LDL Cholesterol, Apolipoprotein B, and Cardiovascular Disease: Mechanisms and Evidence

If you’ve watched videos promoting fad diets like the “keto diet” and the “carnivore diet,” you may have heard claims that your cholesterol numbers don’t matter and aren’t relevant to developing heart disease or experiencing a stroke. This is bad advice that, if followed, could have catastrophic implications for your health and longevity.

In previous posts, we’ve explored the causes of heart disease, the role of saturated fat in elevating LDL cholesterol, the mechanisms by which saturated fat elevates LDL cholesterol, and other related topics. Here, we take a look at the exact mechanisms by which LDL cholesterol and Apolipoprotein B contribute to the development of atherosclerosis.

We begin with an easy to understand explanation in layman’s terms, followed by a more detailed explanation.

Understanding LDL Cholesterol, Apolipoprotein B, and Heart Disease in Simple Terms

Heart disease often starts with problems in your arteries, the blood vessels that carry oxygen-rich blood throughout your body. Two important players in this process are LDL cholesterol (“bad cholesterol”) and apolipoprotein B (apoB), a protein attached to certain cholesterol particles. Here’s an easy way to understand how they contribute to heart disease.

What Is LDL Cholesterol?

LDL cholesterol acts like a delivery truck, carrying cholesterol from your liver to different parts of your body. Your body needs cholesterol for things like building cells, but too much LDL cholesterol in your blood can be harmful. When there’s too much, it can sneak into the walls of your arteries, especially in areas where the blood flow is slow or uneven.

How Does LDL Cholesterol Cause Problems?

1. Sneaking into Arteries: LDL cholesterol gets stuck in the walls of your arteries.
2. Getting Damaged: Once it’s stuck, LDL can get damaged by “free radicals,” harmful molecules your body produces. This damaged LDL is called “oxidized LDL.”
3. Triggering Inflammation: Your immune system sees oxidized LDL as a threat. White blood cells come to “clean it up” and eat the LDL, turning into foam cells. These foam cells pile up and create fatty streaks—the early signs of clogged arteries.
4. Plaque Formation: Over time, these fatty streaks grow into plaques. Plaques are like bumps on the inside of your arteries. Some plaques can get hard and narrow the artery, making it harder for blood to flow.
5. Dangerous Ruptures: Sometimes, plaques can burst open, causing a blood clot to form. If this happens in an artery leading to your heart or brain, it can cause a heart attack or stroke.

What Is Apolipoprotein B (apoB)?

ApoB is a protein found on LDL and similar particles. Think of it like a tag that every bad cholesterol particle has. Each LDL particle has one apoB, so measuring apoB gives you the exact number of these particles in your blood. This is important because more particles mean more chances for cholesterol to sneak into your arteries.

Why Is apoB Important?

• More Particles, Higher Risk: Even if your cholesterol levels look normal, having too many particles (high apoB) increases your risk of heart problems.
• Stickier Particles: These particles can stick to the artery walls more easily, making it more likely for plaques to form.

How Do LDL Cholesterol and apoB Work Together?

LDL cholesterol measures how much cholesterol is in your blood, but it doesn’t tell you how many particles are carrying it. ApoB measures the number of particles, which is often more important because smaller, more numerous particles can cause more damage.

What Does Science Say?

Research shows that high levels of apoB are a stronger warning sign of heart disease than just high LDL cholesterol. This means some people might have normal LDL cholesterol levels but still be at risk if their apoB is high. Doctors are starting to pay more attention to apoB because of this.

• Landmark Studies: Research has shown that oxidized LDL sparks inflammation and triggers the buildup of plaques in arteries.
• Genetic Links: Studies on genes have found that people with naturally higher apoB levels are more likely to develop heart disease.

What Can Be Done?

• Better Testing: Doctors can measure both LDL cholesterol and apoB to get a clearer picture of your heart health.
• New Treatments: Medications like PCSK9 inhibitors and other drugs are being developed to lower both LDL cholesterol and apoB.
• Healthy Habits: Eating well, exercising, and not smoking can help reduce your LDL cholesterol and apoB levels.

In Summary

LDL cholesterol and apoB work together to increase your risk of heart disease. LDL cholesterol is like a delivery truck, and apoB tells you how many trucks are on the road. Too many trucks carrying too much cholesterol can clog your arteries, leading to heart attacks and strokes. By understanding both, doctors can better predict and prevent heart problems. Simple lifestyle changes and new medications can make a big difference in keeping your heart healthy.

Low-density lipoprotein (LDL) cholesterol and apolipoprotein B (apoB) are central players in lipid metabolism and have pivotal roles in the development and progression of cardiovascular disease (CVD). Their involvement spans the molecular, cellular, and systemic levels, underpinning the atherogenic processes that lead to plaque formation, arterial narrowing, and clinical cardiovascular events. Here we explore the detailed mechanisms and research findings highlighting their contribution to CVD.

Now here’s a more detailed explanation that goes into a bit more depth.

