versions of cholesterol, have a nearly identical structure and can form crystals that are difficult to differentiate from cholesterol crystals.

Phytosterols can be delivered to arterial walls by red blood cells, as they can be incorporated into the cell membrane in the same way as cholesterol. Unlike cholesterol, which tends to remain in droplet form when released from cells, phytosterols are more readily expelled in crystalline form.

This is significant because phytosterols are found in many plant-based foods and are often promoted as heart-healthy due to their cholesterol-lowering effects. However, there's growing evidence that high levels of phytosterols may actually be harmful to cardiovascular health.

The Dangers of Seed Oils and Oxidation

The conversation about heart disease and atherosclerosis wouldn't be complete without addressing the role of seed oils and oxidation in cardiovascular health.

Seed Oils and Phytosterols

Seed oils, including vegetable oils, contain significant amounts of phytosterols. While these plant sterols are often praised for their cholesterol-lowering effects, their impact on cardiovascular health is far more complex and potentially harmful.

For most people, only about 1% of consumed phytosterols are absorbed and assimilated into tissues. However, some individuals have a condition called sitosterolemia, where they absorb much larger amounts (15-60%) of these plant sterols. This condition can lead to severe cardiovascular complications, with at least one reported case of a 5-year-old dying from sudden cardiac death due to excessive phytosterol accumulation.

Despite this, products containing plant sterols are often marketed for cardiovascular health, even though there's little evidence of cardiovascular benefit and significant evidence of potential harm.

Oxidation and Its Effects

One of the major reasons seed oils contribute to atherosclerosis is their chemical structure. Many seed oils are high in polyunsaturated fats, which contain unstable bonds prone to oxidation. Oxidation is a chemical reaction where an electron is ripped away from a molecule, similar to the process of rusting.

When oxidized oils are consumed, oxidation products are absorbed into the body. The more oxidized the oil, the higher the level of blood oxidation products. This is particularly problematic for individuals with poor blood sugar control, as oxidation products can persist in their bloodstream for much longer.

Oxidation stress in the blood causes clotting or thrombosis, which we now understand to be the source of atherosclerotic plaques. According to research, oxidative stress is involved in all of the major processes involved in the development of thrombosis.

The LDL Connection

While LDL itself isn't inherently dangerous, oxidized LDL is a different story. When LDL particles become oxidized, they change in size and density, becoming what's often referred to as "small, dense LDL." These oxidized LDL particles are strongly associated with heart disease risk.

Oxidized LDL can damage the glycocalyx, a protective layer lining our blood vessels that most people, including many doctors, have never heard of. The glycocalyx plays a crucial role in protecting against atherosclerosis by shielding the artery wall from coagulation particles, secreting substances that inhibit clot formation, and stimulating the production of nitric oxide, another potent inhibitor of coagulation.

Rethinking Statin Use and Coronary Artery Calcification

The use of statins, a class of drugs commonly prescribed to lower cholesterol levels, needs to be reevaluated in light of our evolving understanding of atherosclerosis.

Statins and DNA Damage

Statins have been shown to cause DNA damage, a fact that was apparent to the Japanese scientists who initially researched the mold toxin that eventually became the first statin. They stopped their research due to an increased rate of cancer in dogs. This DNA damage may explain why statin use is associated with a significant increase in coronary artery calcification.

Coronary Artery Calcification and Heart Attack Risk

Coronary artery calcification is a crucial factor in heart attack risk. High calcium scores indicate an increased tendency for atherosclerotic plaques to rupture. When a plaque ruptures, it can lead to the formation of a large thrombus that completely occludes the vessel, resulting in a heart attack.

Interestingly, coronary artery calcium scores are a much better predictor of cardiac death than vessel narrowing itself. Once calcium scores exceed 100, representing the presence of unstable plaques, the risk of cardiac events or death remains the same regardless of whether blood vessels are narrowed.

The Limitations of Stenting

This understanding challenges the effectiveness of common interventions like stenting. While stenting can partially open occluded blood vessels and help with symptoms like angina, it doesn't eliminate the risk of sudden blockage, which is what actually kills people.

Multiple large-scale studies have shown that stenting provides no mortality benefit over drug management alone in patients with heart disease. This includes a 2007 study of 2,287 patients and a 2020 study of 5,179 patients, both of which found no survival advantage for stenting over medication management.

The Role of Inflammation and Matrix Metalloproteinases

Understanding what makes atherosclerotic plaques vulnerable to rupture is crucial in addressing heart disease risk. The integrity of the fibrous cap of connective tissue covering the plaque plays a significant role in its stability.

Foam Cells and Plaque Instability

Foam cells, which are macrophages that have ingested oxidized LDL, play a key role in plaque instability. After ingesting oxidized LDL, these foam cells secrete enzymes called matrix metalloproteinases (MMPs) that break down connective tissue, including the protective cap over atherosclerotic plaques.

These MMPs have been independently associated with both the tendency of plaques to rupture and cardiac mortality. Interestingly, statins inhibit the release of these plaque-destabilizing MMPs, which may contribute to their marginal mortality benefit in those who have already had heart disease.

Diabetes and Heart Disease Risk

Diabetes significantly increases the risk of death from heart disease and stroke, with diabetics facing a tripling of this risk compared to non-diabetics.

Blood Sugar and Oxidative Stress

High levels of sugar in the blood are problematic due to the oxidative stress they generate. Both high and fluctuating blood glucose levels create oxidative stress at the mitochondrial level. This is particularly concerning when combined with the consumption of seed oils, as oxidation products can persist in the blood of diabetics for extended periods.

The Triglyceride to HDL Ratio

The presence of oxidized LDL is reliably associated with the triglyceride to HDL ratio. A low ratio is associated with a reduced risk of cardiovascular disease, and this can be easily assessed using a standard blood lipid panel.

The Potential of Antioxidants

Given the central role of oxidation in heart disease, it's worth considering the potential benefits of antioxidant supplements. Some studies have found protective effects against heart disease from antioxidants like N-acetyl cysteine and coenzyme Q10.

Historical Perspective on Seed Oils and Heart Disease

The consumption of seed oils began to rise in the early 1900s, coinciding with the onset of the heart disease epidemic. Several randomized controlled trials have demonstrated harms from consuming seed oils:

1. A 1965 study found that heart attack patients supplemented with corn oil or olive oil had a higher rate of repeat heart attacks compared to a control group.

2. The Sydney Diet Heart Study, completed in 1973 but fully published only in 2013, found that increased intake of polyunsaturated fats (as found in seed oils) increased the risk of death by 62% in men who had had heart attacks.

3. The Minnesota Coronary Experiment, also completed in 1973 but fully published only in 2016, similarly found that increased seed oil intake increased the chance of death.

4. The Women's Health Initiative study, published in 2006, found that females with a history of heart disease faced a 26% increased chance of complications like heart attacks if they followed a low saturated fat diet.

Insulin Resistance: A Unifying Theory

Insulin resistance is increasingly considered the root cause of many chronic modern diseases, including cardiovascular disease, type 2 diabetes, and certain cancers.

The Mechanism of Insulin Resistance

Insulin resistance refers to a state where insulin does not work as it should. To compensate, the pancreas often secretes more insulin than usual, leading to high insulin levels. The key to understanding insulin resistance is to realize that it's not caused by a problem with insulin itself, but rather by the receptors upon which insulin acts.

Lipid Rafts and Insulin Receptors

The missing link in understanding insulin resistance comes down to structures in cell membranes called lipid rafts. These are small islands within the cell membrane that contain high concentrations of cholesterol and house insulin receptors. Anything that disrupts these lipid rafts can disrupt the function of the insulin receptors.

How Sugar and Seed Oils Cause Insulin Resistance

Both excess sugar intake and seed oil consumption can contribute to insulin resistance by disrupting lipid rafts:

1. Sugar: Excess dietary fructose results in the overproduction of ceramides, waxy lipid molecules that disturb lipid raft function and lead to insulin resistance.

2. Seed Oils: Seed oils contain large amounts of phytosterols, which can be incorporated into cell membranes and disrupt lipid rafts. Depletion of cholesterol from lipid rafts (which can be caused by statins) has also been proven to impair insulin receptor activation.

This theory provides a unifying explanation for how both sugar and seed oils can cause insulin resistance, and why statins can worsen the condition.

Conclusion

Our understanding of atherosclerosis and heart disease has come a long way from the simplistic view of LDL cholesterol clogging arteries like fat in a drain. The evidence points to a more complex picture involving blood clots, oxidative stress, and insulin resistance.

Key takeaways include:

1. LDL cholesterol itself is not the primary cause of heart disease.
2. Blood clots and thrombosis play a central role in the development of atherosclerotic plaques.
3. Oxidative stress, often caused by seed oils and high blood sugar, is a major contributor to heart disease risk.
4. Phytosterols, often promoted as heart-healthy, may actually contribute to cardiovascular problems.
5. Coronary artery calcification is a better predictor of heart attack risk than vessel narrowing.
6. Insulin resistance, influenced by both sugar and seed oil consumption, is a root cause of many chronic diseases including heart disease.

This new understanding challenges many conventional approaches to preventing and treating heart disease. It suggests that focusing solely on lowering LDL cholesterol may be misguided, and that more attention should be paid to reducing oxidative stress, managing blood sugar, and avoiding harmful seed oils.

As our knowledge evolves, so too should our strategies for maintaining cardiovascular health. This may involve rethinking dietary guidelines, reconsidering the widespread use of statins, and developing new approaches to prevent and treat atherosclerosis based on the latest scientific evidence.

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