LDL Cholesterol and Atherogenesis

LDL particles, which transport cholesterol from the liver to peripheral tissues, play a dual role. While essential for physiological functions such as cell membrane synthesis and steroid hormone production, their elevated levels initiate and propagate atherogenic processes. These mechanisms include:

1. Endothelial Dysfunction and LDL Infiltration: LDL particles infiltrate the endothelium of arterial walls, a process facilitated by regions of disturbed blood flow, such as arterial bifurcations. Dysfunctional endothelium, characterized by decreased nitric oxide availability, allows LDL retention within the subendothelial space.
2. Oxidation of LDL: Once in the subendothelial space, LDL particles undergo oxidative modifications by reactive oxygen species (ROS) produced by endothelial and immune cells. Oxidized LDL (oxLDL) is a critical driver of inflammation, attracting circulating monocytes to the site.
3. Foam Cell Formation: Monocytes migrate into the arterial intima, differentiate into macrophages, and engulf oxLDL via scavenger receptors (e.g., SR-A, CD36). These macrophages transform into foam cells, forming the foundation of fatty streaks—the earliest detectable atherosclerotic lesions.
4. Plaque Progression: Fatty streaks evolve as smooth muscle cells migrate from the media to the intima, proliferating and synthesizing extracellular matrix components. This leads to fibrous cap formation, which stabilizes the plaque but narrows the arterial lumen.
5. Plaque Instability and Rupture: Over time, plaques can become unstable due to inflammatory cell-mediated degradation of the fibrous cap. Rupture exposes the thrombogenic lipid core to circulating blood, triggering acute thrombus formation. This event is the precipitating cause of myocardial infarction and ischemic stroke.

Apolipoprotein B’s Role in Atherosclerosis

ApoB is the principal structural protein of atherogenic lipoproteins, including chylomicron remnants, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and LDL. Its role extends beyond a structural component to a marker and mediator of CVD risk.

1. Marker of Lipoprotein Particle Number: Unlike LDL cholesterol, which measures cholesterol content, apoB reflects the total number of atherogenic lipoprotein particles. Each particle contains one apoB molecule, making apoB a precise indicator of lipoprotein particle burden. This is critical as smaller, cholesterol-depleted LDL particles remain atherogenic despite low cholesterol levels.
2. Enhanced Atherogenic Potential: High apoB concentrations are associated with increased LDL particle retention in the arterial wall. ApoB-containing particles interact with arterial proteoglycans, leading to prolonged retention and heightened susceptibility to oxidation.
3. Stronger Predictive Value for CVD: Numerous studies have demonstrated that apoB is a superior predictor of CVD risk compared to LDL cholesterol or non-HDL cholesterol. This is particularly evident in discordant cases where individuals have low LDL cholesterol but high apoB levels, reflecting an elevated number of small, dense LDL particles.

Comparative Insights and Pathophysiological Synergy

1. LDL Cholesterol Versus ApoB: LDL cholesterol quantifies the cholesterol mass carried by LDL particles, while apoB indicates particle number. Since LDL particles vary in cholesterol content, relying solely on LDL cholesterol can underestimate risk in individuals with many small LDL particles. Conversely, apoB provides a more accurate measure of atherogenic particle load.
2. Inflammation and Immune Activation: Both LDL cholesterol and apoB contribute to a pro-inflammatory milieu. OxLDL acts as a damage-associated molecular pattern (DAMP), activating innate immune pathways such as toll-like receptors (TLRs). ApoB-containing particles exacerbate this by promoting the chronic immune response, sustaining inflammation, and fostering plaque progression.
3. Plaque Characteristics: Elevated apoB levels correlate with plaques that are lipid-rich, inflamed, and prone to rupture. Studies using imaging modalities such as intravascular ultrasound (IVUS) and optical coherence tomography (OCT) have validated these associations.

Supporting Research

1. Role of Oxidized LDL: A landmark study by Steinberg et al. (1999) identified oxLDL as a key initiator of the inflammatory cascade in atherosclerosis (Circulation Research). Subsequent work has detailed the molecular pathways linking oxLDL to foam cell formation and plaque instability.
2. ApoB as a Risk Marker: A meta-analysis by Sniderman et al. (2011) highlighted apoB’s superiority over LDL cholesterol in predicting cardiovascular events, particularly in populations with metabolic syndrome and diabetes (Journal of Clinical Lipidology).
3. Insights from Genetic Studies: Mendelian randomization studies, such as those by Ference et al. (2017), have demonstrated that genetic variants associated with higher apoB levels confer a higher risk of coronary artery disease, independent of LDL cholesterol levels (JAMA Cardiology).

Clinical Implications

1. Guideline Recommendations: The European Society of Cardiology (ESC) and American Heart Association (AHA) recommend considering apoB as an additional risk marker, particularly in individuals with metabolic disorders or discordant lipid profiles.
2. Therapeutic Targets: Newer lipid-lowering therapies, such as PCSK9 inhibitors and antisense oligonucleotides targeting apoB (e.g., mipomersen), aim to reduce both LDL cholesterol and apoB levels, offering dual benefits in risk reduction.
3. Personalized Risk Stratification: ApoB measurements can refine cardiovascular risk assessment, enabling tailored interventions for high-risk individuals who might otherwise be missed by LDL cholesterol-centric approaches.

In conclusion, LDL cholesterol and apoB are intricately involved in the pathogenesis of cardiovascular disease. While LDL cholesterol remains a cornerstone of risk assessment and treatment, apoB provides critical insights into lipoprotein particle burden and atherogenic potential. Ongoing research and clinical advancements underscore the importance of integrating both metrics into comprehensive CVD management strategies.

Final thoughts

If you’re trying to cut down on foods high in saturated fats (meat, dairy, coconut oil, etc.) in order to lower your LDL cholesterol and ApoB, avoid replacing them with ultra processed foods and refined carbohydrates. Instead, choose from a wide variety of vegetables, fruits, legumes, whole grains, nuts, and seeds.